A Placebo-Controlled, Double-Blind, Parallel-Group, Bayesian Adaptive Randomization Design and Dose Regimen-finding Study With an Open-Label Extension Phase to Evaluate Safety, Tolerability and Efficacy of BAN2401 in Subjects With Early Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer's Disease
Sponsor: Eisai Inc.

Synoptic Clinical Study Report 
BAN2401-G000-201 
 
16.1.1 
Protocol and Protocol Amendments 
Listed below are all versions of the global protocol and country-specific protocol for this study.  
The corresponding documents are provided on the following pages. 
Global Protocol 
Version 
Protocol Date 
Revised per Amendment 20 
V23.0 
24 Sep 2023 
Revised per Amendment 19 
V22.0 
31 Aug 2023 
Revised per Amendment 18 
V21.0 
15 Dec 2022 
Revised per Amendment 17 
V20.0 
16 Feb 2022 
Revised per Amendment 16 
V19.0 
23 Feb 2021 
Revised per Amendment 15 
V18.0 
08 Sep 2020 
Revised per Amendment 14 
V17.0 
18 Mar 2020 
Revised per Amendment 13 
V16.0 
14 Jan 2019 
Revised per Amendment 12 
V15.0 
15 Nov 2018 
Revised per Amendment 11 
V14.0 
14 Sep 2018 
Revised per Amendment 10 
V13.0 
16 Mar 2018 
Revised per Amendment 09 
V12.0 
09 Nov 2017 
Revised per Amendment 08 
V11.0 
19 Feb 2016 
Revised per Amendment 07 
V10.0 
30 Jul 2015 
Revised per Amendment 07 
V9.0 
26 Jun 2015 
Revised per Amendment 06 
V8.0 
20 Nov 2014 
Revised per Amendment 05 
V7.0 
11 Aug 2014 
Revised per Amendment 04 
V6.0 
09 Jul 2014 
Revised per Amendment 03 
V5.0 
18 Sep 2013 
Revised per Amendment 02 
V4.0 
27 Jun 2013 
Revised per Amendment 01 
V3.0 
22 Apr 2013 
Original Protocola 
V2.0 
20 Nov 2012 
Spain Protocol 
Version 
Protocol Date 
Revised per Amendment 18 
V22.0 
24 Sep 2023 
Revised per Amendment 17 
V21.0 
31 Aug 2023 
Revised per Amendment 16 
V20.0 
16 Feb 2022 
Revised per Amendment 15 
V19.0 
08 Sep 2020 
Revised per Amendment 14 
V18.0 
18 Mar 2020 
Revised per Amendment A 
V17.0 
15 Oct 2019 
a  V2.0 was the first version implemented and submitted to regulatory authorities. 
 
Eisai
Confidential
Page 1 of 5021

 
Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 1 of 235 
CONFIDENTIAL 
 
 REVISION HISTORY 
Revisions to Version 22.0 
New version/date:  Version 23.0/24 Sep 2023 (per Amendment 20)
Change
Rationale
Affected Protocol Sections
Updated to include expedited 
reporting for all intracerebral 
hemorrhages >1 cm. 
Per regulatory requirement 
Section 9.5.1.5 
Appendix 4 
Appendix 5 
Clarification that the terms 
"single macrohemorrhage 
>10 mm at greatest diameter, 
symptomatic or not" is 
equivalent to the term 
"intracerebral hemorrhage 
>1 cm" 
Clarification 
Synopsis Section 2:  
 
ARIA Management 
Appendix 4 
Appendix 5 
 
Grammatical, typographical, and 
formatting changes  
Document quality and 
consistency 
Throughout 
 
 
 
Page 2 of 5021

 
Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 2 of 235 
CONFIDENTIAL 
 
Revisions to Version 21.0 
New version/date:  Version 22.0/31 Aug 2023 (per Amendment 19)
Change
Rationale
Affected Protocol Sections
Addition of Extension Phase B 
To allow continued treatment 
with lecanemab, with reduced 
study assessments, for those 
subjects in countries where 
lecanemab is not commercially 
available 
Throughout 
Appendix 5 
Figure 1 
Updated Protocol Signature 
Page 
Updated study personnel 
 
Protocol signature page 
Grammatical, typographical, and 
formatting changes  
Document quality and 
consistency 
Throughout 
 
 
Page 3 of 5021

 
Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 3 of 235 
CONFIDENTIAL 
 
 
Revisions to Version 20.0 
New version/date:  Version 21.0/15 Dec 2022 (per Amendment 18) 
Change 
Rationale 
Affected Protocol Sections 
Revision of GCP statement 
Per regulatory 
requirements 
Title Page 
Section 5.2 
Clarification of study phase of 
development for subjects in Japan 
Per regulatory 
requirements 
Title Page 
Synopsis Section 2:  
 
Study Period and 
Phase of Development 
 
Conduct of the 
Extension Phase 
During the 
Coronavirus Disease 
2019 (COVID-19) 
Pandemic and Other 
Extenuating 
Circumstances  
Section 9.1.3  
Section 9.1.2.2 
 
Update of duration of treatment in 
Japan 
Per regulatory 
requirements 
Synopsis Section 2:  
 
Duration of Treatment 
for Extension Phase 
Appendix 4  
Updates to Investigational Plan for 
subjects in Japan 
Per regulatory 
requirements 
 
Study Design for 
Extension Phase 
Section 9.1.3 
Section 9.1.2.2 
Section 9.5.1.5 
Section 9.5.4.1 
Section 9.5.4.2 
Section 9.5.5 
Appendix 4  
Table 13 
Updates to retention of records in 
Japan 
Per regulatory 
requirements 
Section 11.6 
Updated Clinical Pharmacology 
contact information 
Study personnel change 
Protocol Signature Page 
 
 
 
Page 4 of 5021

 
Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 4 of 235 
CONFIDENTIAL 
 
 
Revisions to Version 19.0 
New version/date:  Version 20.0/16 Feb 2022 (per Amendment 17) 
Change 
Rationale 
Affected Protocol Sections 
Added optional substudy 
implementing changes in dosing 
frequency of BAN2401 in the 
Extension Phase 
To assess the effects of dosing 
regimen (10 mg/kg IV monthly 
and 10 mg/kg IV every 
3 months) on the safety, PK 
exposure, biomarker, and 
clinical efficacy 
Synopsis  
 Objectives 
 Study Design 
 Study Treatment(s) and 
Response Adaptive 
Randomization (RAR) 
 Assessments 
 Statistical Methods 
Section 9.1.2.2 
Appendix 4 
Addition of aducanumab (and 
any other approved AD disease 
modifiers) to current therapeutic 
options for AD, and study  
prohibited medications 
To account for FDA approval of 
AD disease modifier treatment  
Synopsis  
 Concomitant Drug/Therapy 
Section 7.1.1 
Appendix 2 
 Listing 2.1 
Appendix 4 
Updated QTc study 
requirements  
Clarification 
Appendix 4 
Clarification of reporting of 
results of medical claims 
substudy 
Clarification 
Synopsis  
 Study Design 
 Assessments 
Section 9.1.2.2 
Section 9.5.1.6 
Appendix 4 
Revised the definition of the 
OLE Full Analysis Set 
(Extension Phase) 
For consistency with the SAP; 
updated to include all efficacy 
endpoints 
Synopsis  
 Statistical Methods OLE 
Appendix 4 
Revised the definition of the 
Safety Analysis Set (Extension 
Phase) 
To comply with updated Eisai 
standard 
Synopsis  
 Statistical Methods 
Appendix 4 
 
Relaxed guidance on 
investigator and subject contact 
during extenuating 
circumstances 
To ease burden on subjects and 
investigators 
Synopsis  
 
Conduct of the Extension 
Phase During the 
Coronavirus Disease 2019 
(COVID-19) Pandemic 
and Other Extenuating 
Circumstances   
Appendix 4 
 
Page 5 of 5021

 
Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 5 of 235 
CONFIDENTIAL 
 
Revisions to Version 19.0 
New version/date:  Version 20.0/16 Feb 2022 (per Amendment 17) 
Change 
Rationale 
Affected Protocol Sections 
Added guidance regarding the 
timing of COVID-19 
vaccination 
Subject safety 
Appendix 4 
 
Revised restrictions of 
concomitant use of biologic 
drugs in the Extension Phase 
Allowance of biologic drugs 
will better reflect the clinical 
practice in real life.  Due to the 
small sample size of Extension 
Phase, open label treatment, and 
well-established safety 
monitoring plan, no major risks 
and no major impact on 
BAN2401 mode of action is 
foreseen. 
Synopsis  
 Concomitant Drug/Therapy 
Appendix 2 Listing 1 
Appendix 4 
Clarified investigator 
description in synopsis from 
“unknown” to “multicenter” 
Clarification; the investigators 
are no longer unknown  
Synopsis  
 Investigator(s) 
 
Revised language of compliance 
for follow-up visits 
All subjects have the human 
right to discontinue from any 
experiment at any time they 
wish, with no requirement to 
attend further visits 
Synopsis  
 Study Design 
Section 9.1.2.2 
Table 8 
Appendix 4 
 
Updated sponsor address 
Administrative change (physical 
address change) 
Title page 
Updated protocol signature page 
Personnel change 
Protocol signature page 
Updated reference list 
Document quality and 
consistency 
Section 10 
Appendix 4 
Grammatical, typographical, and 
formatting changes 
Document quality and 
consistency 
Throughout 
 
 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 6 of 235 
CONFIDENTIAL 
 
Revisions to Version 18.0 
New version/date:  Version 19.0/23 Feb 2021 (per Amendment 16) 
Change 
Rationale 
Affected Protocol Sections 
Addition of medical claims 
substudy for US subjects 
To evaluate data as exploratory 
objective 
Section 2 – Exploratory 
Objectives (Extension Phase), 
Study Design (Extension Phase), 
Other Assessments, Exploratory 
Endpoints (Extension Phase) 
Section 5.3 
Section 8 
Section 9.1.3 
Section 9.5.1.6 
Appendix 4 
Inclusion of International 
Nonproprietary Name (INN) 
INN published 
Title Page 
Section 2 
Section 9.4.2.1 
Protocol Signature Page 
Investigator Signature Page 
Grammatical, typographical, and 
formatting changes  
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consistency 
Throughout 
 
 
 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 7 of 235 
CONFIDENTIAL 
 
 
Revisions to Version 17.0 
New version/date:  Version 18.0/08 Sep 2020 (per Amendment 15) 
Change 
Rationale 
Affected Protocol Sections 
Added option for sites to 
perform remote clinical 
assessments if subjects cannot 
return to the study site for 
regularly scheduled visit(s) 
To allow clinical assessments to 
be performed during site 
closures and travel restrictions 
as a result of the Coronavirus 
Disease 2019 (COVID-19) 
pandemic (or similar situations), 
where permitted  
 
Synopsis  
 
Conduct of the Extension 
Phase During the 
Coronavirus Disease 2019 
(COVID-19) Pandemic 
and Other Extenuating 
Circumstances 
Section 9.6.1 
Appendix 4 
Extended the duration of the 
Extension Phase from 
24 months (2 years) to 
60 months (5 years), with 
corresponding updates to study 
assessments and estimated study 
end date 
To allow for subjects to 
continue receiving BAN2401 in 
the Extension Phase for up to 
60 months (5 years), until the 
drug is commercially available 
in the country where the subject 
resides, or until the 
benefit-to-risk ratio from 
treatment with BAN2401 is no 
longer considered favorable, 
whichever comes first 
Synopsis  
 Study Period and Phase of 
Development 
 Objectives (Extension 
Phase) 
 Study Design 
 Study Design (Extension 
Phase) 
 Duration of Treatment 
 Concomitant Drug/Therapy 
(Extension Phase) 
 
Assessments 
(Pharmacokinetic 
Assessments - Core Study 
and Extension Phase, 
Other Assessments – 
Extension Phase) 
 Study Endpoints 
(Extension Phase) 
Section 8 
Section 9.1 
Figure 1 
Section 9.1.3 
Section 9.4.3 
Appendix 4 
Table 11 
Table 13 
Clarification of procedures 
performed at Extension Phase 
unscheduled visit 
Clarification  
Table 13 
Clarification of clinical 
assessments and study dosing 
(may be performed as split visits 
on consecutive days as 
Clarification 
Table 13 
Page 8 of 5021

 
Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 8 of 235 
CONFIDENTIAL 
 
Revisions to Version 17.0 
New version/date:  Version 18.0/08 Sep 2020 (per Amendment 15) 
Change 
Rationale 
Affected Protocol Sections 
described in Schedule of 
Assessments) 
Clarification of packaging of 
study drug in Extension Phase 
Clarification  
Appendix 4 
Clarification of reference to 
Extension Phase Follow-Up 
Visit 
Clarification 
Throughout
Updates to study personnel  
Change of study personnel 
Protocol Signature Page 
Grammatical, typographical, and 
formatting changes  
Document quality and 
consistency 
Throughout 
 
 
 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 9 of 235 
CONFIDENTIAL 
 
Revisions to Version 16.0 
New version/date:  Version 17.0/18 Mar 2020 (per Amendment 14) 
Change 
Rationale 
Affected Protocol Sections 
Added home infusion as an 
option for study drug 
administration at select visits 
during and following the 
Coronavirus Disease 2019 
(COVID-19) pandemic if 
approved by the Sponsor 
To allow subjects to continue 
study drug dosing during 
temporary site closures and 
travel restrictions due to 
COVID-19, and to allow the 
option to continue in the study 
following resolution of 
COVID-19-related restrictions 
Synopsis  
 Study Design 
Section 9.1 
Section 9.1.2.1 
Section 9.1.3 
Section 9.4.5 
Table 8 
Appendix 4 
Table 13 
 
 
 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 10 of 235 
CONFIDENTIAL 
 
 
Revisions to Version 15.0 
New version/date:  Version 16.0/14 Jan 2019 (per Amendment 13) 
Change 
Rationale 
Affected Protocol Sections 
Modification of safety 
monitoring plan for ARIA-E for 
Japan sites only 
Modifications made based on 
official consultation meeting 
with Pharmaceuticals and 
Medical Devices Agency 
(PMDA) in December 2018  
Synopsis  
 Study Design 
Appendix 4 
 
 
 
 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 11 of 235 
CONFIDENTIAL 
 
 
Revisions to Version 14.0 
New version/date:  Version 15.0/15 Nov 2018 (per Amendment 12) 
Change 
Rationale 
Affected Protocol Sections 
Revised requirements for 
baseline amyloid positron 
emission tomography (PET) 
scan before dosing in the 
Extension Phase.   
To ensure that subjects who 
underwent amyloid PET for 
inclusion into the Study 201 
Core eligibility undergo PET at 
the baseline of the Extension 
Phase with the same imaging 
agent that was used at baseline 
in the Core.  
Synopsis  
 Study Design 
 Assessments 
Section 9.1.3 
Appendix 4 
Table 13 
Revised tracers for PET 
longitudinal substudy; revised 
PET longitudinal substudy 
assessment timing for subjects 
in Japan.   
Due to tracer availability in US 
and Japan.  
Synopsis  
 Study Design 
 Assessments 
Section 7.2.2.1 
Section 9.1.2.2 
Appendix 4 
Table 13 
Modification of assessment of 
amyloid-related imaging 
abnormality hemorrhage 
(ARIA-H) and amyloid-related 
imaging abnormality 
edema/effusion (ARIA-E). 
To increase subject safety, 
following a Voluntary 
Harmonisation Procedure (VHP) 
request received in October 
2018. 
Synopsis  
 Study Design 
Appendix 4 
 
Updates to Extension Phase 
inclusion and exclusion criteria. 
To expand inclusion criteria for 
the Extension Phase. 
Synopsis  
 Study Design 
 Inclusion Criteria 
 Exclusion Criteria 
Appendix 4 
 
Revised Extension Phase 
screening criteria for MRI 
assessment.   
To increase flexibility related to 
timing of the MRI within the 
Screening period. 
Table 13 
Revised concomitant 
medications.  
Clarification of restricted and 
permitted concomitation 
medications 
Synopsis  
 Inclusion Criteria 
 Exclusion Criteria 
Section 9.4.7.2 
Appendix 2 
Appendix 4 
Grammatical, typographical, and 
formatting changes  
Document quality and 
consistency 
Throughout 
 
 
 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 12 of 235 
CONFIDENTIAL 
 
Revisions to Version 13.0 
New version/date:  Version 14.0/14 Sep 2018 (per Amendment 11) 
Change 
Rationale 
Affected Protocol Sections 
Added initiation of an open-
label Extension Phase following 
the Core Study  
The Extension Phase will be 
initiated following the Core 
Study to allow subjects to 
receive open-label BAN2401 10 
mg/kg biweekly for up to 24 
months (2 years), until the drug 
is commercially available in the 
country where the subject 
resides, or until the 
benefit-to- risk ratio from 
treatment with BAN2401 is no 
longer considered favorable, 
whichever comes first. 
Title Page 
Synopsis  
 Study Protocol Title 
 Study Period and Phase of 
Development 
 Objectives 
 Study Design 
 Inclusion Criteria 
 Exclusion Criteria 
 
Study Treatment(s) and 
Response Adaptive 
Randomization (RAR) 
 Concomitant Drug/Therapy 
 
Duration of Treatment  
 
Assessments 
 
Statistical Methods 
 Sample Size Rationale 
Section 8  
Section 9.1 
Section 9.1.1.2 
Section 9.3.3 
Section 9.4.1 
Section 9.4.2 
Section 9.4.3 
Section 9.4.6 
Section 9.4.7.2 
Section 9.5.1.3 
Section 9.5.1.4 
Table 6 
Section 9.5.1.5 
Section 9.5.2.1 
Table 7 
Section 9.5.5 
Section 9.7.1.6 
Section 9.7.1.7 
Appendix 2 
Appendix 4 
Figure 1 
Table 8 
Table 13 
Protocol Signature Page 
Investigator Signature Page 
Extension Phase amyloid 
positron emission tomography 
Florbetapir will be the sole 
imaging agent used in the 
Synopsis  
 Study Design 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 13 of 235 
CONFIDENTIAL 
 
Revisions to Version 13.0 
New version/date:  Version 14.0/14 Sep 2018 (per Amendment 11) 
Change 
Rationale 
Affected Protocol Sections 
(PET) will be performed in US 
and Japan only using florbetapir 
and only in subjects who agreed 
to participate in the longitudinal 
PET substudy. 
Extension substudy, and its 
availability is limited outside of 
the US and Japan 
 Assessments 
Section 5.3 
Section 7.2.2.1 
Section 9.1.1.1 
Section 9.1.2.2 
Section 9.5.1.6 
Table 8 
Appendix 4 
 
Removed cerebrospinal fluid 
(CSF) biomarker exploratory 
objective and endpoint 
Projected lack of enrollment in 
substudy 
Synopsis  
 Objectives 
 Study Design 
 Assessments 
 Statistical Methods  
Section 8 
Appendix 4 
 
Clarified drug product 
formulation 
The current formulation of the 
drug product may be 
progressively phased out as 
stocks near the end of their shelf 
life, and will be replaced by a 
newer formulation. 
Synopsis  
 
Study Treatment(s) and 
Response Adaptive 
Randomization (RAR) 
Section 9.4.2 
Appendix 4 
Clarified that the Drug Safety 
Monitoring Board (DSMB) will 
monitor safety only in the Core 
Study 
All subjects in Extension Phase 
will receive open-label 
BAN2401 10 mg/kg biweekly 
Synopsis  
 Study Design 
 Assessments 
Section 7.2  
Section 9.1 
Updated pharmacokinetic (PK) 
sampling times 
Addition of early timepoint 
assessments in Extension Phase 
Synopsis – Study Design 
Table 11 
Appendix 4 
Table 13 
Updated Clinical Experience 
To reflect completed and 
ongoing study data 
Section 7.1.2.3 
Table 2 
Section 7.2.1.2 
Grammatical, typographical, and 
formatting changes  
Document quality  
Throughout 
 
 
 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 14 of 235 
CONFIDENTIAL 
 
Revisions to Version 12.0 
New version/date:  Version 13.0/16 Mar 2018 (per Amendment 10) 
Change 
Rationale 
Affected Protocol Sections 
Updated key secondary, 
secondary, and exploratory 
objectives, endpoints, and 
efficacy analyses 
Rearranged key secondary 
objectives and secondary 
objectives to emphasize disease 
pathophysiology based on 
18 month data.  
Updated analysis methods to 
account for the lack of subjects 
positive for apolipoprotein є4 
variant (APOE4) in the 
10 mg/kg biweekly dose group 
due to a change in the middle of 
randomization following a 
Regulatory request by European 
Health Authorities in July, 2014.  
Synopsis  
 Key Secondary Objectives 
 Secondary Objectives 
 Exploratory Objectives 
 Statistical Methods 
 Key Secondary Endpoints 
 Secondary Endpoints 
 Exploratory Endpoints 
 Analysis for Key 
Secondary Endpoints 
 Analysis for Other 
Secondary Endpoints 
 Analysis for Exploratory 
Endpoints 
Section 8 
Section 9.7 
Section 9.7.1.1 
Section 9.7.1.6 
 
 
 
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Clinical Study Protocol Amendment 20 
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Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 15 of 235 
CONFIDENTIAL 
 
 
 
Revisions to Version 11.0 
New version/date:  Version 12.0/09 Nov 2017 (per Amendment 09) 
Change 
Rationale 
Affected Protocol Sections 
Key Secondary Objectives/ 
Endpoints specified  
Bayesian analysis for Key 
Secondary Endpoint: change 
from baseline in Alzheimer's 
Disease Composite Score 
(ADCOMS) at 18 months 
included to identify the simplest 
dose regimen with highest 
predictive probability of being 
the ED90 dose. 
 
Specified that the conventional 
analysis for change from 
baseline in ADCOMS at 18 
months is based on the ED90 
dose identified from the 18 
month Bayesian analysis   
Design clarification 
 
Extend the Bayesian analysis to 
include 18 month endpoints. 
 
 
 
 
 
 
 
 
Relate the Bayesian and 
conventional analyses for 
change from baseline in 
ADCOMS at 18 months   
Synopsis  
 Objectives 
 Study Design 
 Extension Phase 
 Study Endpoints 
 Efficacy Analyses 
 Interim Analyses 
Section 8 
Section 9.1 
Section 9.7 
Section 9.7.1.1 
Section 9.7.1.6 
Section 9.7.2 
Appendix 4 
Correction of errors from 
Amendment 08 
For consistency and accuracy 
Throughout 
Grammatical, typographical, and 
formatting changes  
Document quality 
Throughout
 
 
 
 
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Clinical Study Protocol Amendment 20 
BAN2401-G000-201
 
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 16 of 235 
CONFIDENTIAL 
 
 
Previous Version (Amendment 07): v10.0 
Current Version (Amendment 08): v11.0 
Date of Revisions:  19 Feb 2016 
Change 
Rationale 
Affected Protocol Sections 
Grammatical, typographical, and 
formatting changes  
 
Throughout 
Addition of a 60-month open-label 
Extension Phase, to be conducted 
only if early success is achieved at 
any interim analysis (IA) or at the 
Bayesian analysis at 12 months of 
treatment. 
To assess long-term safety and 
tolerability in subjects who elect 
to continue open-label treatment.  
Subjects will be administered 1 
dose throughout the Open-label 
Extension Phase; 1 or 2 doses of 
BAN2401 will be studied in the 
Extension Phase, and dosing will 
be established upon early success. 
Synopsis  
 Study Period and Phase 
of Development 
 Objectives 
 Study Design 
 Conduct of the Study 
 Inclusion Criteria 
 Exclusion Criteria  
 Study Treatment and 
RAR 
 Duration of Treatment 
 Concomitant 
Drug/Therapy 
 Assessments 
 Statistical Methods 
 Sample Size Rationale  
Section 8 
Section 9.1 
Section 9.1.2 
Section 9.1.2.1  
Section 9.1.3 
Section 9.1.2.2 
Section 9.1.2.3 
Section 9.3.3 
Section 9.4.1 
Section 9.4.3 
Section 9.4.5 
Section 9.4.6 
Section 9.5.1.3 
Section 9.5.1.4 
Section 9.5.1.5 
Section 9.5.2.1 
Section 9.5.5 
Section 9.7.1.1 
Section 9.7.1.6 
Section9.7.1.7 
Appendix 4 
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Clinical Study Protocol Amendment 20 
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Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 17 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 07): v10.0 
Current Version (Amendment 08): v11.0 
Date of Revisions:  19 Feb 2016 
Change 
Rationale 
Affected Protocol Sections 
Additional consent required for 
subjects who consent to participate 
in the imaging or CSF subgroup in 
the Extension Phase, but who had 
not consented to the imaging or 
CSF subgroup in the Core Study.  
These subjects must undergo a 
baseline PET scan or CSF 
collection in the Core Study. 
Subjects who did not consent to 
the imaging or CSF subgroup in 
the Core Study will have the 
opportunity to consent to 
longitudinal PET or CSF 
assessments in the Extension 
Phase of the study. 
Section 5.3 
Section 9.1.1 
Section 9.5.1.6 
Section 9.5.2.1 
 
Historical amyloid positive PET 
scans may be used for eligibility 
upon evaluation by the central 
imaging CRO.  Historical PET 
scans may not be used as baseline 
scans for longitudinal assessments 
in the imaging subgroup 
Clarification 
Synopsis  
 Inclusion Criteria 
Section 9.3.1 
 
 
BAN2401 must be infused with a 
terminal in-line filter when 
administered 
Clarification 
Synopsis  
 Study Treatment(s) and 
Response Adaptive 
Randomization (RAR) 
Section 9.4.1 
 
Subjects with skin rash due to 
study drug are considered other 
events of interest and need not be 
removed from the study 
Correction 
Section 9.3.3 
Added Biogen, RTP as a 
manufacturer of BAN2401 
Updated information 
Section 9.4.2 
Changed the reporting term of 
vasogenic edema to vasogenic 
edema (ARIA-E) and clarified new 
“cerebral” microhemorrhages 
Clarification for coding purposes 
Section 9.5.4.3 
Added measurement of 
neutralizing antibodies 
The assay has been developed 
Section 9.7.1.8 
 
 
 
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Clinical Study Protocol Amendment 20 
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Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 18 of 235 
CONFIDENTIAL 
 
 
Previous Version (Amendment 07): v9.0 
Current Version (Amendment 07): v10.0 
Date of Revisions:  30 Jul 2015 
Change 
Rationale 
Affected Protocol Sections 
Addition of a Visit 6 (Week 7) 
safety MRI at European sites only.  
This safety MRI will not be 
accompanied by volumetric MRI 
sequences. 
The Visit 6 safety MRI will be 
conducted in Europe per request 
from European Regulatory 
Authorities. 
Synopsis  
 Conduct of the Study 
 Pharmacogenetic and 
Biomarker 
Assessments 
Section 7.2.2.2 
Section 9.1.2.1 
Section 9.5.1.4 
Section 9.5.2.1, Table 8 
Grammatical, typographical, and 
formatting changes  
 
Throughout
 
 
 
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Clinical Study Protocol Amendment 20 
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Page 19 of 235 
CONFIDENTIAL 
 
 
Previous Version (Amendment 06): v8.0 
Current Version (Amendment 07): v9.0 
Date of Revisions:  26 Jun 2015 
Change 
Rationale 
Affected Protocol Sections 
Revised to allow 40 randomized 
Japanese subjects 
To explore preliminary data in 
Japanese subjects for consistency 
of treatment effect between 
populations 
Synopsis 
 
Sites 
 
Objectives 
 
Number of Subjects 
 
Inclusion Criteria 
 
Concomitant 
Drug/Therapy 
 
Statistical Methods 
Section 1 
Section 6 
Section 8 
Section 9.1 
Section 9.3.1 
Section 9.4.3 
Section 9.4.7.2 
Section 9.7.1.6 
Section 9.7.1.7 
Section 9.7.1.9 
Section 9.7.1.8 
Section 9.7.2 
Revised Inclusion Criterion #7, to 
specify that subjects must consent 
to both baseline CSF and PET 
before the eligibility results for 
either subgroup study are 
confirmed 
Operational efficiency 
Synopsis  
 
Inclusion Criteria 
Section 9.3.1 
Section 9.5.1.6 
Revised Inclusion Criterion #16 
with regard to informed 
consent/assent 
Early AD subjects may lack 
capacity to consent at screening.  
Furthermore early AD subjects 
who had capacity to consent at 
screening may lose capacity to 
consent over time. 
Synopsis  
 
Inclusion Criteria 
Section 5.3 
Section 9.3.1 
Revised Exclusion Criterion #7, 
specific to meningiomas and 
arachnoid cysts 
Clarification 
Synopsis  
 
Exclusion Criteria 
Section 9.3.2 
Revised requirement for post 
infusion in clinic stay, whereby 
subjects no longer need to remain 
in clinic for 2 hours following 
infusion at all Visits 
Potential untoward effects are 
sufficiently characterized to allow 
for safe flexibility 
Section 9.5.1.4 
Table 8 
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Clinical Study Protocol Amendment 20 
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Page 20 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 06): v8.0 
Current Version (Amendment 07): v9.0 
Date of Revisions:  26 Jun 2015 
Change 
Rationale 
Affected Protocol Sections 
Revised home infusions whereby 
subjects who enrolled after 
implementation of Amendment 07; 
however, those subjects who 
initiated home infusions will be 
allowed to continue such for the 
duration of their participation in 
the study 
Operational optimization of 
method of study drug 
administration due to low number 
of participation in home infusion 
option 
Synopsis  
 
Study Design 
Section 9.1 
Section 9.1.2.1 
Section 9.4.5 
Table 8 
Revised timing of CSF and PET 
during Baseline  
To allow for scheduling flexibility
Section 9.1.1.2 
Table 7 
Revised to expand amyloid PET 
substudy outside the US 
Due to increased availability of 
approved agents in other regions. 
Synopsis  
 
Study Design 
 
Assessments 
Section 7.2.2.1 
Section 9.1.1.2 
Section 9.5.1.2 
Section 9.5.1.6 
Section 9.7.1.9 
Revised LP collection method 
Clarification 
Section 9.5.1.4 
Revised overall duration of study 
from 41 months to 67 months with 
an approximate study end of Jun 
2018 
To account for current enrollment 
rate 
Synopsis  
 
Study Period and 
Phase of 
Development 
Assessments 
Section 9.1 
 
Revised text regarding PI review of 
screening assessments for 
eligibility  
Clarification 
Section 9.1.2 
Revised text regarding no APOE4 
positive subjects to be enrolled 
Clarification 
Section 9.3 
Section 9.7.2 
Revised imaging substudy  sample 
size from 260 to 306 
To increase the statistical power 
and increase likelihood of 
detecting an effect on amyloid 
Synopsis  
 
Study Design 
 
Assessments 
 
Sample Size 
Rationale 
Section 9.1.1.2 
Section 9.5.1.2 
Section 9.5.1.6 
Section 9.7.1.9 
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Clinical Study Protocol Amendment 20 
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Page 21 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 06): v8.0 
Current Version (Amendment 07): v9.0 
Date of Revisions:  26 Jun 2015 
Change 
Rationale 
Affected Protocol Sections 
Revised text regarding when 
statistical analyses will be done 
Clarification 
Section 9.7 
Revised terminology for derived 
Composite Clinical Score  to 
ADCOMS 
ADCOMS is more readily known 
and acceptable 
Throughout protocol 
 
 
 
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Clinical Study Protocol Amendment 20 
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FINAL (v23.0):  24 Sep 2023 
Page 22 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 05): v7.0 
Current Version (Amendment 06): v8.0 
Date of Revisions:  20 Nov 2014 
Change 
Rationale 
Affected Protocol Sections 
Revised inclusion criteria for 
Wechsler Memory Scale (WMS) to 
apply to all subjects, not only 
subjects with MCI 
Mild AD dementia subjects 
should also exhibit deficits in 
episodic memory to be eligible 
for the study. 
Synopsis –  
 
Study Design 
 
Inclusion Criteria 
Section 9.1.1 
Section 9.3.1 
Section 9.5.2.1  
Table 7 
Table 8, footnote b 
 
Positive amyloid load can be 
indicated by either PET or CSF 
Aβ(1-42) assessment.  Subjects 
who consent to both amyloid PET 
and CSF subgroups need a positive 
amyloid result in only one of the 
2 measures. 
The addition of CSF as an 
eligibility criterion for amyloid 
load in the brain allows for 
potential study expansion to sites 
and countries that might not have 
amyloid PET imaging 
capabilities.   
Synopsis –  
 
Inclusion Criteria 
 
Other Assessment 
Section 5.3 
Section 9.1.1.1 
Section 9.1.1.2  
Section 9.3 
Section 9.3.1 
Section 9.5.2.1 
Table 7 
Table 8 
Section 9.5.1.4 
Section 9.5.1.6 
Figure 2 
 
 
Revised inclusion criteria to 
include subjects with a BMI of >17 
Per Netherland’s request via the 
VHP process 
Synopsis –  
 
Inclusion Criteria 
Section 9.3.1 
 
Other tests of thyroid function with 
results outside the normal range 
should only be exclusionary if they 
are considered clinically significant 
by the investigator. 
Only subjects who have 
hypothyroidism as indicated by 
elevated TSH will need to be 
excluded. 
Synopsis –  
 
Exclusion Criteria 
Section 9.3.2 
 
Updated the required timing of the 
MRI assessments  
To provide site flexibility 
Section 9.5.1.2 
Section 9.5.2.1 
 
 
Revised to require subjects who 
discontinue the study due to APOE 
status to return for the Early 
Termination and Follow-Up Visits. 
Clarification as part of the normal 
discontinuation process for a 
study-specific situation.  Subjects 
who discontinue the study due to 
Synopsis –  
 
Conduct of the 
Study 
Section 9.1.2.2 
Section 9.3.3 
Section 9.5.2.1 
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Clinical Study Protocol Amendment 20 
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Page 23 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 05): v7.0 
Current Version (Amendment 06): v8.0 
Date of Revisions:  20 Nov 2014 
Change 
Rationale 
Affected Protocol Sections 
APOE status cannot rescreen for 
Study 201. 
Table 7, footnote b 
Section 9.5.5 
 
Revised to allow subjects who 
discontinue study drug are required 
to return after the Early 
Termination Visit for each 
scheduled visit when clinical 
efficacy assessments are to be 
conducted per the Schedule of 
Procedures/Assessments. 
Clarification of procedure 
Synopsis –  
 
Conduct of the 
Study 
Section 9.5.2.1 
Table 7, footnote b 
Section 9.5.5 
 
Subjects who need treatment with 
short-term (<4 weeks) 
anticoagulant therapy post 
randomization do not have to be 
withdrawn from study drug, but 
will be required to withhold study 
drug during treatment with 
anticoagulant.  Subjects who need 
to start chronic (>4 weeks) 
anticoagulant treatment during the 
study for concomitant diseases will 
be withdrawn from study drug. 
Subjects may have to undergo 
procedures which require short 
term (<4 weeks) treatment with 
anticoagulants for prophylaxis of 
thromboembolic disease. This 
provision reduces the risk of CNS 
hemorrhage arising from the 
combination of anticoagulant and 
study drug (due to ARIA-H).  
Synopsis –  
 
Concomitant 
Drug/Therapy 
Section 9.4.7.2 
Appendix 2, Listing 1 
 
Revised to allow unblinding of all 
subjects who undergo Early 
Termination due to ARIA  
Implemented to allow for 
continuous monitoring of the risk 
factors for development of ARIA 
Section 7.1.2.3 
Section 9.3.3 
Section 9.5.5 
Section 9.5.1.2  
Table 8, footnote b 
 
 
 
Updated the BAN2401 clinical 
experience with respect to the 
number of ARIA cases to date. 
Updated based on current 
information as of 27 October, 
2014 
Section 7.1.2.3 
Any approved imaging agent may 
be used in the US, Canada, EU, or 
any region in which the study is 
conducted.  Florbetapir is the 
preferred agent in the US.  Those 
subjects in the US who participate 
in the imaging substudy must use 
florbetapir as the imaging agent. 
Allows for the use of alternative 
imaging agents and options when 
the need arises, but maintains 
consistency for the quantitative 
longitudinal assessment 
Section 7.2.2.1 
Section 9.5.1.6 
 
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Clinical Study Protocol Amendment 20 
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Page 24 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 05): v7.0 
Current Version (Amendment 06): v8.0 
Date of Revisions:  20 Nov 2014 
Change 
Rationale 
Affected Protocol Sections 
Guidelines are provided where 
procedures need not be repeated 
for rescreen subjects  
Clarification.  Subjects who were 
discontinued due to APOE status 
are not allowed to re-screen. 
Section 9.1.1.2 
Section 9.5.2.1 
 
 
Events of vasogenic edema, 
macrohemorrhage, an area of 
superficial siderosis or a 
symptomatic microhemorrhage, 
must be reported on the SAE form 
with the same reporting 
requirements as an SAE, but these 
events are not automatically 
considered serious events. 
Correction and clarification 
Section 9.5.1.5 
 
For hypersensitivity reactions in 
the skin, subjects need not be 
discontinued from study drug if 
such reactions are mild to moderate 
in intensity and respond to 
treatment, after discussion with 
sponsor medical monitor.  
Otherwise, the investigator should 
discontinue study drug in subjects 
whose skin hypersensitivity 
reactions are severe, or respond 
poorly to treatment, or likely to 
worsen with continued exposure to 
study drug. 
Clarification 
Section 9.5.1.5 
 
Revised text to explicitly state that 
safety MRIs require passing both a 
local read and a central read prior 
to administration of the next dose 
of study drug. 
Implemented as an additional 
safety check  
Synopsis –  
 
Safety Assessments 
Section 9.1.2.1 
Section 9.5.1.2, Table 8 
Section 9.5.1.5 
Added urinalysis to Screening, 
Baseline, Weeks 1, 3, 7, 13, 19, 27, 
39, 53, 65, 79, early termination 
and follow-up visits  
Corrected an omission from the 
Schedule of Assessments 
 
Section 9.5.2.1 
Added PK sampling to early 
termination visit 
To determine PK exposure in 
ARIA subjects and subjects who 
withdraw due to AEs 
Section 9.5.1.2, Table 8 
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Clinical Study Protocol Amendment 20 
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Page 25 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 05): v7.0 
Current Version (Amendment 06): v8.0 
Date of Revisions:  20 Nov 2014 
Change 
Rationale 
Affected Protocol Sections 
If no untoward effects of infusions 
on vital signs are detected ≥2 hours 
after infusion, vital sign 
assessments at subsequent study 
visits may be conducted at a 
shorter interval after infusion.  
Subject must still be present in the 
clinic at least 2 hours after the 
infusion. 
Clarification 
Section 9.5.1.2  
Table 8, footnote d 
Section 9.5.1.5 
 
For those subjects who consent, 
CSF collection at Visit 29 is to be 
collected 2 – 4 days after the study 
drug infusion.  CSF collection at 
Visit 42 has been moved to Visit 
41. At Visit 41 CSF will be 
collected predose on the day of the 
infusion visit. Serum PK samples 
are to be collected immediately 
following CSF collection.   
CSF collection has been moved to 
coincide to 2 to 4 days after the 
last visit at which study drug is 
administered (Visit 29).  This 
change allows for collection of 
BAN2401 PK in CSF following 
dosing and coincides with the 
CSF Cmax.  
At Visit 41, CSF is collected 
predose to determine CSF Cmin. 
Serum PK samples are collected 
immediately after CSF sampling 
for PK modelling at Visit 29 and 
Visit 41.the collection of plasma 
BAN2401 PK 
Section 9.5.1.2, Table 8 
Sections 9.5.1.4 
Section 9.5.1.6 
 
Updated infusion reaction grading 
system  
To align the grading system with 
the current version of the 
NCI-CTCAE. 
Section 9.5.1.5 
Revised list of cognitive enhancer 
list  
Updated with newly approved 
enhancers  
Appendix 2, Listing 1 
 
 
 
 
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Page 26 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 04): v6.0 
Current Version (Amendment 05): v7.0 
Date of Revisions:  11 Aug 2014 
Change 
Rationale 
Affected Protocol Sections 
APOE4 positive subjects will 
not be randomized to the 
10 mg/kg biweekly dose. 
The Voluntary Harmonisation 
Procedure (VHP) committee 
requested that subjects who are 
confirmed APOE4 positive 
(APOE4 hetero- or 
homozygous) not be randomized 
to the 10 mg/kg, biweekly dose. 
Synopsis –  
 
Study Design 
 
Conduct of the Study 
 
Study Treatment and 
Response Adaptive 
Randomization (RAR) 
 
Interim Analyses 
Section 7.1.2.3 
Section 9.1 
Table 3 
Section 9.1.1.2 
Section 9.2 
Section 9.4.3 
Section 9.7.2 
 
 
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Page 27 of 235 
CONFIDENTIAL 
 
 
Previous Version (Amendment 03): v5.0 
Current Version (Amendment 04): v6.0 
Date of Revisions:  09 Jul 2014 
Change 
Rationale 
Affected Protocol Sections 
Added safety and volumetric 
MRIs at Week 9 (Visit 7) of 
treatment 
Recommended by the Data 
Safety Monitoring Board to 
allow early detection of ARIA-E 
prior to the Week 13 MRI scan. 
This measure will prevent the 
further dosing of subjects with 
early ARIA-E to minimize the 
risk of further progression. 
Synopsis –  
 
Conduct of Study 
 
Assessments – Safety 
Assessments 
Table 7 
Modified the randomization 
algorithm so as NOT to 
randomize APOE4 homozygous 
subjects to the 10 mg/kg, 
biweekly dose 
Recommended by the Data 
Safety Monitoring Board after 
unblinded review of all 
asymptomatic and symptomatic 
cases of ARIA-E in Study 201 
Synopsis –  
 
Study Design 
 
Conduct of Study 
 
Response Adaptive 
Randomization (RAR) 
 
Statistical Methods – 
Interim Analysis 
Section 7.1.2.3 
Section 9.1 
Table 3 
Section 9.1.1 
Section 9.2 
Section 9.4.3 
Section 9.7.2 
 
 
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Page 28 of 235 
CONFIDENTIAL 
 
 
Previous Version (Amendment 02): v4.0 
Current Version (Amendment 03): v5.0 
Date of Revisions:  18 Sep 2013 
Change 
Rationale 
Affected Protocol Sections 
Home infusions will not be 
allowed at study sites in 
Germany 
Requested by Germany 
regulatory authorities through 
the Voluntary Harmonization 
Procedure process 
Synopsis, Study Design 
Section 9.1 
Section 9.1.2.1 
Table 7, footnote “l” 
Section 9.4.5 
 
For study inclusion, MMSE 
scores must be ≥22 or ≤28 in the 
United Kingdom, Spain, 
Germany, Sweden, France, and 
the Netherlands. 
Requested by European Union 
regulatory authorities through 
the Voluntary Harmonization 
Procedure process 
Synopsis, Inclusion Criterion  
Section 9.3.1 
 
 
 
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Clinical Study Protocol Amendment 20 
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Page 29 of 235 
CONFIDENTIAL 
 
Previous Version (Amendment 01): v3.0 
Current Version (Amendment 02): v4.0 
Date of Revisions:  27 Jun 2013 
Change 
Rationale 
Affected Protocol Sections 
Amyvid can now be used in the 
European Union. 
To allow the use of Amyvid in 
the European Union 
Section 7.2.2.1 
Section 9.5.1.6 
The imaging subgroup will be 
comprised of subjects in the US 
only. 
It is anticipated relatively few 
subjects will be imaged with 
Amyvid in the European Union, 
so for consistency, only those 
subjects in the US will be in the 
imaging subgroup. 
Synopsis, Study Design 
Synopsis, Sample Size 
Rationale 
Synopsis, Assessments 
Section 7.2.2.1 
Section 9.1.1.2 
Section 9.5.1.6 
Section 9.7.1.9 
Text deleted indicating Amyvid 
is not yet approved in Europe. 
Amyvid was recently approved 
in Europe. 
Section 7.2.2.1 
 
 
 
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Clinical Study Protocol Amendment 20 
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FINAL (v23.0):  24 Sep 2023 
Page 30 of 235 
CONFIDENTIAL 
 
Previous Version (Original Protocol): v2.0 
Current Version (Amendment 01): v3.0 
Date of Revisions:  22 Apr 2013 
Change 
Rationale 
Affected Protocol Sections 
Grammatical, typographical, and 
formatting changes  
General consistency and 
accuracy of text 
Throughout 
Mild Alzheimer’s dementia 
change to mild Alzheimer’s 
disease dementia 
For consistency to align with 
NIA-AA (National Institute of 
Aging-Alzheimer’s Association) 
terminology 
Throughout 
Clarified the wording around 
futility and the primary endpoint 
in the study design 
The endpoint is change from 
baseline in the clinical 
composite score.  However, the 
analysis of that endpoint 
compares to change in placebo.  
This analysis is covered 
correctly throughout the rest of 
the protocol. 
 Synopsis, Study Design 
 Section 9.1 
 
Reworded scales as they relate 
to timing of diagnosis and 
relevance to eligibility criteria 
Clarified that all 3 clinical scales 
are to be assessed prior to 
diagnosis and to further clarify 
the role of WMS criteria in 
eligibility (for MCI due to AD 
only). 
 Synopsis, Study Design 
 Section 9.1.1 
 Section 9.5.2, Table 6, 
(footnote c) 
Clarification of administration 
of home infusions  
Clarified that home infusions 
will be conducted according to 
country and local regulations. 
 Synopsis, Study Design 
 Section 9.1 
 Section 9.1.2.1 
 Section 9.4.5 
 Section 9.5.2, Table 7 
(footnote l) 
The timing of the WMS-IV 
LMII relative to the WMS-IV 
LMI was revised. 
This was changed to correct an 
error in the protocol around the 
timing for WMS-IV LMII 
relative to WMS-IV LMI. 
 Synopsis, Study Design 
 Section 9.1.1 
 Section 9.5.2.1, Table 6 
(footnote c) 
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Page 31 of 235 
CONFIDENTIAL 
 
Previous Version (Original Protocol): v2.0 
Current Version (Amendment 01): v3.0 
Date of Revisions:  22 Apr 2013 
Change 
Rationale 
Affected Protocol Sections 
Clarified the assessments 
expected for subjects who 
discontinue early from study 
drug.  
Subjects who discontinue from 
study drug must undergo all 
assessments for the Early 
Termination Visit and the 
3-month Follow-Up Visit as 
outlined in the Schedule of 
Procedures/Assessments.  In 
addition, subjects are expected 
to return for all visits at which 
clinical efficacy assessments are 
scheduled to undergo clinical 
assessments (MMSE, CDR, 
ADAS-Cog, and FAQ) and to 
provide information on con 
meds, AE and SAE.  
 Synopsis, Study Design 
 Synopsis, Assessments 
 Section 9.1.2.2 
 Section 9.3.3 
 Section 9.5.1.5 
 Section 9.5.2, Table 7, 
footnote b 
 Section 9.5.5 
 Section 9.7.1.3 
Clarified inclusion criterion #4 
for MCI due to AD subjects 
with objective impairment in 
episodic memory according to 
WMS 
Subjects who score below the 
age-adjusted range (not above) 
are also eligible, and thus the 
inclusion criterion for MCI due 
to AD revised to clarify this 
point.  
 Synopsis, Inclusion Criteria 
 Section 9.3.1 
Corrected inclusion criterion 
#14 
Subjects must be on stable doses 
of all other permitted 
concomitant medications for at 
least 4 weeks prior to Baseline, 
not Screening. 
 Synopsis, Inclusion Criteria 
 Section 9.3.1 
Revised inclusion criterion #15 
For consistency between the 
synopsis and the body of the 
protocol 
 Synopsis, Inclusion Criteria 
 Section 9.3.1 
Clarified exclusion criterion #11 
regarding thyroid function 
To enable subjects who are 
euthyroid and otherwise well 
and suitable for the study to be 
eligible. 
 Synopsis, Exclusion Criteria 
 Section 9.3.2 
Exclusion #24 was corrected to 
state that biologics are not 
allowed for 6 months prior to 
Baseline, and not 1 year 
Correction 
 Synopsis, Exclusion Criteria 
 Section 9.3.2 
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Page 32 of 235 
CONFIDENTIAL 
 
Previous Version (Original Protocol): v2.0 
Current Version (Amendment 01): v3.0 
Date of Revisions:  22 Apr 2013 
Change 
Rationale 
Affected Protocol Sections 
Futility: 
 
Update definition of futility 
and how it will be addressed 
 
Clarified that the 
continuation of study (after 
declaration of futility) is 
defined as the continuation 
of subject randomization 
 
The futility boundary is 
statistical in nature, and the 
sponsor will make the final 
decision on futility and how 
to proceed with study 
conduct.  Note that 
statistical futility is still 
considered binding for this 
study. 
 
Restated for more precise 
definition of study 
continuation. 
 Synopsis, Statistical Methods 
 Section 9.1 
 Section 9.7.1 
 Section 9.7.1.6 
Include sensitivity analyses for 
the primary endpoint 
To include analyses that do not 
censor data based on compliance 
or changes in AD medication 
 Synopsis, Statistical Methods 
 Section 9.7.1.6 
Added provision for statistical 
analysis in event of early 
success 
To specify the statistical 
analysis to be conducted if early 
success is achieved. 
 Synopsis, Statistical Methods 
 Section 9.7.1.6 
Revised prohibited concomitant 
medication criteria window 
from prior to Screening to prior 
to Baseline 
To allow subjects additional 
time to meet the criteria for 
concomitant medication. 
 Section 9.4.7.2 
 Appendix 2 
Scheduled infusion window was 
increased from 3 to 8 days 
To minimize the number of 
missed infusions while still 
ensuring adequate exposure to 
study drug. 
 Section 9.4.8 
 Section 9.5.2, Table 7 
(footnote a) 
Revised Physical activities will 
not be recorded in this study  
This information is not vital data 
for the conduct or objectives of 
the study. 
 Section 9.5.1.2 
 Section 9.5.2, Table 6  
Clarified that the Geriatric 
Depression Scale (GDS) is also 
clinician assisted 
While subjects can usually 
report this information on their 
own, it is important to clarify 
that the instrument is clinician 
assisted in the event that a 
subject is not capable of self-
reporting. 
 Section 9.5.1.2 
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Page 33 of 235 
CONFIDENTIAL 
 
Previous Version (Original Protocol): v2.0 
Current Version (Amendment 01): v3.0 
Date of Revisions:  22 Apr 2013 
Change 
Rationale 
Affected Protocol Sections 
Clarified timing of PK sampling 
relative to initial infusion done 
at Visit 3 and all subsequent 
infusions and visits 
Subjects are required to stay in 
the clinic for 4 hours following 
the initial infusion (Visit 3) to 
ensure that no infusion and/or 
hypersensitivity reactions are 
noted after the initial infusion.   
Subjects will be required to stay 
in the clinic for at least 2 hours 
at all subsequent visits. 
 Section 9.5.1.4 
 Section 9.5.2, Table 7, 
(footnote m) 
Deleted details of plasma 
collection timepoints samples 
will be collected 
Information captured in other 
placed in protocol (eg, Table of 
assessments) 
 Section 9.5.1.4 
Revised such that 
pharmacogenomics and 
biomarker analyses samples 
may be collected/analyzed 
To allow flexibility, as 
pharmacogenomics and 
biomarker analyses may not be 
warranted. 
 Section 9.5.1.4 
 Section 9.7.1.7 
Description of volumetric MRI 
assessment moved from Safety 
Assessments to 
Pharmacogenomic and 
Biomarker Assessments.   
Also removed reference to the 
use of the boundary shift 
integral for analysis of 
volumetric MRI data 
While collected immediately 
after the collection of Safety 
MRI data (ie, from the same 
scan with appropriate parameter 
changes), volumetric MRI is a 
biomarker assessment.   
The reference to the use of the 
boundary shift integral for 
analysis was removed to allow 
for flexibility for analysis in the 
event the field evolves toward 
changes in the use of software 
for volumetric MRI analysis at 
the time these data will be 
analyzed.  Moreover, it is 
uncommon for clinical study 
protocols to specify which 
software package will be used 
for analysis of volumetric MRI 
data. 
 Section 9.5.1.4 
 Section 9.5.1.5 
Clarification of collection of 
SAEs 
Subjects are required to return 
for a follow-Up visit 3 months 
after the last dose, so this is 
technically the time at which 
SAEs should be collected. 
 Section 9.5.1.5 
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Previous Version (Original Protocol): v2.0 
Current Version (Amendment 01): v3.0 
Date of Revisions:  22 Apr 2013 
Change 
Rationale 
Affected Protocol Sections 
Provided further detail for 
follow up of hypersensitivity 
reactions 
For clarity and subject safety 
 Section 9.5.1.5 
Corrected text regarding blood 
will be collected at Baseline and 
that it is for anti-BAN2401 
antibody assays. 
Error in previous version of 
protocol. 
 Section 9.5.2.1, Table 6 
Safety analysis for collection of 
ECGs was modified. 
Since QT data are not collected 
for statistical analysis but only 
for AE and SAE determinations. 
 Section 9.7.1.8 
Corrected error in the 
numbering of footnotes in Table 
7 of the Schedule of 
Procedures/Assessments 
Corrected error in numbering 
 Section 9.5.2, Table 7 
Clarification on collection of 
exploratory biomarker and 
pharmacogenomic samples  
Exploratory biomarker and 
pharmacogenomic samples will 
not be collected in those 
countries whose local 
regulations require the return of 
these data to subjects. 
 Appendix 3 
Updated Product Creation Unit 
name 
To reflect recent unit name 
change 
 Signature Page 
Removed 
 
as medical monitor as 
 
 is the medical monitor for 
this study 
Corrected Medical Monitor 
information 
 Signature Page 
 
 
 
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Previous Version:  v1.0 
Current Version:  v2.0 
Date of Revisions: 20 November 2012 
Change 
Rationale 
Affected Protocol Sections 
Randomization such that at least 
60% of the total number of 
subjects will have MCI due to 
AD – intermediate likelihood 
and at least 30% will have mild 
Alzheimer’s disease dementia 
Increase proportion of subjects 
with MCI due to Alzheimer’s 
disease in response to narrowing 
the eligibility range for mild AD 
subjects brought forth by a 
change to overall MMSE range 
(from 20-30 to 22-30) for 
eligibility. 
 Synopsis, Study Design 
 Section 9.1 
 Section 9.4.3 
Correct size of imaging 
subgroup to n = 260. 
Correct an error in the previous 
protocol version. 
 Synopsis Study Design, Other 
Assessments, Amyloid PET 
(Imaging Subgroup) 
 Section 9.1.1.2 
 Section 9.5.1.2 
 Section 9.5.1.6 
 Section 9.7.1.9 
Clarify that for all subjects at all 
safety MRI time points, vMRI 
sequences will be taken after all 
safety MRI assessments, and 
specify the visits at which vMRI 
sequences will be analyzed.    
To clarify that while analyses of 
vMRI assessments are specified 
only for the Screening Visit and 
Visits 16, 29, and 42, taking 
sequences after ALL safety MRI 
assessments will allow the 
option of conducting additional 
analyses at those visits if 
warranted.  This approach is 
also easier for sites to 
implement and results in no 
additional cost. 
 Synopsis, Study Design, 
Pharmacogenomic and 
Biomarker Assessment 
 Section 7.2.2.2 
 Section 9.1.2.1 
 Section 9.5.1.4 
 Section 9.5.1.5 
 Table 7, footnote j 
Add text explaining that clinical 
efficacy data will be censored if 
AD treatment is initiated or if 
stable AD treatment is altered 
while subjects are on treatment. 
State the analyses for the 
primary endpoint. 
 Synopsis, Concomitant 
Drug/Therapy 
 Section 9.7.1.6 
Correct use of abbreviations 
Aβ(1-42), Cmax,ss, Cmin,ss, and 
t1/2,ss for consistency throughout 
text. 
Editorial quality 
 Synopsis, Bioanalytical 
Methods 
 Abbreviation list 
 Table 2 
 Table 4 
Add that if futility is declared, 
the study will be considered as 
failed even if it continues after 
this declaration. 
Clarify that futility is binding. 
 Synopsis, Efficacy Analysis, 
Statistical Methods 
 Section 9.1 
 Section 9.7.1 
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Previous Version:  v1.0 
Current Version:  v2.0 
Date of Revisions: 20 November 2012 
Change 
Rationale 
Affected Protocol Sections 
 Section 9.7.1.6 
Describe the Bayesian analysis 
methods and sensitivity analysis 
to be used for primary endpoint. 
Clarify statistical approaches to 
the primary endpoint. 
 Synopsis, Analysis for the 
Primary Endpoint 
 Section 9.7.1.2 
 Section 9.7.1.6 
Delete statement that if a subject 
misses 3 consecutive doses, data 
will be censored at the time of 
the third missed dose, and re-
define compliance for censoring 
purposes 
Interim analyses and final 
analyses will be censored 
according to 60% compliance.  
 Synopsis, Analysis for the 
Primary Endpoint 
 Section 9.7.1.6 
State that the primary analysis 
will be based on the Full 
Analysis Set with prespecified 
censoring rules applied  
Clarify analysis sets. 
 Synopsis, Analysis for the 
Primary Endpoint 
 Section 9.7.1.6 
State that if the efficacy or 
futility boundary is reached, the 
IMC will communicate with the 
DSMB 
Assure appropriate handling of 
interim analysis outcomes. 
 Synopsis, Interim Analysis 
 Section 9.7.2 
Correct population PK model 
predictions. 
Calculations of several 
parameters were corrected on 
basis of new information. 
 Section 7.1.2.3 
 Section 9.4.4 
 Table 4 
Revise to differentiate screening 
procedures more clearly from 
those conducted subsequently. 
For clarity 
 Section 9.1.1.1 
 Section 9.5.1.2 
 Table 6 (footnote c) 
Stipulate that at Screening, 
psychometric tests must be 
administered before other 
eligibility assessments. 
Minimize unnecessary clinical 
assessments at the Screening 
Visit for ineligible subjects. 
 Section 9.1.1.1 
 Table 6 (footnote c) 
Delete statement that blood will 
be collected at Baseline for anti-
BAN2401 assays. 
Correct an error in the protocol. 
 Section 9.1.1.2 
  Section 9.5.1.2 
Revise instructions for instances 
where a subject may need to 
skip a scheduled dose 
administration. 
Minimize unnecessary 
consultations. 
 Section 9.1.2.1 
 Section 9.4.1 
Relocate a cross-reference to 
inclusion criteria. 
For clarity 
 Section 9.4.3 
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Previous Version:  v1.0 
Current Version:  v2.0 
Date of Revisions: 20 November 2012 
Change 
Rationale 
Affected Protocol Sections 
Correct statement such that 
anticoagulants are prohibited for 
up to 7 days before study drug. 
Correct an inconsistency in text 
and appendix. 
 Section 9.4.7.2 
 Appendix 2, Listing 1 (title) 
Restate requirements for 
prohibited  concomitant drugs 
such that they start at Screening 
rather than Baseline. 
Minimize undesirable drug 
interactions and possible 
confounding of study results.  
 Section 9.4.7.2 
 Appendix 2, Listing 1 
Stipulate that at least 6 days 
must elapse between a PET scan 
and administration of the study 
drug. 
Allow for safety period between 
tracer administration and 
BAN2401 administration. 
 Table 6 and Table 7 footnotes 
Correct a table footnote to delete 
Day 42 from days on which 
weight is to be collected, and to 
state that if a subject misses a 
clinic visit where weight is to be 
collected, the weight 
measurement at the next visit is 
to be entered into the IVRS.  
Correct 2 errors in the protocol 
pertaining to weight data 
collection. 
 Table 7 footnote 
Modify description of ADAS-
Cog. 
Provide a more precise 
description of the ADAS-Cog 
version used in the present 
study. 
 Section 9.5.1.2 
Revise list of drugs of abuse to 
be tested in drug sample. 
Update information pertaining 
to drug testing. 
 Section 9.5.1.2 
Delete “progression of disease” 
as a reason for discontinuation. 
“Progression of disease” will 
take place for all subjects in the 
study, and is unclear and 
difficult to evaluate for 
discontinuation purposes. 
 Section 9.5.5 
 Section 9.7.1.3 
Stipulate that the SAP will be 
finalized before the first interim 
analysis. 
Clarification of timing of SAP 
completion 
 Section 9.7.1 
Redefine the Per Protocol 
Analysis set as subjects in the 
Full Analysis Set who have 
sufficiently complied with 
protocol. 
Clarify statistical method. 
 Section 9.7.1.2 
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Previous Version:  v1.0 
Current Version:  v2.0 
Date of Revisions: 20 November 2012 
Change 
Rationale 
Affected Protocol Sections 
Restate description of 
simulation results 
Clarification 
 Section 9.7.1.9 
Delete dose restrictions on 
concomitant carbamazepine, 
lamotrigine, and valproic acid. 
Eliminate unnecessary 
concomitant medication 
restrictions.   
 Appendix 2 , Listing 4 
Minor editorial corrections 
Document quality 
 Various 
 
 
 
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1 
TITLE PAGE 
 
 
CLINICAL STUDY PROTOCOL 
Study Protocol 
Number: 
BAN2401-G000-201 
Study Protocol 
Title: 
A Placebo-Controlled, Double-Blind, Parallel-Group, Bayesian Adaptive Randomization 
Design and Dose Regimen-Finding Study with an Open-Label Extension Phase to Evaluate 
Safety, Tolerability and Efficacy of BAN2401 in Subjects With Early Alzheimer’s Disease  
Sponsor: 
(revised per 
Amendment 17) 
Eisai Inc. 
200 Metro Blvd.  
Nutley, NJ 07110 
US 
Eisai Ltd. 
European Knowledge 
Centre 
Mosquito Way  
Hatfield, Hertfordshire  
AL10 9SN UK 
Eisai Co., Ltd. 
4-6-10 Koishikawa 
Bunkyo-Ku, 
Tokyo 112 8088 
Japan  
(revised per Amendment 07) 
Investigational 
Product Name: 
BAN2401/lecanemab (revised per Amendment 16) 
Indication: 
Alzheimer’s disease 
Phase: 
2/4 (Japan, approved indication and dosage)  (revised per Amendment 18) 
Approval Date: 
v2.0, 20 Nov 2012 (Original Protocol) 
v3.0, 22 Apr 2013 (Amendment 01) 
v4.0, 27 Jun 2013 (Amendment 02) 
v5.0, 18 Sep 2013 (Amendment 03) 
v6.0, 09 Jul 2014 (Amendment 04) 
v7.0, 11 Aug 2014 (Amendment 05) 
v8.0, 20 Nov 2014 (Amendment 06) 
v9.0, 26 Jun 2015 (Amendment 07) 
v10.0, 30 Jul 2015 (Amendment 07) 
v11.0, 18 Feb 2016 (Amendment 08) 
v12.0, 09 Nov 2017 (Amendment 09) 
v13.0, 16 Mar 2018 (Amendment 10) 
v14.0, 14 Sep 2018 (Amendment 11) 
v15.0, 15 Nov 2018 (Amendment 12) 
v16.0, 14 Jan 2019 (Amendment 13) 
v17.0, 18 Mar 2020 (Amendment 14) 
v18.0, 08 Sep 2020 (Amendment 15) 
v19.0, 23 Feb 2021 (Amendment 16) 
v20.0, 16 Feb 2022 (Amendment 17) 
v21.0, 15 Dec 2022 (Amendment 18) 
v22.0, 31 Aug 2023 (Amendment 19) 
v23.0, 24 Sep 2023 (Amendment 20) 
 
 
 
 
 
 
 
 
 
IND Number: 
105081 
EudraCT 
Number: 
2012-002843-11  
GCP 
Statement: 
This study is to be performed in full compliance with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use and all applicable local GCP and 
regulations (Good Postmarketing Study Practice and Good Vigilance Practice in the case of 
postmarketing study).  All required study documentation will be archived as required by regulatory 
authorities.  (revised per Amendment 18) 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information of Eisai (the sponsor).  Any 
viewing or disclosure of such information that is not authorized in writing by the sponsor is strictly 
prohibited.  Such information may be used solely for the purpose of reviewing or performing this 
study. 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.: 
BAN2401 
Name of Active Ingredient: 
BAN2401/lecanemab (revised per Amendment 16) 
Study Protocol Title: 
A Placebo-Controlled, Double-Blind, Parallel-Group, Bayesian Adaptive Randomization Design and Dose 
Regimen-Finding Study with an Open-Label Extension Phase to Evaluate Safety, Tolerability and Efficacy of 
BAN2401 in Subjects With Early Alzheimer’s Disease  
Investigator(s): 
Multicenter (revised per Amendment 17) 
Site(s): 
Approximately 125 sites including North America, Europe, and Asia-Pacific (revised per Amendment 07) 
Study Period and Phase of Development:  (revised per Amendments 07, 08, and 19)   
Core Study:  Up to 18 months of treatment plus 3 months of follow-up  
Extension Phase Part A:  Up to 60 months of additional treatment plus 3 months of follow-up.   
Extension Phase Part B:  Maximum combined (Part A and Part B) open-label treatment duration of up to 60 months 
(5 years).   
The 3-month Follow-Up visit is not required for any subject who transitions directly from the Extension Phase 
Part A or Part B (including the postmarketing section in Japan) of the study to commercial BAN2401  (revised per 
Amendments 11, 15, 18, and 19). 
Phase 2/Phase 4 (Japan, approved indication and dosage) (revised per Amendment 18) 
Objectives: 
CORE STUDY 
Primary Objectives: 
1. To evaluate the efficacy of BAN2401 compared to placebo by establishing the ED90 (as defined in the 
protocol) for BAN2401 on the Alzheimer’s Disease Composite Score (ADCOMS) at 12 months of 
treatment in subjects with Early Alzheimer’s Disease (EAD), defined as mild cognitive impairment 
(MCI) due to Alzheimer’s disease (AD) – intermediate likelihood or mild Alzheimer’s disease 
dementia 
2. To assess the safety and tolerability of 3 doses and 2 dose regimens of BAN2401 in subjects with EAD 
Key Secondary Objectives:  (revised per Amendments 09 and 10) 
1. To evaluate the effects of BAN2401 compared to placebo on brain amyloid pathophysiology at 
18 months of treatment in subjects with EAD as measured by amyloid positron emission tomography 
(PET) (revised per Amendments 09 and 10) 
2. To evaluate the efficacy of BAN2401 compared to placebo on the ADCOMS at 18 months of treatment 
in subjects with EAD (revised per Amendments 09 and 10) 
3. To evaluate the efficacy of BAN2401 compared to placebo on the Clinical Dementia Rating – Sum of 
Boxes (CDR-SB) at 18 months of treatment in subjects with EAD (revised per Amendment 10) 
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4. To evaluate the efficacy of BAN2401 compared to placebo on Alzheimer’s Disease Assessment Scale 
- Cognitive Subscale (ADAS-Cog) in subjects with EAD at 18 months 
5. To evaluate the effects of BAN2401 compared to placebo at 18 months on clinical status separately 
within subjects with MCI and mild AD dementia for the following assessments: ADCOMS, CDR-SB, 
and ADAS-Cog (revised per Amendment 10) 
6. To evaluate the effects of BAN2401 compared to placebo on cerebrospinal fluid (CSF) biomarkers 
(Aβ[1-42], t-tau, and p-tau) at 18 months of treatment in subjects with EAD (revised per 
Amendment 10) 
7. To evaluate the effects of BAN2401 compared to placebo on total hippocampal volume using 
volumetric magnetic resonance imaging (vMRI) at 18 months of treatment in subjects with EAD 
(revised per Amendments 09 and 10) 
Secondary Objectives: 
1. To evaluate the effects of BAN2401 compared to placebo on brain amyloid pathophysiology at 
12 months of treatment in subjects with EAD as measured by amyloid PET (revised per 
Amendments 09 and 10) 
2. To evaluate the effects of BAN2401 compared to placebo at 12 months on clinical status in subjects 
with EAD for the following assessments: ADCOMS, CDR-SB, and ADAS-Cog (revised per 
Amendments 09 and 10) 
3. To evaluate the effects of BAN2401 compared to placebo at 12 months on clinical status separately 
within subjects with MCI and mild AD dementia for the following assessments: ADCOMS, CDR-SB, 
and ADAS-Cog (revised per Amendment 10) 
4. To evaluate the effects of BAN2401 compared to placebo on CSF biomarkers (Aβ[1-42], t-tau, and 
p-tau) at 12 months of treatment in subjects with EAD (revised per Amendment 10) 
5. To evaluate the effects of BAN2401 compared to placebo on total hippocampal atrophy as measured 
by vMRI at 6 and 12 months, and left and right hippocampus, whole brain and total ventricular volume 
as measured by vMRI at 6, 12, and 18 months of treatment in subjects with EAD (revised per 
Amendment 10) 
Exploratory Objectives: 
1. To evaluate the effects of BAN2401 compared to placebo on clinical status in subjects with EAD by 
assessment of Mini- Mental State Examination (MMSE), and FAQ at time points not listed in Key 
Secondary and Secondary objectives (revised per Amendment 10) 
2. To explore the relationship between change from baseline in clinical status at 12 and 18 months of 
treatment and baseline brain amyloid pathophysiology in subjects with EAD as measured by amyloid 
PET (revised per Amendment 10) 
3. To explore the relationship between change from baseline in clinical status and change from baseline 
in brain amyloid pathophysiology at 12 and 18 months of treatment in subjects with EAD as measured 
by amyloid PET (revised per Amendment 10) 
4. To explore efficacy of BAN2401 compared to placebo and the overall study population on the 
ADCOMS across all clinical assessment time points in Japanese subjects with EAD (revised per 
Amendments 07 and 10) 
5. To characterize the population pharmacokinetics (PK) of BAN2401 in EAD subjects, and to examine 
the effect of intrinsic and extrinsic factors on the PK (revised per Amendment 08) 
EXTENSION PHASE PART A (revised per Amendments 08, 11, 16,17, 18, and 19) 
Primary Objective: 
To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD 
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Secondary Objectives: 
To assess if the treatment benefit in brain amyloid levels (as measured by amyloid PET) at the end of the Core 
Study will be maintained over time in the Extension Phase Part A in subjects with EAD (revised per Amendment 
11) 
Exploratory Objectives: 
1. To evaluate the clinical effects of BAN2401 in subjects with EAD on the ADCOMS, CDR-SB, 
ADAS-Cog, and MMSE over time during the Extension Phase Part A 
2. To assess time to disease progression as evaluated by Clinical Dementia Rating (CDR) global score 
during the Extension Phase Part A 
3. To explore the long-term effects of BAN2401 in subjects with EAD on total hippocampal volume and 
other biomarkers (eg, plasma biomarkers) annually in the Extension Phase Part A (revised per 
Amendment 15) 
4. To characterize population PK of BAN2401 in subjects enrolled in the Extension Phase Part A of the 
study 
5. To evaluate patterns of resource utilization and associated costs of care for subjects with EAD and their 
study partners, using medical claims data (revised per Amendment 16) 
Objectives for the Dosing Regimen Substudy (revised per Amendment 17) 
1. To assess whether amyloid levels are maintained over time at less frequent dosing regimens as 
measured by positron emission tomography PET (standard uptake value ratio) SUVR 
2. To assess the effect of less frequent dosing regimens on the changes in plasma biomarkers  
3. To explore the clinical effects of less frequent dosing regimens in subjects with EAD on ADCOMS, 
CDR-SB, ADAS-Cog, and MMSE over time  
4. To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD at less frequent 
dosing regimens 
5. To characterize population PK and PK/pharmacodynamic (PD) (biomarkers and PET SUVR [when 
available]) of BAN2401 in subjects enrolled in the Dosing Regimen substudy of the study 
EXTENSION PHASE PART B (revised per Amendment 19) 
Primary Objective: 
To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD 
Study Design: 
This will be a multinational, multicenter, double-blind, placebo-controlled, parallel-group study, using a Bayesian 
design with response adaptive randomization (RAR) across placebo or 5 active arms of BAN2401 to determine 
clinical efficacy and to explore the dose response of BAN2401 using a composite clinical score (ie, ADCOMS) 
and a 60-month Extension Phase.  All subjects who are ongoing in the Extension Phase Part A and who have 
completed at least 18 months of treatment in the Extension Phase Part A may take part in an optional Dosing 
Regimen substudy to evaluate effects on safety, PK exposure, biomarker, and clinical efficacy of alternate dosing 
regimens for maintenance dosing of BAN2401.  (revised per Amendments 11, 15, 17, and 19)   
The Core Study is an 18-month study with 5 dose regimens, which comprise 3 dose levels given biweekly (once 
every 2 weeks) and 2 dose levels given monthly (once every 4 weeks).  The dose levels in the Core Study are 2.5, 
5, and 10 mg/kg biweekly and 5 and 10 mg/kg monthly.  (revised per Amendment 11)   
Frequent interim analyses (IA) will be conducted to continually update randomization allocation on the basis of the 
primary clinical endpoint.  (revised per Amendment 01)  This approach allows for ongoing assessment of drug 
futility or evidence for early success and for continued changes in randomization that favor efficacious treatment 
arms.  Thus, the Bayesian approach not only limits exposure of subjects to non-efficacious treatment arms but can 
also mitigate the risks associated with larger and longer trials required to demonstrate clinical efficacy by leading 
to more efficient project termination or early advancement to a successful Phase 3 program.  After the 12-month 
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assessments have been completed, treatment will continue to 18 months to follow the time course of any treatment 
effects observed at 12 months, and to evaluate biomarker and neuroimaging effects that may be consistent with 
potential disease modification.  Should the OLE Phase be implemented, treatment will continue for up to 60 months 
(5 years) of additional treatment to allow for the assessment of the long-term safety and tolerability of BAN2401.  
(revised per Amendment 08)  Subjects will be from 2 clinical subgroups, collectively designated as EAD for the 
purposes of this protocol:  (a) MCI due to AD – intermediate likelihood and (b) mild Alzheimer’s disease dementia.  
At study entry, subjects will be stratified according to clinical subgroup, apolipoprotein E (APOE) status 
(ie, apolipoprotein є4 variant [APOE4] positive and negative) and the presence or absence of ongoing AD treatment 
(ie, acetylcholinesterase inhibitors [AChEIs] or memantine or both).  Subjects will be diagnosed as either MCI due 
to AD or mild Alzheimer’s disease dementia as defined by the protocol after completion of MMSE, Wechsler 
Memory Scale IV-Logical Memory (subscale) I (WMS-IV LMI), Wechsler Memory Scale IV-Logical Memory 
(subscale) II (WMS-IV LMII), and CDR.  Once the diagnosis is made, the WMS-IV LMII inclusion criterion can 
be applied to all subjects (revised per Amendments 01 and 06).    Randomization into the 2 clinical subgroups will 
be reasonably balanced whereby at least 60% of the total number of subjects will have MCI due to AD – 
intermediate likelihood and at least 30% will have mild Alzheimer’s disease dementia.  APOE4 status (positive or 
negative) must be confirmed for all subjects prior to randomization.  Subjects who are confirmed APOE4 positive 
(APOE4 hetero- or homozygous) will not be randomized to the 10 mg/kg, biweekly dose.  (revised per 
Amendment 05)  The first 196 subjects will be randomized according to a fixed schedule (4:2:2:2:2:2; Placebo [4] 
to each of the active arms [2 each]).  After 196 subjects have been randomized into the study, an IA will be 
conducted and the RAR will guide subsequent randomization into dose groups.  Interim analyses and RAR will be 
repeated after 250 subjects have been randomized and again after each additional 50 subjects until all 800 subjects 
are randomized, and will then be repeated at 3-month intervals until all subjects complete 12 months of treatment. 
(revised per Amendment 07)  A Bayesian analysis will be conducted at 12 months of treatment to assess for early 
success, and at 18 months of treatment, regardless of whether early success is achieved at 12 months.  (revised per 
Amendment 09) 
Drug Safety Monitoring Board 
A separate unblinded Drug Safety Monitoring Board (DSMB) will be employed at regular intervals to monitor the 
overall safety of the study and will make recommendations to the sponsor as appropriate.  In addition, the DSMB 
will meet when a predetermined number of subjects are randomized to assess whether the option for home infusions 
is feasible during the Core Study (per DSMB charter, if allowed and conducted according to country and local 
guidelines; home infusions will not be allowed in Germany.  (revised per Amendment 14) Upon implementation 
of Amendment 07, newly enrolled subjects will not be offered the option for home infusions during the Core Study.  
(revised per Amendment 14) Subjects opting for home infusions before implementation of Amendment 07 will be 
allowed to continue with home infusions for the duration of their participation in the Core Study.  (revised per 
Amendments 01, 03, 07, and 14) Details regarding DSMB membership and operational characteristics will be 
provided in the DSMB Charter.  The DSMB will be responsible for monitoring the safety of the study only in the 
Core Study.  (revised per Amendment 11) 
Core Study (revised per Amendment 11) 
The Core study will consist of a Prerandomization Phase and a Randomization Phase.  (revised per Amendment 08)
The Prerandomization Phase (revised per Amendment 08) may last up to 60 days, and will consist of a Screening 
Period (up to 30 days duration) and a Baseline Period (up to 30 days duration).  During the Screening Period 
(Day -60 to –31; Visit 1) and Baseline Period (Day -30 to -1; Visit 2), all subjects will be assessed for eligibility 
using clinical tests, safety MRIs, and amyloid PET assessments to confirm that subjects meet the diagnostic criteria 
for MCI due to AD – intermediate likelihood or mild Alzheimer’s disease dementia and that they do not have other 
medical conditions that may interfere with study participation.    
Clinical assessments for eligibility will be conducted in the morning (whenever possible) at the Screening Visit in 
the following order:  MMSE, Wechsler Memory Scale –IV Logical Memory I and II (WMS-IV LMI and WMS-IV 
LMII), and CDR.  The WMS-IV LMII is to be administered 20 to 30 minutes after the completion of LMI.  Subject 
information should be collected in the 20 to 30 minutes between the WMS-IV LM1 and LMII.  Subjects will also 
be evaluated on the Geriatric Depression Scale (GDS) for eligibility.  (revised per Amendment 01)  Subjects who 
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pass this initial screen for eligibility will be assessed by safety magnetic resonance imaging (MRI) for brain 
abnormalities that may affect eligibility, and all subjects will undergo an additional scanning sequence immediately 
following the safety MRI for vMRI during the Screening visit.  The safety and vMRI assessments conducted during 
Screening will also be used as the baseline MRI assessments for these respective measures in subjects who are 
eligible.   
Further assessments will be conducted during the Baseline Period, including additional clinical evaluations, 
mandatory blood sampling for pharmacogenomics (PGx) (APOE4 status) per Appendix 3, and CSF sampling for 
those who consent to soluble CSF biomarker analysis.  (revised per Amendment 01)  At the Baseline Visit, clinical 
assessments are to be conducted in the morning (whenever possible) in the following order:  MMSE, CDR, 
ADAS-Cog, and FAQ.  For further assessment of eligibility, within 20 days after the Baseline Visit all qualified 
subjects will undergo amyloid PET to confirm the presence of amyloid in the brain.  Baseline amyloid PET data 
will serve as the baseline data for subjects in the imaging subgroup (target n=306 total) who will receive amyloid 
PET at 12 and 18 months of treatment (revised per Amendments 02 and 07).  APOE4 status (positive or negative) 
must be confirmed for all subjects prior to randomization.  Subjects who are confirmed APOE4 positive (APOE4 
hetero- or homozygous) will not be randomized to the 10 mg/kg, biweekly dose.  (revised per Amendment 05) 
The Randomization Phase (revised per Amendment 08) will consist of an 18-month Treatment Period and a 
3-month Follow-Up Period.  Subjects will be randomized at Visit 3 (Day 1) to receive placebo or 1 of 5 treatment 
arms of BAN2401, administered as an approximate 60-minute intravenous (IV) infusion every 2 weeks.  All 
subjects will undertake assessments of cognitive function, safety, pharmacokinetic (PK), safety MRI, and vMRI 
while select subjects will undertake additional CSF biomarkers or amyloid PET or both per the Schedule of 
Assessments.  (revised per Amendment 01) At designated study visits, clinical assessments will be conducted in 
the morning (whenever possible) in the following order:  MMSE, CDR, ADAS-Cog, and FAQ.  The Follow-Up 
Visit will take place 3 months after the last treatment. 
A Visit 6 abbreviated MRI (safety MRI to detect amyloid-related imaging abnormalities (ARIA) lasting 8 to 
10 minutes, with no vMRI sequences) will be conducted at European sites only.  (revised per Amendment 07)  An 
early safety MRI will also be conducted at Visit 7(revised per Amendment 04).   Clinical assessment of efficacy 
endpoints and safety MRIs will be conducted every 3 months until the End of Treatment or until Discontinuation 
from the study (revised per Amendment 01).  Volumetric MRI sequences will be taken from all subjects 
immediately following all safety MRI assessments.  Analysis of vMRI assessments will be conducted at the 
Screening Visit and at Visits 16, 29, and 42.  In some cases, unscheduled visits will be needed to follow up on 
regularly scheduled safety or safety MRI findings, and the related assessments (outlined in the Schedule of 
Assessments) will depend on the nature of the unscheduled visit as determined by the investigator.  Amyloid PET 
will be collected for subjects who consent to undergo this scan at 12 and 18 months of treatment.  Physical 
examinations, safety assessments, assessments for antidrug antibodies, standard laboratory assessments, blood for 
PK and exploratory biomarker assessments, and CSF for soluble CSF biomarker assessments will be collected as 
specified in Appendix 3. 
Subjects who have completed Visit 42 (Week 79) of the Core Study (and do not participate in the Extension Phase) 
will undergo the 3-month Follow-Up Visit after their last dose of study drug in the Core Study per the Schedule of 
Assessments.  (revised per Amendment 08)  Subjects who discontinue the Core Study or study drug early must 
comply with the Early TerminationVisit (within 7 days after the last dose of study drug) and the Follow-Up Visit 
(3 months after the last dose of study drug).  (revised per Amendment 08)  In addition, subjects who discontinue 
study drug in the Core Study are required to return after the Early Termination Visit for each scheduled visit when 
clinical efficacy assessments are to be conducted (Visits 9, 16, 22, 29, 35, and 42) per the Schedule of 
Procedures/Assessments for the Core Study.  (revised per Amendments 06 and 08)  At these visits, clinical efficacy 
assessments (MMSE, ADAS-Cog, CDR, and FAQ) will be conducted and information on concomitant medications, 
adverse events (AEs), and serious adverse events (SAEs) will be collected.  Subjects who discontinue 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 01)   
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Extension Phase Part A (revised per amendments 08, 11, 14, 15, 16, 17, 18, and 19) 
The Extension Phase Part A will be initiated following the Core Study to allow subjects to receive open-label 
BAN2401 10 mg/kg biweekly or if the subject enters the Dosing Regimen substudy, 1 of the 2 alternative dosing 
regimens (either BAN2401 10 mg/kg once every 4 weeks [Q4W] or BAN2401 10 mg/kg once every 3 months 
[Q3M]).  All subjects who are ongoing in the Extension Phase Part A and who have completed at least 18 months 
of treatment in the Extension Phase Part A may take part in an optional Dosing Regimen substudy to evaluate the 
effects on safety, PK exposure, biomarker, and clinical efficacy of alternate dosing regimens for maintenance 
dosing of BAN2401.  Subjects may choose to enter this substudy at any study visit according to their prior biweekly 
schedule of assessments.  Subjects who participate in this substudy will be randomized to 1 of 2 intravenous dosing 
regimens; either BAN2401 10 mg/kg Q4W or BAN2401 10 mg/kg Q3M.  Subjects will adopt a new schedule of 
assessments specific to the Dosing Regimen substudy.  At any point during the Dosing Regimen substudy, a subject 
can withdraw consent from the substudy and revert back to open-label BAN2401 10 mg/kg biweekly 
administration. 
All infusions will take place in the clinic; however, if approved by the Sponsor and allowable and conducted 
according to country and local guidelines, subjects will be offered the option of home infusions for approved visits.  
Home infusions are being implemented as a result of the COVID-19 pandemic to allow subjects who cannot visit 
clinical sites for various reasons to continue receiving treatment.  Home infusions will be allowed per Sponsor 
approval according to country and local guidelines during the COVID-19 pandemic and following its resolution, 
where permitted.  (revised per Amendment 14)   
Any subject who completed study treatment (Visit 42 [Week 79] of the Core Study) and fulfills the Extension Phase 
Part A inclusion and exclusion criteria will have the option to participate in the Extension Phase Part A.  Subjects 
who previously completed the Core Study (through the Follow-Up Visit, Visit 43) at any time before 
implementation of the Extension Phase in Part A, and/or fulfill the Extension Phase Part A inclusion and exclusion 
criteria, will also be eligible to participate Extension Phase in Part A.  Subjects who discontinued the Core Study 
will be eligible to participate in the Extension Phase Part A, provided they meet the inclusion and exclusion criteria 
for the Extension Phase Part A.  Subjects in Extension Phase Part A will transition to commercial supplies upon 
availability for individual subjects at each study site.  All subjects ongoing in Extension Part A upon implementation 
of Protocol Amendment 19 will transition to Extension Part B.  Extension Phase Part A and Part B combined will 
continue for up to 60 months (5 years), or until BAN2401 is commercially available for individual subjects at each 
study site, at which time the subjects will switch to commercial BAN2401, or in the cases where drug is not yet 
commercially available, treatment will continue until the benefit to risk ratio from treatment with BAN2401 is no 
longer considered favorable, whichever comes first.  (revised per Amendments 11, 15, 17, and 19) 
Extension Phase Part A will continue for up to 60 months (5 years), or until BAN2401 is commercially available 
for individual subjects at each study site, at which time the subjects will switch to commercial BAN2401, or until 
implementation of Protocol Amendment 19, or in the cases where drug is not yet commercially available, treatment 
will continue until the benefit to risk ratio from treatment with BAN2401 is no longer considered favorable, 
whichever comes first.  (revised per Amendment 19) 
Upon approval of BAN2401 in Japan, subjects who meet the approved indication and dosage of BAN2401 will 
continue in Extension Phase Part A or Part B of this study as a postmarketing part in Japan.  (revised per 
Amendment 19) 
The Follow-Up Visit will take place 3 months after the last dose of study drug.  Subjects may discontinue from 
study drug for any reason.  Subjects who discontinue the study drug are requested to undertake the Early 
Termination Visit (within 7 days after the last dose of study drug) and the Follow-Up Visit (3 months after the last 
dose of study drug).  The 3-month Follow-Up visit is not required for any subject who transitions directly (including 
the postmarketing part in Japan) to commercial BAN2401.  (revised per Amendments 17, 18, and 19) 
For those subjects who transition to commercial BAN2401 (including the postmarketing part in Japan), the end of 
the study will be the date of the last study evaluation prior to transitioning to commercial BAN2401.  At that time, 
all assessments included in Week 261/Early Termination Visit are to be performed according to the Schedule of 
Assessments.  (revised per Amendment 19).   
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Safety assessments will be performed and all AEs and SAEs will be recorded.  Vital signs will be assessed when 
study drug is administered both at predose and after infusion.  Hematology, blood chemistry assessments, and 
urinalysis will be performed at Extension Baseline (Extension Screening Visit), at Extension Phase Weeks 3, 7, 13, 
19, 27, and every 6 months thereafter.  Safety and vMRIs will be performed at baseline (Extension Screening Visit), 
at Extension Phase Weeks 9, 13, 27, and every 6 months thereafter.  Clinical assessments will be administered at 
baseline (Extension Screening Visit) and every 6 months in the morning (whenever possible) in the following order:  
MMSE, CDR, and the ADAS-Cog.  Blood for serum PK and anti-BAN2401 antibodies will be collected at 
Extension Phase Week 1 (Visit 44); Extension Weeks 3, 9, 13, 27, 39, and 53, and every 24 to 26 weeks thereafter, 
through to Extension Week 261, and the Follow-Up Visit.  In the Dosing Regimen substudy, subjects will undertake 
a baseline plasma blood draw upon entry to the substudy and will attend site visits every 4 weeks, regardless of 
dosing regimen for the 1st year of the Dosing Regimen substudy.  Blood will be drawn at each Dosing Regimen 
substudy visit for plasma biomarker monitoring to assess that baseline levels (at substudy entry) are maintained 
over the course of treatment at each dosing regimen.  The sponsor will assess the plasma biomarker responses 
periodically, and if an optimal regimen is established, that regimen will be administered to all subjects in the 
substudy.  For those subjects who are also enrolled in the optional longitudinal PET substudy, a Dosing Regimen 
substudy baseline amyloid PET assessment should be conducted before substudy Visit 1 (Week 1), unless it has 
been conducted within 3 months of the Dosing Regimen substudy Visit 1.  Subjects may participate in home 
infusions with sponsor and medical monitor approval, and in accordance with local guidelines.  (revised per 
Amendments 15, 17, and 19)   
All subjects who underwent amyloid PET for inclusion in the Core Study should receive a baseline amyloid PET 
scan before dosing in the Extension Phase Part A.  The baseline amyloid PET scan must be conducted with the 
same imaging tracer that was used for inclusion at the baseline visit for the Core Study.  In addition, qualified 
subjects located in the US and Japan will have the option to participate in the longitudinal PET substudy.  (revised 
per Amendment 12)  In this imaging substudy, florbetapir will be used in the US and flutemetamol will be used in 
Japan, and only subjects who consent to the longitudinal assessments per the Extension Phase Schedule of 
Assessments will be allowed to participate in this imaging substudy.  At the Extension Screening Visit, subjects 
who consented to the longitudinal imaging substudy will be stratified into 2 cohorts based on their treatment 
allocation during the Core Study.  For Part A, Cohort 1 will have amyloid PET assessments performed at baseline 
(Extension Screening Visit), Visit 50 (Extension Week 13), Extension Phase Visit 70 (Extension Week 53), and 
annually thereafter; Cohort 2 will have amyloid PET assessments performed at baseline (Extension Screening 
Visit), Visit 57 (Extension Week 27), at Extension Phase Visit 70 [Extension Week 53], and annually thereafter.  
In Japan, those who consented to the longitudinal imaging substudy will only undergo amyloid PET at Extension 
Phase Visit 70 [Extension Week 53], and annually thereafter.  (Revised per Amendments 12, 15, 17, and 19) 
Extension Phase Part B (revised per Amendment 19) 
All subjects ongoing in Extension Part A upon implementation of Protocol Amendment 19 will transition to 
Extension Part B.  Extension Phase Part A and Part B combined will continue for up to 60 months (5 years), or 
until BAN2401 is commercially available for individual subjects at each study site, at which time the subjects will 
switch to commercial BAN2401, or in the cases where drug is not yet commercially available, treatment will 
continue until the benefit to risk ratio from treatment with BAN2401 is no longer considered favorable, whichever 
comes first.  Upon transition to Extension Phase Part B, Dosing Regimen substudy subjects will be given the option 
to remain on their current dosing regimen or transition back to BAN2401 10mg/kg biweekly infusions.   
Subjects in Extension Phase Part B will have procedures and assessments including periodic safety assessments at 
approximately 6 monthly intervals (±4 weeks) or as unscheduled assessments, when required.  (revised per 
Amendment 19) 
All infusions will take place in the clinic; however, if approved by the Sponsor and allowable and conducted 
according to country and local guidelines, subjects will be offered the option of home infusions for approved visits.  
Home infusions are being implemented as a result of the COVID-19 pandemic to allow subjects who cannot visit 
clinical sites for various reasons to continue receiving treatment.  Home infusions will be allowed per Sponsor 
approval according to country and local guidelines during the COVID-19 pandemic and following its resolution, 
where permitted.  (revised per Amendment 14)   
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Subjects will continue in Extension Phase B for a maximum combined (Part A and Part B) open-label treatment 
duration of up to 60 months (5 years), or until BAN2401 is commercially available for individual subjects at each 
study site, at which time the subjects will switch to commercial BAN2401, or in the cases where drug is not yet 
commercially available, treatment will continue until the benefit to risk ratio from treatment with BAN2401 is no 
longer considered favorable, whichever comes first.  (revised per Amendment 19) 
Upon approval of BAN2401 in Japan, subjects who meet the approved indication and dosage of BAN2401 will 
continue in Extension Phase Part B of this study as a postmarketing part in Japan.  (revised per Amendment 19) 
The Follow-Up Visit will take place 3 months after the last dose of study drug.  Subjects may discontinue from 
study drug for any reason.  Subjects who discontinue the study drug are requested to undertake the Early 
Termination Visit (within 7 days after the last dose of study drug) and the Follow-Up Visit (3 months after the last 
dose of study drug).  The 3-month Follow-Up visit is not required for any subject who transitions directly (including 
the postmarketing part in Japan) to commercial BAN2401.  (revised per Amendments 17, 18, and 19) 
For those subjects who transition to commercial BAN2401 (including the postmarketing part in Japan), the end of 
the study will be the date of the last study evaluation prior to transitioning to commercial BAN2401.  At that time, 
all assessments included in the Early Termination Visit are to be performed.  (revised per Amendment 19).   
Safety assessments will be performed, and all AEs and SAEs will be recorded.  Vital signs will be assessed when 
study drug is administered both at predose and after infusion.  Safety MRIs will be performed every 6 months.  
(revised per Amendments 15,17, 19, and 20)  
ARIA Management  
Subjects who develop asymptomatic Amyloid Related Imaging Abnormality-hemorrhage (ARIA-H), will continue 
on the study uninterrupted per the Schedule of Assessments and do not require additional MRI follow-up outside 
the regularly scheduled assessments.  Subjects who develop multiple (>10) asymptomatic cerebral 
microhemorrhages, superficial siderosis, or a single macrohemorrhage (greater than 10 mm at greatest diameter; 
also referred to within this protocol as intracerebral hemorrhage >1 cm), will continue on the study uninterrupted 
per the Schedule of Assessments, and will undertake an unscheduled safety visit (with MRI) at approximately 30 
days after the MRI features (asymptomatic ARIA-H) were first identified.  Thereafter, all subjects who develop 
these events will have further safety visits (with MRI) at approximately every 30 days (which may be an 
unscheduled or a scheduled visit) until the asymptomatic ARIA-H has stabilized radiographically.  Subjects who 
develop symptomatic ARIA-H (including symptomatic microhemorrhages, symptomatic superficial siderosis, 
symptomatic macrohemorrhage) on MRI will have study drug administration temporarily stopped.  All subjects 
who develop these events will undertake an unscheduled safety visit (with MRI) at approximately 30 days after the 
MRI features (ARIA-H) were first identified.  Thereafter they will have further safety visits (with MRI) at 
approximately every 30 days (which may be unscheduled or scheduled visit) until the ARIA-H has stabilized and 
is no longer symptomatic.  During treatment interruption, time will elapse on the Schedule of Assessments when 
the scheduled visit would otherwise occur.  They may then resume treatment for the study duration and study 
assessments remaining treatment on the Schedule of Assessments.  Resumption of treatment following 
symptomatic ARIA-H can only occur twice, after which the subject must be discontinued from the study.  (revised 
per Amendments 12 and 20) 
Subjects who develop asymptomatic, radiographically mild or moderate Amyloid Related Imaging 
Abnormality-Edema/Effusion (ARIA-E) on MRI will continue on the study uninterrupted per the Schedule of 
Assessments.  They will undertake an unscheduled safety visit (with MRI) at approximately 30 days and another 
safety visit (with MRI) at approximately 90 days (which may be unscheduled or scheduled visit) after the MRI 
features were first identified.  They will continue with study drug treatment if their ARIA-E does not become severe 
radiologically and remains asymptomatic.  
Those subjects who develop symptomatic or radiographically severe treatment emergent ARIA-E will be 
temporarily stopped from study drug administration until the ARIA-E resolves radiographically, and will be 
followed up to resolution of the event (including symptoms, if any).  They will undertake an unscheduled safety 
visit (with MRI) at approximately 30 days and another safety visit (with MRI) at approximately 90 days (which 
may be unscheduled or scheduled visit) after the symptomatic or severe ARIA-E was first identified.  Thereafter, 
these subjects will have a safety visit (with MRI) at approximately 30 days (which may be an unscheduled or a 
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scheduled visit) until the ARIA-E has resolved both radiologically and clinically.  During treatment interruption, 
time will elapse on the Schedule of Assessments when the scheduled visit would otherwise occur.  Once the ARIA-
E has resolved both radiologically and clinically, they may then resume treatment for the study duration and study 
assessments on the Schedule of Assessments.  Resumption of treatment following symptomatic ARIA-E can only 
occur twice, after which the subject must be discontinued from the study.  (revised per Amendment 12) 
In Japan only, subjects who develop asymptomatic, radiographically mild ARIA-E on MRI will continue on the 
study uninterrupted per the Schedule of Assessments.  They will undertake an unscheduled safety visit (with MRI) 
at approximately 30 days and another safety visit (with MRI) at approximately 90 days (which may be unscheduled 
or scheduled visit) after the MRI features were first identified.  They will continue with study drug treatment if 
their ARIA-E does not become moderate or severe radiologically and remains asymptomatic.  Those subjects who 
develop symptomatic or radiographically moderate or severe treatment emergent ARIA-E will be temporarily 
stopped from study drug administration until the ARIA-E resolves radiographically, and will be followed up to 
resolution of the event (including symptoms, if any).  They will undertake an unscheduled safety visit (with MRI) 
at approximately 30 days and another safety visit (with MRI) at approximately 90 days (which may be unscheduled 
or scheduled visit) after the symptomatic or moderate or severe ARIA-E was first identified.  Thereafter, these 
subjects will have a safety visit (with MRI) at approximately 30 days (which may be an unscheduled or a scheduled 
visit) until the ARIA-E has resolved both radiologically and clinically.  During treatment interruption, time will 
elapse on the Schedule of Assessments when the scheduled visit would otherwise occur.  Once the ARIA-E has 
resolved both radiologically and clinically, they may then resume treatment for the study duration and study 
assessments on the Schedule of Assessments.  Resumption of treatment following symptomatic and/or 
radiographically moderate or severe ARIA-E can only occur twice, after which the subject must be discontinued 
from the study.  (revised per Amendment 13) 
Radiographic severity is defined as follows:  (revised per Amendment 12) 
No ARIA-E present:  No signs of ARIA-E. 
Questionable ARIA-E:  Subtle sulcal or cortical fluid-attenuated inversion recovery (FLAIR) hyperintensity, 
most likely artifactual. 
Mild ARIA-E:  Mild FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white matter (with or 
without gyral swelling and sulcal effacement), which affects an area of less than 5 cm in a single greatest 
dimension.  Only a single region of involvement detected. 
Moderate ARIA-E:  Moderate involvement (area of FLAIR hyperintensity measuring 5-10 cm in single 
greatest dimensions), or more than one site of involvement, each measuring less than 10 cm in a single greatest 
dimension. 
Severe ARIA-E:  Severe involvement (area of FLAIR hyperintensity measuring greater than 10 cm in single 
greatest dimension [white matter and/or sulcal involvement with associated gyral swelling and sulcal 
effacement]).  One or more separate/independent sites of involvement may be noted. 
Should a subject discontinue from study treatment from one of these events, such subjects will undergo the Early 
Termination Visit within 7 days of discontinuation and will undergo the 3-month Follow-Up Visit per protocol.  
These subjects will continue to be followed with safety MRIs on a monthly basis thereafter, until the finding has 
either resolved or stabilized.   
Dosing Regimen Substudy Assessments 
Subjects entering the substudy will follow the substudy-specific schedule of assessments.  Consenting subjects may 
enter the Dosing Regimen substudy at any time during the Extension Phase Part A after they have completed 
18 months in the Extension Phase Part A.  Subjects may choose to enter this substudy at any study visit according 
to their prior biweekly schedule of assessments.  (revised per Amendments 16 and 19). 
Medical Claims Substudy  
In the US only, subjects and study partners who have participated in any phase of the study (Core Study or Extension 
Phase) will have the option to participate in an optional medical claims substudy.  The purpose of this substudy is 
to use medical claims data to further understand patterns of resource utilization and associated costs of care for 
subjects with EAD and their study partners.  Additionally, study partners will have the option to participate in a 
survey, which will provide supplemental information on the experience of those individuals who are responsible 
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for the care of subjects with EAD.  This medical claims substudy will require a separate consent.  Medical claims 
data for subjects and study partners who consent to this substudy will be collected for up to 5 years before study 
enrollment, for the duration of the Core Study, the duration of the period between the end of the Core Study and 
the Extension Baseline (if applicable), the duration of the Extension Phase (if applicable), and for up to 3 years 
after the end of the Core Study or Extension Phase (where applicable).  The results of the medical claims substudy 
will be presented in a separate report.  (revised per Amendments 16 and 17) 
Conduct of the Extension Phase During the Coronavirus Disease 2019 (COVID-19) Pandemic and Other 
Extenuating Circumstances  (revised per Amendment 15) 
All study assessment and visit information affected by any extenuating circumstances (eg, the COVID-19 
pandemic) will be collected on the case report forms (CRFs).  These include but are not limited to any visits or 
assessments that are missed or not done, any assessments that are performed remotely/offsite or in person/onsite, 
and any home infusions offered and completed.   
During the COVID-19 pandemic and under other extenuating circumstances, every attempt should be made to 
have Visits 57, 70, 83, 96, 109, 122, 135, 148, 161, End of Study Visit (Visit 174 or Early Termination Visit), and 
the Follow-Up Visit (visits with clinical assessments) conducted at the study site.  However, if this is not feasible 
under these extenuating circumstances, home infusion at applicable visits may be permitted, only with sponsor 
approval and only where permitted according to country and local guidelines.  During these visits, the clinical 
assessmentsMMSE, CDR, ADAS-Cog14, and Columbia Suicide Severity Rating Scale (C-SSRS), may be 
conducted remotely via a sponsor-approved telehealth system, following sponsor approval.  Where feasible, raters 
for these assessments should remain unchanged for each subject.  Every effort should be made to have the End of 
Study Visit (Visit 174 or Early Termination Visit) and the Follow-Up CDR assessment performed at the study 
site.  
COVID-19 vaccines and booster shots may be administered during the Extension Phase, but vaccination should 
be timed such that it will be administered at least 7 days after the previous infusion and at least 7 days before the 
next infusion.  The duration between COVID-19 vaccination and study drug infusions may be reduced to less 
than 7 days according to the clinical judgement of the investigator, following discussion with the medical 
monitor.  (revised per Amendment 17). 
During the Extension Phase Part A or Part B, if subjects cannot return to clinical sites due to extenuating 
circumstances (ie, the COVID-19 pandemic) and home infusion is not an option, the investigator/designee will 
instruct the subjects to contact the site promptly if there are changes in their medical condition including new AEs 
and changes in medication.  The investigator should maintain close contact with the subjects (eg, via telephone or 
via a sponsor approved telehealth system) to ensure medical and safety oversight at least every 6 weeks.  During 
this contact, the investigator/designee will collect, at minimum, all AEs and concomitant medication information.  
Additionally, with sponsor approval, remote clinical assessments for the CDR and C-SSRS will be performed as 
per protocol Schedule of Assessments.  (revised per Amendment 17) 
If for any reason, study drug dosing is interrupted (due to the COVID-19 pandemic or other extenuating 
circumstances), every effort should be made to have all missed safety and efficacy assessments performed as 
soon as possible during a scheduled or unscheduled visit, unless the next scheduled assessment(s) is (are) 
expected to occur within 30 days.  For subjects missing 3 or more consecutive doses, and who have not had any 
safety assessments performed either in-clinic or at the home infusion visit(s) during the period of dose 
interruption, the following safety assessments must be performed (either at the study site or during a home 
infusion visit) before resuming study drug dosing:  AE and concomitant medication assessments, vital signs, 
weight, routine physical (where feasible) or symptom directed physical (if routine physical is not feasible), 
clinical laboratory assessments, C-SSRS, and ECG.  Study drug dosing may resume on the same day as these 
assessments (ie, before receipt of the clinical laboratory assessments results) based on the clinical judgement of 
the investigator.  All laboratory results should be promptly evaluated by the investigator before the subsequent 
visit to ensure safety of continued study drug dosing.  If ECG or clinical laboratory assessments cannot be 
conducted before restarting study drug dosing, study drug dosing may resume based on the clinical judgement of 
the investigator.  However, these assessments must be performed as soon as possible and results should be 
promptly evaluated by the investigator before subsequent visits to ensure safety of continued study drug dosing.   
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Subjects who discontinue the study or study drug early are requested to undertake the Early Termination Visit 
(within 7 days after the discontinuation of study drug) and the Follow-Up Visit (3 months after the last dose of 
study drug).  The 3-month Follow-Up Visit is not required for any subject who transitions directly from the 
Extension Phase Part A or Part B (including the postmarketing section in Japan) of the study to commercial 
BAN2401.  (revised per Amendment 18) Every effort should be made to have the Early Termination Visit and 
Follow-Up Visit, conducted at the study site.  However, with approval from the sponsor, subjects who cannot 
visit clinical sites for various reasons may have these visits performed by the home infusion staff.  (revised per 
Amendments 17 and 19) 
For those subjects who are taking part in the dosing regimen substudy, subjects are to contact sites between their 
scheduled clinic visits if there are any changes in their medical condition including new AEs and changes in 
medication.  If for any reason study reasons are missed, the investigator should maintain close contact with the 
subjects (eg, via telephone) to ensure medical and safety oversight, at least every 6 weeks.  (revised per 
Amendment 17) 
Number of Subjects: 
Approximately 3200 subjects will be screened to provide a maximum of 800 randomized subjects.  Sites in Japan 
will screen approximately 160 subjects in order to randomize at least 40 Japanese subjects, even if early success is 
declared or the study achieves 800 subjects randomized.  (revised per Amendment 07)  
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Inclusion Criteria: 
CORE STUDY 
Diagnosis  
Mild Cognitive Impairment due to Alzheimer’s Disease – intermediate likelihood:  (revised per Amendment 06) 
1. Subjects who meet the National Institute of Aging – Alzheimer’s Association (NIA-AA) core clinical 
criteria for MCI due to Alzheimer’s disease – intermediate likelihood 
2. Subjects who have a CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline 
3. Subjects who report a history of subjective memory decline with gradual onset and slow progression over 
the last 1 year before Screening; MUST be corroborated by an informant 
Mild Alzheimer’s Disease Dementia: 
4. Subjects who meet the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia  (revised 
per Amendment 01) 
5. Subjects who have a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater at Screening and 
Baseline 
Key Inclusion Criteria that must be met by ALL Subjects: 
6. Subjects with objective impairment in episodic memory as indicated by at least 1 standard deviation below 
age-adjusted mean in the WMS-IV LMII, as follows:  (revised per Amendments 01 and 06) 
a) ≤15 for age 50 to 64 years 
b) ≤12 for age 65 to 69 years 
c) ≤11 for age 70 to 74 years 
d) ≤9 for age 75 to 79 years 
e) ≤7 for age 80 to 90 years 
7. Positive amyloid load as indicated by 1 of the following:   
a. 
PET assessment of imaging agent uptake into brain 
b. CSF assessment of Aβ(1-42) (revised per Amendment 06)  
Subjects may consent to both the PET and CSF assessments, but need a positive amyloid result in only 
one of the 2 procedures to confirm eligibility (ie, even if 1 of the 2 results does not meet its respective 
eligibility criterion).  Subjects who initially consent for only one of the amyloid screening assessments 
will only be allowed to subsequently consent for the second assessment should the first assessment result 
be positive or they have not yet been informed of the results of the first assessment.  Subjects who 
consent to Amyloid PET or CSF Amyloid are not required to participate in the respective substudies.  
(revised per Amendments 06 and 07) 
Any historical amyloid positive PET scan may be used for eligibility upon evaluation by the central 
imaging contract research organization (CRO).  For subjects who wish to participate in the longitudinal 
imaging substudy, historical amyloid PET scans may not be used as baseline scans for the longitudinal 
imaging substudy.  Required details regarding historical images should be submitted to the CRO medical 
monitor for evaluation.  (revised per Amendment 08) 
8. Male or female subjects aged between 50 and 90 years, inclusive 
9. MMSE score equal to or greater than 22, and equal to or less than 30 at Screening and Baseline, except 
for the following countries, where MMSE score must be equal to or greater than 22 and equal to or less 
than 28 at Screening and Baseline:  United Kingdom, Spain, Germany, Sweden, France, and the 
Netherlands (revised per Amendment 03) 
10. Body Mass Index (BMI) >17 and <35 at Screening (revised per Amendment 06) 
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11. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative human 
β-chorionic gonadotropin assay [ß-hCG].  A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of study drug. 
12. 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). 
13. 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 (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 35 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 35 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 35 days 
after study drug discontinuation.  
14. Subjects who are receiving an AChEIs or memantine or both for AD must be on a stable dose for at least 
12 weeks prior to Baseline.  Treatment-naïve subjects for AD can be entered into the study.  Unless 
otherwise stated, subjects must have been on stable doses of all other (ie, non-AD related) permitted 
concomitant medications for at least 4 weeks prior to Baseline.  Use of memantine will not be allowed for 
Japanese subjects (revised per Amendments 01 and 07) 
15. Must have an identified caregiver/informant (defined as a person able to support the subject for the 
duration of the study and who spends at least 8 hours per week with the subject).  The caregiver/informant 
must provide separate written informed consent.  In addition, this person must be 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/informant can reliably fulfill the study requirements.  A permanent caregiver/informant need not 
be living in the same residence with the subject.  For such a caregiver/informant not residing with the 
subject, the investigator has to be satisfied that the subject can contact the caregiver/informant readily 
during the times when the caregiver/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.  
Caregivers/informants need only to be present at visits where clinical assessment of CDR and FAQ takes 
place.  (revised per Amendment 01) 
16. Provide written informed consent.  If a subject lacks capacity to consent in the investigator's opinion, the 
subject's assent should be obtained, if required in accordance with local laws, regulations and customs, 
plus the written informed consent of a legal representative should be obtained (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local laws and 
regulations).  (revised per Amendment 07) 
17. Willing and able to comply with all aspects of the protocol 
EXTENSION PHASE PART A (revised per Amendments 08, 11, 12, and 19) 
18. Have completed Visit 42 (Week 79) of the Core Study or who discontinued study drug during the Core 
Study due to any of the following reasons:  
a. 
ARIA-E 
b. ARIA-H (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage) 
c. 
Prohibited or restricted medications that were prohibited during Core Study conduct but are no 
longer prohibited in the Extension Phase  
d. Subjects who were APOE4 positive and receiving treatment with BAN2401 10 mg/kg biweekly 
e. 
Any reason for discontinuation not related to prohibited medications, including any AE that was 
considered not related to study drug, and that was not severe or life-threatening  
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19. 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 
20. Provide written informed consent.  If a subject lacks capacity to consent in the investigator's opinion, the 
subject's assent should be obtained, if required in accordance with local laws, regulations and customs, 
plus the written informed consent of a legal representative should be obtained (capacity to consent and 
definition of legal representative should be determined in accordance with applicable local laws and 
regulations).   
21. Must be able to physically attend clinic visits and be willing and able to comply with all aspects of the 
protocol  
EXTENSION PHASE PART B  (revised per Amendment 19) 
1. Must be currently enrolled in Extension Phase Part A  (revised per Amendment 19).
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Exclusion Criteria: 
CORE STUDY 
Key Exclusion Criteria: 
1. Any neurological condition that may be contributing to cognitive impairment above and beyond that 
caused by the subject’s AD 
2. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of Screening 
3. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that could 
interfere with study procedures in the subject  
4. GDS score ≥8 at Screening 
5. Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal 
implants (eg, in skull and cardiac devices other than those approved as safe for use in MR scanners) 
6. Evidence of other clinically significant lesions that could indicate a dementia diagnosis other than AD on 
brain MRI at Screening.  All MRIs will be acquired using a standardized procedure that will be outlined 
in the Imaging Charter and Imaging Acquisition Guidelines (IAG) and will be read by an approved 
centralized reader. 
7. Other significant pathological findings on brain MRI at Screening, including but not limited to:  more than 
4 microhemorrhages (defined as 10 mm or less at the greatest diameter); a single macrohemorrhage greater 
than 10 mm at greatest diameter; an area of superficial siderosis; evidence of 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 <1cm at their greatest diameter need not be exclusionary) (revised 
per Amendment 07) 
8. Hypersensitivity to BAN2401 or any of the excipients, or to any monoclonal antibody treatment 
9. Any immunological disease which is not adequately controlled, or which requires treatment with biologic 
drugs during the study 
10. Subjects with a bleeding disorder that is not under adequate control (including a platelet count <50,000 or 
international normalized ratio [INR] >1.5) 
11. Subjects who have thyroid stimulating hormone (TSH) above normal range.  Other tests of thyroid 
function with results outside the normal range should only be exclusionary if they are considered clinically 
significant by the investigator.  This applies to all subjects whether or not they are taking thyroid 
supplements.  (revised per Amendments 01 and 06).   
12. 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). 
13. A prolonged QT/QTc interval (QTc >450 ms) as demonstrated by a repeated electrocardiogram (ECG) 
14. Known to be human immunodeficiency virus (HIV) positive 
15. Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests or ECG 
at Screening or Baseline which in the opinion of the principal investigator (PI), require further 
investigation or treatment or which may interfere with study procedures or safety 
16. Uncontrolled Type 1 or Type 2 diabetes mellitus.  Evidence of uncontrolled diabetes mellitus includes 
hemoglobulin A1c (HbA1c) >9%.  
17. Uncontrolled hypertension with a history of blood pressure consistently above 165/100 mm Hg at 
Screening 
18. History of uncontrolled cardiovascular disease within 6 months of Screening, including acute coronary 
syndrome, clinically significant valvular heart disease, uncompensated heart failure (New York Heart 
Association [NYHA] Class III and Class IV), or uncontrolled arrhythmia  
19. Subjects with malignant neoplasms within 3 years of Screening (except for basal or squamous cell 
carcinoma in situ of the skin, or localized prostate cancer in male subjects).  Subjects who had malignant 
neoplasms but who have had at least 3 years of documented uninterrupted remission before Screening 
need not be excluded.  
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20. Has a “yes” answer to Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, 
or any suicidal behavior assessment within 6 months before Screening, at Screening, or at the Baseline 
Visit, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening  
21. Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a 
positive urine drug test at Screening.  Subjects who test positive for benzodiazepines or opioids in urine 
drug testing 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 and 
not due to drug abuse. 
22. Any other medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) which 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 
23. Subjects who are taking prohibited medications 
24. Participation in a clinical study involving any therapeutic monoclonal antibody, protein derived from a 
monoclonal antibody, immunoglobulin therapy, or vaccine within 6 months before Screening (revised per 
Amendment 01) 
25. Participation in a clinical study involving any new chemical entities for AD within 6 months prior to 
Screening unless it can be documented that the subject was in a placebo treatment arm 
26. Participation in any other investigational medication or device study in the 8 weeks or 5 half-lives 
(whichever is longer) of the medication before randomization unless it can be documented that the subject 
was in a placebo treatment arm 
27. Planned surgery which 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 day case 
without inpatient stay postoperatively need not result in exclusion if in the opinion of the PI this operation 
does not interfere with study procedures and subject safety. 
28. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests 
accurately 
EXTENSION PHASE PART A (revised per Amendments 08, 11, and 19) 
29. Subjects who discontinued from the study drug or from the Core Study for reasons other than the 
following: 
a. 
ARIA-E 
b. ARIA-H (superficial siderosis, macrohemorrhage, or symptomatic microhemorrhage) 
c. 
Prohibited or restricted medications that were prohibited during Core Study conduct but are no 
longer prohibited in the extension phase (revised per Amendment 12) 
d. Subjects who were APOE4 positive and receiving treatment with BAN2401 10 mg/kg biweekly 
e. 
AE that was considered not related to study drug, and that was not severe or life-threatening 
30. Females who are breastfeeding or pregnant at Extension Phase Baseline (Extension Screening Visit, as 
documented by a negative β-hCG assay).  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. 
31. Females of childbearing potential who:  
 
Had unprotected sexual intercourse within 30 days before Extension Phase Baseline and 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 
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 becoming sexually active during the study period or for 28 days after study drug discontinuation.   
 
Are who are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the same 
contraceptive during the study and for 28 days after study drug discontinuation. 
(NOTE:  All females will be considered to be of childbearing potential unless they are postmenopausal 
[amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other 
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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]). 
32. Subjects who develop the following conditions from the time of completion of the Core Study to the start 
of the Extension Phase:  
a. 
Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic 
metal implants (eg, in skull and cardiac devices other than those approved as safe for use in MRI 
scanners) 
b. Other significant pathological findings on brain MRI at Extension Phase Baseline (Extension 
Screening Visit), including but not limited to:  any macro-hemorrhage (greater than 10 mm at 
greatest diameter), which is currently symptomatic or worsened since the Core Study; any area 
of superficial siderosis which is currently symptomatic or worsened since the Core Study; 
evidence of vasogenic edema, which is severe or symptomatic; aneurysms, vascular 
malformations, infective lesions, evidence of multiple lacunar infarcts or stroke involving a major 
vascular territory, severe small vessel, or white matter disease or space occupying lesions or brain 
tumors (however lesions diagnosed as meningiomas or arachnoid cysts and <1cm at their greatest 
diameter need not be exclusionary)  
c. 
Any immunological disease which is not adequately controlled, or which requires treatment with 
biologic drugs during the study  
d. Bleeding disorder that is not under adequate control (including a platelet count <50,000 or 
INR >1.5) 
e. 
Receiving treatment with anticoagulant therapy but anticoagulation control is not optimized and 
is stable for at least 4 weeks before Extension Phase Baseline (Extension Screening Visit) 
f. 
Any other clinically significant abnormalities in physical examination, vital signs, laboratory 
tests or ECG at Extension Phase Baseline (Extension Screening Visit), which in the opinion of 
the PI, require further investigation or treatment or which may interfere with study procedures or 
safety 
g. Malignant neoplasms within 3 years of Extension Phase Baseline (Extension Screening Visit) 
(except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in 
male subjects).  Subjects who had malignant neoplasms but who have had at least 3 years of 
documented uninterrupted remission before Extension Phase Baseline (Extension Screening 
Visit) need not be excluded 
h. Known or suspected history of drug or alcohol abuse or dependence within 2 years before 
Extension Phase Baseline (Extension Screening Visit) or a positive urine drug test at Extension 
Phase Baseline (Extension Screening Visit).  Subjects who test positive for benzodiazepines or 
opioids in urine drug testing 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 and not due to drug abuse 
i. 
Any other medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) which 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 
j. 
Subjects who are taking restricted or prohibited medications (revised per Amendment 12) 
k. Participation in a clinical study involving any therapeutic monoclonal antibody, protein derived 
from a monoclonal antibody, immunoglobulin therapy, or vaccine during the time between the 
Core Study and Extension Phase Baseline (Extension Screening Visit)  
l. 
Participation in a clinical study involving any new chemical entities for AD during the time 
between the Core Study and Extension Phase Baseline (Extension Screening Visit) 
m. Participation in any other investigational medication or device study during the time between the 
Core Study and Extension Phase Baseline (Extension Screening Visit) 
n. Planned surgery which 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 day case without inpatient stay postoperatively need not result in exclusion if in 
the opinion of the PI this operation does not interfere with study procedures and subject safety 
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33. Severe visual or hearing impairment that would prevent the subject from performing psychometric tests 
accurately 
Study Treatment(s) and Response Adaptive Randomization (RAR): 
CORE STUDY 
BAN2401 drug product is supplied as a sterile aqueous solution containing 10 mg/ml BAN2401, 25 mM sodium 
citrate/citric acid, 125 mM sodium chloride, and 0.02% (w/v) polysorbate 80 at pH 5.7 in a 10-ml glass vial.  
BAN2401 will be administered in normal saline as 60 minute IV infusions.  An infusion system containing a 
terminal 0.22-µm in-line filter is required for administration of BAN2401 drug product.  (revised per 
Amendment 08) 
BAN2401 will be administered on a mg/kg basis at doses of 2.5, 5, or 10 mg/kg biweekly (once every 2 weeks), or 
5 or 10 mg/kg monthly (once every 4 weeks).  All subjects will receive biweekly infusions, and subjects who have 
monthly dosing of BAN2401 will have placebo infusion alternating with BAN2401. 
Response Adaptive Randomization 
APOE4 status (positive or negative) must be confirmed for all subjects prior to randomization.  (revised per 
Amendment 05)  Subjects who are confirmed APOE4 positive (hetero- or homozygous) will not be randomized to 
the 10 mg/kg, biweekly dose (revised per Amendments 04 and 05).  Randomization to placebo or 1 of 5 treatment 
arms of BAN2401 will be fixed for the first 196 subjects randomized in the study (4:2:2:2:2:2; placebo [4] to each 
of the active arms [2 each]).  Randomization probabilities to each arm will be updated at each IA such that the 
randomization probability will be increased for the placebo arm and arms that represent the potential target dose 
(ED90), and simultaneously decreased for other active arms. 
EXTENSION PHASE PART A  (revised per Amendments 08, 11, 17, and 19) 
BAN2401 drug product is currently supplied as a sterile aqueous solution containing 10 mg/mL BAN2401, 
25 mM sodium citrate/citric acid, 125 mM sodium chloride, and 0.02% (w/v) polysorbate 80 at pH 5.7 in a 10-mL 
glass vial.  This current formulation of the drug product may be progressively phased out as stocks near the end of 
their shelf life and replaced by a newer formulation containing 100 mg/mL BAN2401.  The newer formulation 
(100 mg/mL BAN2401) was developed to reduce the number of vials of drug product required per dose and to 
reduce demand for storage space in a pharmacy.  The newer (100 mg/mL BAN2401) formulation is supplied as a 
sterile aqueous solution containing 100 mg/mL BAN2401, 50 mmol/L citric acid, 0.05% (w/v) polysorbate 80, and 
350 mmol/L arginine, at pH 5.0, in glass vials containing 5 mL solution.  The phasing out of the older formulation 
will only occur after appropriate regulatory authority approval for the newer formulation has been obtained, and 
adequate training of any pharmacy staff involved in the preparation of the final drug product for infusion has been 
completed.  The appearance of the 2 different formulations after dilution in normal saline is identical. 
Subjects, including those who are confirmed APOE4 positive (hetero- or homozygous), will be administered the 
BAN2401 10 mg/kg biweekly dose.  For subjects participating in the dosing regimen substudy, BAN2401 10 mg/kg 
will be administered either at Q4W or Q3M intervals until the end of the study.  BAN2401 will be administered in 
normal saline as 60 minute IV infusions.  An infusion system containing a terminal 0.22-µm in-line filter is required 
for administration of BAN2401 drug product.  (revised per Amendment 17)  
EXTENSION PHASE PART B (revised per Amendment 19) 
All subjects will be administered the BAN2401 10 mg/kg biweekly dose.  For subjects who previously participated 
in the Dosing Regimen substudy, BAN2401 10 mg/kg will be administered either at the biweekly dose or they may 
continue with their prior dose of Q4W or Q3M intervals.  BAN2401 will be administered in normal saline as 
60 minute IV infusions.  An infusion system containing a terminal 0.22-µm in-line filter is required for 
administration of BAN2401 drug product.  (revised per Amendment 19)   
Duration of Treatment  (revised per Amendments 08, 11, 15, 18, and 19) 
Core Study:  up to 18 months of treatment.   
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Extension Phase Part A:  Treatment will continue until BAN2401 is commercially available for individual 
subjects at each study site, at which time the subjects will switch to commercial BAN2401.  For those subjects 
who seamlessly transition to commercial BAN2401 (including postmarketing part in Japan), the end of the study 
will be the date of the last study evaluation prior to transitioning to commercial BAN2401 and at which time, all 
assessments included in Week 261/Early Termination Visit are to be performed.  (revised per Amendments 18 
and 19) 
Extension Phase Part B:  Subjects will continue in Extension Phase B for a maximum combined (Part A and 
Part B) open-label treatment duration of up to 60 months (5 years).  Treatment will continue until BAN2401 is 
commercially available for individual subjects at each study site, at which time the subjects will switch to 
commercial BAN2401.  In the cases where drug is not yet commercially available, treatment will continue until 
the benefit to risk ratio from treatment with BAN2401 is no longer considered favorable, whichever comes first.  
Upon approval of BAN2401 in Japan, subjects who meet the approved indication and dosage of BAN2401 will 
continue in this study as a postmarketing study.   For those subjects who seamlessly transition to commercial 
BAN2401 (including postmarketing part in Japan), the end of the study will be the date of the last study 
evaluation prior to transitioning to commercial BAN2401 and at which time, all assessments included in 
Week 261/Early Termination Visit are to be performed.  (revised per Amendment 19) 
Concomitant Drug/Therapy: 
Core Study: 
The following therapies are not permitted for the listed intervals prior to Baseline and until the Follow-Up Visit 
(Visit 43, for subjects who participate in the Core Study only (revised per Amendments 08, 09, and 11) 
 
Immunoglobulin therapy, 6 months 
 
Biologic drugs, 6 months 
 
Anticoagulants (eg, warfarin, dabigatran), 7 days or 5 half-lives, whichever is longer  
Short-term treatment (<4 weeks) with anticoagulants is permitted for randomized subjects who undergo 
procedures requiring anticoagulants for prophylaxis of thromboembolic disease after approval by the 
sponsor’s medical monitor.  While these subjects need not be discontinued, study drug will be temporarily 
suspended for these subjects during anticoagulant therapy.  (revised per Amendment 06) 
The following requirements apply to use of AChEIs or memantine or both for the treatment of AD:  (revised per 
Amendment 01) 
 
Subjects should be on a stable dose for 12 weeks before Baseline, and subjects are not to change their dose 
of AD medications before randomization.  (revised per Amendment 08) 
 
Subjects should remain on a stable dose while on study  
 
Memantine is not permitted for Japanese subjects (revised per Amendment 07) 
 
Subjects who initiate AD treatment or who adjust their AD dosing regimen while on study will continue 
to study completion.  However, the clinical efficacy data (ie, derived Clinical Composite Score, MMSE, 
CDR-SB, ADAS-Cog, and FAQ) from these subjects will be censored at the time of AD treatment 
initiation or adjustment for the purposes of subsequent IA and for the final analysis.  
The following requirements apply to all other medications not intended to treat AD: 
 
Subjects must be on stable dose for at least 4 weeks prior to Baseline, except for medications which are 
administered as short courses of treatment (eg, anti-infectives) or which are to be used as needed (PRN). 
 
Medications which are used on a PRN basis or as a short course of treatment, and which are central nervous 
system (CNS) active and may affect cognitive function are not permitted during a period of 72 hours prior 
to cognitive testing. 
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 
Subjects may receive (PRN) prophylactic medications prior to infusion of study drug (outlined in the 
protocol) to minimize the risk of immunologic reaction or infusion reaction during or shortly after the 
infusion. 
 
Subjects who initiate treatment or undertake dose adjustment with drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if in the opinion of the PI this will not 
interfere with study procedures or subject safety and are not prohibited above.  
Extension Phase Part A and Part B:  (revised per Amendments 11 and 19) 
 
During the course of the Extension Phase, immunoglobulin therapy may be allowed, if clinically indicated 
and after a documented discussion with the medical monitoring team.  In this case, an interval of 30 days 
between study drug infusion and immunoglobulin therapy should be observed.  (revised per 
Amendment 17).  Subjects who require treatment with thrombolytic drugs do not have to be discontinued 
from the study, but study drug will be temporarily suspended for these subjects during thrombolytic 
therapy until stabilization or resolution of the medical condition which required thrombolytic drugs 
treatment. 
 
Flu, shingles, pneumococcal, hepatitis B, COVID-19 (including the booster shot), and other vaccines can 
be administered during the treatment period, but vaccination should be timed such that it will be 
administered at least 7 days after the previous infusion and at least 7 days before the next infusion.  The 
duration between COVID-19 vaccination and study drug infusions may be reduced to less than 7 days 
according to the clinical judgement of the investigator.  (revised per Amendment 17) 
 
Subjects who are on anticoagulants at Extension Phase Baseline (Extension Screening Visit) are required 
to have their anticoagulation status optimized and stable for at least 4 weeks before Extension Screening 
Visit.   
 
Subjects who initiate AD treatment or who adjust their AD dosing regimen while on study will continue 
to study completion.  However, if aducanumab (or other approved amyloid-targeting AD treatments) is 
started during the study, then subjects are required to immediately discontinue from study drug.  (revised 
per Amendment 17) 
The following requirements apply to all other medications: 
 
Subjects must be on a stable dose for at least 4 weeks prior to Extension Phase Baseline (Extension 
Screening Visit), except for medications which are administered as short courses of treatment (eg, 
anti-infectives) or which are to be used as needed. 
 
Medications which are used on a PRN basis or as a short course of treatment, and which are CNS active 
and may affect cognitive function are not permitted during a period of 72 hours prior to cognitive testing. 
 
Subjects may receive PRN prophylactic medications prior to infusion of study drug (outlined in the 
protocol) to minimize the risk of immunologic reaction or infusion reaction during or shortly after the 
infusion. 
 
Subjects who initiate treatment or undertake dose adjustment with drugs not intended for treatment of 
cognitive impairment during the study may continue in the study if in the opinion of the PI this adjustment 
will not interfere with study procedures or subject safety and are not prohibited above.  
Assessments: 
Efficacy Assessments - (Core Study and Extension Phase Part A) 
ADCOMS:  This composite clinical score represents a new approach to the analysis of selected items (12 total) 
from 3 fully validated and well-established clinical tools, including the MMSE, the CDR, and the ADAS-Cog.  The 
data from 4 studies, including the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (MCI subset), ADCS-008, 
E2020-A001-412 and E2020-E033-415 have been used in a statistically validated model aimed at optimizing 
sensitivity to disease progression over time in the MCI population.  The MMSE, the CDR, and the ADAS-Cog will 
each be administered to subjects using standard methods, and results will be used to calculate the ADCOMS.  
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Pharmacokinetic Assessments - (Core Study and Extension Phase Part A) 
Blood samples will be collected from all subjects for determination of serum BAN2401 levels at approximately 
12-week intervals during the Randomization Phase. 
Blood for serum PK will be collected at Extension Week 1 (Visit 44), Extension Weeks 3, 9, 13, 27, 39, 53, and 
every 24 to 26 weeks thereafter, through to Extension Week 261, and the Follow-Up Visit.  (revised per 
Amendments 08, 11, and 15) 
Pharmacogenomic and Biomarker Assessments - (Core Study and Extension Phase Part A) 
Apolipoprotein є4 variant (APOE4) genotyping will be conducted to allow stratification by APOE status (APOE4 
positive and negative).  APOE4 homozygous or heterozygous status will be used in the statistical analysis to 
determine the effects on treatment response and safety, including the development of ARIA, which include 
vasogenic edema, microhemorrhages, and superficial hemosiderosis.  Remaining DNA from the APOE4 
genotyping may be used to examine the role of DNA sequence variability in the absorption, distribution, 
metabolism, and elimination of BAN2401.  Variations in BAN2401 exposure or the occurrence of AEs observed in 
the study population may be evaluated by correlation of single-nucleotide polymorphisms with PK, safety, or 
pharmacodynamic (PD) data. 
Pharmacogenomic  and biomarker samples obtained from participants of this study may be analyzed by global 
proteomic, metabolomic, or lipidomic and single or multiplex assays in an effort to identify predictive biomarkers 
for PK and PD.  In addition, biomarkers identified in other BAN2401 or AD clinical studies may also be assessed 
in samples collected from subjects enrolled in this study. 
vMRI imaging will be used to evaluate the effects of BAN2401 on rates of atrophy in the EAD population to 
provide evidence for disease modification.  All subjects will undergo a vMRI imaging sequence immediately 
following all safety MRI assessments except the Visit 6 abbreviated MRI assessment (safety MRI to detect ARIA 
lasting 8 to 10 minutes, with no vMRI sequences) conducted only at European sites (revised per Amendment 07).  
vMRI sequences will be analyzed at the Screening Visit and at Visits 16, 29, and 42 (6, 12, and 18 months of 
treatment) during the Core Study.  vMRI sequence collections will occur at all safety MRI assessments during the 
Extension Phase.  (revised per Amendment 08)  Total hippocampal, whole brain, and ventricular volumes will be 
assessed. 
CSF concentrations of AD-related biomarkers (including, but not restricted to Aß and other isoforms, total tau 
[t-tau] and phospho-tau [p-tau]), will be measured in consenting subjects at Baseline and at 12 and 18 months of 
treatment during the Core Study only.  (revised per Amendments 01 and 11) 
Safety Assessments  
Safety will be assessed by monitoring and recording all AEs and SAEs, monitoring of hematology, blood chemistry 
and urinalysis, measurement of vital signs, ECGs, brain MRI, and the performance of physical examinations.  
Core Study  
During the Screening Period and at 3-month intervals during the Randomization Phase, all subjects will undergo 
noncontrast brain MRI, including FLAIR, Gradient Recalled Echo (GRE), 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 (AV) malformation, micro- and macrohemorrhages, superficial 
siderosis, and vasogenic edema.  The results of this MRI assessment will also be used as the Baseline Period MRI, 
against which changes after drug administration will be compared.  Details of the MRI protocol can be found in the 
IAG.  Safety brain MRI assessments will be performed at Visit 7, every 3 months postdose, and as clinically 
necessary (in unscheduled visits).  (revised per Amendment 04)  MRI acquisition and interpretation will be 
organized centrally to ensure reproducibility and consistency between units involved.  
The PI is required to evaluate any immunological reactions to the study medication based on clinical findings and 
laboratory results from hematology, biochemistry, and urinalysis, and decide if the subject should be withdrawn 
from treatment or receive prophylactic medications prior to the next infusion.  Blood for anti-BAN2401 antibody 
assessments will be collected during the treatment period as specified in the Schedule of Assessments.   
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At any time during the treatment period, subjects will be withdrawn from further dosing if they develop 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 Early Termination Visit (within 7 days 
after discontinuation) and will attend the Follow-Up Visit (3 months after this decision).  They will also undertake 
an unscheduled visit (with MRI) at approximately 30 days after the visit at which such MRI features were first 
identified.  MRI will also be performed at approximately the time of the Follow-Up Visit.  Additional visits for 
safety may be arranged if clinically indicated in the opinion of the investigator, including after 90 days since the 
final dose of study drug.  In addition, subjects who discontinue from study drug are expected to return after the 
Early Termination Visit for each scheduled visit when the clinical efficacy assessments are to be conducted per the 
Schedule of Procedures/Assessments  At these visits, safety information (in addition to efficacy assessments) on 
concomitant medications, AEs, and SAEs will be collected.  (revised per Amendment 01) 
At any time during the Treatment Period, subjects who have nonsymptomatic, 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 
30 days after the visit at which such MRI features were found.  They will also continue with the scheduled MRI 
scans.  The safety MRI must be reviewed by both the imaging vendor and a local reader prior to administration of 
the next dose of study drug for each respective visit.  (revised per Amendment 06)  Additional unscheduled MRI 
scans may be arranged on an individual subject basis in discussion with the study medical monitor.   
An assessment of suicidality using the C-SSRS will be performed at Screening and Baseline and at designated time 
points. 
Extension Phase Part A (revised per Amendments 08, 11, 16, and 17) 
During the Extension Phase, safety assessments will be performed according to the Schedule of Assessments and 
all AEs and SAEs recorded.   
Subjects entering the dosing regimen substudy will follow the substudy-specific schedule of assessments.  
Consenting subjects may enter the dosing regimen substudy at any time during the Extension Phase after they 
have completed 18 months in the Extension Phase.  Subjects may choose to enter this substudy at any study visit 
according to their prior biweekly schedule of assessments.  (revised per Amendment 17) 
Extension Phase Part B (revised per Amendment 19) 
Safety assessments will be performed according to the Schedule of Assessments and all AEs and SAEs recorded.  
Other Assessments  
Amyloid PET and CSF Aβ(1-42) 
Core Study  
Amyloid PET imaging or CSF Aβ(1-42) assessment will be used to confirm that all subjects with EAD have 
amyloid deposition in the brain.  (revised per Amendment 06)  This criterion will allow for the definition of subjects 
with MCI due to AD – intermediate likelihood and will confirm amyloid pathology in mild Alzheimer’s disease 
dementia subjects.  
Amyloid PET or CSF Aβ(1-42) assessment is required at Baseline during the Prerandomization Phase for all 
subjects to qualify for study inclusion per the protocol, and subjects who consent to participate in the imaging 
subgroup (target n=306 total) will receive amyloid PET imaging at 12 and 18 months of treatment.  Duration of the 
PET scan and its timing relative to injection of the imaging agent will be as per the imaging agent manufacturer's 
guidance.  (revised per Amendments 02, 06, and 07) 
Extension Phase Part A (revised per Amendments 08, 11, 12, and 19) 
All subjects who underwent amyloid PET for inclusion in the Core Study should receive a baseline amyloid PET 
scan before dosing in the Extension Phase Part A.  The baseline amyloid PET scan must be conducted with the 
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same imaging tracer that was used for inclusion at the baseline visit for the Core Study. In addition, qualified 
subjects located in the US and Japan will have the option to participate in the longitudinal PET substudy.  
Florbetapir will be used in the US and flutemetamol will be used in Japan for longitudinal amyloid PET analysis.  
At Extension Screening Visit, subjects who consented to the longitudinal imaging substudy will be stratified into 
2 cohorts based on their treatment allocation during the Core Study.  Cohort 1 will have amyloid PET assessments 
performed at baseline (Extension Screening Visit), Visit 50 (Extension Week 13), Extension Phase Visit 70 
[Extension Week 53], and annually thereafter; Cohort 2 will have amyloid PET assessments performed at baseline 
(Extension Screening Visit), Visit 57 (Extension Week 27), at Extension Phase Visit 70 [Extension Week 53], and 
annually thereafter.  In Japan, those who consented to the longitudinal imaging substudy will only undergo amyloid 
PET at Extension Phase Visit 70 [Extension Week 53], and annually thereafter.  (revised per Amendment 15) 
Exploratory Plasma Biomarkers (Core Study and Extension Phase Part A) (revised per Amendments 11 and 19) 
Blood will be collected from subjects at Baseline during the Prerandomization Phase prior to amyloid PET 
assessment and at 12 and 18 months of treatment to evaluate potential novel biomarkers of AD that may include 
amyloid isoforms, tau, microRNA, metabolites, and other protein biomarkers (eg, NFL) for association with AD 
diagnosis and amyloid load.  Similarly, biomarker discovery and validation may be performed along with samples 
from AD subjects, to identify blood and genetic biomarkers which may be useful to predict subject PK and PD 
responses, treatment response, subject stratification or adverse effects related to BAN2401. 
Medical Claims Substudy  (revised per Amendment 16) 
In the US only, subjects and study partners who have participated in any phase of the study (Core Study or Extension 
Phase) may consent to the optional medical claims substudy.  Medical claims data for subjects and study partners 
who consent to this substudy will be collected for up to 5 years before study enrollment, for the duration of the 
Core Study, the duration of the period between the end of the Core Study and the Extension Baseline (if applicable), 
the duration of the Extension Phase (if applicable), and for up to 3 years after the end of the Core Study or Extension 
Phase (where applicable).  The results of the medical claims substudy will be presented in a separate report.  (revised 
per Amendments 16 and 17) 
Bioanalytical Methods: 
Cerebrospinal fluid levels of Aβ(1-42), t-tau, and p-tau will be assessed.  Aβ(1-42), t-tau, and p-tau biomarkers are 
proposed to be tested using commercially available kits validated for use by a CRO.   
Serum concentrations of BAN2401 will be measured by the validated immunoprecipitation- liquid chromatography 
– tandem mass spectrometry (IP/LC-MS/MS) methods using anti-human IgG antibody to precipitate BAN2401 
from a serum sample.  CSF concentrations of BAN2401 will be measured by a separately validated IP/LC-MS/MS 
method.  Precipitated BAN2401 will be isolated and will undergo proteolytic enzyme digestion to yield smaller 
peptides.  The amount of peptide with a sequence unique to BAN2401 will be measured by liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) to provide a quantification of BAN2401. 
Statistical Methods:  All statistical tests will be based on the 10% level of significance, except for the Bayesian 
methods on the primary endpoint.  (revised per Amendments 09 and 10)   
Study Endpoints 
Core Study 
Primary Endpoint: 
 
Change from baseline in the ADCOMS at 12 months 
Key Secondary Endpoints:  (revised per Amendments 09 and 10) 
 
Change from baseline at 18 months in brain amyloid pathophysiology as measured by amyloid PET   
 
Change from baseline in the ADCOMS at 18 months (revised per Amendment 09) 
 
Change from baseline in CDR-SB at 18 months    
 
Change from baseline in ADAS-Cog at 18 months   
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 
Change from baseline in CSF biomarkers (Aβ[1-42], t-tau, and p-tau) at 18 months  (revised per 
Amendment 10) 
 
Change from baseline in total hippocampal volume at 18 months using vMRI   
Secondary Endpoints:  (revised per Amendment 10) 
 
Change from baseline at 12 months in  brain amyloid pathophysiology as measured by amyloid PET   
 
Change from baseline at 12 months on clinical status for the following assessments:  ADCOMS, CDR-
SB, and ADAS-Cog    
 
Change from baseline in CSF biomarkers (Aβ[1-42], t-tau, and p-tau) at 12 months  
 
Change from baseline in total hippocampal at 6 and 12 months, and in left and right hippocampus, whole 
brain, and total ventricular volume as measured by vMRI at 6, 12, and 18 months   
Exploratory Endpoints: 
 
Change from baseline in clinical status at time points not analyzed in Key Secondary and Secondary 
sections for each of the following:  ADCOMS, ADAS-Cog, CDR-SB, MMSE, and FAQ  
Extension Phase Part A (revised per Amendments 08, 11, 15, 16, 17, and 19) 
Primary Endpoint 
 
Safety assessments will be based on medical review of AE reports and the results of vital sign 
measurements, ECG, physical examinations, clinical laboratory tests, anti-drug antibody (ADA) test 
results, and any relevant test of cognitive function to evaluate decline.  Additionally, MRI assessments of 
microhemorrhage, vasogenic edema, and other clinically significant abnormalities will be evaluated. 
Secondary Endpoints (revised per Amendment 11) 
 
Change from baselines in brain amyloid levels as measured by amyloid PET at 3 months (Visit 50 
[Extension Week 13], Cohort 1) or 6 months (Visit 57 [Extension Week 27], Cohort 2), 12  months and 
annually thereafter in the Extension Phase  (revised per Amendment 15)  
 
Change from end of Core Study in brain amyloid levels as measured by amyloid PET at the baseline of 
Extension Phase 
 
Proportion of amyloid positive subjects over time 
Exploratory Endpoints 
 
Change from baselines in ADCOMS, CDR-SB, ADAS-Cog, and MMSE at each visit assessed (revised 
per Amendment 11) 
 
Time to worsening of CDR global scores, eg, the worsening of global CDR score is defined as an increase 
from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits at which 
global CDR is measured 
 
Change from baselines in total hippocampal volume and other biomarkers annually in the Extension Phase.  
(revised per Amendments 11 and 15) 
 
Describe the characteristics, comorbidities, treatments, associated costs for subjects with EAD, and study 
partner burden up to 5 years before study enrollment, for the duration of the Core Study, the duration of 
the period between the end of the Core Study and the Extension Baseline (if applicable), the duration of 
the Extension Phase (if applicable), and for up to 3 years after the end of the Core Study or Extension 
Phase (where applicable).  (revised per Amendment 16) 
Dosing Regimen Substudy Endpoints (revised per Amendment 17) 
 
Change from substudy baseline in brain amyloid levels as measured by amyloid PET  
 
Change from substudy baseline in plasma Aβ42/40 ratio and plasma p-tau181 
 
Change from substudy baseline in ADCOMS, CDR-SB, ADAS-Cog, and MMSE at each visit assessed 
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 
Safety assessments including, but not limited to AEs, vital signs, ECG, physical examinations, clinical 
laboratory tests, ADA.  MRI assessments of microhemorrhage, vasogenic edema, and other clinically 
significant abnormalities  
 
Population PK parameters of BAN2401 in serum, including but not limited, to area under the concentration 
vs. time curve (AUC), Cav, Correlation of PK exposure with biomarkers, safety parameters, and efficacy  
Extension Phase Part B  (revised per Amendment 19) 
Primary Endpoint 
 
Safety assessments will be based on medical review of AE reports and the results of vital sign 
measurements, and physical examinations.  Additionally, MRI assessments of microhemorrhage, 
vasogenic edema, and other clinically significant abnormalities will be evaluated. 
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 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 PK Analysis Set is the group of subjects with at least 1 quantifiable BAN2401 serum concentration 
with a documented dosing history. 
 
The PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 1 PD 
parameter. 
 
The Per Protocol (PP) Analysis Set is the subset of subjects in the Full Analysis Set who sufficiently 
complied with the protocol.   
Extension Phase Part A (revised per Amendments 08, 11, 17, and 19) 
 
The OLE Full Analysis Set (OLE-FAS) is the group of subjects who receive at least 1 dose of study drug 
during the Extension Phase and who have a baseline assessment and at least 1 postdose efficacy 
measurement during the Extension Phase Part A.  The baseline assessment is defined as the last 
measurement before 1st dose of BAN2401.  (revised per Amendment 17) 
 
The OLE Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug during 
the Extension Phase Part A .  This analysis set is the analysis population used for all safety analyses which 
will be based on the as-treated principle.  (revised per Amendment 17) 
 
The OLE PK Analysis Set is the group of subjects with at least 1 quantifiable BAN2401 serum 
concentration with a documented dosing history during the Extension Phase Part A. 
 
The OLE PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 1 PD 
parameter during the Extension Phase Part A. 
Extension Phase Part B  (revised per Amendment 19) 
 
The OLE Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug during 
the Extension Phase Part B.  This analysis set is the analysis population used for all safety analyses which 
will be based on the as-treated principle. 
Similar analysis sets will be defined for the dosing regimen substudy.  The details will be included in the statistical 
analysis plan (SAP).  (revised per Amendment 17) 
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Efficacy Analyses (revised per Amendment 19) 
Core Study 
In this Phase 2 dose-finding study of BAN2401 for the treatment of EAD, response adaptive randomization will be 
used to allocate subjects to placebo or 1 of the 5 active dose regimens with the goal of characterizing the dose 
response.  The study will be monitored for early success and early futility.  If the study continues to randomize 
subjects after futility is declared, it will be considered a failed study.  (revised per Amendment 01) 
Key definitions relevant to the Bayesian aspects of the adaptive design are given below.  
Study Definitions  
Clinically Significant Difference (CSD):  The CSD used in the adaptive model relative to the change from baseline 
over time for placebo in the ADCOMS.  The CSD for this study represents an approximate 25% reduction compared 
to placebo in the progression of AD as measured by the ADCOMS. 
Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment effect  
ED90:  The ‘simplest’ dose regimen that achieves at least 90% of the dMax treatment effect.  The term ‘simplest’ 
reflects the preference for dosing frequency and amount when considering the treatment arms for the study and 
while taking efficacy into account (monthly administration is preferred over biweekly administration and lower 
doses are preferred over higher doses, with priority placed on frequency of administration).  Thus, the rank order 
of prioritized doses (beginning with the simplest) is:  5 mg/kg Q4wk, 10 mg/kg Q4wk, 2.5 mg/kg Q2wk, 5 mg/kg 
Q2wk, and 10 mg/kg Q2wk. 
Early Success:  The study meets early success criteria if the probability that the ED90 at 12 months of treatment is 
better than the placebo by the CSD is at least 0.95.  Early success is achieved before all subjects complete 12 months 
of treatment and can only be determined once ≥350 subjects are randomized.  If early success is declared prior to 
full randomization, the randomization of new subjects will stop, outside Japan.  (revised per Amendment 08)  Sites 
in Japan will be allowed to randomize at least 40 Japanese subjects, even if the early success is declared or the 
study achieves 800 subjects randomized.  All randomized Japanese subjects will receive up to 18 months of 
treatment in the Core Study and are eligible to participate in the Extension Phase Part A if implemented.  (revised 
per Amendments 07, 08, 11, and 19) 
Futility:  The study meets statistical futility criteria if the probability that the ED90 is better than the placebo by the 
CSD is less than 0.05 (with ≤300 subjects randomized) or 0.075 (with ≥350 subjects randomized) at 12 months of 
treatment.  If the study meets statistical futility criteria, the sponsor will make the final decision pertaining to study 
futility after reviewing recommendations by the DSMB.  Based on sponsor's final decision, if the study continues 
to randomize subjects, it will be considered a failed study.  (revised per Amendment 01) 
Study Success:  The study will be considered a success if either of the following criteria are met for the 12-month 
treatment endpoint: 
 
The study meets early success criteria (as outlined above) 
 
The study reaches complete randomization and the Bayesian analysis at completion of 12 months of 
treatment results in an ED90 with at least an 80% probability of being better than the placebo by the CSD  
(revised per Amendment 09)  
Analysis for the Primary Endpoint 
The primary analysis will be based on subjects from the Full Analysis Set with the prespecified censoring rules 
applied.  Japanese subjects who are randomized after early success is declared or the study achieves 800 subjects 
randomized will not be included in the primary analysis.  (revised per Amendment 07)  The primary endpoint is 
the change from baseline to 12 months in the ADCOMS.  The dose-response of the primary endpoint is modeled 
with a 2-dimensional 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 the CSD compared to the placebo arm.  At each analysis, 3 Bayesian probabilities 
will be summarized for each active dose:  the probability of being the ED90 dose, the probability of being statistically 
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superior to placebo, and the probability of being statistically superior to placebo by the CSD.  The study will be 
considered a success in the Bayesian analysis at the completion of 12 months of treatment if there is at least an 80% 
probability that the ED90 achieves the CSD from placebo.  (revised per Amendment 09) 
For the clinical efficacy data (ie, derived Clinical Composite Score, MMSE, CDR-SB, ADAS-Cog, and FAQ), 
subjects will be censored at the time of initiation of new AChEIs or memantine treatment regimens if they were not 
on AChEIs or memantine at randomization, and will be censored at the time of dose adjustment of AChEIs or 
memantine if they were already on stable treatment of AChEIs or memantine at randomization.  The value of the 
primary endpoint for censored subjects will be imputed using data up to the censoring time and Bayesian imputation 
methods. 
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 (revised per Amendment 01):  
 
The primary endpoint will be analyzed regardless of initiation of new AChEIs or memantine or dose 
adjustment of stable AChEIs or memantine using the same Bayesian method as in the primary analysis.  
(revised per Amendment 01) 
 
In case of early success, the primary analysis as well as the above sensitivity analyses will be repeated 
after all subjects have completed 12 months of follow up or have been lost to follow-up.  
Statistical methods for the conventional analyses of primary efficacy endpoint will use a mixed effects model with 
repeated measures (MMRM) comparing placebo to the identified ED90 dose from the Bayesian analysis.  (revised 
per Amendment 09)  The model will include randomization stratification variables; clinical subgroup (MCI due to 
AD, mild AD), the presence or absence of ongoing AD treatment (ie, AChEIs or memantine or both), APOE4 status 
(positive, negative) and baseline ADCOMS as covariates.  These analyses will be performed on the Full Analysis 
Set as well as the PP set based on the ITT principle.  In case of early success, the conventional analyses will also 
be performed using the data collected prior to the IA.  (revised per Amendment 01) 
Analysis for the Key Secondary Endpoints 
Key Secondary endpoints were ordered to reflect the most recent FDA Draft Guidance and EMA Final Guideline 
that prioritizes effects on pathophysiology in EAD, as measured by biomarkers (February, 2018).  Conventional 
analysis will be performed using all available data at the time of success (if applicable), and at 18 months of 
treatment, regardless of success.  An MMRM will be used to compare the combined 10 mg dose group (including 
biweekly and monthly regimens) with placebo for the key secondary endpoints:  (revised per Amendments 09 and 
10)  The rationale for combining the two 10-mg dose regimens is to account for the loss of subjects positive for 
APOE4 in the 10 mg/kg biweekly dose group and the inability to randomize APOE4 carriers to the 10 mg/kg 
biweekly group following a Regulatory request by European Health Authorities in July, 2014.  The key Secondary 
endpoint based on clinical status (ADCOMS, CDR-SB, and ADAS-Cog) will be analyzed in subjects with EAD as 
well as separately within subjects with MCI and mild AD dementia.  (revised per Amendment 10) 
In addition, as sensitivity analysis, MMRM analysis will be performed for the following treatment comparisons:  
(revised per Amendment 10) 
 
Combining 2 high doses (10 mg biweekly + 10 mg monthly), 2 middle doses (5 mg biweekly + 5 mg 
monthly), and the 2.5 mg biweekly dose, resulting in 3 treatment comparisons with placebo (for dose 
response)  (revised per Amendment 10) 
 
ED90 dose of BAN2401 versus placebo, where the ED90 dose of BAN2401 will be established by 
Bayesian analysis at 18 months as described in the next paragraph  (revised per Amendment 10) 
 
By treatment regimen (10 mg biweekly, 10 mg monthly, 5 mg biweekly, 5 mg monthly, 2.5 mg 
biweekly, placebo)  (revised per Amendment 10) 
 
Combining the top 3 doses (10 mg biweekly, 10 mg monthly, and 5 mg biweekly) versus placebo  
(revised per Amendment 10) 
Change from baseline in the ADCOMS at 18 months will be analyzed, as a sensitivity analysis to the conventional 
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analysis, using the same Bayesian methodology as that for analysis of change from baseline in the ADCOMS at 
12 months, but using the full 18 months of efficacy data with the model projecting to 18 months of treatment.  The 
Bayesian analysis of change from baseline in the ADCOMS at 18 months is positive if the analysis results in an 
ED90 dose with at least an 80% probability of being better than the placebo by the CSD.  The ED90 dose will be 
identified based on change from baseline in the ADCOMS at the 18 month Bayesian analysis and will be used to 
compare ED90 dose of BAN2401 and placebo in the above sensitivity analyses for all key secondary endpoint 
analyses.  (revised per Amendments 09 and 10) 
Analysis for Other Secondary Endpoints 
The same analysis described above for key secondary endpoints will be performed for other secondary endpoints.  
(revised per Amendment 10) 
Analysis for Exploratory Endpoints 
The same analysis described above for key secondary endpoints will be performed for exploratory endpoints.  
(revised per Amendment 10) 
The effect of baseline brain amyloid pathophysiology as measured by amyloid PET on change from baseline in 
clinical status at 12 and 18 months of treatment will be explored using correlation analysis and evaluated using 
statistical models as appropriate.  (revised per Amendment 10) 
The relationship between change from baseline in clinical status and change from baseline in brain amyloid 
pathophysiology at 12 and 18 months of treatment as measured by amyloid PET will be explored by correlation 
analysis.  (revised per Amendment 10) 
Change in ADCOMS and its components, ADAS-Cog, CDR-SB, and MMSE across all clinical assessment time 
points between BAN2401 and placebo in Japanese subjects will be evaluated using the descriptive statistics within 
Japanese subjects as well as with the overall population.  (revised per Amendments 07 and 10)   
Extension Phase Part A  (revised per Amendments 08, 11, and 19) 
An MMRM will be used to analyze the change from baseline secondary efficacy endpoints.  Proportion of amyloid 
positive subjects over time will be summarized.  MMRM will also be used to analyze the following exploratory 
endpoints: 
 
Change from baseline in the ADCOMS, CDR-SB, ADAS-Cog score, and MMSE score  
For each endpoint at a scheduled visit in the Extension Phase, a 90% 1-sided confidence interval will be constructed 
to test the null hypothesis that the treatment difference between subjects who took placebo in Core Study and those 
who took 10 mg/kg biweekly in the Core Study is no more than 50% of the treatment difference at the end of Core 
Study.  If the lower limit of this confidence interval is greater than 0, the null hypothesis is rejected.  In addition, 
comparisons between subjects who took placebo at Core Study and those who took 10 mg/kg biweekly in the Core 
Study will be performed for each endpoint at scheduled visits in the Extension Phase.  (revised per Amendment 11) 
Time to worsening of CDR global scores will be analyzed on the FAS using Cox regression model.  Time to 
worsening of CDR global score is defined as time from the first treatment in the Extension Phase to worsening of 
the CDR score (ie, the first worsening in 2 consecutive scheduled visits).  For subjects whose CDR scores have not 
worsened by the end of study, the time to worsening of the CDR score will be censored at the date of last CDR 
assessment for these subjects.  (revised per Amendment 11) 
Change from baseline in total hippocampal volume and other biomarkers will be summarized using descriptive 
statistics at scheduled visits in the Extension Phase.  Biomarker and efficacy analysis in the dosing regimen 
substudy will also be performed similarly by dosing regimen.  The details will be included in SAP.  (revised per 
Amendment 17) 
Additional analyses and summaries will be performed as appropriate. 
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Pharmacokinetic and Pharmacodynamic Analyses (Core Study and Extension Phase Part A) 
Pharmacokinetics: 
The Safety Analysis Set will be used for individual BAN2401 serum and CSF concentration listings (Core Study 
only).  The PK Analysis Set will be used for summaries of BAN2401 serum and CSF concentrations (Core Study 
only).  (revised per Amendment 11) 
A population PK approach will be used to characterize the PK of BAN2401.  The effect of covariates 
(ie, demographics) on BAN2401 PK will be evaluated.  The PK model will be parameterized for clearance (CL) 
and volumes of distribution.  Derived exposure parameters such as area under the concentration-time curve (AUC) 
will be calculated from the model using the individual posterior estimate of CL and dosing history.   
Pharmacodynamics: 
The PD Analysis Set will be used for the summaries and analyses of CSF biomarkers (Core Study only).  (revised 
per Amendment 11)  CSF Aβ(1-42), t-tau, and p-tau will be assessed and data 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-Pharmacodynamic: 
The PK/PD relationship between CSF biomarker levels (Core Study only) and serum PK parameters or CSF 
concentrations of BAN2401 will be explored graphically and any emergent relationship will be explored through 
population PK/PD modeling (revised per Amendment 11).  These serum PK parameters include steady state (SS), 
maximum observed concentrations (Cmax),  and AUC(0-t) derived from the population PK model.  The PK/PD 
relationship between serum PK parameters and CSF concentrations of BAN2401 with other biomarkers may also 
be explored using similar methods. 
Additionally, the relationship between various serum PK parameters or CSF concentrations of BAN2401 (Core 
Study only) and the ADCOMS at 12, 18, 30, and 42 months, and the relationship between various serum PK 
parameters or CSF concentrations of BAN2401 (Core Study only) and the change from Baseline for 12, 18, 30, and 
42 months in the ADAS-Cog, the CDR, and the MMSE will be explored graphically.  (revised per Amendments 
08 and 11)  Any emergent relationship will be explored through population PK/PD modeling. 
The relationship between exposure to BAN2401 and most frequent AEs will also be explored. 
Extension Phase Part B (revised per Amendment 19) 
No PK or PD analyses will be performed. 
Safety Analyses  
Core Study 
Evaluations of safety will be performed on the Safety Analysis Set of the Core Study.  (revised per Amendment 
08)  The incidence of AEs (including changes from baseline in physical examination), out-of-normal-range 
laboratory safety test variables, abnormal ECG findings, out-of-range vital signs, and suicidality (C-SSRS), along 
with change from baseline in laboratory safety test variables, ECGs, brain MRI, ADAs (screening and neutralizing) 
and vital sign measurements, will be summarized by treatment group using descriptive statistics.  
Extension Phase Part A  (revised per Amendments 08, 17, and 19) 
Safety analysis will be performed similarly to the Core Study.  All safety analyses will be based on Safety Analysis 
Set of the Extension Phase.  The incidence of treatment emergent adverse events (TEAEs), laboratory test variables, 
ECG findings, vital signs, brain MRI, and ADAs will be summarized using descriptive statistics.  Safety analysis 
in the Dosing Regimen substudy will also be performed similarly by dosing regimen.  The details will be included 
in SAP.  (revised per Amendment 17 and 19) 
 
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Extension Phase Part B  (revised per Amendment 19) 
Safety analysis will be performed similarly to the Core Study.  All safety analyses will be based on Safety Analysis 
Set of the Extension Phase Part B.  The incidence of TEAEs, vital signs, and brain MRI, will be summarized using 
descriptive statistics.  The details will be included in the SAP.  (revised per Amendment 19) 
Interim Analyses (Core Study only)  (revised per Amendment 11) 
An unblinded independent Interim Monitoring Committee (IMC) will provide oversight to ensure that the response 
adaptive randomization process and IA perform as expected.  An independent data analysis group will perform all 
of the IA and provide the results to the IMC. 
Randomization to placebo or 1 of 5 dose arms of BAN2401 will be fixed for the first 196 subjects randomized in 
the study (4:2:2:2:2:2; placebo [4] to each of the active arms [2 each]).  After this initial burn-in, adaptive 
randomization will begin.  Randomization probabilities to each arm will be updated at each IA such that the 
randomization probability will be increased for the placebo arm and arms that represent the potential target dose 
(ED90), and simultaneously decreased for other active arms.  Subjects who are confirmed APOE4 positive (APOE4 
hetero- or homozygous) will not be randomized to the 10 mg/kg, biweekly dose.  (revised per Amendment 05)  
Details of the estimation of the randomization probabilities will be presented in the Statistical Analysis Plan. 
The study will be monitored for early success and early futility (see definitions in Study Definitions).  The first IA 
will be conducted when 196 subjects are randomized, again when 250 subjects are randomized, and after each 
additional 50 subjects until all 800 subjects are randomized.  Sites in Japan will randomize at least 40 Japanese 
subjects, even if early success is declared or the study achieves 800 subjects randomized.  In these circumstances, 
subjects in Japan will be allocated treatment according to the latest (or last) allocation schedule.  If the study reaches 
its maximum of 800 randomized subjects, additional IA will be conducted every 3 months until all subjects 
complete 12 months of treatment.  Only those subjects who were randomized before the target of 800 was met will 
contribute to these additional IA, except for the full 12 and 18 month Bayesian analyses.  The study will be 
monitored for futility at each IA and for success starting at the 350-subject IA, until the full 12 months of treatment 
have been completed.  (revised per Amendment 09)  Each IA will be conducted on data for ADCOMS, which is 
the derived score optimized to capture AD-related clinical progression.  If the efficacy or futility boundary is 
reached, the IMC will communicate directly with the DSMB members.  (revised per Amendment 07)  The study 
may be stopped for safety reasons at any time. 
Sample Size Rationale 
Core Study 
Primary Endpoint - ADCOMS 
The sample size and design characteristics to test the hypothesis under primary objective based on the primary 
endpoint, the ADCOMS at 12 months, were determined by means of simulations.  Extensive trial simulations have 
shown that a total of 800 subjects will be sufficient to demonstrate that the most likely ED90 dose achieves a CSD 
from placebo with a probability of at least 95% in the IA and greater than 80% in the final analysis if the trial does 
not stop for early success.  There is at least 80% probability of study success for the dose response scenarios where 
the treatment was considered to have a clinically meaningful treatment effect.  Simulations have also shown that if 
there is no efficacy at all for any dose, the probability of falsely claiming superiority to placebo is no more than 
10.0% assuming a 20% dropout rate.  
For each of the 6 treatment groups (5 active dose regimens and placebo), the final number of subjects per group 
will differ depending on the observed interim treatment responses.  The simulation plan will be described in the 
Appendix section of the Statistical Analysis Plan, which will present further details. 
vMRI 
The null hypothesis is that there is no difference between active dose and placebo.  There are 5 null hypotheses 
corresponding to 5 active dose regimens.  The alternative hypothesis is that at least 1 null hypothesis is false 
(1-sided).  The null hypotheses will be tested using the Dunnett 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 to placebo would be 15%, 20%, 25%, 15%, and 
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20% corresponding to the 5 dose regimens (2.5, 5, and 10 mg/kg biweekly, 5 and 10 mg/kg monthly interval), 
respectively.  The estimated power for actual planned study sample size is 0.764 at 12 months and 0.694 at 
18 months assuming an attrition rate of 20% at 12 months and an exponential dropout model.  Under a stronger 
dose-response assumption (ie, the percent reduction in change from baseline of total hippocampal volume compared 
to placebo is twice as much as that in the moderate dose-response assumption), the estimated power is at least 
99% at both 12 and 18 months.  
Amyloid PET (Imaging Subgroup) 
The null and alternative hypotheses and statistical test are the same as that for vMRI.  To estimate the sample size 
for amyloid PET imaging subgroup at 18 months, a common standard deviation of change from baseline was 
estimated as 0.4 and a reasonable mean difference between treatment and placebo was estimated as 0.25 standard 
uptake value ratio (SUVR).  The corresponding standard deviation and mean difference at 12 months were 
estimated as 0.27 and 0.17, respectively.  Assuming a moderate dose response that the best dose regimen would 
achieve a difference of 0.25 (SUVR) and that the 2 middle and 2 low dose regimens would achieve a difference of 
0.2 and 0.15 (SUVR), respectively, it would require a total 230 subjects from all 6 arms at 18 months to achieve an 
80% power.  This sample size took into account possible unequal number of subjects per arm.  Under the same 
attrition rate assumption as that for vMRI, a total sample size of 306 at 12 months is sufficient to obtain 230 subjects 
at 18 months.  The estimated power with 306 subjects at 12 months is approximately 85%.  The postbaseline 
amyloid PET in the imaging subgroup will be planned for the first 306 subjects who have consented and who are 
still on treatment at 12 months.  (revised per Amendments 02 and 07)   
Extension Phase Part A and Part B (revised per Amendments 08, 11, and 19) 
There is no sample size calculation for the Extension Phase.   
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3 
TABLE OF CONTENTS 
REVISION HISTORY 
1 
1 
TITLE PAGE 
39 
2 
CLINICAL PROTOCOL SYNOPSIS 
40 
3 
TABLE OF CONTENTS 
71 
LIST OF IN-TEXT TABLES 
74 
LIST OF IN-TEXT FIGURES 
74 
LIST OF APPENDICES 
75 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
76 
5 
ETHICS 
80 
5.1 
Institutional Review Boards/Independent Ethics Committees 
80 
5.2 
Ethical Conduct of the Study 
80 
5.3 
Subject Information and Informed Consent 
81 
6 
INVESTIGATORS AND STUDY PERSONNEL 
83 
7 
INTRODUCTION 
84 
7.1 
Indication 
84 
7.1.1 
Current Therapeutic Options 
84 
7.1.2 
BAN2401 
84 
7.1.2.1 
Therapeutic Pathway 
84 
7.1.2.2 
Mechanism of Action 
85 
7.1.2.3 
Clinical Experience with BAN2401 
85 
7.2 
Study Rationale 
89 
7.2.1 
Clinical Assessment Rationale 
90 
7.2.1.1 
Rationale for Conducting the Study in MCI due to AD 
– Intermediate Likelihood and Mild Alzheimer’s 
Disease Dementia Subjects 
90 
7.2.1.2 
Efficacy Assessment – Composite Clinical Score 
91 
7.2.2 
Biomarker Rationale 
93 
7.2.2.1 
Amyloid PET 
93 
7.2.2.2 
Volumetric MRI 
94 
7.2.2.3 
Soluble Biomarkers in Cerebrospinal Fluid (CSF) 
95 
8 
STUDY OBJECTIVES 
96 
9 
INVESTIGATIONAL PLAN 
99 
9.1 
Overall Study Design and Plan 
99 
9.1.1 
Prerandomization Phase 
102 
9.1.1.1 
Screening Period 
103 
9.1.1.2 
Baseline Period 
105 
9.1.2 
Randomization Phase 
106 
9.1.2.1 
Treatment Period 
106 
9.1.2.2 
Follow-Up Period 
108 
9.1.2.3 
Unscheduled Visits 
108 
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9.1.3 
Extension Phase 
109 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
112 
9.3 
Selection of Study Population 
113 
9.3.1 
Inclusion Criteria 
113 
9.3.2 
Exclusion Criteria 
115 
9.3.3 
Removal of Subjects From Therapy or Assessment 
117 
9.4 
Treatments 
119 
9.4.1 
Treatments Administered 
119 
9.4.2 
Identity of Investigational Product(s) 
119 
9.4.2.1 
Chemical Name, Structural Formula of BAN2401 
119 
9.4.2.2 
Comparator Drug 
120 
9.4.2.3 
Labeling for Study Drug 
120 
9.4.2.4 
Storage Conditions 
120 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
121 
9.4.4 
Selection of Doses and Dose Regimens in the Study 
122 
9.4.5 
Selection and Timing of Dose for Each Subject 
123 
9.4.6 
Blinding 
124 
9.4.7 
Prior and Concomitant Therapy 
124 
9.4.7.1 
Drug-drug Interactions 
125 
9.4.7.2 
Core Study Prohibited Concomitant Therapies and 
Drugs 
125 
9.4.8 
Treatment Compliance 
125 
9.4.9 
Drug Supplies and Accountability 
126 
9.5 
Study Assessments 
127 
9.5.1 
Assessments 
127 
9.5.1.1 
Demography 
127 
9.5.1.2 
Baseline Assessments 
127 
9.5.1.3 
Efficacy Assessments 
130 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Assessments 
131 
9.5.1.5 
Safety Assessments 
134 
9.5.1.6 
Other Assessments 
144 
9.5.2 
Schedule of Procedures/Assessments 
147 
9.5.2.1 
Schedule of Procedures/Assessments 
147 
9.5.2.2 
Total Volume of Blood and CSF 
154 
9.5.3 
Appropriateness of Measurements 
154 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Other 
Events of Interest 
155 
9.5.4.1 
Reporting of Serious Adverse Events 
155 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug 
Through Breastfeeding 
157 
9.5.4.3 
Reporting of Other Events of Interest 
157 
9.5.4.4 
Expedited Reporting 
158 
9.5.4.5 
Breaking the Blind 
159 
9.5.4.6 
Regulatory Reporting of Adverse Events 
159 
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9.5.5 
Completion/Discontinuation of Subjects 
159 
9.5.6 
Abuse or Diversion of Study Drug 
160 
9.5.7 
Confirmation of Medical Care by Another Physician 
160 
9.6 
Data Quality Assurance 
160 
9.6.1 
Data Collection 
161 
9.6.2 
Clinical Data Management 
161 
9.7 
Statistical Methods 
161 
9.7.1 
Statistical and Analytical Plans 
161 
9.7.1.1 
Study Endpoints 
162 
9.7.1.2 
Definitions of Analysis Sets 
162 
9.7.1.3 
Subject Disposition 
163 
9.7.1.4 
Demographic and Other Baseline Characteristics 
164 
9.7.1.5 
Prior and Concomitant Therapy 
164 
9.7.1.6 
Efficacy Analyses 
164 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Analyses 
168 
9.7.1.8 
Safety Analyses 
169 
9.7.1.9 
Determination of Sample Size 
172 
9.7.2 
Interim Analysis 
173 
9.7.3 
Other Statistical/Analytical Issues 
174 
9.7.4 
Procedure for Revising the Statistical Analysis Plan 
174 
10 
REFERENCE LIST 
175 
11 
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) 
178 
11.1 
Changes to the Protocol 
178 
11.2 
Adherence to the Protocol 
178 
11.3 
Monitoring Procedures 
178 
11.4 
Recording of Data 
179 
11.5 
Identification of Source Data 
179 
11.6 
Retention of Records 
179 
11.7 
Auditing Procedures and Inspection 
180 
11.8 
Handling of Study Drug 
180 
11.9 
Publication of Results 
180 
11.10 Disclosure and Confidentiality 
180 
11.11 Discontinuation of Study 
181 
11.12 Subject Insurance and Indemnity 
181 
12 
APPENDICES 
182 
 
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LIST OF IN-TEXT TABLES 
Table 1 
Mean (SD) of CSF and Serum Concentrations and CSF:Serum Ratios in 
Cohorts SAD6 (15 mg/kg) at 24 Hours Postdose, MAD1 (0.3 mg/kg), 
MAD2 (1 mg/kg), and MAD 3 (3 mg/kg) at 24 Hours Post-Dose 4, and 
MAD4 (10 mg/kg) at 24 Hours and 14 Days Post-Dose 7 
87 
Table 2 
Summary of Treatment-Emergent ARIA-E by ApoE4 Status (Safety 
Analysis Set) (revised per Amendment 11) 
89 
Table 3 
Sample Size Requirements for the ADCOMS Across 3 Treatment Effect 
Sizes Compared to ADAS-Cog and CDR in MCI Subjects and Enriched 
MCI Subjects 
92 
Table 4 
BAN2401 Dose Regimens – Core Study 
100 
Table 5 
Model-predicted CSF Exposures at Steady State at BAN2401 Doses of 2.5 
to 10 mg/kg Biweekly, or 5 to 10 mg/kg Monthly 
123 
Table 6 
Clinical Laboratory Tests (Revised per Amendment 11) 
139 
Table 7 
Schedule of Screening and Baseline Procedures/Assessments (Visits 1 and 
2), Study BAN2401-G000-201 – Core Study 
148 
Table 8 
Schedule of Procedures/Assessments, Core Study BAN2401-G000-201, 
Panel A, Visits 3 through 27, Weeks 1 through 49 – Core Study 
150 
Table 9 
Summary of Blood and CSF Sample Volumes 
154 
Table 10 
Predictive Variables for the ADCOMS 
166 
Table 11 
Summary of Blood Sample Volumes in the Extension Phase Part A  
(revised per Amendment 15 and 19) 
205 
Table 12 
Summary of Blood Sample Volumes in the Extension Phase Part A 
Dosing Regimen Substudy (revised per Amendments 17 and 19) 
205 
Table 13 
Schedule of Procedures/Assessments for Study BAN2401-G000-201:  
Extension Phase Part A (revised per Amendments 12, 14, 15, 17, 18, and 
19) 
212 
Table 14 
Dosing Regimen Substudy Schedule of Assessments (Visits 1 through 25, 
Weeks 1 through 97)  (revised per Amendment 17) 
217 
Table 15 
Dosing Regimen Substudy Schedule of Assessments – (Visits 26 through 
Follow-Up, Weeks 101 through 157) (revised per Amendment 17) 
219 
Table 16 
Extension Phase Part B – Schedule of Assessments (revised per 
Amendment 19) 
230 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Design of Study BAN2401-G000-201 
102 
Figure 2 
Schematic Overview of Eligibility Assessments 
103 
Figure 3 
Model-Predicted PET SUVr after Various Dosing Regimens (revised per 
Amendment 17) 
208 
Figure 4 
Model-Predicted Plasma Aβ42/40 Ratio after Various Dosing Regimens 
(revised per Amendment 17) 
209 
Figure 5 
Model-Predicted Plasma p-tau181 After Various Dosing Regimens 
(revised per Amendment 17) 
210 
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LIST OF APPENDICES 
Appendix 1 
Sponsor’s Grading for Laboratory Values 
182 
Appendix 2 
List of Permitted and Prohibited Prior/Concomitant Medications 
184 
Appendix 3 
Pharmacogenomic and Biomarker Bioanalysis 
190 
Appendix 4 
EXTENSION PHASE PART A (revised per Amendments 11, 16, 17, 18, 
and 19) 
193 
Appendix 5 
EXTENSION PHASE PART B  (revised per Amendment 19) 
224 
 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
A 
amyloid beta 
A(1-42) 
amyloid beta monomer from amino acid 1 to 42 
AChEI 
acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADA 
anti-drug antibody 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale - Cognitive Subscale 
ADCOMS 
Alzheimer's Disease Composite Score 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
AE 
adverse event 
APOE 
Apolipoprotein E 
APOE4 
apolipoprotein є4 variant 
ARIA 
amyloid-related imaging abnormalities 
ARIA-E 
amyloid-related imaging abnormality edema/effusion 
ARIA-H 
Amyloid-related imaging abnormality hemorrhage 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration vs. time curve   
AUC(0-14 days)_ 
area under the concentration vs. time curve between time 0 and 14 days 
AUC(0-τ) 
area under the concentration vs. time curve between time 0 and time τ at 
steady state, where τ is the dosing interval 
AUC(0-t) 
area under the concentration vs. time curve between time 0 and time t 
BAN2401 
a humanized IgG1 monoclonal antibody 
BMI 
body mass index 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating – Sum of Boxes 
CFR 
Code of Federal Regulations 
CL 
clearance 
Cmax 
maximum observed concentration 
Cmax,ss 
maximum observed concentration at steady state 
Cmin 
minimum observed concentration 
Cmin,ss 
minimum observed concentration at steady state 
CNS 
central nervous system 
COVID-19 
Coronavirus Disease 2019 
CPMP 
Committee for Proprietary Medicinal Products 
CRA 
Clinical Research Associate 
CRP 
C-reactive protein 
CRO 
contract research organization 
CSD 
clinically significant difference 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
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Abbreviation 
Term 
CV 
curriculum vitae 
dMax 
the dose that achieves the greatest treatment effect 
DSMB 
Drug Safety Monitoring Board 
EAD 
early Alzheimer’s Disease 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED90 
the ‘simplest” dose regimen that achieves at least 90% of the dMax 
treatment effect 
EU 
European Union 
FAQ 
Functional Assessment Questionnaire (revised per Amendment 01) 
FDA 
United States Food and Drug Administration 
FLAIR 
fluid attenuating inversion recovery 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GPSP 
good postmarketing study practice 
GRE 
Gradient Recalled Echo 
GVP 
good vigilance practice 
Hb1Ac 
hemoglobin 1Ac 
IA 
interim analyses 
IAG 
Imaging Charter and Imaging Acquisition Guidelines 
IC50 
concentration that produces 50% inhibition 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMC 
Interim Monitoring Committee 
INR 
international normalized ratio 
IP/LC-MS/MS 
Immunoprecipitation liquid chromatography-tandem mass spectrometry 
IRB 
Institutional Review Board 
IV 
intravenous 
IVRS 
Interactive Voice Response System 
LC-MS/MS 
liquid chromatography – tandem  mass spectrometry 
LLN 
lower limit of normal 
LNH 
low, normal, high compared to laboratory reference range 
LP 
lumbar puncture 
mAb158 
monoclonal antibody 158 (a code designation) 
MAD 
multiple ascending dose 
MCI 
mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model with repeated measures 
MMSE 
Mini-Mental State Examination 
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Abbreviation 
Term 
MRI 
magnetic resonance imaging 
NIA-AA 
National Institute of Aging-Alzheimer’s Association 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse 
Events 
NOAEL 
no observed adverse effect level 
OLE 
open-label Extension 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PG 
pharmacogenomic 
PI 
principal investigator 
PiB 
Pittsburgh compound B 
PK 
pharmacokinetic 
PLS 
Partial Least Squares 
PO 
by the oral route 
PRN 
as needed 
p-tau 
phospho-tau 
Q3M 
every 3 months 
Q4W 
every 4 weeks 
QTc 
corrected QT interval 
QTcF 
corrected QT interval by Fredericia 
RAR 
response adaptive randomization 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOP 
standard operating procedure 
SUVR 
standard uptake value ratio 
SS 
steady state 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
t1/2,ss  
terminal elimination half-life at steady state 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TSH 
thyroid stimulating hormone 
t-tau 
total tau 
ULN 
upper limit of normal 
vMRI 
volumetric magnetic resonance imaging 
VHP 
Voluntary Harmonisation Procedure 
WMS-IV LM I 
Wechsler Memory Scale IV -Logical Memory (subscale) I 
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Abbreviation 
Term 
WMS-IV LM II 
Wechsler Memory Scale IV -Logical Memory (subscale) II 
 
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5 
ETHICS 
5.1 
INSTITUTIONAL REVIEW BOARDS/INDEPENDENT ETHICS COMMITTEES 
The protocol, informed consent form (ICF), and appropriate related documents must be reviewed 
and approved by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
constituted and functioning in accordance with International Council for Harmonisation (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[s] [CRA], 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 (PI) with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend 
or terminate the study, the investigator will immediately send the notice of study suspension or 
termination by the IRB/IEC to the sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to the 
IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator(s) or the sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines and local IRB/IEC 
standards of practice.  Upon completion of the study, the investigator will provide the IRB/IEC 
with a brief report of the outcome of the study, if required. 
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority within 
90 days.  The end of the study will be the date of the last study visit for the last subject in the study.  
The sponsor should also provide the IRB/IEC with a summary of the study’s outcome. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and regulatory authorities within 15 calendar days, and a detailed written explanation of 
the reasons for the termination/halt should be given. 
5.2 
ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required by 
the Committee for Proprietary Medicinal Products (CPMP) following: 
 
Principles of the World Medical Association Declaration of Helsinki, 2008 version 
 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products 
(CPMP), International Council for Harmonisation of Pharmaceuticals for Human Use 
(ICH) 
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 
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312 
 
European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any European Union (EU) country.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, 
to the Competent Authorities of all involved EU member states. 
 
Good Postmarketing Study Practice (GPSP) and Good Vigilance Practice (GVP) – once 
BAN2401 is approved by Japanese regulatory authority  (revised per Amendment 18)  
 
Other applicable regulatory authorities’ requirements or directives 
5.3 
SUBJECT INFORMATION AND INFORMED CONSENT 
As part of administering the informed consent document to the subject, the investigator must 
explain to each subject and caregiver/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 information must also be given to the caregiver/informant. 
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 
caregiver/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 caregiver/informant, and after the subject has 
orally consented to his or her participation in the study and has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  At the Screening Visit, the 
subject will be asked to sign an ICF before any study-specific procedures are performed.  No 
subject can enter the study before his/her informed consent has been obtained.  In the case of a 
subject lacking capacity to consent in the investigator's opinion, subject's assent plus written 
informed consent of a legal representative should be obtained, if required in accordance with local 
laws, regulations and customs.  Capacity to consent and definition of legal representative should 
be determined in accordance with applicable local laws and regulations.  The Investigator shall re-
assess consent capacity at periodic intervals during the subject’s involvement in the study, and 
when a subject's family member expresses concern about the subject's study participation.  The 
method and frequency of re-assessment of capacity is at the investigator’s discretion (taking into 
account any relevant local laws and regulations).  Should a subject decline to the point of lacking 
capacity in the investigator's opinion during the study, the investigator should obtain the assent of 
the subject and consent of a legal representative for the subject to continue in the study.  (revised 
per Amendment 07) 
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The caregiver/informant should also consent to supporting the subject’s participation in the study 
and will be provided with a separate written informed consent form 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 must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The original, 
signed ICF for each subject will be verified by the sponsor and kept on file according to local 
procedures at the site.   
All subjects must consent to either a baseline positron emission tomography (PET) scan or a 
baseline cerebrospinal fluid (CSF) sample to be used to determine study eligibility.  Subjects will 
also be asked to sign separate optional ICFs to enter the CSF and imaging substudies, respectively.  
For those who consent to both CSF and PET collection for eligibility, samples will be collected as 
follows: 
For the Core Study, subjects whose study eligibility is determined by amyloid PET and who have 
consented to both substudies will have:  (revised per Amendment 08) 
 Additional PET scans performed at 12 and 18 months 
 CSF samples collected at Baseline, 12, and 18 months 
For the Core Study, subjects whose study eligibility is determined on CSF and who have consented 
to both substudies will have:  (revised per Amendment 08) 
 PET scans performed at Baseline, 12, and 18 months 
 Additional CSF samples collected at 12 and 18 months 
None of the optional consents are required for study eligibility.  (revised per Amendment 06) 
For the Extension Phase Part A, subjects will need to reconsent for the longitudinal amyloid PET 
substudy (subjects located in US and Japan only) before or at Extension Phase Baseline (Extension 
Screening Visit).  In the US only, subjects and study partners who have participated in any phase 
of the study (Core Study or Extension Phase Part A) will have the option to participate in an 
optional medical claims substudy.  All participants in the substudy will sign a separate informed 
consent.  (revised per Amendments 08, 09, 11, 16, and 19) 
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6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the sponsor) 
at approximately 125 investigational site(s) including North America, Europe, and Asia-Pacific.  
(revised per Amendment 07) 
The name and telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and at the contract research organization(s) (CRO[s]) are listed in the Investigator 
Study File or Regulatory Binder provided to each site. 
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7 
INTRODUCTION 
7.1 
INDICATION  
Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder of unknown etiology and 
the most common form of dementia among older people.  In 2006, there were 26.6 million cases 
of AD in the world (range, 11.4-59.4 million).1  The Alzheimer’s Association has reported that in 
2007 there were more than 5 million people in the US living with AD.2  By the year 2050, the 
worldwide prevalence of AD is predicted to grow to 106.8 million (range, 47.2-221.2 million), 
while in the US alone the prevalence is estimated to be 11 to 16 million.1,2   
The disease is clinically characterized by a global decline of cognitive function that progresses 
slowly and leaves end-stage patients bedridden.  AD is the seventh leading cause of all deaths in 
the US and the fifth leading cause of death in Americans older than the age of 65 years.2  AD 
patients typically survive for only 3 to 10 years after symptom onset, although extremes of 2 and 
20 years are known.3  Mortality due to AD is greatly underestimated because death certificates 
rarely attribute the cause of death to AD.  Co-morbidities, including malnutrition, depression, 
urinary and fecal incontinence, are often associated with AD.4  Cerebrovascular disease (including 
vascular dementia) is present in more than 30% of AD patients.5  Such serious co-morbidity 
contributes considerably to the diminished lifespan of AD patients.  
AD represents a significant economic burden across industrialized countries with a substantial 
impact on healthcare systems and the public purse as well as on patients and their families.  
Without doubt the greatest burden of AD falls on patients and caregivers/informants.  They not 
only suffer from the devastating emotional, social, and physical consequences of this, but also bear 
a substantial economic burden.  In the US alone total payments for 2010 are estimated at $172 
billion, including $123 billion for Medicare and Medicaid.2 
7.1.1 Current Therapeutic Options  
At this time, there is no cure for AD and no way of slowing down the progression of this disease.  
This stems largely from our incomplete knowledge of the true pathophysiology of AD in which 
abnormalities of amyloid  peptide (A) and tau processing, inflammation, oxidative stress, and 
vascular risk factors, amongst others are postulated to contribute.  Present therapeutic agents for 
AD consist of symptomatic therapies which include the acetylcholinesterase inhibitors (AChEIs), 
such as donepezil, the N-methyl-D-aspartate (NMDA)-receptor antagonist, memantine, and the 
amyloid-beta directed antibody aducanumab.  These therapies improve the symptoms of AD such 
as cognitive decline and decline in activities of daily living and behavior, but do not alter the 
underlying progression of the disease.  Thus, an unmet medical need for drugs that slow or prevent 
the progression of the disease still exists.  (revised per Amendment 17) 
7.1.2 BAN2401 
7.1.2.1 Therapeutic Pathway 
Amyloid β (Aβ) peptides exist in a dynamic continuum of conformational states such that species 
tend to progress from monomeric Aβ, to soluble Aβ assemblies that include a range of low 
molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils 
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(plaques).  Various lines of evidence support the “amyloid hypothesis” that Aβ plays a central role 
in the pathogenesis of AD, and a number of immunotherapies have been developed to reduce the 
amount of insoluble Aβ fibrils deposited in the brain.  However, the quantity and progressive 
accumulation of insoluble amyloid plaques does not demonstrate a simple correlation with the 
clinical course of AD.  To that end, Aβ aggregate species have been implicated in mediating early 
neurotoxic events that alter synaptic function, and increasing evidence suggests that these soluble 
Aβ aggregates may better correlate with disease severity and may contribute to early cognitive 
dysfunction, widespread neurodegeneration and dementia in AD.  While therapeutic strategies 
continue to focus on removal of insoluble amyloid plaques, an additional approach to therapy may 
include reducing the toxic Aβ aggregates that may contribute to the neuronal degeneration 
characteristic of AD.6,7,8 
7.1.2.2 Mechanism of Action 
BAN2401 is a humanized IgG1 monoclonal antibody that distinguishes itself from other 
anti-amyloid antibodies in that it demonstrates low affinity for Aβ monomer, while it binds with 
high selectivity to soluble Aβ aggregate species.  Although BAN2401 does interact with Aβ 
monomers and Aβ fibrils, it demonstrates approximately 1000-fold and 5-fold to 10-fold higher 
selectivity for soluble Aβ aggregate species as compared with Aβ monomers or insoluble fibrils, 
respectively.  In contrast, bapineuzumab, another humanized monoclonal antibody with an 
N-terminal epitope, is a high affinity antibody across the entire spectrum of Aβ species, from 
monomers to soluble aggregates to insoluble fibrils.   
Aβ monomers are considered to be largely inert (or possibly physiologically important), while Aβ 
fibrils are thought to be inert or locally toxic.  Therefore, BAN2401 is hypothesized to selectively 
neutralize and clear the toxic Aβ species, whereas bapineuzumab has high affinity for all species 
(whether toxic, inert or physiologically important).  With the relatively high abundance of Aβ 
monomers and insoluble fibrils compared to soluble aggregate species in the AD brain, BAN2401 
is anticipated to have much greater relative activity against the primary toxic amyloid species 
implicated in AD pathology. 
7.1.2.3 
Clinical Experience with BAN2401 
BAN2401 has been evaluated in the first-in-human study, BAN2401-A001-101, in subjects who 
have mild to moderate AD.  The study was conducted in 2 parts: Part A was a single ascending 
dose (SAD) and Part B was a multiple ascending dose (MAD).  Both parts were designed as 
randomized, double-blind, placebo-controlled, sequential ascending dose schemes.  The 
BAN2401-A001-101 study was designed to allow the MAD part to be initiated while the SAD 
part was ongoing. 
A total of 80 subjects were treated in the study.  Specifically, 48 subjects have been dosed in 6 
SAD cohorts, with 8 subjects (6 on active treatment and 2 on placebo) treated in each of the cohorts, 
ie, SAD1 at 0.1 mg/kg, SAD2 at 0.3 mg/kg, SAD3 at 1.0 mg/kg, SAD4 at 3.0 mg/kg, SAD5 at 10 
mg/kg and SAD6 at 15 mg/kg.  Similarly, a total of 32 subjects have been treated in each of the 4 
MAD cohorts with 8 subjects (6 on active treatment and 2 on placebo) in each of the cohorts.  The 
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MAD1, MAD2, and MAD3 cohorts each received 4 infusions of BAN2401 at 28-day intervals, 
and the MAD4 cohort received 7 infusions at 14-day intervals.  Doses administered at each 
infusion were:  MAD1, 0.3 mg/kg; MAD2, 1.0 mg/kg; MAD3, 3.0 mg/kg; MAD4, 10 mg/kg.  
(revised per Amendment 11) 
Pharmacokinetic and Pharmacodynamic Summary 
For all 6 SAD cohorts, noncompartmental analysis was used to estimate pharmacokinetic (PK) 
parameters.  The median tmax occurred at approximately 1.75 to 2 hours from start of infusion.  The 
mean maximum observed concentration (Cmax) and the area under the concentration versus time 
curve (AUC) values for BAN2401 increased approximately proportionally with BAN2401 dose 
across the range of 0.3 to 15 mg/kg for SAD cohorts.  The half-life of BAN2401 ranged from 
approximately 85.2 to 163 hours (3.5 to 6.8 days) at 3 to 15 mg/kg.   
In the MAD cohorts, the mean Cmax and AUC values for the first dose of BAN2401 were each 
consistent with corresponding doses in the SAD cohorts.  The mean Cmax and AUC of the first and 
last doses of BAN2401 in the MAD cohorts increased approximately dose proportionally across 
the range of 0.3 to 10 mg/kg.  The mean half-life of BAN2401 of ranged from approximately 105 
to 133 hours (4.4 to 5.5 days), which was consistent with that found in the SAD cohorts.  The mean 
half-life of BAN2401 after the final dose (Dose 7) in MAD4 (10 mg/kg biweekly) was 120 hours 
(5 days), which was consistent with the half-life in the first dose in MAD cohorts and in the SAD 
cohorts.  Consistent with the half-life in relation to frequency of dosing, minimal accumulation of 
BAN2401 was measured in these studies.  Steady state (SS) was generally achieved after 
approximately 6 weeks of treatment.  The minimum observed concentration (Cmin) at steady state 
was approximately 40 µg/mL and the accumulation factor calculated was 1.39.  (revised per 
Amendment 11) 
Serum concentration data following BAN2401 single ascending doses of 1, 3, 10, and 15 mg/kg 
BAN2401 were modeled using a 2-compartment model.  The final population PK model predicted 
that the serum half-life of BAN2401 would be 166.3 hours (6.9 days).  
Subjects had CSF samples collected by lumbar puncture (LP) at baseline and 24 hours after the 
final dose (Dose 4) of study drug (Day 85) for MAD1-MAD3 cohorts.  Across these 3 cohorts, the 
CSF:serum concentration of BAN2401 at 24 hours post Dose 4 was 0.05% to 0.1%, which is 
consistent with SAD data and predictions from preclinical models.  In MAD4 (10 mg/kg every 
2 weeks), all 8 subjects had CSF sampling at baseline and postdose.  The first 4 subjects who were 
randomized had CSF sampling at 24 hours post Dose 7 (Day 85), whereas the remaining subjects 
had CSF sampling at 14 days post Dose 7 (Day 98).  CSF concentrations were quantifiable from 
all 6 subjects treated with BAN2401, 3 each on Day 85 and Day 98.  The CSF concentrations of 
BAN2401 at 24 hours after the final dose are shown in Table 1 with the corresponding CSF:serum 
concentration ratios. 
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Table 1 
Mean (SD) of CSF and Serum Concentrations and CSF:Serum Ratios in 
Cohorts SAD6 (15 mg/kg) at 24 Hours Postdose, MAD1 (0.3 mg/kg), MAD2 
(1 mg/kg), and MAD 3 (3 mg/kg) at 24 Hours Post-Dose 4, and MAD4 
(10 mg/kg) at 24 Hours and 14 Days Post-Dose 7 
 
Day 2a  or Day 85b 
(24 h postdose of final dose) 
Day 10a or Day 98c 
(10a or 14c days postdose of final dose) 
Cohort /Dose 
CSF 
(ng/mL) 
Serum 
(g/mL) 
CSF:Serum 
Ratio 
CSF 
(ng/mL) 
Serum 
(g/mL) 
CSF:Serum 
Ratio 
SAD6, 15 mg/kg 
96.3 (45.1) 
246 (65.8) 
0.04% 
(0.03%) 
72.2, 624d 
100.7, 76.8d 
0.07%, 
0.81%d 
MAD1, 0.3 
mg/kg 
4.34 (1.02) 
4.49 (1.01) 
0.09% 
(0.02%) 
CSF not collected 
MAD2, 1 mg/kg 
8.89 (5.31) 
17.62 (8.85) 
0.04% 
(0.03%) 
MAD3, 3 mg/kg 
25.0 (13.3) 
44.1 (4.55) 
0.06% 
(0.04%) 
MAD4, 10 mg/kg 
263 (106) 
155 (98.1) 
0.17% 
(0.12%) 
115.6 
(109) 
37.5 (21.8) 
0.31% (0.50%) 
CSF = cerebrospinal fluid, MAD = multiple ascending dose, SAD = single ascending dose 
a: 
SAD6: CSF was collected on Day 2 (24 h postdose) and Day 10 postdose. 
b: 
MAD1-4: CSF was collected on Day 85 (24 h postdose of final dose).  
c: 
MAD4: CSF was collected on Day 98 (14 days postdose of final dose, which was Dose 7). 
d: 
Only 2 subjects treated with BAN2401 at 15 mg/kg had CSF sampling on Day 10 instead of the expected 3 subjects, 
because 1 of these subjects had CSF sampled on Day 2 in error instead of Day 10. Of the 2 subjects with CSF 
concentration on Day 10, 1 was found to have CSF concentration ~624 ng/mL (CSF:serum ratio ~0.81%), which was an 
outlier compared to the CSF:serum ratio of all other subjects who had CSF sampling for BAN2401 concentration. Thus 
for Day 10 CSF concentration the mean is not provided and only the 2 subjects’ individual PK data are shown. 
Population PK modeling using the CSF PK data from SAD6 and MAD1 – MAD4 cohorts was 
also conducted.  Preliminary results from the population PK modeling suggested that in CSF, 
BAN2401 had a t½ of 167.5 hours (7.0 days), which was similar to that in serum.  The tmax in CSF 
was estimated to be 145 hours (6.0 days) postdose, which was slower than in serum, reflecting the 
slow penetration of BAN2401 through the blood brain barrier.  These findings on t½ and tmax in 
CSF based on the modeling were consistent with observed CSF:serum concentration ratios 
(Table 1). 
In MAD1 to MAD4 cohorts, subjects had CSF collected at baseline and after the final dose of 
study drug for PD biomarkers.  CSF PD biomarkers assayed included Aβ (1-42), total tau (t-tau), 
and phospho-tau (p-tau).  Preliminary analysis of the CSF PD data showed no treatment differences 
in subjects on BAN2401 compared to placebo.  There was no validated assay in CSF of AD 
subjects for aggregated forms of Aβ.  Thus, it was not possible to evaluate the PD effects of 
BAN2401 on CSF Aβ aggregated forms. 
Clinical Safety Summary 
In summary, safety and tolerability data from Study BAN2401-A001-101 indicate that BAN2401 
is a safe and well tolerated agent at single doses of up to 15 mg/kg IV and at multiple doses of up 
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to 10 mg/kg IV biweekly.  In particular, no safety concerns related to adverse central nervous 
system (CNS) effects, such as amyloid-related imaging abnormalities (ARIA), including 
vasogenic edema, micro- and macrohemorrhages and superficial hemosiderosis, have been 
identified in the BAN2401-A001-101 study.  Additionally, there have been no cases of classical 
acute or delayed hypersensitivity reactions or clinically significant inflammatory reactions of any 
kind.  Although several cases of possible mild infusion reactions have been documented, all of 
these have been transient, not associated with increasing dose levels or treatment duration and have 
resolved spontaneous without any safety concerns.  While mild and transient CRP elevations have 
been noted across the range of the SAD and the MAD doses, these largely represent isolated 
laboratory abnormalities, not associated with fibrinogen elevations, not accompanied by clinical 
symptoms and, overall, not representing any safety concerns.  Similarly, positive anti-drug 
antibody (ADA) responses identified in the study have been largely asymptomatic and are not 
associated with any safety concerns.  (revised per Amendment 11) 
Emerging data from the Study 201 indicate that positive apolipoprotein є4 variant (APOE4) 
(APOE4 hetero- or homozygous individuals have a higher risk of developing symptomatic 
ARIA-E.  (revised per Amendment 05)  At the time of Amendment 04, there were 9 subjects with 
confirmed cases of ARIA-E, of which 3 cases were symptomatic and associated with brain MRI 
scans showing significant amounts of vasogenic edema consistent with ARIA-E.  All 3 of these 
symptomatic ARIA-E cases took place in APOE4 homozygous subjects.  The study independent 
DSMB, having reviewed all unblinded data, recommended not to randomize APOE4 homozygous 
individuals to the highest dose of 10 mg/kg biweekly.  (revised per Amendment 04)  At the time 
of Amendment 05, there were 10 subjects with confirmed cases of ARIA-E, of which 9 cases were 
in APOE4 positive subjects (APOE4 hetero- or homozygous).  The EU Member States have 
provided a number of safety recommendations based on these data via the Voluntary 
Harmonisation Procedure (VHP) and expanded upon those provided by the independent DSMB.  
Specifically, the VHP committee requested that subjects who are confirmed APOE4 positive 
(APOE4 hetero- or homozygous) not be randomized to the 10 mg/kg, biweekly dose.  The sponsor 
has agreed to this request.  To permit ongoing assessment of risk factors that may be associated 
with ARIA-E, all subjects who underwent early termination due to ARIA were unblinded by the 
sponsor.  (revised per Amendments 05, 06, and 11) 
At the time of Amendment 11, the Core Study was completed.  Preliminary data analysis indicated 
that the incidence of amyloid-related imaging abnormality edema/effusion (ARIA-E) was less than 
10% for the highest BAN2401 dose groups (10 mg/kg biweekly and monthly) and less than 8% 
overall for subjects receiving treatment with any dose level of BAN2401.  There were 5 cases of 
symptomatic ARIA-E in BAN2401 treatment groups (all developed ARIA-E within the first 
12 weeks of treatment):  1 severe ARIA-E on magnetic resonance imaging (MRI) at 2.5 mg/kg 
biweekly, reported as a non-serious AE; 1 mild ARIA-E on MRI at 10 mg/kg monthly, reported 
as an serious adverse event (SAE); 1 moderate ARIA-E on MRI at 10 mg/kg biweekly, reported 
as an SAE; and 2 severe ARIA-E on MRI at 10 mg/kg biweekly, both reported as SAEs.  The 
breakdown of ARIA-E cases by ApoE4 status is provided in Table 2, with the incidence being 
higher in ApoE4 carriers (<15% at top dose) than non-carriers (8% at top dose).  (revised per 
Amendment 11) 
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Table 2 
Summary of Treatment-Emergent ARIA-E by ApoE4 Status (Safety 
Analysis Set) (revised per Amendment 11) 
Category 
Placebo  
(N=245)  
n (%) 
BAN2401
2.5 mg/kg
5 mg/kg
5 mg/kg
10 mg/kg
10 mg/kg
Total
biweekly
monthly
biweekly
monthly
biweekly
BAN2401
(N=52)
(N=51)
(N=92)
(N=253)
(N=161)
(N=609)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
ARIA-E
2 (0.8)
1 (1.9)
1 (2.0)
3 (3.3)
25 (9.9)
16 (9.9)
46 (7.6)
APOE4 positive 2/174
1/38
1/40
3/84
23a/225
7/49
35/436
(1.1)
(2.6)
(2.5)
(3.6)
(10.2)
(14.3)
(8.0)
APOE4 negative 0/71 
0/14 
0/11 
0/8 
2/28
9/112
11/173
(7.1)
(8.0)
(6.4)
APOE4 = apolipoprotein є4 variant, ARIA-E = amyloid-related imaging abnormality edema/effusion, TEAE = treatment-
emergent adverse event 
a:  One additional ApoE4 positive ARIA-E case was observed after 18 month treatment database lock and after treatment 
discontinuation; therefore, by definition was not treatment-emergent and is not counted in this table or TEAE description 
above 
After 18 months of treatment in any BAN2401 dose group overall, there were few reported cases 
of ARIA-E (n=46/609, 7.6%).  Most cases of ARIA-E (approximately 61%) occurred within the 
first 3 months of treatment, were mild to moderate in radiographic severity on MRI, were 
asymptomatic (92%), and typically resolved within 4 to 12 weeks.  (revised per Amendment 11) 
7.2 
STUDY RATIONALE 
Various lines of evidence support the “amyloid hypothesis” that Aβ plays a central role in the 
pathogenesis of AD, and a number of immunotherapies have been developed to reduce the amount 
of insoluble Aβ fibrils (plaques) deposited in the brain.  However, the quantity and progressive 
accumulation of insoluble amyloid plaques does not demonstrate a simple correlation with the 
clinical course of AD.  This shortcoming makes it difficult to identify a direct link between amyloid 
load and clinical symptomatology.  Moreover, the ability to demonstrate an effect on slowing 
disease course is hampered by the lack of sensitive tools for detecting relatively subtle change in 
progression or treatment effect in early disease, highlighting the need for long study durations to 
ensure adequate separation from placebo.  These impediments have resulted in the use of 
biomarkers as surrogates for clinical effect in Phase 2 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.9,10  These findings underscore 
the need for innovative approaches to Phase 2 AD clinical study design to mitigate the risks of 
embarking on larger and longer studies and suggest that Phase 2 studies of potential disease 
modifying agents should be designed to demonstrate clinical efficacy in addition to biomarker 
effects.   
The present Phase 2 study, BAN2401-G000-201, employs the use of a Bayesian response adaptive 
randomization design with frequent interim analyses (IA) to continually update randomization 
such that more subjects are allocated to efficacious doses based on maturing clinical endpoint data.  
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In addition, there will be frequent Drug Safety Monitoring Board (DSMB) meetings to review the 
safety data during the Core Study (revised per Amendments 08 and 11).  This approach allows for 
ongoing assessment of drug futility or evidence for early success and can mitigate the risks 
associated with larger and longer trials required to demonstrate clinical efficacy by leading to more 
efficient project termination or early advancement to a successful Phase 3 program.  
BAN2401-G000-201 represents the core (potentially supportive) Phase 2 study for the BAN2401 
program, and is designed to establish clinical efficacy with a new (more sensitive) clinical tool 
while exploring the dose response of BAN2401 in subjects with Early Alzheimer’s disease (EAD).  
For the purposes of this protocol, EAD is defined as a continuum of subjects from mild cognitive 
impairment (MCI) due to AD – intermediate likelihood to mild Alzheimer’s disease dementia who 
are positive for amyloid pathology in the brain.  Results from this study are expected to guide the 
decision to move into Phase 3 development and the selection of the dosing regimen to be taken 
into Phase 3 registration studies.  
7.2.1 Clinical Assessment Rationale 
7.2.1.1 
Rationale for Conducting the Study in MCI due to AD – Intermediate Likelihood and 
Mild Alzheimer’s Disease Dementia Subjects 
There is a growing consensus within the Alzheimer’s disease field that it may be necessary to 
initiate disease modifying treatments early in the disease course, before the onset of clinical 
dementia.11  During the past 2 decades there have been a number of efforts to test AD treatments 
in early symptomatic patients suffering from MCI without dementia.  These trials have been 
largely negative, due in part to operational difficulties with diagnosis of the MCI population.  New 
MCI diagnostic criteria have recently been offered by the National Institute on Aging – 
Alzheimer’s Association (NIA-AA)11 to address these difficulties by recommending the use of the 
term “MCI due to AD” to refer to the symptomatic predementia phase of AD where primary AD 
pathology has been confirmed.  Moreover, it has recently been suggested that clinical trials 
targeting the early symptomatic AD population “abandon the distinction between MCI and 
dementia in describing the study population and endpoints” and “expand the diagnosis of AD to 
include the subset of subjects with MCI who have AD neuropathology and are likely to progress 
to AD dementia.”12  Thus, the field is moving toward a paradigm where clinical studies in early 
AD incorporate the use of AD pathology biomarkers to define a population consisting of 
predementia subjects with MCI due to AD and mild Alzheimer’s disease dementia subjects. 
BAN2401 represents a putative therapeutic agent that is hypothesized to selectively target soluble 
Aβ aggregate species thought to produce synaptic toxicity, and this antibody has been shown to be 
capable of clearing diffuse amyloid plaques, suggesting that BAN2401 has the potential to 
neutralize the soluble Aβ aggregate species that elicit synaptotoxic events and to alter plaque 
formation in the brain.  Thus, it is hypothesized to be effective at early stages of the disease when 
amyloid has been deposited in the brain, but where the downstream neurodegenerative cascade 
thought to be triggered by the amyloid deposition is relatively early in its course.  Treatment with 
BAN2401 and attempts to slow disease progression should be most fruitful at this early stage 
where limited brain tissue loss has been produced and associated clinical deficits are at a minimum.   
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For these reasons, the appropriate target population for this study is considered to be Early AD.  
We define Early AD as a continuum of AD severity from MCI due to AD – intermediate likelihood 
to mild Alzheimer’s disease dementia.  The study will enroll subjects with mild Alzheimer’s 
disease dementia, who have amyloid pathology and have progressed to dementia,13 but are 
hypothesized to be sufficiently early in the disease course to benefit from therapeutic effect.  In 
addition, this protocol will enroll subjects with MCI due to AD – intermediate likelihood, 
identified in accordance with the NIA-AA criteria,12 ie symptomatic but not demented AD subjects 
with evidence of brain amyloid pathology making them less heterogeneous and more similar to 
mild Alzheimer’s disease dementia subjects in cognitive and functional decline as measured by 
the proposed clinical endpoint for this study, the Composite Clinical Score (Section 7.2.1.2; 
Section 9.5.1.3). 
7.2.1.2 Efficacy Assessment – Composite Clinical Score  
No well-established, validated clinical endpoints exist that are sensitive to change in MCI 
populations in clinical studies.  In fact, there has been concern that the standard cognitive 
instrument, the Alzheimer Disease Assessment Scale-Cognitive Scale (ADAS-Cog), may not have 
sufficient sensitivity to change even in a mild AD population.  Demonstration of an effect on 
slowing clinical progression in an EAD population is hampered by this lack of sensitive tools for 
measuring relatively subtle longitudinal changes or treatment effect in early disease.  
Heterogeneity of the MCI population as measured by established cognitive instruments, such as 
ADAS-Cog, presents another challenge for clinical studies in EAD and points to an acute need for 
a clinical tool that will be responsive to progression and treatment effects in EAD.  
Given these considerations, clinical data from multiple MCI studies were used to develop a new 
score that would demonstrate maximum responsiveness to progression and to treatment in an MCI 
population and that would also perform well in a mild Alzheimer’s disease dementia population.  
This score is described in Section 9.5.1.3, and is designated as the Composite Clinical Score.   
Most notably, the use of ADCOMS allows for substantial sample size reductions in nonenriched 
and enriched MCI populations for a 12-month study by increasing sensitivity and reducing 
heterogeneity (Table 3). 
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Table 3 
Sample Size Requirements for the ADCOMS Across 3 Treatment Effect 
Sizes Compared to ADAS-Cog and CDR in MCI Subjects and Enriched 
MCI Subjects 
  
  
  
Treatment 
Effect 
MCI  
MCI CSF Aβ(1-42) Positive 
Derived 
Clinical 
Composite 
Score 
ADAS-Cog
CDR 
Derived 
Clinical 
Composite 
Score 
ADAS-Cog 
CDR 
Sample Size per 
Arma 
   
25% 
1442 
9490 
1910 
399 
3608 
477 
50% 
362 
2373 
479 
101 
903 
120 
75% 
162 
1056 
213 
46 
402 
54 
% Reduction in 
sample size with the 
ADCOMSb 
25%-75% 
  
85% 
25% 
  
89% 
16% 
Aβ(1-42) = amyloid beta monomer from amino acid 1 to 42, ADAS-Cog = Alzheimer Disease Assessment Scale-Cognitive 
subscale, ADCOMS = Alzheimer's Disease Composite Score, CDR = Clinical Dementia Rating, CSF = cerebrospinal fluid, MCI 
= mild cognitive impairment. 
a: 
Sample size was determined using a 2-sided test with 80% power and alpha=0.05. 
b: 
% reduction per arm over 12 months 
In addition, the ADCOMS shows comparable sensitivity in the MCI due to AD – intermediate 
likelihood (CSF Aβ positive) subgroup and in mild Alzheimer’s disease dementia, indicating that 
subjects with MCI due to AD – intermediate likelihood progress similarly to mild Alzheimer’s 
disease dementia subjects according to the new score and allowing the use of a single clinical tool 
across the EAD population targeted in this study. 
Summary of Efficacy Assessments 
The Core Study was completed at the time of Amendment 11.  Preliminary analysis of Core Study 
efficacy data demonstrated that at 18 months, there was a dose-dependent reduction in amyloid 
level in subjects treated with BAN2401.  Compared with placebo, this reduction was statistically 
significant across all BAN2401 dose groups (P<0.0001).  Furthermore, results of PET image visual 
read showed that there was a dose-dependent conversion from amyloid positive at baseline to 
amyloid negative at 18 months in subjects treated with BAN2401, with 81% of subjects in the 
BAN2401 10 mg/kg biweekly dose group converted from amyloid positive to amyloid negative 
(P<0.0001) at 18 months.   
Reduction in amyloid levels was also accompanied by dose-dependent slowing of clinical decline 
as measured by ADCOMS and ADAS-Cog over 18 months.  The BAN2401 10 mg/kg biweekly 
dose demonstrated a statistically significant reduction on both the ADCOMS (30% reduction 
compared with placebo; P=0.034) and ADAS-Cog (47% reduction compared with placebo; 
P=0.017).  A statistically significant reduction in clinical decline on ADCOMS was observed as 
early as 6 months (P<0.05) and at 12 months (P<0.05).  Consistent with these results, a 
dose-dependent slowing in cognitive decline from baseline was also demonstrated by the CDR-SB.  
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At 18 months, subjects treated with BAN2401 10 mg/kg biweekly demonstrated 26% less 
cognitive decline compared with placebo.  (revised per Amendment 11) 
7.2.2 Biomarker Rationale 
7.2.2.1 Amyloid PET 
Amyloid positron emission tomography (PET) imaging will be performed in this study for 
2 primary reasons:  1) to confirm the presence of amyloid pathology in the brain of MCI and mild 
Alzheimer’s disease dementia subjects in the screening phase of the study; and 2) to evaluate the 
effects of BAN2401 on amyloid levels in the brain, both by whole brain analysis (the average of 
5 - 6 cortical regions) and brain region analysis. 
A large body of clinical findings and clinical pathology data have shown that amyloid imaging 
provides a sensitive in vivo approach to detect amyloid plaques across the cortex.  Studies with 
11C-Pittsburgh Compound B (11C-PiB) show that 20% to 30% of healthy controls, 60% to 70% of  
MCI subjects, and 80% to 90% of Alzheimer’s disease dementia subjects are positive for 
amyloid.14,15,16,17  Apolipoprotein ε4 variant (APOE4) carriers show significantly greater rates of 
amyloid retention when compared to noncarriers, supporting the rationale for inclusion of 
apolipoprotein E (APOE) genotype as a key covariate in the analysis of the baseline and 
longitudinal PET amyloid data.18  The rationale for performing amyloid imaging in MCI subjects 
is supported by the fact that amyloid positive MCI subjects are likely to convert to AD within 2 to 
3 years.  Further, the presence of brain amyloid shows strong correlations with smaller 
hippocampal volume and worse performance on assessments of episodic memory.19  Several 
18F amyloid tracers, including florbetapir and flutemetamol20 have been developed with 
substantially longer half-life compared to 11C (20 minutes).  Florbetapir, florbeaben, and 
flutemetamol are currently used in the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI 2) 
and have been approved by the Food and Drug Administration (FDA) and in Europe (revised per 
Amendments 02 and 07).  Florbetapir, flutemetamol, florbetaben, or any approved agent may be 
used in Canada, the EU, or any other region in which the study is conducted.  For Screening 
purposes, the imaging agent of choice will be florbetapir at study sites in the US, while in other 
regions the choice of imaging agent will depend on local availability of imaging agent, thus 
allowing for use of florbetaben or flutemetamol as well as florbetapir.  While, florbetapir is the 
preferred agent in the US, flutemetamol, florbetaben, or any approved agent may be used in the 
US if needed.  For the longitudinal amyloid PET substudy (Core Study), only florbetapir will be 
used in the US, while in other regions the choice of imaging agent will depend on local availability 
of the imaging agent, but the same tracer must be used across all PET assessments per subject.  
Florbetapir will be used in the US and flutemetamol will be used in Japan for longitudinal amyloid 
PET analysis in qualified subjects who participate in the imaging substudy in the Extension Phase 
(US and Japan only).  (revised per Amendments 02, 06, 07, 11, and 12) 
The inclusion of amyloid PET imaging to evaluate treatment effects is based on recent data 
showing that the murine homolog, monoclonal antibody 158 (mAb158), significantly reduced 
plaque load in aged Tg2576 mice (approximately 19 months old) treated for 3 months (50 mg/kg, 
weekly, IP) compared to untreated controls.  Amyloid plaque load was reduced in hippocampus 
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by 12.9% and cortex by 9.5% with a possible preferential effect on diffuse (6E10-positive) versus 
core plaque.  In a separate study conducted in 12.5 month old Tg2576 mice, 18 weeks treatment 
with 12 and 24 mg/kg mAb158 reduced 6E10-positive plaques.  
Recent longitudinal amyloid PET studies show annual increases of 1.5%, 2.1%, and 5.7% in the 
healthy control, MCI and AD groups, respectively until the late stages of AD when levels tend to 
plateau or decline.7  Such changes have shown to only weakly correlate with declines in cognitive 
functioning.  In light of the above findings, amyloid PET will be conducted at 12 and 18 months 
of treatment in a subgroup of subjects from any participating country (revised per Amendments 02 
and 07) (imaging subgroup) to demonstrate target engagement and to assess amyloid clearance as 
a potential mechanism of action for BAN2401. 
7.2.2.2 Volumetric MRI 
Volumetric magnetic resonance imaging (vMRI) will be used to evaluate the effects of BAN2401 
on rates of atrophy in the EAD study population across the different treatment arms and to provide 
evidence that effective treatment is associated with disease modification.  A large body of data has 
demonstrated that structural MRI reliably tracks the course of the disease.  Atrophy tends to occur 
preferentially in the lateral temporal and posterior parietal regions during the early stages of disease 
(early AD) and progresses towards the anterior regions of the brain (frontal cortex) in its later 
stages.  For this reason, hippocampal volume has been selected as the secondary endpoint and it is 
predicted that clinically efficacious doses will be associated with a slowing in the rate of 
hippocampal atrophy compared to rates observed in the placebo and nonefficacious treatment 
arms.  Whole brain and ventricular volumes will be considered exploratory endpoints.   
Annualized rates of change of 2% to 3% have been reported for the AD brain compared to 1% in 
MCI subjects and <1% in age-matched controls.  However, subjects with MCI due to AD – 
intermediate likelihood (CSF Aβ <192 or positive amyloid imaging) show rates of atrophy 
comparable to those observed in Alzheimer’s disease dementia subjects,21,22,23,24 supporting the 
notion that such subjects are on similar trajectories.  Lower CSF Aβ(1-42), amyloid positivity on 
PET imaging, and higher CSF tau in addition to the presence of the APOE4 allele have been 
associated with greater rates of brain atrophy and will be entered as covariates in various proposed 
analyses.25,26  Hippocampal atrophy has been shown to be a significant predictor of clinical 
progression, independent of amyloid levels in the brain.27  Brain volume (total ventricular volume, 
whole brain, temporal lobe) generally shows a modest correlation with performance on a number 
of cognitive scales.21,22,23,28  These relationships and the effects of treatment will be further 
explored.  Although it is hypothesized that treatment will be associated with declines in rates of 
atrophy, worsening atrophy has been described following immunotherapy treatment.  Reasons for 
this paradoxical effect remain unclear but may be possibly related to osmotic shifts or the effects 
of inflammatory factors produced by activated microglia in response to treatment.  To address this 
issue, baseline brain volumes will be entered in the analysis of volumetric change and 
consideration will be given to undertaking comprehensive regional analysis, including cortical 
thickness maps, which may be less susceptible to such effects.   
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volumetric magnetic resonance imaging (vMRI) sequences will be collected at all study visits at 
which safety MRIs are conducted except for the Visit 6 abbreviated MRI assessment (safety MRI 
to detect ARIA lasting 8 to 10 minutes, with no vMRI sequences) conducted only at European 
sites (revised per Amendment 07).  vMRI analysis will be conducted at the Screening Visit and 
Visits 16, 29, and 42 (6, 12, and 18 months of treatment).  Recent advances in analysis software 
have made structural imaging more sensitive to detect small changes and able to reliably measure 
rates of atrophy at 6-month intervals, particularly in the posterior parietal and the lateral temporal 
regions during the early stages of disease.22  Given these observations, a demonstration of 
significant slowing or stabilization in the rate of atrophy in response to treatment compared to 
placebo will offer further support for disease modification and will therefore represent a key 
element in the drug development strategy for BAN2401. 
7.2.2.3 Soluble Biomarkers in Cerebrospinal Fluid (CSF) 
BAN2401 is a low-affinity Aβ(1-42) monomer antibody that targets soluble Aβ aggregates and 
has been shown to clear Aβ plaques in preclinical studies.  Since BAN2401 targets soluble 
aggregate Aβ species, it is possible that BAN2401 may alter the dynamics of Aβ aggregation and 
result in changes in total Aβ(1-42) monomer levels.  Moreover, it is postulated that clearance of 
Aβ plaque (and possibly aggregates) may lead to changes in total Aβ monomer levels as a 
byproduct of the fibril degradation process.  For these reasons, changes in Aβ(1-42) levels will be 
explored in CSF and may provide a central pharmacological readout for target engagement of 
BAN2401. 
Total tau and p-tau are sensitive biomarkers of neurodegeneration.  It has been demonstrated that 
they increase in parallel to progression of Alzheimer’s disease.  Cerebrospinal fluid (CSF) tau 
measurements have been correlated with cerebral atrophy.  The ratios of p-tau and t-tau to 
A(1-42) levels have provided useful predictors of cognitive decline and conversion to AD.28  
Recent work from a Phase 2 mild-to-moderate AD study using bapineuzumab suggests that 
decreases in p-tau may be a downstream effect of altering amyloid load using A-targeted 
immunotherapeutics.29  Therefore, monitoring CSF levels of p-tau and t-tau may provide 
supportive evidence of disease modification by BAN2401. 
Baseline levels of Aβ(1-42), t-tau, and p-tau will also help elucidate the extent of amyloid and tau 
pathology at entry.  Considered together with baseline levels of Aβ and baseline imaging variables, 
these soluble biomarkers may correlate with differences in treatment response. 
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8 
STUDY OBJECTIVES 
CORE STUDY 
Primary Objectives: 
1. To evaluate the efficacy of BAN2401 compared to placebo by establishing the ED90 (as 
defined in the protocol) for BAN2401 on the ADCOMS at 12 months of treatment in 
subjects with EAD, defined as mild cognitive impairment (MCI) due to Alzheimer’s 
disease (AD) – intermediate likelihood or mild Alzheimer’s disease dementia 
2. To assess the safety and tolerability of 3 doses and 2 dose regimens of BAN2401 in subjects 
with EAD 
Key Secondary Objectives:  (revised per Amendments 09 and 10) 
1. To evaluate the effects of BAN2401 compared to placebo on brain amyloid 
pathophysiology at 18 months of treatment in subjects with EAD as measured by amyloid 
PET  (revised per Amendments 09 and 10) 
2. To evaluate the efficacy of BAN2401 compared to placebo on the ADCOMS at 18 months 
of treatment in subjects with EAD (revised per Amendments 09 and 10) 
3. To evaluate the efficacy of BAN2401 compared to placebo on the Clinical Dementia 
Rating – Sum of Boxes (CDR-SB) at 18 months of treatment in subjects with EAD (revised 
per Amendment 10) 
4. To evaluate the efficacy of BAN2401 compared to placebo on ADAS-Cog in subjects with 
EAD at 18 months (revised per Amendment 10) 
5. To evaluate the efficacy of BAN2401 compared to placebo at 18 months on clinical status 
separately within subjects with MCI and mAD dementia for the following assessments: 
ADCOMS, CDR-SB, and ADAS-Cog (revised per Amendment 10) 
6. To evaluate the effects of BAN2401 compared to placebo on CSF biomarkers (Aβ[1-42], 
t-tau, and p-tau) at 18 months of treatment in subjects with EAD  (revised per Amendment 
10) 
7. To evaluate the effects of BAN2401 compared to placebo on total hippocampal volume 
using vMRI at 18 months of treatment in subjects with EAD  (revised per Amendments 09 
and 10) 
Secondary Objectives: 
1. To evaluate the effects of BAN2401 compared to placebo on brain amyloid 
pathophysiology at 12 months of treatment in subjects with EAD as measured by amyloid 
PET (revised per Amendments 09 and 10) 
2. To evaluate the effects of BAN2401 compared to placebo at 12 months on clinical status 
in subjects with EAD for the following assessments:  ADCOMS, CDR-SB, and 
ADAS-Cog (revised per Amendments 09 and 10) 
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3. To evaluate the effects of BAN2401 compared to placebo at 12 months on clinical status 
separately within subjects with MCI and mild AD dementia for the following assessments: 
ADCOMS, CDR-SB, and ADAS-Cog  (revised per Amendment 10) 
4. To evaluate the efficacy of BAN2401 compared to placebo on CSF biomarkers (Aβ[1-42], 
t-tau, and p-tau) at 12 months of treatment in subjects with EAD  (revised per 
Amendment 10) 
To evaluate the effects of BAN2401 compared to placebo on total hippocampal atrophy as 
measured by vMRI at 6 and 12 months, and left and right hippocampus, whole brain and 
total ventricular volume as measured by vMRI at 6, 12, and 18 months of treatment in 
subjects with EAD  (revised per Amendment 10) 
Exploratory Objectives: 
1. To evaluate the effects of BAN2401 compared to placebo on clinical status in subjects 
with EAD by assessment ADCOMS, ADAS-Cog, CDR-SB, MMSE and FAQ at time 
points not listed in Key Secondary and Secondary objectives  (revised per 
Amendment 10) 
2. To explore the relationship between change from baseline in clinical status at 12 and 
18 months of treatment and baseline brain amyloid pathophysiology in subjects with 
EAD as measured by amyloid PET  (revised per Amendment 10) 
3. To explore the relationship between change from baseline in clinical status and change 
from baseline in brain amyloid pathophysiology at 12 and 18 months of treatment in 
subjects with EAD as measured by amyloid PET  (revised per Amendment 10) 
4. To explore efficacy of BAN2401 compared to placebo and the overall study population on 
the ADCOMS across all clinical assessment time points in Japanese subjects with EAD 
(revised per Amendments 07 and 10) 
5. To characterize the population pharmacokinetics (PK) of BAN2401 in EAD subjects, and 
to examine the effect of intrinsic and extrinsic factors on the PK (revised per 
Amendment 08) 
EXTENSION PHASE PART A  (REVISED PER AMENDMENTS 08, 11, 16, AND 19) 
Primary Objective 
To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD 
Secondary Objective 
To assess if the treatment benefit in brain amyloid levels (as measured by amyloid PET) at the end 
of the Core Study will be maintained over time in the Extension Phase Part A in subjects with 
EAD 
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Exploratory Objectives 
1. To evaluate the clinical effects of BAN2401 in subjects with EAD on the ADCOMS, 
CDR-SB, ADAS-Cog, and MMSE over time during the Extension Phase Part A 
2. To assess time to disease progression as evaluated by Clinical Dementia Rating (CDR) 
global score during the Extension Phase Part A 
3. To explore the long-term effects of BAN2401 in subjects with EAD on total hippocampal 
volume and other biomarkers (eg, plasma biomarkers) annually in the Extension Phase 
Part A  (revised per Amendment 15) 
4. To characterize population PK of BAN2401 in subjects enrolled in the Extension Phase 
Part A of the study 
5. To evaluate patterns of resource utilization and associated costs of care for subjects with 
EAD and their study partners, using medical claims data  (revised per Amendment 16) 
EXTENSION PHASE PART B  (REVISED PER AMENDMENT 19) 
Primary Objective 
To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD 
 
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9 
INVESTIGATIONAL PLAN 
9.1 
OVERALL STUDY DESIGN AND PLAN 
This double-blind, parallel-group, placebo-controlled, multicenter and multinational study will 
utilize a dose-finding response adaptive randomization (RAR) design to evaluate the safety, 
tolerability, and efficacy of BAN2401 in subjects who have MCI due to Alzheimer’s disease – 
intermediate likelihood, or who have mild Alzheimer’s disease dementia.  The study will take 
place over approximately 130 months at approximately 125 sites including North America, 
Europe, and Asia-Pacific countries.  (revised per Amendment 08)  Approximately 3200 subjects 
will be screened to provide approximately 800 subjects to receive BAN2401 or matching placebo.  
Sites in Japan will screen approximately 160 subjects in order to randomize at least 40 Japanese 
subjects, even if early success is declared or the study achieves 800 subjects randomized.  (revised 
per Amendment 07)  An Extension Phase (Part A and Part B) will be implemented to allow for up 
to 60 months (5 years) of additional treatment.  (revised per Amendments 08, 09, 11, 15, and 19)   
The present study incorporates a Bayesian RAR design with frequent IA during the Core Study to 
continually update randomization allocation on the basis of the primary clinical endpoint.  (revised 
per Amendment 01)  This approach allows for ongoing assessment of drug futility or evidence for 
early success and for continued changes in randomization that favor efficacious treatment arms.  
Thus, the Bayesian approach not only limits exposure of subjects to nonefficacious treatment arms 
but can also mitigate the risks associated with larger and longer trials required to demonstrate 
clinical efficacy by leading to more efficient project termination or early advancement to a 
successful Phase 3 program.  In the Core Study, after the 12-month assessments have been 
completed, treatment will continue to 18 months to follow the time course of any treatment effects 
observed at 12 months, and to evaluate biomarker and neuroimaging effects that may be consistent 
with potential disease modification (revised per Amendment 08).   
Subjects will be from 2 clinical subgroups, collectively designated as EAD for the purposes of this 
protocol:  (a) MCI due to AD – intermediate likelihood and (b) mild Alzheimer’s disease dementia.  
At study entry, subjects will be stratified according to clinical subgroup, APOE status (APOE4 
positive and negative), and the presence or absence of ongoing AD treatment with AChEIs or 
memantine or both.  (revised per Amendment 01) Randomization into the 2 clinical subgroups (see 
Inclusion Criteria, Section 9.3.1) is to remain reasonably balanced whereby at least 60% of the 
total number of subjects will have MCI due to AD – intermediate likelihood clinical subgroup and 
at least 30% will have mild Alzheimer’s disease dementia.  APOE4 status (positive or negative) 
must be confirmed for all subjects prior to randomization.  (revised per Amendment 05)  Subjects 
who are confirmed APOE4 positive (APOE4 hetero-or homozygous) will not be randomized to the 
10 mg/kg, biweekly dose.  APOE4 negative subjects will be randomized into 1 of 6 treatment 
groups (Table 4), while APOE4 positive subjects will be randomized into 1 of 5 treatment groups 
as explained in Sections 9.4.3 (revised per Amendments 04 and 05).  Randomization in the Core 
Study will initially be fixed to each of these dose groups (4:2:2:2:2:2 ratio, placebo to each of the 
5 active treatment arms) (revised per Amendment 08).  All study personnel and subjects will be 
blinded with respect to the dose regimens.  After 196 subjects have been randomized into the study, 
an IA will be conducted and RAR will guide subsequent randomization into dose groups.  Interim 
analyses and RAR will be repeated after 250 subjects have been randomized and again after each 
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additional 50 subjects until all 800 subjects are randomized, and will then be conducted at 3-month 
intervals until all subjects complete 12 months of treatment.  (revised per Amendment 07)  
A Bayesian analysis will be conducted at 12 months of treatment to assess for early success, and 
at 18 months of treatment, regardless of whether early success is achieved at 12 months.  (revised 
per Amendment 09) 
Table 4 
BAN2401 Dose Regimens – Core Study 
 Study Arm 
BAN2401 Dose (mg/kg) 
Infusion frequency 
1 
Placebo 
Biweeklya 
2 
2.5 
Biweeklya 
3 
5.0 
Biweeklya 
4 
10.0b 
Biweeklya 
5 
5.0 
4-week intervalsc 
6 
10.0 
4-week intervalsc 
a: 
Biweekly = 2-week intervals 
b: 
Subjects who are confirmed APOE4 positive (APOE4 hetero-or homozygous) will not be randomized to the 
10 mg/kg, biweekly dose. (revised per Amendments 04 and 05) 
c: 
Subjects receiving study drug at 4-week intervals will receive placebo at intervening 2-week time points. (revised 
per Amendment 04) 
Oversight of the IA and RAR will be conducted by an independent Interim Monitoring Committee 
(IMC).  The IMC will consist of 3 members who are external to the company with expertise in 
Bayesian adaptive design in clinical trials. 
The IA and RAR will be conducted by an unblinded external independent data analysis group in 
accordance with the protocol.  This independent group will provide the IA outcomes to the IMC 
at each interim look.  The IMC will ensure the integrity of the IA and response adaptive 
randomization process through review of primary efficacy data.  In addition, the IMC will act in 
an independent advisory capacity to monitor the Bayesian IA outcomes according to the early 
success and futility boundaries pre-specified in the protocol.  The IMC will inform the sponsor if 
the boundaries for early success or futility have been crossed.  If the study continues to randomize 
subjects after statistical futility boundary confirmed by the IMC is crossed, it will be considered a 
failed study.  The IMC will not be charged with any subject safety issues, as this will be the 
responsibility of an independent DSMB.  (revised per Amendment 01) 
A separate unblinded DSMB will be employed at regular intervals to monitor the overall safety of 
the Core Study and will make recommendations to the Sponsor as appropriate (revised per 
Amendments 08 and 11).  In addition, the DSMB will meet when a predetermined number of 
subjects are randomized to assess whether the option for home infusions is feasible during the Core 
Study (per DSMB charter, if allowed and conducted according to country and local guidelines; 
home infusions will not be allowed in Germany.  (revised per Amendment 14)  
Upon implementation of Amendment 07, newly enrolled subjects will not be offered the option 
for home infusions during the Core Study.  (revised per Amendment 14) Subjects opting for home 
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infusions before implementation of Amendment 07 will be allowed to continue with home 
infusions for the duration of their participation in the Core Study (revised per Amendments 01, 03, 
07, and 14).  Details regarding DSMB membership and operational characteristics will be provided 
in the DSMB Charter.  The DSMB will be responsible for monitoring the safety of the study only 
in the Core Study.  (revised per Amendment 11) 
If the statistical futility boundary as confirmed by the IMC is crossed, the IMC will inform the 
DSMB.  The DSMB will make risk-benefit assessments after reviewing emerging safety and 
efficacy signals and will provide its recommendations to the sponsor.  The sponsor will make the 
final decision pertaining to study futility after reviewing recommendations by the DSMB.  (revised 
per Amendment 01) 
The following estimates are provided: 
 The study will end when the last visit for the last subject is concluded. 
 The study is planned to begin no later than December 2012 and to end in approximately 
2025 or until the drug is commercially available in the country where the subject resides, 
whichever comes first.  (revised per Amendments 07, 08, and 15) 
 The maximum estimated period for each subject on study is approximately 86 months.  
(revised per Amendments 08, 11, and 15) 
Administration of BAN2401 to an individual subject may be stopped on the basis of safety-related 
findings as outlined in Section 9.3.3. 
An overview of the study design is presented in Figure 1.  
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Figure 1 
Design of Study BAN2401-G000-201 
(revised per Amendments 08, 11, 15, and 19) 
Subjects not continuing into the Extension Phase Part A will have a follow-up visit 3 months after the last dose of 
study drug.  However, subjects who previously completed the Core Study (through the Follow-Up Visit, Visit 43) at 
any time before implementation of the Extension Phase Part A, and/or fulfill the Extension Phase Part A inclusion 
and exclusion criteria, will also be eligible to participate.  Subjects in Extension Phase Part A will transition to 
commercial supplies upon availability for individual subjects at each study site.  All subjects ongoing in Extension 
Part A upon implementation of Protocol Amendment 19 will transition to Extension Part B.  Extension Phase Part A 
and Part B combined will continue for up to 60 months (5 years), or until BAN2401 is commercially available for 
individual subjects at each study site, at which time the subjects will switch to commercial BAN2401, or in the cases 
where drug is not yet commercially available, treatment will continue until the benefit to risk ratio from treatment 
with BAN2401 is no longer considered favorable, whichever comes first.  BW = biweekly; M = monthly; IV = 
intravenous; Q3W = every 3 weeks; Q4W = every 4 weeks; R = randomization. 
9.1.1
Prerandomization Phase 
The Prerandomization Phase in the Core Study will last for up to 60 days and will include a 
Screening Period and a Baseline Period.  (revised per Amendment 08)  The assessments conducted 
during this phase will include a series of assessments specifically to determine eligibility for 
randomization into the study.  Subjects will be diagnosed according to NIA-AA criteria as either 
MCI due to AD or mild Alzheimer’s disease dementia as defined by the protocol after completion 
of MMSE, Wechsler Memory Scale IV-Logical Memory (subscale) I (WMS-IV LMI), Wechsler 
Memory Scale IV-Logical Memory (subscale) II (WMS-IV LMII), and CDR.  Once the diagnosis 
is made, the WMS-IV LMII inclusion criterion can be applied to all subjects (revised per 
Amendments 01 and 06).  A schematic overview of the process for determining eligibility is shown 
in Figure 2.
Phase:
Period:
Day/Month:
Prerandomization
Randomization
Screening
Baseline
Extension A
Day 1
R
6 Months
12 Months
18 Months
BAN2401 2.5 mg/kg BW
3-
Month
Follow-
up
18 months
10 mg/kg
BW
BAN2401 –  10 mg/kg BW
BAN2401  – 
10 mg/kg Q3W
BAN2401  – 
10 mg/kg Q4W
Implemented 
Amendment 19
Day -60
to -31
Day -30
to -1
BAN2401 5 mg/kg BW
BAN2401 10 mg/kg BW
BAN2401 5 mg/kg M
BAN2401 10 mg/kg M
Placebo –  IV BW
Extension B
BAN2401 –  10 mg/kg BW
BAN2401  –  10 mg/kg Q3W
BAN2401  –  10 mg/kg Q4W
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Figure 2 
Schematic Overview of Eligibility Assessments 
CSF = cerebrospinal fluid, MRI = magnetic resonance imaging, PET = positron emission tomography. 
(revised per Amendment 06) 
9.1.1.1 Screening Period 
The Screening Visit will occur during the Screening Period, between Day -60 and Day -31.  
Screening assessments and timing thereof are shown in the Schedule of Screening and Baseline 
Assessments/Procedures (Table 7). 
The purpose of the Screening Period is to obtain informed consent to participate in the study and 
to establish protocol eligibility.  Informed consent will be obtained after the study has been fully 
explained to each subject and caregiver/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.  All subjects must consent to either a baseline PET scan or a baseline 
CSF sample to be used to determine study eligibility.  Subjects will also be asked to sign separate 
optional ICFs to enter the CSF and imaging substudies, respectively.  For those who consent to 
both CSF and PET collection for eligibility, samples will be collected as follows: 
Subjects in the Core Study whose study eligibility is determined by amyloid PET and who have 
consented to both substudies will have:  (revised per Amendment 08) 
 Additional PET scans performed at 12 and 18 months 
 CSF samples collected at Baseline, 12, and 18 months. 
 
MRI 
Amyloid PET 
or  
CSF Aβ(1-42) 
Not eligible 
Not eligible 
Randomize into 
study 
Inclusion/exclusion 
criteria, 
lab tests 
clinical assessments 
d t
t
Not eligible 
Exclude 
from study 
Baseline 
Day -30 to Day -1 
Screen 
Day -60 to Day -31 
Inclusion/exclusion 
criteria, 
lab tests, 
clinical assessments 
Not eligible 
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Subjects whose study eligibility is determined on CSF and who have consented to both substudies 
will have:  (revised per Amendment 08) 
 PET scans performed at Baseline, 12, and 18 months 
 Additional CSF samples collected at 12 and 18 months 
None of the optional consents are required for study eligibility.  (revised per Amendment 06) 
For the Extension Phase Part A, subjects will need to reconsent for the longitudinal amyloid PET 
substudy before the Extension Screening visit in order to participate.  (revised per Amendments 08, 
09, 11, and 19) 
Consent to blood collection for pharmacogenomic (PG) testing is mandatory for eligibility to enter 
the study.  (revised per Amendment 06) 
Study site personnel will interview the subject and caregiver/informant to obtain demographic and 
clinical information as described in Section 9.5.1.1, and will review inclusion and exclusion 
criteria as described in Sections 9.3.1 and 9.3.2.  Prior medications and medications currently being 
taken by the subject will be reviewed.  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. 
Subjects who remain eligible for study entry after review of inclusion and exclusion criteria and 
prior and concomitant medications will then undergo safety assessments.  Vital signs will be 
assessed, height and weight measurements will be taken, and a complete physical examination will 
be conducted as described in Section 9.5.1.2.  Blood will be drawn for a serum pregnancy test in 
females of childbearing potential only (Section 9.5.1.2), and for clinical laboratory tests in all 
subjects (Section 9.5.1.2).  A urine sample will be collected for drug screening (Section 9.5.1.2).  
Clinical assessments for eligibility will be conducted during the Screening Visit as described in 
Section 9.5.1.2.  Every effort should be made to conduct these assessments in the morning, but if 
this is not possible due to the timing of the visit, they should be conducted at the same time of day 
at all subsequent visits.  Testing during the Screening Visit should begin with the clinical 
assessments in the following order:  Mini-mental State Examination (MMSE), Wechsler Memory 
Scale-IV Logical Memory (subscale) I and II (WMS-IV LMI and LMII), and CDR.  The WMS-IV 
LMII is to be administered 20 to 30 minutes after the completion of LMI.  Subject information 
should be collected in the 20 to 30 minutes between the WMS-IV LM1 and LMII.  Subjects who 
meet criteria for objective memory impairment as determined by the WMS LMII score (See 
Inclusion Criteria) will also be evaluated on the Geriatric Depression Scale (GDS) for eligibility.  
Subjects who meet criteria for the GDS will be administered the Columbia-Suicide Severity Rating 
Scale (C-SSRS) as a safety assessment (Section 9.5.1.5), and all remaining Screening Visit 
assessments will be conducted.  The caregiver/informant needs to be present at this visit.  (revised 
per Amendment 01) 
Subjects who are eligible following the Screening Visit for eligibility will then undergo 
noncontrast brain MRI for brain abnormalities that may exclude study participation 
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(Section 9.5.1.5).  The MRI imaging will include fluid attenuating inversion recovery (FLAIR), 
Gradient Recalled Echo (GRE), T1 and diffusion-weighted sequences to determine the presence 
of focal lesions that may exclude study participation.  An additional scanning sequence will be 
conducted in all subjects immediately following the safety MRI to obtain vMRI data, as described 
in Section 9.5.1.3.  Results of these MRI assessments will be used as the Baseline Period MRI, 
against which changes after drug administration will be compared.   
9.1.1.2 Baseline Period 
Baseline assessments and timing thereof are listed in Table 7 and described in Section 9.5.1.2. 
During the Baseline Period, which will extend from Day -30 to Day -1, the subject will return to 
the study site for additional assessments.   
Inclusion/exclusion criteria will again be reviewed, vital signs and weight will be recorded, and a 
single 12-lead electrocardiogram (ECG) will be conducted.  (revised per Amendment 01)  A 
routine physical examination will be conducted and a urine pregnancy test will be conducted for 
females of childbearing potential.  Blood will be collected from all subjects for clinical laboratory 
tests.  The MMSE, the CDR, the ADAS-Cog, and the Functional Assessment Questionnaire (FAQ) 
will be administered to the subject in the stated order.  The caregiver/informant needs to be present 
at this visit.  The C-SRSS will also be administered. 
Blood will be collected from all subjects for PG analyses of APOE4 and blood may be collected 
for exploratory biomarker analyses as outlined in Appendix 3.  (Section 9.5.1.4).  (revised per 
Amendment 01) 
Cerebrospinal fluid may be obtained at this visit from subjects who have consented to this 
procedure, for PK and PD assessments (Section 9.5.1.4, Appendix 3).  (revised per 
Amendment 07) 
For further assessment of eligibility, all subjects who pass the preceding screens will then undergo 
amyloid PET or CSF Aβ(1-42) assessment (revised per Amendment 06) within 20 days after the 
Baseline Visit, as an eligibility criterion (Section 9.5.1.2, Section 9.5.1.6).  Baseline amyloid PET 
data will serve as the baseline data for amyloid PET results at 12 and 18 months of treatment for 
those subjects who consent to be included in the imaging subgroup (total target n=306).  The 
Baseline Visit CSF sample will be used to confirm eligibility and for use as the baseline CSF 
assessment for those subjects who consent to be included in the CSF substudy.  For subjects who 
screen fail at the Baseline assessment, the Screening Disposition 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.  (revised per Amendments 06 and 07) 
Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Section 9.3.1 and Section 9.3.2) will begin the Randomization Phase. 
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APOE4 status (positive or negative) must be confirmed for all subjects prior to randomization.  
Subjects who are confirmed APOE4 positive (APOE4 hetero- or homozygous) will not be 
randomized to the 10 mg/kg, biweekly dose.  (revised per Amendment 05) 
Some subjects who screen fail during the Prerandomization Phase may be eligible for rescreening 
following sponsor approval.  Note that when a subject is rescreened, a new subject number will be 
issued.  All screening and baseline assessments should be repeated with the following exceptions: 
 MRI – No repeat needed if the date of the rescreen is <90 days from the date of the original 
screening MRI. 
 Pharmacogenetics – If a sample was collected, processed, and APOE4 results issued 
during the previous screening procedure, another sample is not required to be collected 
when a subject is rescreened.  Great care must be taken to link the APOE status information 
with the new subject number.  
 PET/CSF – No repeat needed for eligibility if confirmed amyloid positive (via CSF or 
PET) during the original screening procedure.  If a subject will participate in the 
longitudinal PET or CSF substudies, quantitative PET or CSF collection should be repeated 
if the original PET/CSF collection was done >6 months from the date of the original 
screening procedure.  (revised per Amendment 07) 
The new subject number will be linked to the initial subject number and the outcomes for 
procedures that need not be repeated as outlined above.  (revised per Amendment 06) 
9.1.2 Randomization Phase 
The Randomization Phase of the Core Study will consist of a Treatment Period of 18 months 
(78 weeks) duration and a Follow-Up Period 3 months after the last dose of study drug.  Subjects 
whose screening assessments and evaluations are completed and reviewed by the PI, or designee 
(including confirmation of categorization by the 2 clinical subgroups (MCI due to AD – 
intermediate likelihood or mild Alzheimer’s disease dementia), by APOE status (APOE4 positive 
and negative), and by ongoing treatment with AChEIs or memantine or both) and who continue to 
meet all of the inclusion/exclusion criteria will enter the Randomization Phase.  (revised per 
Amendment 07)  As described in Section 9.4.3, the first 196 subjects will be randomized in a 
4:2:2:2:2:2 ratio; Placebo (4) to each of the active treatment arms (2 each).  Randomization 
probabilities to each arm will be updated at each IA such that the randomization probability will 
be increased for the placebo arm and arms that represent the potential target dose (ED90; the dose 
that achieves 90% maximum efficacy) and simultaneously decreased for other active arms.  
Subjects who complete the scheduled visits including the Follow-Up Visit will be considered to 
have completed the study. 
9.1.2.1 Treatment Period  
Subjects will be randomized at the beginning of the Treatment Period, and will receive study drug 
by infusion at every visit except the last visit, except for those subjects participating in the 
Extension Phase, as indicated in the Schedule of Assessments/Procedures (Table 8, and Table 13 
for the Extension Phase Part A).  (revised per Amendment 08 and 19)  Double-blinding to study 
treatments will be in effect throughout the Core Study.  Doses will not be changed.  (revised per 
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Amendment 08)  If a given subject cannot tolerate a give dose regimen, the subject will be 
discontinued from the study and will undergo an Early Termination Visit.  During the Treatment 
Period, a subject may develop acute medical conditions unrelated to the study drug which in the 
opinion of the PI, may make them unsuitable to receive the study drug for 1 or more dose 
administrations.  In this situation, the investigator should exercise clinical judgment as to whether 
or not to withhold a dose.  As a general principle, temporary suspension of dosing may be 
considered and resumed after the acute medical condition has improved.   
The DSMB will review the safety of the study drug after a predetermined number of subjects have 
been randomized to assess whether the option for home infusions is feasible during the Core Study 
(per DSMB charter, if allowed and conducted according to country and local guidelines; home 
infusions will not be allowed in Germany.  (revised per Amendment 14)  Upon implementation of 
Amendment 07, newly enrolled subjects will not be offered the option for home infusions during 
the Core Study.  (revised per Amendment 14)  Subjects opting for home infusions before 
implementation of Amendment 07 will be allowed to continue with home infusions for the duration 
of their participation in the Core Study (revised per Amendments 01, 03, 07, and 14).  If the DSMB 
allows this option of home administrations, site permitting, the investigator has to assess if a 
subject is suitable for home infusions after the first 4 months of treatment have taken place in the 
clinic.  If a subject has shown acceptable tolerability for the infusions and is considered by the 
investigator to be at low risk of developing AEs related to study drug infusion which may require 
acute medical treatment, and has shown no clinically significant  findings on other safety measures 
related to study drug infusion during the first 4 months of their treatment, they may be allowed to 
receive infusions at home during subsequent study visits that do not otherwise require the subject 
to be in the clinic.   
At all study visits, safety assessments will consist of vital signs (both predose and after study drug 
infusion) and querying for AEs.  Queries for concomitant medications will also take place at study 
visits, at approximately 6-week intervals.  During the first 3 months, study procedures including 
clinical laboratory tests, routine physical examinations, 12-lead ECG recordings, blood collection 
for serum anti-BAN2401 assays, concomitant medication information, clinical assessments 
(MMSE, CDR, ADAS-Cog, and FAQ), and AE queries will be conducted as shown in Table 8.  
(revised per Amendment 08) 
Beginning with Week 13, the following safety assessments will take place at approximately 
3-month intervals:  weight measurements, routine physical examinations, 12-lead ECG recordings, 
a urine pregnancy test (females of childbearing potential only), clinical laboratory tests (and an 
additional time point at 19 weeks), blood samples for anti-BAN2401 assays, and the C-SSRS.  
Psychometric tests will be administered at these intervals.  Blood samples will also be taken for 
PK assessments at time points specified in Table 8.  (revised per Amendment 08)  A safety MRI 
will be conducted at any time following the preceding visit and prior to each of the following visits 
according to the Schedule of Procedures/Assessments:  Visit 6 at European sites only (revised per 
Amendment 07), Visits 7, 9, 16, 22, 29, 35, and 42 of the Core Study, Early Termination, and at 
the Follow-Up Visit (Visit 43).  In all cases, the safety MRI must be reviewed by the imaging 
vendor and a local reader prior to receiving the next dose of study drug.  (revised per Amendment 
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06)  Details are given in Table 8 for the Core Study, Table 13 for Extension Phase Part A, and 
Table 16 for Extension Phase Part B.  (revised per Amendment 08 and 19) 
As shown in Table 8 (revised per Amendment 08), vMRI sequences will be collected at all visits 
where safety MRI is conducted except for the Visit 6 abbreviated MRI assessment (safety MRI to 
detect ARIA lasting 8 to 10 minutes, with no vMRI sequences) conducted at European sites only 
(revised per Amendment 07).  vMRI data will be analyzed at Screening and at Visits 16, 29, and 
42 (6, 12, and 18 months of treatment).  In consenting subjects, an amyloid PET scan will be 
conducted and CSF will be collected at 12 and 18 months in the Core Study.  (revised per 
Amendments 08 and 11)     
9.1.2.2 Follow-Up Period 
Subjects who are not eligible or who do not elect to participate in the Extension Phase Part A will 
be required to continue into the Follow-Up Period in the Core Study.  (revised per Amendment 08)  
During the Follow-Up Period, a single visit will take place approximately 3 months after the last 
dose of study drug.  At this visit, safety assessments will be conducted including vital signs, a 
routine physical examination, weight measurements, a single 12-lead ECG, clinical laboratory 
tests, blood for serum anti-BAN2401, a safety MRI, the C-SSRS, and review of concomitant 
medications and AEs.  (revised per Amendment 01)  Clinical tests will be administered consisting 
of the MMSE, the CDR, the ADAS-Cog, and the FAQ.   
Subjects who discontinue the study or study drug early must comply with the Early Termination 
Visit (within 7 days after the last dose of study drug) and the Follow-Up Visit (3 months after the 
last dose of study drug).  The 3-month Follow-Up Visit is not required for any subject who 
transitions directly from the Extension Phase Part A or Part B (including the postmarketing section 
in Japan) of the study to commercial BAN2401 (revised per Amendments 18 and 19).  
Unscheduled visits for safety assessments may also be conducted.  Subjects who discontinue due 
to APOE status are expected to return for an Early Termination Visit and 3-month Follow-Up Visit 
(ie, 3 months after the last dose of study drug).  (revised per Amendment 06).  In addition, all 
subjects who discontinue from study drug are expected to return after the Early Termination Visit 
for each scheduled visit when clinical assessments of efficacy are to be conducted per the Schedule 
of Procedures/Assessments (Table 8).  (revised per Amendment 08)  At these visits, clinical 
efficacy assessments (MMSE, CDR, ADAS-Cog, and FAQ) will be conducted and information on 
concomitant medications, AEs, and SAEs will be collected.  Regularly scheduled clinical efficacy 
visits do not need to be attended if they fall within 8 days (visit window) after the Early 
Termination Visit or within ±8 days of the 3-month Follow-Up Visit.  Subjects who discontinue 
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 01) 
9.1.2.3 Unscheduled Visits  
Study assessments that are expected to be performed at unscheduled visits are shown in Table 8.  
(revised per Amendment 08)  The investigator will, however, have the discretion to deviate from 
this list at these visits and to perform other assessments according to specific visit needs. 
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9.1.3 
Extension Phase 
Extension Phase Part A 
The Extension Phase Part A will be initiated following the Core Study to allow subjects to receive 
open-label BAN2401 10 mg/kg biweekly (or if the subject chooses to enter the Dosing Regimen 
substudy, 1 of the 2 alternative dosing regimens (either BAN2401 10 mg/kg once every 4 weeks 
[Q4W] or BAN2401 10 mg/kg once every 3 months [Q3M]) for up to 60 months (5 years), until 
the drug is commercially available in the country where the subject resides, or in the cases where 
drug is not yet commercially available, treatment will continue until the benefit-to-risk ratio from 
treatment with BAN2401 is no longer considered favorable, whichever comes first.  Any subject 
who completed study treatment (Visit 42 [Week 79] of the Core Study) and fulfills the Extension 
Phase Part A inclusion and exclusion criteria (Appendix 4) will have the option to participate.  
Subjects who previously completed the Core Study (through the Follow-Up Visit, Visit 43) at any 
time before implementation of the Extension Phase Part A and/or fulfill the Extension Phase Part A 
inclusion and exclusion criteria (Appendix 4) will also be eligible to participate.  Subjects who 
discontinued the Core Study will be eligible to participate in the Extension Phase Part A, provided 
they meet the inclusion and exclusion criteria for the Extension Phase Part A.  (revised per 
Amendments 11, 15, 17, and 19) 
All subjects will receive the BAN2401 10 mg/kg biweekly dose (or Q4W or Q3M if enrolled in 
the Dosing Regimen substudy) during Part A of the Extension Phase, including subjects who are 
confirmed APOE4 positive (hetero- or homozygous).  (revised per Amendment 19).  All infusions 
will take place in the clinic; however, if approved by the Sponsor and allowable and conducted 
according to country and local guidelines, subjects will be offered the option of home infusions 
for approved visits.  Home infusions are being implemented as a result of the Coronavirus Disease 
2019 (COVID-19) pandemic to allow subjects who cannot visit clinical sites for various reasons 
to continue receiving treatment.  Home infusions will be allowed per Sponsor approval according 
to country and local guidelines during the COVID-19 pandemic and following its resolution, where 
permitted.  (revised per Amendment 14)  
The Follow-Up Visit will take place 3 months after the last dose of study drug.  Subjects may 
discontinue from study drug for any reason.  Subjects who discontinue the study drug are requested 
to undertake the Early Termination Visit (within 7 days after the last dose of study drug) and the 
Follow-Up Visit (3 months after the last dose of study drug).  The 3-month Follow-Up Visit is not 
required for any subject who transitions directly (including the postmarketing section in Japan) to 
commercial BAN2401.  (revised per Amendments 17, 18, and 19) 
Extension Phase Part A will continue for up to 60 months (5 years), or until BAN2401 is 
commercially available for individual subjects at each study site, at or until BAN2401 is 
commercially available for individual subjects at each study site, at which time the subjects will 
switch to commercial BAN2401, or until implementation of Protocol Amendment 19, or in the 
cases where drug is not yet commercially available, treatment will continue until the benefit to risk 
ratio from treatment with BAN2401 is no longer considered favorable, whichever comes first.  
Subjects in Extension Phase Part A will transition to commercial supplies upon availability for 
individual subjects at each study site.  All subjects ongoing in Extension Part A upon 
implementation of Protocol Amendment 19 will transition to Extension Part B.  Extension Phase 
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Part A and Part B combined will continue for up to 60 months (5 years), or until BAN2401 is 
commercially available for individual subjects at each study site, at which time the subjects will 
switch to commercial BAN2401, or in the cases where drug is not yet commercially available, 
treatment will continue until the benefit to risk ratio from treatment with BAN2401 is no longer 
considered favorable, whichever comes first.  (revised per Amendment 19) 
Upon approval of BAN2401 in Japan, subjects who meet the approved indication and dosage of 
BAN2401 will continue in this study as a postmarketing part in Japan.  Treatment will continue 
until BAN2401 is commercially available for individual subjects at each study site, at which time 
the subjects will switch to commercial BAN2401.  For those subjects who transition to commercial 
BAN2401 (including the postmarketing section in Japan), the end of the study will be the date of 
the last study evaluation prior to transitioning to commercial BAN2401.  At this time, all 
assessments included in Week 261/Early Termination Visit are to be performed according to the 
Schedule of Assessments of Part A.  (revised per Amendment 18) 
All subjects who underwent amyloid PET for inclusion in the Core Study should receive a baseline 
amyloid PET scan before dosing in the Extension Phase Part A.  The baseline amyloid PET scan 
must be conducted with the same imaging tracer that was used for inclusion at the baseline visit 
for the Core Study.  In addition, qualified subjects located in the US and Japan will have the option 
to participate in the longitudinal PET substudy.  In Japan, those who consented to the longitudinal 
imaging substudy will only undergo amyloid PET at Extension Phase Visit 70 [Extension Week 
53] and annually thereafter.  Florbetapir will be used in the US and flutemetamol will be used in 
Japan in this imaging substudy, and only subjects who consent to the longitudinal assessments per 
the Extension Phase Part A Schedule of Procedures/Assessments (Table 13) will be allowed to 
participate in this imaging substudy.  (revised per Amendments 11, 12, 15, 17, and 19)  
All subjects who are ongoing in the Extension Phase Part A and who have completed at least 
18 months of treatment in the Extension Phase Part A may take part in an optional Dosing Regimen 
substudy to evaluate the effects on safety, PK exposure, biomarker, and clinical efficacy of 
alternate dosing regimens for maintenance dosing of BAN2401.  Subjects may choose to enter this 
substudy at any study visit according to their prior biweekly schedule of assessments.  Subjects 
who participate in this substudy will be randomized to 1 of 2 intravenous dosing regimens; either 
BAN2401 10 mg/kg Q4W or BAN2401 10 mg/kg Q3M.  Subjects will adopt a new schedule of 
assessments specific to the Dosing Regimen substudy, and the substudy will continue for the 
duration of the Extension Phase Part A.  Subjects will undertake a baseline plasma blood draw 
upon entry to the substudy and will attend site visits Q4W, regardless of dosing regimen for the 
1st year of the Dosing Regimen substudy.  Blood will be drawn at each Dosing Regimen substudy 
visit for plasma biomarker monitoring to assess that baseline levels (at substudy entry) are 
maintained over the course of treatment at each dosing regimen.  The sponsor will assess the 
plasma biomarker responses periodically, and if an optimal regimen is established, that regimen 
will be administered to all subjects in the substudy.  For those subjects who are also enrolled in 
the optional longitudinal PET substudy, a Dosing Regimen substudy baseline amyloid PET 
assessment should be conducted before substudy Visit 1 (Week 1), unless it has been conducted 
within 3 months of the Dosing Regimen substudy Visit 1.  Subjects may participate in home 
infusions with sponsor and medical monitor approval, and in accordance with local guidelines.  
(revised per Amendments 17 and 19) 
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Extension Phase Part B 
All subjects ongoing in Extension Part A upon implementation of Protocol Amendment 19 will 
transition to Extension Part B.  Extension Phase Part A and Part B combined will continue for up 
to 60 months (5 years), or until BAN2401 is commercially available for individual subjects at each 
study site, at which time the subjects will switch to commercial BAN2401, or in the cases where 
drug is not yet commercially available, treatment will continue until the benefit to risk ratio from 
treatment with BAN2401 is no longer considered favorable, whichever comes first.  Upon 
transition to Extension Phase Part B, Dosing Regimen substudy subjects will be given the option 
to remain on their current dosing regimen or transition back to BAN2401 10 mg/kg biweekly 
infusions .   
Subjects in Extension Phase Part B will have procedures and assessments including periodic safety 
assessments at approximately 6 monthly intervals (±4 weeks) or as unscheduled assessments, when 
required.  (revised per Amendment 19) 
All infusions will take place in the clinic; however, if approved by the Sponsor and allowable and 
conducted according to country and local guidelines, subjects will be offered the option of home 
infusions for approved visits.  Home infusions are being implemented as a result of the COVID-
19 pandemic to allow subjects who cannot visit clinical sites for various reasons to continue 
receiving treatment.  Home infusions will be allowed per Sponsor approval according to country 
and local guidelines during the COVID-19 pandemic and following its resolution, where 
permitted.  (revised per Amendment 14)   
Subjects will continue in Extension Phase B for a maximum combined (Part A and Part B) open-
label treatment duration of up to 60 months (5 years), or until BAN2401 is commercially available 
for individual subjects at each study site, at which time the subjects will switch to commercial 
BAN2401, or in the cases where drug is not yet commercially available, treatment will continue 
until the benefit to risk ratio from treatment with BAN2401 is no longer considered favorable, 
whichever comes first.   
Upon approval of BAN2401 in Japan, subjects who meet the approved indication and dosage of 
BAN2401 will continue in Extension Phase Part A or B of this study as a postmarketing part in 
Japan.  (revised per Amendment 19) 
The Follow-Up Visit will take place 3 months after the last dose of study drug.  Subjects may 
discontinue from study drug for any reason.  Subjects who discontinue the study drug are requested 
to undertake the Early Termination Visit (within 7 days after the last dose of study drug) and the 
Follow Up Visit (3 months after the last dose of study drug).  The 3 month Follow Up visit is not 
required for any subject who transitions directly (including the postmarketing part in Japan)  to 
commercial BAN2401.  (revised per Amendments 17,18, and 19) 
For those subjects who transition to commercial BAN2401 (including the postmarketing part in 
Japan), the end of the study will be the date of the last study evaluation prior to transitioning to 
commercial BAN2401.  At that time, all assessments included in the Early Termination Visit are 
to be performed .  (revised per Amendment 19).   
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Medical Claims Substudy  
In the US only, subjects and study partners who have participated in any phase of the study (Core 
Study or Extension Phase) will have the option to participate in an optional medical claims 
substudy.  The purpose of this substudy is to use medical claims data to further understand patterns 
of resource utilization and associated costs of care for subjects with EAD and their study partners.  
Additionally, study partners will have the option to participate in a survey, which will provide 
supplemental information on the experience of those individuals who are responsible for the care 
of subjects with EAD.  This medical claims substudy will require a separate consent.  Medical 
claims data for subjects and study partners who consent to this substudy will be collected for up to 
5 years before study enrollment, for the duration of the Core Study, the duration of the period 
between the end of the Core Study and the Extension Baseline (if applicable), the duration of the 
Extension Phase (if applicable), and for up to 3 years after the end of the Core Study or Extension 
Phase (where applicable).  The results of the medical claims substudy will be presented in a 
separate report.  (revised per Amendments 16 and 17) 
For a full description of Extension Phase Part A and Part B, see Appendix 4 and Appendix 5, 
respectively. (revised per Amendments 08 and 16)   
9.2 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL GROUPS 
The primary endpoints will be assessed after 12 months of treatment.  Study drug will then 
continue for an additional 6 months in order to detect effects that are possibly not seen at 12 months 
and to assess the time course of any observed treatment effects that may be consistent with 
neuroimaging and biomarker findings. 
The present study employs a Bayesian response adaptive randomization design with frequent IA 
during the Core Study to continually update randomization allocation based on maturing clinical 
endpoint data from multiple sources.  This approach allows for ongoing assessment of drug futility 
or evidence for early success and can mitigate the risks associated with larger and longer studies 
required to demonstrate clinical efficacy by leading to more efficient project termination or early 
advancement to a successful Phase 3 program.   
To sample the anticipated dose response as fully as possible on the basis of data from the 
BAN2401-A001-101 study, subjects will be randomized to placebo and 5 dose regimens 
comprising 3 different dose levels and 2 different administration frequencies (monthly and 
biweekly administration) to fully interrogate the dose response.  The doses to be investigated are 
10, 5, and 2.5 mg/kg biweekly, and 10 and 5 mg/kg monthly.   
Randomization will be used in this study to avoid bias in the assignment of subjects to treatment, 
to increase the likelihood that known and unknown subject attributes (eg, demographics and 
baseline characteristics) are balanced across treatment groups, and to ensure the validity of 
statistical comparisons across treatment groups.  For safety reasons, subjects who are confirmed 
APOE4 positive (APOE4 hetero- or homozygous) will not be randomized to the 10 mg/kg, 
biweekly dose (revised per Amendments 04 and 05).  After each IA, the randomization probability 
vector will be split between APOE4 positive and APOE4 negative strata to ensure no APOE4 
positive subjects are enrolled on the 10 mg/kg biweekly dose.  The overall probabilities as 
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suggested by RAR will still be preserved (revised per Amendments 05 and 07).  Blinding to 
treatment will be used to reduce potential bias during data collection and evaluation of endpoints.  
A control group is required for assessment of possible treatment effects in this proof-of-concept 
study. 
9.3 
SELECTION OF STUDY POPULATION 
The study population will consist of subjects who have EAD.  Two subpopulations will be 
evaluated:  those who have MCI due to AD – intermediate likelihood, and those who have mild 
Alzheimer’s disease dementia.  Diagnostic criteria will consist of selected cognitive assessments 
(Section 9.5.1.2), followed by amyloid PET or CSF Aβ(1-42) assessment (revised per Amendment 
06) to confirm deposition of amyloid in the brain.  So as to ensure as much as possible that 
treatment effects are not confounded by disorders unrelated to AD, subjects will be evaluated per 
inclusion and exclusion criteria (Section 9.3.1 and Section 9.3.2).  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 
Diagnosis 
Mild Cognitive Impairment due to Alzheimer’s Disease – Intermediate Likelihood: (revised per 
Amendment 06) 
1. Subjects who meet the NIA-AA core clinical criteria for mild cognitive impairment due to 
Alzheimer’s disease - intermediate likelihood 12  
2. Subjects who have a CDR score of 0.5 and a memory box score of 0.5 or greater at 
Screening and Baseline 
3. Subjects who report a history of subjective memory decline with gradual onset and slow 
progression over the last 1 year before Screening; MUST be corroborated by an informant 
Mild Alzheimer’s Disease Dementia: 
4. Subjects who meet the NIA-AA core clinical criteria for probable Alzheimer’s disease 
dementia13  
5. Subjects who have a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater at 
Screening and Baseline 
Key Inclusion Criteria that must be met by ALL Subjects: 
6. Subjects with objective impairment in episodic memory as indicated by at least 1 standard 
deviation below age-adjusted mean in the WMS-IV LMII, as follows: 
a) ≤15 for age 50 to 64 years 
b) ≤12 for age 65 to 69 years 
c) ≤11 for age 70 to 74 years 
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d) ≤9 for age 75 to 79 years 
e) ≤7 for age 80 to 90 years 
(revised per Amendments 01 and 06) 
7. Positive amyloid load as indicated by 1 of the following:   
a. PET assessment of imaging agent uptake into brain 
b. CSF assessment of Aβ(1-42) (revised per Amendment 06)  
Subjects may consent to both the PET and CSF assessments, but need a positive amyloid 
result in only one of the 2 procedures to confirm eligibility (ie, even if one of the 2 results 
does not meet its respective eligibility criterion).  Subjects who initially consent for only 
one of the amyloid screening assessments will only be allowed to subsequently consent for 
the second assessment should the first assessment result be positive or they have not yet 
been informed of the results of the first assessment.  Subjects who consent to Amyloid PET 
or CSF Amyloid are not required to participate in the respective substudies (revised per 
Amendments 06 and 07)   
Any historical amyloid positive PET scan may be used for eligibility upon evaluation by 
the central imaging CRO.  For subjects who wish to participate in the longitudinal imaging 
substudy, historical amyloid PET scans may not be used as baseline scans for the 
longitudinal imaging substudy.  Required details regarding historical images should be 
submitted to the CRO medical monitor for evaluation.  (revised per Amendment 08) 
8. Male or female subjects aged between 50 and 90 years, inclusive 
9. MMSE score equal to or greater than 22, and equal to or less than 30 at Screening and 
Baseline, except for the following countries, where MMSE score must be equal to or 
greater than 22 and equal to or less than 28 at Screening and Baseline:  United Kingdom, 
Spain, Germany, Sweden, France, and the Netherlands (revised per Amendment 03) 
10. Body Mass Index (BMI) >17 and  <35 at Screening (revised per Amendment 06) 
11. Females must not be lactating or pregnant at Screening or Baseline (as documented by a 
negative beta-human chorionic gonadotropin assay [ß-hCG]).  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 
72 hours before the first dose of study drug. 
12. 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). 
13. 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 
(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 
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vasectomized partner with confirmed azoospermia) throughout the entire study period and 
for 35 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 35 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 35 days after study drug discontinuation. 
14. Subjects who are receiving AChEIs or memantine or both for AD must be on a stable dose 
for at least 12 weeks prior to Baseline.  Treatment naïve subjects can be entered into the 
study.  Unless otherwise stated, subjects must have been on stable doses of all other 
permitted concomitant medications (ie, non-AD related) for at least 4 weeks prior to 
Baseline.  Use of memantine will not be allowed for Japanese subjects (revised per 
Amendments 01 and 07) 
15. Must have an identified caregiver/informant (defined as a person able to support the subject 
for the duration of the study and who spends at least 8 hours per week with the subject).  
The caregiver/informant must provide separate written informed consent.  In addition, this 
person must be 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/informant can 
reliably fulfill the study requirements.  A permanent caregiver/informant need not be living 
in the same residence with the subject.  For such a caregiver/informant not residing with 
the subject, the investigator has to be satisfied that the subject can contact the 
caregiver/informant readily during the times when the caregiver/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.  Caregivers/informants need 
only to be present at visits where clinical assessment of CDR and FAQ takes place.  
(revised per Amendment 01)   
16. Provide written informed consent.  If a subject lacks capacity to consent in the investigator's 
opinion, the subject's assent should be obtained, if required in accordance with local laws, 
regulations and customs, plus the written informed consent of a legal representative should 
be obtained (capacity to consent and definition of legal representative should be determined 
in accordance with applicable local laws and regulations).  (revised per Amendment 07) 
17. Willing and able to comply with all aspects of the protocol 
9.3.2 Exclusion Criteria 
1. Any neurological condition that may be contributing to cognitive impairment above and 
beyond that caused by the subject’s AD 
2. History of transient ischemic attacks, stroke, or seizures within 12 months of Screening 
3. Any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or 
delusions) that could interfere with study procedures in the subject  
4. GDS score ≥8 at Screening 
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5. Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, 
ferromagnetic metal implants (eg, in skull and cardiac devices other than those approved 
as safe for use in MR scanners) 
6. Evidence of other clinically significant lesions that could indicate a dementia diagnosis 
other than AD on brain MRI at Screening.  All MRIs will be acquired using a standardized 
procedure that will be outlined in the Imaging Charter and Imaging Acquisition Guidelines 
(IAG) and will be read by an approved centralized reader. 
7. Other significant pathological findings on brain MRI at Screening, including but not 
limited to:  more than 4 micro-hemorrhages (defined as 10 mm or less at the greatest 
diameter), a single macro-hemorrhage greater than 10 mm at greatest diameter; an area of 
superficial siderosis; evidence of vasogenic edema; evidence of cerebral contusion, 
encephalomalacia, aneurysms, vascular malformations, infective lesions, evidence of 
multiple lacunar infarcts or stroke involving a major vascular territory, severe small vessel, 
or white matter disease or space occupying lesions or brain tumors (however lesions 
diagnosed as meningiomas or arachnoid cysts and <1cm at their greatest diameter need not 
be exclusionary) (revised per Amendment 07) 
8. Hypersensitivity to BAN2401 or any of the excipients, or to any monoclonal antibody 
treatment 
9. Any immunological disease which is not adequately controlled, or which requires 
treatment with biologic drugs during the study  
10. Subjects with a bleeding disorder that is not under adequate control (including a platelet 
count <50,000 or international normalized ratio [INR] >1.5) 
11. Subjects who have thyroid stimulating hormone (TSH) above normal range.  Other tests of 
thyroid function with results outside the normal range should only be exclusionary if they 
are considered clinically significant by the investigator.  This applies to all subjects whether 
or not they are taking thyroid supplements.  (revised per Amendments 01 and 06) 
12. 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). 
13. A prolonged QT/QTc interval (QTc >450 ms) as demonstrated by a repeated ECG 
14. Known to be human immunodeficiency virus (HIV) positive 
15. Any other clinically significant abnormalities in physical examination, vital signs, 
laboratory tests or ECG at Screening or Baseline which in the opinion of the PI, require 
further investigation or treatment or which may interfere with study procedures or safety 
16. Uncontrolled Type 1 or Type 2 diabetes mellitus.  Evidence of uncontrolled diabetes 
mellitus includes hemoglobin A1c (HbA1c) >9% 
17. Uncontrolled hypertension with a history of blood pressure consistently above 
165/100 mm Hg at Screening 
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18. History of uncontrolled cardiovascular disease within 6 months of Screening , including 
acute coronary syndrome, clinically significant valvular heart disease, uncompensated 
heart failure (New York Heart Association Class III and Class IV), or uncontrolled 
arrhythmia  
19. Subjects with malignant neoplasms within 3 years of Screening (except for basal or 
squamous cell carcinoma in situ of the skin, or localized prostate cancer in male subjects).  
Subjects who had malignant neoplasms but who have had at least 3 years of documented 
uninterrupted remission before Screening need not be excluded.  
20. Has a “yes” answer to the C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior 
assessment within 6 months before Screening, at Screening, or at the Baseline Visit; or has 
been hospitalized or treated for suicidal behavior in the past 5 years before Screening  
21. Known or suspected history of drug or alcohol abuse or dependence within 2 years before 
Screening or a positive urine drug test at Screening.  Subjects who test positive for 
benzodiazepines or opioids in urine drug testing 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 and not due to drug abuse. 
22. Any other medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) 
which 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 
23. Subjects who are taking prohibited medications (revised per Amendment 01) 
24. Participation in a clinical study involving any therapeutic monoclonal antibody, protein 
derived from a monoclonal antibody, immunoglobulin therapy, or vaccine within 6 months 
before Screening (revised per Amendment 01)  
25. Participation in a clinical study involving any new chemical entities for AD within 
6 months prior to Screening, unless it can be documented that the subject was in a placebo 
treatment arm 
26. Participation in any other investigational medication or device study in the 8 weeks or 
5 half-lives (whichever is longer) of the medication before randomization, unless it can be 
documented that the subject was in a placebo treatment arm 
27. Planned surgery which 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 day case without inpatient stay postoperatively need not result in exclusion 
if in the opinion of the PI this operation does not interfere with study procedures and subject 
safety.  
28. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately 
9.3.3 Removal of Subjects From Therapy or Assessment 
The investigator may withdraw the subject from the study at any time for safety or administrative 
reasons.  The subject may stop study drug or withdraw from the study at any time for any reason. 
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In the Core Study, study drug will be stopped in a subject if any 1 of the following is observed in 
MRI of the brain:  (revised per Amendment 11) 
 Evidence of vasogenic edema 
 Development of any macrohemorrhages, an area of superficial siderosis, or symptomatic 
treatment-emergent microhemorrhages 
The MRI findings of subjects who develop such features will be investigated together with all 
accumulated data to date as described in the IAG. 
Administration of study drug to an individual subject will be discontinued if any of the following 
clinical features is observed: 
 Infusion reactions associated with administration of study drug, of Grade 3 severity or 
above as defined in the National Cancer Institute - Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) 
 Clinical features which indicate meningoencephalitis (eg, combination of 1 or more of the 
following: headache, worsening confusion, neck stiffness, impaired consciousness, focal 
neurological signs) 
 Hypersensitivity reactions with clinical features of tissue injury (eg, arthritis, 
glomerulonephritis, mononeuritis multiplex) (revised per Amendment 08)  
Subjects who meet any of the above criteria, whether on MRI or otherwise, will be discontinued 
from the study.  Subjects who discontinue the study or study drug early must comply with the 
Early Termination Visit (within 7 days after the last dose of study drug) and the Follow-Up Visit 
(3 months after the last dose of study drug).  They may also have unscheduled visits for safety 
assessments.  In addition, it is expected that subjects who discontinue study drug are required to 
return after the Early Termination Visit for each scheduled visit when clinical efficacy assessments 
are to be conducted per the Schedule of Procedures/Assessments.  (revised per Amendment 06)  
At these visits, clinical efficacy assessments (MMSE, CDR, ADAS-Cog, and FAQ) will be 
conducted and information on concomitant medications, AEs, and SAEs will be collected.  
Regularly scheduled clinical efficacy visits do not need to be attended if they fall within 8 days 
(visit window) after the Early Termination Visit or within ±8 days of the 3-month Follow-Up Visit.  
Subjects who discontinue from study drug are considered on study as long as they return for their 
regularly scheduled clinical efficacy visits as outlined above (revised per Amendments 08 and 11).  
The timing of unscheduled visits for safety assessments may be decided on a case-by-case basis in 
the clinical judgment of the investigator in consultation with the sponsor’s medical monitor.  
(revised per Amendment 01) 
The primary reason for discontinuation and all other reason(s) contributing to the subject’s 
discontinuation from study drug(s) should be collected in the Early Discontinuation from Study 
Drug eCRF.  In addition, the date of last dose of study drug(s) will be recorded on the Study Drug 
Administration eCRF page.  If a subject discontinues study treatment and the study at the same 
time, the end-of-study procedures (Final Visit) will be followed (see Section 9.5.5). 
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9.4 
TREATMENTS 
9.4.1 Treatments Administered 
For the Core Study, the test drug is BAN2401 and the control drug consists of placebo.  As shown 
in Table 4, there will be 6 treatment arms.  Subjects in Study Arms 1, 2, 3, and 4, respectively, will 
receive placebo, 2.5, 5, and 10 mg/kg BAN2401 once every 2 weeks for the duration of the 
Randomization Phase (18 months).  Subjects assigned to Study Arms 5 and 6, respectively, will 
receive 5 and 10 mg/kg BAN2401 once every 4 weeks for the duration of the study.  To maintain 
blinding and ensure equivalent frequency of infusion-related clinical procedures for all subjects, 
the subjects assigned to receive BAN2401 at 4-week intervals will have placebo infusions 
alternating with BAN2401.  An infusion system containing a terminal 0.22-µm in-line filter is 
required for administration of BAN2401 drug product.  (revised per Amendment 08) 
Study drug doses will not be reduced during the study.  If a subject is unable to tolerate the assigned 
study treatment, the treatment will be discontinued and no further infusions will be administered.  
Interruptions in scheduled dosing may be necessary in the clinical judgment of the investigator 
due to illness or other occurrences in study subjects that are not related to study drug but that might 
interfere with the efficacy or the safety of the study drug.   
9.4.2 Identity of Investigational Product(s) 
BAN2401 is a humanized IgG1 monoclonal antibody that binds to soluble Aβ aggregates.  
BAN2401 is manufactured at Patheon Ltd, United Kingdom (UK) and at Biogen, RTP, under 
contract to Eisai (revised per Amendment 08).  During the Core Study, BAN2401 is supplied as a 
sterile clear solution for injection containing 10 mg/mL, in a single use 10-mL vial (total 
100 mg/vial).  The drug product is formulated in 25 mM sodium citrate, 125 mM sodium chloride, 
0.02% (w/v) polysorbate 80 and has a pH of 5.7.  (revised per Amendment 11) 
During the Core Study, BAN2401 and placebo will be supplied by the sponsor in labeled 
containers.  The product release certificates for BAN2401 and placebo will be included in the 
clinical study report for this protocol.  (revised per Amendment 11) 
During the Core Study, study drug will be packaged such that there is 1 vial per dispenser, and 
will be dispensed in a blinded manner by an unblinded pharmacist at each site according to the 
subject randomization created by the Interactive Voice Response System (IVRS).  At the time that 
the study drug is dispensed for administration to the subject, the tear-off label on the dispenser 
must be removed and placed in the study drug accountability log at the time of dispensing.  (revised 
per Amendment 11) 
See Appendix 4 and Appendix 5 for the identity of the investigation product during the Extension 
Phase Part A and Part B, respectively.  (Revised per Amendments 11 and 19) 
9.4.2.1 Chemical Name, Structural Formula of BAN2401 
● Test drug code:  BAN2401 
● Generic name:  lecanemab  (revised per Amendment 16) 
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● Chemical name:  not yet assigned 
● Molecular formula:  The heavy chain consists of 454 amino acids and the light chain has 
219 amino acids. 
● Molecular weight:  The apparent molecular weight determined by matrix-assisted 
desorption ionization time-of-flight mass spectrometry (MALDI TOF-MS) for BAN2401 
drug substance is 149,704 Da. 
● Structural formula:  BAN2401 is composed of 4 polypeptide chains, 2 identical gamma (γ) 
heavy chains consisting of 454 amino acids each and 2 identical kappa (κ) light chains 
consisting of 219 amino acids each.  The 4 chains are held together by a combination of 
covalent (disulfide) and noncovalent bonds.  There are 32 cysteine residues, and 
accordingly 16 potential disulfide bonds per residue.  The heavy chain subunit contains 
2 consensus sequences for potential N-linked glycosylation. 
9.4.2.2 Comparator Drug 
Matching placebo will be manufactured at Patheon Ltd, UK, under contract to Eisai.  It will be 
supplied as a sterile clear solution for injection, in single use 10-mL vials and should be diluted in 
0.9% sodium chloride before use in accordance with the guidance provided. 
9.4.2.3 Labeling for Study Drug 
The investigational medicinal product, BAN2401, 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: 
(US only) Caution:  New Drug – Limited by Federal Law (US) to Investigational Use Only 
Protocol number 
Name and address of the sponsor 
Chemical name/drug identifier 
Vial number 
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 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. 
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9.4.3 Method of Assigning Subjects to Treatment Groups 
The study is to randomize a maximum of 800 subjects who have EAD.  There will be 2 clinical 
subgroups:  those with MCI due to Alzheimer’s disease (AD) – intermediate likelihood, and those 
with mild Alzheimer’s disease dementia (collectively referred to as EAD for the purposes of this 
protocol).  The subjects will be randomized to receive 1 of 5 dose regimens of BAN2401, which 
comprise 3 dose levels given biweekly and 2 dose levels given monthly (2.5, 5, and 10 mg/kg 
biweekly and 5 and 10 mg/kg monthly [ie, once every 4 weeks]).  The randomization of subjects 
will be stratified by the 2 clinical subgroups (see Inclusion Criteria; MCI due to AD – intermediate 
likelihood or mild Alzheimer’s disease dementia), by APOE status (APOE4 positive and negative), 
and by ongoing treatment with AChEIs or memantine or both.  Enrollment into the 2 clinical 
subgroups will be reasonably balanced whereby at least 60% of the total number of subjects will 
have MCI due to AD – intermediate likelihood and at least 30% will have mild Alzheimer’s disease 
dementia.   
The first 196 subjects will be randomized according to a fixed schedule (4:2:2:2:2:2); Placebo (4) 
to each of the active arms (2 each).  Interim analyses will be conducted when 196 and 250 subjects 
have been randomized and again after every 50 subjects until all 800 subjects are randomized.  The 
RAR will be updated according to results of the IA.  Sites in Japan will randomize at least 40 
Japanese subjects, even if the early success is declared or the study achieves 800 subjects 
randomized.  In these circumstances, subjects in Japan will be allocated treatment according to the 
latest (or last) allocation schedule.  If the study reaches its maximum of 800 randomized subjects, 
additional IA will be conducted every 3 months until all 800 complete 12 months of treatment.  
Only those subjects who were randomized before the target of 800 was met will contribute to these 
additional IA (revised per Amendment 07).  Each IA will be conducted on data for the derived 
Clinical Composite Score.  On the basis of each IA, the randomization probabilities will be updated 
for all treatment arms to favor those arms for which the ADCOMS results more closely 
approximate the potential target dose (ED90).  Subjects who are confirmed APOE4 positive 
(APOE4 hetero- or homozygous) will not be randomized to the 10 mg/kg, biweekly dose (revised 
per Amendments 04 and 05).  The algorithm for computing response adaptive randomization 
probabilities is further explained in Section 9.7.2. 
Oversight of IA and response adaptive randomization will be conducted by an IMC.  The IMC 
will consist of 3 members who are external to the company and who have with expertise in 
Bayesian adaptive design for clinical trials. 
The IA and RAR will be conducted by an unblinded external independent statistical group in 
accordance with the protocol.  This independent group will provide the IA outcomes to the IMC 
at each interim look.  The IMC will ensure the integrity of the IA and response adaptive 
randomization process through review of primary efficacy data.  In addition, the IMC will act in 
an independent advisory capacity to monitor the Bayesian IA outcomes according to the early 
success and futility boundaries prespecified in the protocol.  The IMC will inform the sponsor if 
the boundaries for early success or futility have been crossed.  The IMC will not be charged with 
any subject safety issues, as this will be the responsibility of an independent DSMB. 
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Subjects who were admitted to the Core Study with EAD and who completed Visit 42 (Week 79) 
of the Core Study and/or fulfill the Extension Phase Part A inclusion and exclusion criteria 
(Appendix 4) are eligible to participate in the 60-month Extension Phase.  Subjects who previously 
completed the Core Study (through the Follow-Up Visit, Visit 43) at any time before 
implementation of the Extension Phase Part A, and/or fulfill the Extension Phase Part A inclusion 
and exclusion criteria (Appendix 4), will also be eligible to participate.  See Appendix 4 for details 
on assignment of study drug in the Extension Phase.  All subjects ongoing in Extension Part A 
upon implementation of Protocol Amendment 19 will transition to Extension Part B.  Extension 
Phase Part A and Part B combined will continue for up to 60 months (5 years), or until BAN2401 
is commercially available for individual subjects at each study site, at which time the subjects will 
switch to commercial BAN2401, or in the cases where drug is not yet commercially available, 
treatment will continue until the benefit to risk ratio from treatment with BAN2401 is no longer 
considered favorable, whichever comes first (Appendix 5).  Subjects will continue in Extension 
Phase B for a maximum combined (Part A and Part B) open-label treatment duration of up to 
60 months (5 years), or until BAN2401 is commercially available for individual subjects at each 
study site, at which time the subjects will switch to commercial BAN2401, or in the cases where 
drug is not yet commercially available, treatment will continue until the benefit to risk ratio from 
treatment with BAN2401 is no longer considered favorable, whichever comes first.  Upon approval 
of BAN2401 in Japan, subjects who meet the approved indication and dosage of BAN2401 will 
continue in Extension Phase Part A or B of this study as a postmarketing part in Japan.  (revised 
per Amendments 08, 11, 15, and 19) 
9.4.4 Selection of Doses and Dose Regimens in the Study 
At the present time, there are no nonclinical or clinical data on the PK/PD relationship for 
functional or behavioral endpoints with BAN2401.  In nonclinical studies in Tg mice, BAN2401 
treatment produced a reduction of CSF and brain soluble Aβ aggregate species.  However, in the 
BAN2401-A001-101 study, there was no validated assay to measure CSF soluble Aβ aggregated 
forms.  Thus, it was not possible to guide human dose selection based on PD effects of BAN2401 
in human CSF. 
In the absence of a relevant clinical PD effect, the planned dosing interval and proposed dose range 
for this study are based on the integrated review of the safety and PK information collected in the 
combined Phase 1 SAD/MAD study (BAN2401-A001-101) and nonclinical PK/PD modeling of 
soluble Aβ aggregate brain reduction in mice. 
Pharmacokinetic and PD analyses in the Tg-APP ArcSwe mice relating CSF Cmin to reductions in 
brain soluble Aβ aggregate concentrations yielded a CSF IC50 value of 15.1 ng/mL.  Doses of 
0.3 mg/kg to 10 mg/kg in Tg-APP ArcSwe mice treated for 17 weeks showed reductions in brain 
soluble Aβ aggregates.  The mean CSF Cmin of these doses ranged from 27 to 1300 ng/mL.  To 
identify suitable doses, available PK data from SAD and MAD cohorts were modeled to yield CSF 
exposure estimates for dosing every 2 weeks versus monthly (Table 5).  These doses provide a 
wide range of CSF concentrations.  The predicted CSF Cmin at SS (Cmin,ss) in the present study 
covers the range of CSF concentrations present in the Tg-APP ArcSwe mice during the 17-week 
studies.  The predicted CSF concentrations in Table 5 also exceed the CSF IC50 (15.1 ng/mL) for 
reduction of brain amyloid aggregates in the Tg-APP ArcSwe mice studies.  The exposure of the 
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NOAEL dose of BAN2401 (100 mg/kg) studied in nonhuman primates in the 39-week toxicology 
study (Cmax,ss = 4150 μg/mL, AUC(0-14 days) = 926,000 μg·h/mL at SS) is at least 16- and 30-fold 
higher than the predicted serum Cmax at steady state (Cmax,ss) (251 μg/mL) and AUC(0-τ) at SS 
(30,864 μg·h/mL at 14 days dosing interval), respectively, for the highest dose of 10 mg/kg 
biweekly in the present study. 
Table 5 
Model-predicted CSF Exposures at Steady State at BAN2401 Doses of 2.5 
to 10 mg/kg Biweekly, or 5 to 10 mg/kg Monthly 
BAN2401 
Dose 
CSF 
Cmax,ss 
(ng/mL) 
 
CSF 
Cmin,ss 
(ng/mL) 
CSF 
AUC(0-t),ss 
(ng.h/mL) 
2.5 mg/kg biweekly 
65 
44 
19,661 
5 mg/kg biweekly 
131 
86 
38,943 
10 mg/kg biweekly 
261 
169 
77,508 
5 mg/kg monthlya 
103 
19 
39,007 
10 mg/kg monthlya 
206 
37 
77,599 
AUC(0-t),ss = area under the concentration vs. time curve at time t, steady state, CSF = cerebrospinal fluid, Cmax,ss   =  
maximum observed concentration,  Cmin,ss =  minimum observed concentration at steady state 
 
a: 
‘Monthly’ doses are administered once every 4 weeks 
 
It is recognized that a biweekly treatment regimen could represent a significant burden to AD 
subjects, particularly those who are early in the disease course and who remain highly functional.  
Exploring the possibility of monthly (ie, once every 4 weeks) dosing of BAN2401 is therefore of 
interest, and the current study design aims to assess this possibility as well.  The doses of 5 mg/kg 
and 10 mg/kg monthly are predicted to have CSF Cmin,ss that cover the lower end of the range of 
CSF Cmin in the Tg-APP ArcSwe mice study.  Therefore, these doses may still have clinical 
efficacy.  
9.4.5 Selection and Timing of Dose for Each Subject 
All infusions will be administered by study personnel.  BAN2401 or placebo will be infused over 
an approximately 60-minute interval in a volume of 250 mL in normal saline.  Drug administration 
will be performed after breakfast.  The infusion pump model and other infusion components will 
be specified in a manual to be distributed to the study sites.  The timing of infusions relative to 
other study procedures and assessments is given in the Schedule of Procedures/Assessments 
(Table 8 and Table 13 for those subjects who participate in the Extension Phase).  (revised per 
Amendment 08) 
During the beginning of the study, infusions will take place in the clinic.  The DSMB will review 
the safety of BAN2401 after a predetermined number of subjects have been randomized, and 
decide if it will be acceptable to offer the option of home infusions during the Core Study (per 
DSMB charter, if allowed and conducted according to country and local guidelines; home 
infusions will not be allowed in Germany) to be available to subjects following 4 months of 
treatment.  (revised per Amendment 14) Upon implementation of Amendment 07, newly enrolled 
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subjects will not be offered the option for home infusions during the Core Study.  (revised per 
Amendment 14) Subjects opting for home infusions before implementation of Amendment 07 will 
be allowed to continue with home infusions for the duration of their participation in the Core Study  
(revised per Amendments 01, 03, 07, and 14).  The investigator should then decide for individual 
subjects (site permitting) if home infusions are suitable after they have had 4 months of infusions 
in clinic.  
9.4.6 Blinding 
This is a double-blind Core Study with an open-label Extension Phase.  (revised per 
Amendment 08)  During the Randomization Phase of the Core Study, the subject and all personnel 
involved with the conduct and the interpretation of the study, including the investigators, 
investigational site personnel, and Eisai will be blinded to the treatment codes, except that the 
study pharmacist will be unblinded.  Randomization data will be kept strictly confidential until 
study completion when the last subject completes the last visit in the Extension Phase (revised per 
Amendment 08), filed securely by an appropriate group in Eisai, and accessible only to authorized 
persons as per Standard Operating Procedures until the time of unblinding.  Designated 
independent statisticians will be allowed access to the blinded data in order to perform IA and 
response adaptive randomization (see Section 9.4.3 and Section 9.7.2 for details). 
Study drug will be dispensed by an unblinded pharmacist at each site according to the subject 
randomization generated by the IVRS vendor.  A master list of all treatments and the subject 
numbers associated with them will be maintained in a sealed envelope by the clinical supply 
vendor, the IVRS vendor, and the sponsor.  In the event that emergency conditions require 
knowledge of the study treatment given, the blind may be broken via the code breaker facility 
within the IVRS.  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.  The investigator is to make a careful note of the date, time of 
opening, and the reason for breaking the code. 
Subjects in Treatment Arms 5 and 6 will receive BAN2401 infusions once every 4 weeks, whereas 
all other subjects will receive infusions at biweekly intervals.  To maintain blinding across all 
treatment arms, subjects in Treatment Arms 5 and 6 will receive blinded placebo infusions at 
2-week intervals preceding and following each infusion of BAN2401.  Refer to Appendix 4 for 
treatment of subjects in the Extension Phase.  (revised per Amendments 08 and 11)  
9.4.7 Prior and Concomitant Therapy 
Any medication (including over-the-counter medications) or therapy administered to the subject 
during the study (starting at the date of informed consent) will be recorded on the Prior and 
Concomitant Medication eCRF or the 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. 
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9.4.7.1 Drug-drug Interactions 
Not applicable. 
9.4.7.2 Core Study Prohibited Concomitant Therapies and Drugs 
Anticoagulants (eg, warfarin, dabigatran) are not permitted for -7 days or 5 half-lives, whichever 
is longer, before Baseline until the Follow-Up Visit (Appendix 2, Listing 1).  (revised per 
Amendment 01).  Subjects who need to start chronic (>4 weeks) anticoagulant treatment during 
the study for concomitant diseases will be withdrawn from study drug.  However, short-term 
(<4 weeks) treatment with anticoagulants is permitted for randomized subjects who undergo 
procedures requiring anticoagulants for prophylaxis of thromboembolic disease after approval by 
the sponsor’s medical monitor.  While these subjects need not be discontinued, study drug will be 
temporarily suspended during anticoagulant therapy.  (revised per Amendment 06) 
Immunoglobulin therapy and therapy with biologic drugs are not permitted for 6 months prior to 
the Baseline until the Follow-Up Visit.  (revised per Amendment 01) 
Subjects who are on AChEIs or memantine or both are required to be on a stable dose for 12 weeks 
before Baseline.  During the study, if a subject starts, changes dose, or stops any of these 
medications, the subject will continue with study visits and assessments to study completion but 
the data from that subject will be censored as described in Section 9.7.1.6.  Use of memantine will 
not be allowed for Japanese subjects (revised per Amendments 01 and 07). 
Medications which are used as needed (PRN) or as short courses of treatment and which are central 
nervous system-active and may affect cognitive function are not permitted during a period of 
72 hours prior to cognitive testing (Appendix 2, Listing 3). 
Subjects who are taking other medications will be required to be on a stable dose for at least 
4 weeks prior to Baseline, except for medications which are administered as short courses of 
treatment (eg, anti-infectives) or which are to be used PRN.  (revised per Amendment 01)  During 
the study, subjects who initiate treatment with drugs not intended for treatment of cognitive 
impairment during the study or who change the doses of such drugs may continue in the study if 
in the opinion of the PI these drugs will not interfere with study procedures or subject safety and 
are not prohibited above.  However, if such drugs may affect cognitive function, subjects should 
not undertake cognitive assessments until they have been on a stable dose for at least 4 week. 
Subjects may receive prophylactic medications as needed prior to infusion of study drug to 
minimize the risk of immunologic reaction or infusion reaction during or shortly after the infusion. 
Restricted and permitted drugs for the Extension Phase are described in Appendix 2.  (revised per 
Amendments 11 and 12) 
9.4.8 Treatment Compliance 
All study treatments will be administered by study personnel.  The scheduled infusion may occur 
up to 8 days earlier or later than the scheduled date if advisable, as for example due to illness.  
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(revised per Amendment 01)  If 1 or more infusions are missed, the investigator and sponsor should 
evaluate whether or not the subject should continue in the study. 
9.4.9 Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the investigator 
until the following documentation has been received by the sponsor: 
 A signed and dated confidentiality agreement 
 A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator 
 Written proof of approval of the protocol, the ICFs, and any other information provided to 
the subjects by the IRB/IEC for the institution where the study is to be conducted 
 A copy of the IRB/IEC-approved ICF and any other documentation provided to the subjects 
to be used in this study 
 The IRB/IEC membership list and statutes or Health and Human Services Assurance 
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 Form FDA 1572, where applicable 
 (in EU):  Approval by a Designated Qualified Person 
 Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 1572, 
where applicable 
 A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license or medical registration number on the CV 
 A signed and dated clinical trials agreement 
 A copy of the regulatory authority approval for the country in which the study is being 
conducted and the Import License  
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.  
The site must maintain an accurate and timely record of the following:  receipt of all study drugs, 
administration of study drugs to the subject, collection and reconciliation of unused study drugs 
that are shipped to site, and return of reconciled study drugs to the sponsor or (where applicable) 
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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 drug dispensing/return reconciliation log, 
(c) study drug accountability log, (d) all shipping service receipts, (e) documentation of returns to 
the sponsor, and (f) certificates of destruction for any destruction of study drugs that occurs at the 
site.  All forms will be provided by the sponsor.  Any comparable forms that the site wishes to use 
must be approved by the sponsor. 
The study drug 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, 
MHRA).  As applicable, all unused study drugs and empty and partially empty containers from 
used study drugs are to be returned to the investigator by the subject and together with unused 
study drugs that were shipped to the site but not administered 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.  
Upon completion of drug accountability and reconciliation procedures by the site’s personnel and 
documentation procedures by the sponsor’s personnel, study drugs that are to be returned to the 
sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back to the 
central or local depot(s) following all local regulatory requirements.  In some regions, study drugs 
may be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.   
Drug accountability will be reviewed during site visits and at the completion of the study. 
9.5 
STUDY ASSESSMENTS 
Refer to Appendix 4 and Appendix 5 for a description of Assessments in the Extension Phase Part 
A and Part B, respectively.  (revised per Amendments 11 and 19) 
9.5.1 Assessments 
9.5.1.1 Demography 
Subject demography information will be collected at the Screening Visit.  Demographic 
information is to include date of birth (or age), sex, race/ethnicity, native language, and years of 
education.  
9.5.1.2 
Baseline Assessments 
MEDICAL HISTORY AND CLINICAL ASSESSMENTS 
At the Screening Visit, assessments will be conducted to ensure that subjects do not have medical 
conditions which may interfere with study participation.  Medical and surgical history, current 
medications including AChE inhibitors and memantine, and current medical conditions will be 
recorded at this Visit.  (revised per Amendment 01)  All pertinent medical and surgical history 
within 10 years must be noted in the Medical History and Current Medical Conditions eCRF.   
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A complete physical examination will be performed at the Screening Visit.  This physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest (including 
heart and lungs), abdomen, limbs, skin, and a complete neurological examination.  A urogenital 
examination will only be required in the presence of clinical symptoms related to this region.  
Documentation of physical examinations will be included in the source documentation at the site.  
Significant findings at the Screening Visit will be recorded on the Medical History and Current 
Medical Conditions eCRF.   
Additionally, at the Screening Visit, inclusion/exclusion criteria and prior medications will be 
reviewed with the subject and caregiver/informant, vital signs will be assessed, height and weight 
will be recorded for calculation of BMI, blood will be collected for clinical laboratory tests, and a 
serum pregnancy test (females of childbearing potential only) will be conducted.  A urine sample 
will be collected and tested for common drugs of use/abuse: (eg, amphetamine, barbiturates, 
benzodiazepines, 
cocaine, 
methamphetamine, 
methadone, 
opiates, 
phencyclidine, 
tetrahydrocannabinol and tricyclic antidepressants). 
At the Baseline Visit, inclusion/exclusion criteria and prior medication data will again be reviewed.  
Vital signs will again be measured and blood will again be collected for clinical laboratory tests 
and for exploratory plasma biomarker assessments.  In addition, a single 12-lead ECG will be 
conducted.  (revised per Amendment 01) 
PSYCHOMETRIC ASSESSMENTS 
At the Screening Visit, all subjects will be assessed for eligibility, using psychometric assessments 
to confirm that subjects meet the diagnostic criteria for MCI due to AD – intermediate likelihood 
or mild Alzheimer’s disease dementia.  These clinical assessments will begin the Screening 
assessments and will consist of the MMSE, the WMS-IV LMI and LMII, and the CDR, and will 
be administered in that order.  These assessments will be administered in the morning whenever 
possible, and at the same time of day in all subsequent visits.  The WMS-IV LMII is to be 
administered 20 to 30 minutes after the completion of LMI.  Subject information should be 
collected in the 20 to 30 minutes between the WMS-IV LM1 and LMII.  (revised per Amendment 
01)  Subjects will also be evaluated on the GDS for eligibility.  Caregivers/informants (defined as 
persons able to support the subject for the duration of the study) should be present at this visit.  
Subjects who are considered ineligible for this study based on these assessments should not 
continue with the rest of the assessments for this visit.  (revised per Amendment 01) 
At the Baseline Visit, in the morning when possible, subjects will be administered the MMSE, the 
CDR, the ADAS-Cog, and the FAQ in that order.  Test results from the CDR will again be used 
as inclusion criteria.  Caregivers/informants should be present at these visits when the clinical 
assessments are administered. 
The MMSE, the CDR, the ADAS-Cog, and the FAQ will be administered as indicated in the 
Schedule of Assessments during the Randomization Phase in the order stated. 
The C-SSRS will be administered at Screening, Baseline, and at designated Visits as indicated in 
the Schedule of Assessments. 
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Mini-Mental State Examination (MMSE)  
The MMSE is a cognitive instrument commonly used for screening purposes, but also often 
measured longitudinally in AD clinical trials.30  It is a 30-point scale with higher scores indicating 
less impairment and lower scores indicating more impairment.  Seven items measuring orientation 
to time and place, registration, recall, attention, language, and drawing will be assessed. 
Wechsler Logical Memory Test 
The WMS-IV Logical Memory II Test (Delayed Paragraph Recall)31 consists of 2 stories for the 
assessment of free recall.  This modified version now contains a paragraph recall for the older age 
range of 65 to 90 years of age, where a new story was developed with content more relevant for 
this age group.  The new story is shorter and repeated once to enable an adequate floor through 
age 90.  Stories are not repeated for subjects who do not fall into the age range.  Immediate (LMI) 
and delayed recall (LMII) scores will be obtained.  Test result criteria for inclusion in the study 
based on LMII are provided in Section 9.3.1. 
Clinical Dementia Rating (CDR)  
The CDR is a clinical scale that describes 5 degrees of impairment in performance on each of 
6 categories of function including memory, orientation, judgment and problem solving, 
community affairs, home and hobbies, and personal care.32  The ratings of degree of impairment 
obtained on each of the 6 categories of function are synthesized into 1 global rating of dementia 
CDR score (ranging from 0 to 3).  A sum of boxes score provides an additional measure of change 
where each category has a maximum possible score of 3 points and the total score is a sum of the 
category scores giving a total possible score of 0 to 18 with higher scores indicating more 
impairment.  The global score will be used as a clinical measure of severity of dementia.  Test 
result criteria for inclusion in the study are given in Section 9.3.1. 
Geriatric Depression Scale 
The Geriatric Depression Scale (GDS): (Short Form) is a self-reported, clinician-assisted scale 
designed to identify symptoms of depression in the elderly.33  (revised per Amendment 01)  The 
scale consists of 15 printed questions that the subject is asked to answer by circling yes or no on 
the basis of how they felt over the past week.  The items are presented on a single page with more 
benign items presented first.  Answers to 5 of the items are negatively oriented for depression (eg, 
Do you feel full of energy?) and 10 positively oriented (eg, Do you often feel helpless?).  One 
point is given for each appropriate positive or negative answer indicative of a symptom of 
depression, for a possible total of 15 points.  Total scores of 0 to 5 are considered normal and 
scores of 6 to 15 are considered depressed.  Test result criteria for inclusion in the study are given 
in Section 9.3.2. 
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS- cog)  
The ADAS-Cog is the most widely used cognitive scale in Alzheimer's disease trials.  It is a 
structured scale that evaluates memory (word recall, delayed word recall, and word recognition), 
reasoning (following commands), language (naming, comprehension), orientation, ideational 
praxis (placing letter in envelope) and constructional praxis (copying geometric designs).34  
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Ratings of spoken language, language comprehension, word finding difficulty, ability to remember 
test instructions, maze, and number cancellation are also obtained.  The modified version used in 
this study is scored from 0 to 90 points with a score of 0 indicating no impairment, and a score of 
90 indicating maximum impairment.  
IMAGING ASSESSMENTS 
During the Screening Visit, subjects who meet psychometric assessment criteria for eligibility will 
undergo an eligibility assessment using safety MRI to detect brain abnormalities which may 
exclude study participation.  Safety MRI assessments will be conducted at regularly scheduled 
visits according to the Schedule of Procedures/Assessments.  In all cases, the safety MRI must be 
reviewed by both the imaging vendor and a local reader prior to administration of the next dose of 
study drug for each respective visit.  (revised per Amendment 06)  An additional scanning 
sequence will be conducted in all subjects to obtain vMRI assessments.  The safety and vMRI 
assessments conducted during Screening will also be used as the baseline MRI assessments for 
these respective measures in eligible subjects.  Methods for MRI assessments are described in 
Section 9.5.1.5.  
For further assessments of eligibility, all qualified subjects will then undergo amyloid positron 
emission tomography (amyloid PET) or CSF Aβ(1-42) at the Baseline Visit to confirm deposition 
of amyloid in the brain.  Baseline amyloid PET data will serve as the baseline data for subjects 
who consent to participate in the imaging subgroup (target n=306 total who complete 12 months 
of treatment in the Core Study) and who receive amyloid PET at 12 and 18 months of treatment.  
(revised per Amendment 08)  Methods for amyloid PET are described in Section 9.5.1.6.  (revised 
per Amendments 02, 06, and 07) 
Descriptions and detailed instructions for all imaging will be distributed to all imaging sites. 
BIOMARKER AND PHARMACOGENETIC SAMPLING 
At the Baseline Visit, blood samples will be drawn for PG assessment (mandatory APOE4) and 
for exploratory biomarkers consistent with Appendix 3, related to potential PD and safety readouts.  
(revised per Amendment 01) 
Also at the Baseline Visit, consenting subjects will undergo CSF sampling by LP.  Lumbar 
punctures for CSF sampling will again be performed at 12 and 18 months after the start of 
treatment.  Each subject should undergo all 3 LPs at approximately the same time of day.  The 
Baseline LP CSF sample will be used for eligibility and for establishing the subject’s baseline for 
the longitudinal assessment.  (revised per Amendment 06)  
9.5.1.3 Efficacy Assessments 
RATIONALE FOR PRIMARY EFFICACY ENDPOINT 
No well-established, validated clinical endpoints exist that are sensitive to change in MCI 
populations in clinical trials.  In fact, there has been concern that the standard cognitive instrument, 
the ADAS-Cog, may not have sufficient sensitivity to change even in a mild Alzheimer's disease 
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dementia population.  Demonstration of an effect on slowing clinical progression in an EAD 
population is hampered by this lack of sensitive tools for measuring relatively subtle longitudinal 
changes or treatment effect in early disease.  Heterogeneity of the MCI population as measured by 
established cognitive instruments, such as ADAS-Cog, presents another challenge for clinical trials 
in EAD and points to an acute need for a clinical tool that will be responsive to progression and 
treatment effects in EAD.  
Clinical data were utilized from multiple MCI trials to develop a new score that would demonstrate 
maximum responsiveness to progression and to treatment in an MCI population and that would 
also perform well in a mild Alzheimer’s disease dementia population.  A partial least squares (PLS) 
regression model used placebo data from 4 MCI studies over 12 months to select the combination 
of cognitive and functional items which is most sensitive to change over time, using items from a 
variety of well-established and validated scales.  The PLS regression coefficients from the model 
were used to form a weighted composite score.  The resulting composite comprises ADAS-Cog, 
MMSE and CDR items.  Responsiveness was assessed by comparing the Mean to Standard 
Deviation Ratio between the composite and standard scales in an MCI population.  Responsiveness 
was also assessed in enriched MCI subgroups (CSF Aβ positive and apolipoprotein E4 [APOE4] 
positive), in the presence of a treatment effect and in a mild Alzheimer’s disease dementia subject 
population combining placebo data from 3 studies.   
The new score is termed the Composite Clinical Score, and represents a new approach to the 
analysis of selected items (12 total) from the ADAS-Cog (4 items), the MMSE (2 items), and the 
CDR (all 6 items).  The composite score is more sensitive to clinical progression compared to 
currently existing clinical batteries and requires smaller sample sizes for clinical studies in EAD.  
(revised per Amendment 01)  It also shows sensitivity to treatment effects with AChEIs.  The 
composite score shows similar behavior in MCI due to AD and Mild Alzheimer’s disease 
dementia.  This score assesses both cognitive and functional domains and can be offered as a single 
primary clinical endpoint.  The Composite Clinical Score is calculated as described in 
Section 9.7.1.6.  It has a range from 0 to 1.97. 
To obtain a Composite Clinical Score each subject will be administered the MMSE, the CDR, and 
the ADAS-Cog.  Items from these 3 psychometric tests will be used as described in the calculation 
in Section 9.7.1.6 to derive the composite score.  The timing of these assessments is shown in the 
Schedule of Procedures/Assessments (Table 7 and Table 8 for the Core Study and Table 13 for the 
Extension Phase).  (revised per Amendment 08)  They should be administered in the morning or 
(if not possible for a given subject) consistently at the same time of day. 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic 
Assessments 
PHARMACOKINETIC ASSESSMENTS 
During the Randomization Phase, blood samples (3 ml each) will be collected from all subjects for 
determination of serum BAN2401 levels at approximately 12-week intervals (Table 8).  (revised 
per Amendment 08)   
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At Visit 3, blood will be taken for the BAN2401 assay approximately 4 hours after the end of 
infusion.  Subjects must stay in clinic for the full 4 hours following infusion during this first 
infusion visit.  At Visits 9, 16, 22, 29, 35, and 41, blood for this assay will be drawn both predose 
and at least 2 hours after the end of infusion.  These samples should not be taken from the same 
arm as that in which the study drug is infused.  Subjects must stay in clinic for at least 2 hours 
following infusion up through Week 13, Visit 9.  After the Week 13 Visit (Visit 9), if no untoward 
effects of infusion are noted, or if infusion reactions can be prevented with prophylaxis as per 
Section 9.5.1.5, subjects may be discharged from clinic 30 minutes after the end of infusion if 
judged medically stable by the investigator.  (revised per Amendment 07)  Subjects are required 
to remain in clinic for at least 2 hours following infusion at visits where PK samples are taken 
(except Visit 3, the first infusion visit).  PK samples should be taken at least 2 hours after the end 
of infusion.  These samples can be taken any time after those 2 hours and should generally be taken 
just prior to the subject leaving the site.  Each of the study sites will be provided with a laboratory 
manual describing the collection, handling, and shipping procedures for PK samples.  For subjects 
who participate in the CSF substudy, serum PK sample should also be taken immediately following 
the CSF collection that is to take place 2 to 4 days after study drug infusion at Visit 29.  For the 
same CSF substudy subjects, the CSF sample should be taken predose at Visit 41 and the predose 
serum PK sample at Visit 41 should be taken immediately after the CSF sampling.  (revised per 
Amendment 06)  Cerebrospinal fluid samples (see below, this Section, for CSF collection 
methods) will also be used for PK analyses.  Blood for PK analyses may also be drawn at the first 
report of a SAE and at its resolution.  (revised per Amendment 01)  
Samples from all subjects receiving active treatment will be analyzed.  Analyses of serum 
concentrations of BAN2401 will be performed by a CRO using a validated tandem 
immunoprecipitation liquid chromatography – tandem mass spectrometry (IP/LC-MS/MS) 
method in which anti-human IgG antibody precipitates BAN2401 from a serum sample.  
Precipitated BAN2401 will be isolated and will undergo proteolytic enzyme digestion to yield 
smaller peptides.  The amount of peptide with a sequence unique to BAN2401 will be measured 
by liquid chromatography – tandem mass spectrometry (LC-MS/MS) to provide a quantification 
of BAN2401.  Concentrations of BAN2401 in CSF will be measured by a similar, validated 
IP/LC-MS/MS method.   
PHARMACODYNAMIC ASSESSMENTS 
Not applicable. 
PHARMACOGENOMIC AND BIOMARKER ASSESSMENTS 
From subjects who have consented to participate in the CSF substudy, CSF (12 mL) will be drawn 
via LP at the Baseline Visit and at Visit 29 and Visit 41 (12 and 18 months) (Table 8 for the Core 
Study) (revised per Amendments 06 and 08).  The LPs at Baseline and Visits 29 and 41 should 
each be conducted at approximately the same time of day (revised per Amendment 06).  If for 
logistical reasons CSF fluid cannot be collected on the date specified for the Baseline Visit (Day -
30 to Day -1), collection may take place at an earlier date provided that consent has been obtained.  
Each of the study sites will be provided with a laboratory manual describing the preparation of 
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subjects for LP and the collection method (ie, only gravity drip method allowed), handling, and 
shipping procedures for PD samples.  (revised per Amendment 07)  
The Baseline LP CSF sample will be used for eligibility and for establishing the subject’s baseline 
for the longitudinal assessment.  CSF will be drawn via LP 2 to 4 days after the scheduled study 
Visit 29 (12 months).  CSF samples should be collected predose on the day of the Visit 41 infusion.  
For those subjects who also consent to both CSF assessment and to amyloid PET, CSF should be 
collected 2 to 4 days after study drug infusion at Visit 29, and the amyloid PET procedure should 
be scheduled to take place on a separate day within 10 days of Visit 29, but after CSF collection.  
(revised per Amendment 06)  
Cerebrospinal fluid concentrations of AD-related biomarkers including, but not restricted to Aβ 
and other isoforms, t-tau, and p-tau will be measured at Baseline and at 12 and 18 months of 
treatment in consenting subjects.  (revised per Amendment 01)  Amyloid and tau biomarkers are 
proposed to be tested using commercially available kits validated for use by a CRO.  CSF samples 
that are left over from the above analyses may be stored and analyzed for biomarkers related to 
disease mechanism or study drug for up to 15 years after the completion of the study (defined as 
submission of the CSR to appropriate regulatory agencies). 
Blood may also be drawn for exploratory plasma biomarker assessments at Baseline and at 12 and 
18 months of treatment to evaluate potential novel biomarkers of AD that may include amyloid 
isoforms, tau, microRNA, metabolites, and other protein biomarkers (eg, NFL) for association 
with AD diagnosis and amyloid load (see Appendix 3).  (revised per Amendment 11)  Similarly, 
biomarker discovery and validation may be performed to identify blood and genetic biomarkers 
which may be useful to predict subject PK and PD response, treatment response, subject 
stratification or adverse effects related to BAN2401. (revised per Amendment 01)  During the 
Prerandomization Phase, plasma samples will also be collected from all subjects at Baseline prior 
to amyloid PET assessment and at Visits 3, 9, 16, 29, 35, and 42.  (revised per Amendment 08) 
vMRI sequences will be collected for all subjects immediately following all safety MRI scans (as 
described in Section 9.5.1.5) except the Visit 6 abbreviated MRI assessment (safety MRI to detect 
ARIA lasting 8 to 10 minutes, with no vMRI sequences) conducted only at European sites (revised 
per Amendment 07).  vMRI data will be analyzed at the Screening Visit and at Visits 16, 29, and 
42 (6, 12, and 18 months of treatment) .  vMRI will be conducted at either 1.5T or 3T and across 
multiple scanner types and the type of scanner used will be documented.  vMRI analysis will be 
performed by a central imaging laboratory on MRI scans obtained at the Screening Visit and Visits 
16, 29, and 42 (6, 12, and 18 months) , according to standard QC 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. 
(revised per Amendment 01) 
Apolipoprotein E4 (APOE4) genotyping will be conducted (Appendix 3) and APOE4 negative or 
APOE4 homozygous or heterozygous status will be used in the statistical analysis to determine the 
effects on treatment response and safety.  This analysis will also assess possible relationships 
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between APOE4 genotype and the development of amyloid-related imaging abnormalities 
(ARIA), including vasogenic edema, microhemorrhages, macrohemorrhages, and superficial 
hemosiderosis.  (revised per Amendment 01) 
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 (Appendix 3).  
Because it is not possible to prospectively define every avenue of future testing, all samples 
collected will be single or double coded (according to ICHE15 guidelines:  Definitions for 
Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories EMEA/CHMP/ICH/437986/2006) to maintain the ethical principles underlying the 
provision of informed consent.  The focus of research will be the study of genetic factors likely to 
influence BAN2401 pharmacokinetics, therapeutic response, or susceptibility to Alzheimer's 
disease.  DNA that is left over may be stored and analyzed for up to 15 years after the completion 
of the study (defined as submission of the CSR to appropriate regulatory agencies).  The DNA 
may be used to examine the role of genetic variability in subjects’ absorption, distribution, 
metabolism, and excretion, or development of AEs.  Variation in BAN2401 exposure or AEs may 
be evaluated by correlation of single-nucleotide polymorphisms with PK, safety or PD data.   
PG and biomarker samples obtained from study subjects may be analyzed by global proteomic, 
metabolomic, or lipidomic and single or multiplex assays in an effort to identify predictive 
biomarkers for PK and PD.  In addition, biomarkers identified in other BAN2401 or AD clinical 
studies may also be assessed in samples collected from subjects enrolled in this study. 
Pharmacogenomic and biomarker analyses will be performed and reported separately.  Details of 
these analyses may be described in a separate analysis plan. 
9.5.1.5 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular monitoring 
of hematology, blood chemistry, and urine values; periodic measurement of vital signs and ECGs; 
and performance of physical examinations.  Additional safety assessments specific to this study 
will include brain MRI, anti-BAN2401 antibody assays, and the C-SSRS. 
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 BAN2401. 
The criteria for identifying AEs are: 
● Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product 
● Any new disease or exacerbation of an existing disease  
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● 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 withdrawal 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 43, as shown in Table 8 for the Core Study) (revised 
per Amendments 08, 09, and 11).  SAEs will be collected  up to 3 months after the last dose of 
study drug or through the last visit, whichever is longer.  This includes those subjects who 
discontinue from study drug and who return for regularly scheduled visits where clinical 
assessments are conducted.  (revised per Amendment 01)  
For subjects who transition to commercial BAN2401 (including the postmarketing section in 
Japan), all AEs (including SAEs) will be followed until the end of the study, which will be the date 
of the last study evaluation prior to transitioning to commercial BAN2401 and at which time all 
assessments included in Week 261/Early Termination Visit (Part A) and Early Termination Visit 
(Part B) are to be performed according to the Schedule of Assessments of Part A and Part B, 
respectively are to be performed.  (revised per Amendment 18 and 19) 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE.  Any laboratory abnormality considered 
to constitute an AE should be reported on the Adverse Event eCRF.  
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.   
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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 (1) the QTc interval is >450 ms and there is an 
increase of >60 ms from baseline, or (2) the QTc interval is >500 ms.  Any ECG abnormality that 
the investigator considers as an AE should be reported as such.   
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects and to 
determine if any of these results constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether or not an isolated suicidality rating scale response should be 
classified as an AE. 
Every effort must be made by the investigator to categorize each AE according to its severity 
and its relationship to the study treatment. 
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 Serious 
Adverse Events and Other Events of Interest (Section 9.5.1.5) for the definition of an SAE). 
ASSESSING RELATIONSHIP TO STUDY TREATMENT 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
● Temporal relationship of the onset of the event to the initiation of the study treatment 
● The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
● Whether the event is known to be associated with the study treatment or with other similar 
treatments 
● The presence of risk factors in the study subject known to increase the occurrence of the 
event 
● The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
CLASSIFICATION OF CAUSALITY 
Not Related 
A causal relationship between the study treatment and the AE is not a 
reasonable possibility. 
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Related 
A causal relationship between the study treatment and the AE is a 
reasonable possibility.  The investigator must further qualify the degree of 
certainty as “possible” or “probable.” 
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
An SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (ie, the subject was at immediate risk of death from the adverse 
event as it occurred; this does not include an event that, had it occurred in a more 
severe form or was allowed to continue, might have caused death) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or 
may require intervention to prevent 1 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.  Intracerebral hemorrhages >1 cm 
should always be classified as an important medical event and reported as an SAE, even if they do 
not meet other serious criteria.  (revised per Amendment 20) 
In addition to the above, other events of interest include pregnancy, any treatment-emergent 
significant laboratory abnormality, and vasogenic edema, macrohemorrhages, superficial 
siderosis, or new microhemorrhages on brain MRI, infusion reactions (any grade of severity as per 
NCI-CTCAE criteria), skin rash considered to be due to study drug, other hypersensitivity 
reactions, or a “yes” response to C-SSRS suicidal ideation type 4 or 5, an increase in body 
temperature to greater than 38ºC within 24 hours postdose, or AEs associated with study drug 
overdose, or medication error.  These events of interest are to be captured using the SAE 
procedures but are to be considered as SAEs only if they meet 1 of the above criteria, except for 
intracerebral hemorrhages >1 cm, which should always be classified as an important medical event 
and reported as an SAE even if they do not meet other serious 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 ‘other events of interest’ noted above, including those that are asymptomatic, are considered 
as AEs for the purposes of this protocol.  (revised per Amendment 20) 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(ie, there is no untoward medical occurrence) associated with the hospitalization: 
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● Hospitalizations for respite care  
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
● Hospitalization for administration of study drug or insertion of access for administration of 
study drug 
● Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
If possible, a blood sample for the measurement of study drug concentration should be drawn at 
the first report of an SAE or a severe unexpected AE and at its resolution.  (revised per Amendment 
01) 
LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, are 
summarized in Table 6.  Subjects should be in a seated or supine position during blood collection.  
The Schedule of Procedures/Assessments (Table 7 and Table 8 for the Core Study and Table 13 
for the Extension Phase) shows the visits and time points at which blood (10 mL) for clinical 
laboratory tests and urine for urinalysis will be collected in the study.  (revised per Amendment 
08)  All blood and urine samples will be collected and sent to the central laboratory on the day of 
collection.  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.  Results from the central laboratory 
will be electronically transferred to the clinical database.  If laboratory results suggest symptoms 
of hypersensitivity, the case should be discussed with the sponsor medical team and further 
investigations will be conducted as necessary. 
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Table 6 
Clinical Laboratory Tests (Revised per Amendment 11) 
Category 
Parameters 
Hematology 
hematocrit, hemoglobin, platelets, RBC count, and WBC count with 
differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils)  (revised per Amendment 01) 
Chemistry 
 
 
Electrolytes 
Bicarbonate, chloride, potassium, sodium  
 
Liver function tests 
alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin 
 
Renal function parameters 
blood urea/blood urea nitrogen, creatinine 
 
Other 
albumin, calcium, cholesterol, globulin, glucose, lactate dehydrogenase, 
total protein, triglycerides, uric acid 
Urinalysis 
Color, appearance, bacteria, casts, crystals, epithelial cells, glucose, 
ketones, occult blood, pH, protein, RBCs, specific gravity, WBCs, 
bilirubin, urobilinogen, yeast, mucus, nitrite, leucocyte esterase 
Other 
At screening only:  free T3, free T4, TSH, Vitamin B12, and HbA1c.  
 
At screening and Extension Screening Visit::  clotting screen 
(prothrombin time [PT, INR], activated partial thromboplastin time 
[APTT]) 
HbA1c =  hemoglobulin A1c, INR = international normalized ratio, RBC = red blood cell, T3 = triiodothyronine, 
T4 = thyroxine, TSH = thyroid stimulating hormone, WBC = white blood cell. 
Clinical laboratory tests during the study will be performed by the central laboratory for this study.  
Laboratory certification will be included in the final clinical study report for this study. 
Blood samples will be collected and stored and measurements of biomarkers related to 
hypersensitivity reactions may be conducted on these samples if safety data on hypersensitivity 
reactions (see Hypersensitivity Reactions below) indicate that it is appropriate to do so. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Adverse Events and Other Events of Interest [Section 9.5.1.5]) and the eCRF 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 Serious Adverse Events and Other 
Events of Interest, this Section), the site must fax or email the SAE report including the laboratory 
report (as regionally required) to the sponsor using the SAE form (see Reporting of Serious 
Adverse Events [Section 9.5.4.1]). 
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INFUSION REACTIONS 
Study drug infusion reactions (within 24 hours of infusion) must be reported as AEs of interest.  
They 
will 
be 
graded 
according 
to 
the 
NCI-CTCAE, 
Version 
4.0, 
grading 
of 
allergic/hypersensitivity reactions/cytokine release, as follows: (revised per Amendment 06) 
•Grade 1:  
mild reaction, infusion interruption not indicated, intervention not indicated  
•Grade 2:  
infusion interruption or treatment indicated, but responds promptly to 
symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory 
drugs (NSAIDs), IV fluids); prophylactic medications indicated for <24 hours 
•Grade 3:  
prolonged (eg, not rapidly responsive to symptomatic medications and/or brief 
interruption of infusion); recurrence of symptoms following initial 
improvement; hospitalization required for clinical sequelae (eg, renal 
impairment)  
•Grade 4:  
life-threatening consequences; urgent treatment needed (eg, vasopressor or 
ventilatory support) 
•Grade 5:  
death 
Infusion reactions of any grade outlined above (Grade 1-5) should be reported as AEs of special 
interest.  Subjects who experience infusion reactions of Grade 3 or 4 will be discontinued from 
study drug and will have an Early Termination Visit and a Follow-Up Visit 3 months after the last 
dose of study drug.  In addition, subjects who discontinue study drug are required to return after 
the Early Termination Visit for each scheduled visit when the clinical assessments of efficacy are 
to be conducted per the Schedule of Procedures/Assessments.  (revised per Amendment 06)  At 
these visits, safety information (in addition to efficacy assessments) on concomitant medications, 
AEs, and SAEs will be collected.  Unscheduled visits for safety may also be conducted as 
warranted in the clinical judgment of the investigator.  (revised per Amendment 01) 
The following are treatment guidelines for BAN2401 infusion reactions: 
Grade 2:  Stop the infusion.  Administer diphenhydramine hydrochloride 25 to 50 mg orally (PO) 
or dexamethasone 10 mg intravenously (IV) and acetaminophen 650 mg to 1 g PO.  (revised per 
Amendment 06)  The investigator may also use other antihistamines, corticosteroids, and anti-
inflammatory drugs as per local treatment guidelines.  If the infusion reaction improves or resolves, 
infusion may be resumed if the investigator considers it safe to do so in his/her clinical judgment.  
If so, then resume the infusion at 50% of the prior rate once the infusion reaction has resolved; the 
infusion duration should not exceed 2 hours.  Monitor for worsening of condition.  (revised per 
Amendment 06)   
For subsequent infusions, the investigator should consider premedicating with diphenhydramine 
hydrochloride 25 to 50 mg (PO or IV), dexamethasone (10 mg IV) and acetaminophen 650 mg to 
1 g orally.  Other antihistamines, corticosteroids, and anti-inflammatory drugs as per local 
treatment guidelines may be used as alternatives.  Use of dexamethasone or any other 
corticosteroids for premedication should be done with caution.  (revised per Amendment 06)  The 
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investigator should consider administering infusions at 50% of the original study rate.  If a subject 
does not experience infusion reactions upon the next several administrations, the investigator may 
stop premedicating the subject and may increase the infusion as per original study rate for 
subsequent infusions. 
Grade 3:  Stop the infusion and disconnect the infusion tubing from the subject.  Administer 
diphenhydramine hydrochloride 25 to 50 mg PO or IV, dexamethasone 10 mg IV (or equivalent), 
acetaminophen 650 mg to 1 g orally, bronchodilators for bronchospasms, and IV fluids for 
hypotension.  Administer other medications/treatments as medically indicated.  Hospital admission 
for observation may be indicated.  (revised per Amendment 06)  Discontinue subject from study 
drug and conduct an Early Termination Visit within 7 days of discontinuation and a Follow-Up 
Visit 3 months later.  (revised per Amendment 01) 
Grade 4:  Stop the infusion and disconnect the infusion tubing from the subject.  Administer 
diphenhydramine hydrochloride 25 to 50 mg PO or IV dexamethasone 10 mg IV (or equivalent), 
and acetaminophen 650 mg to 1 g orally, bronchodilators for bronchospasm, IV fluids and IV 
adrenaline for hypotension.  Administer other medications/treatments as medically indicated.  
Hospital admission for treatment is likely indicated.  Discontinue subject from study drug and 
conduct an Early Termination Visit within 7 days of discontinuation and a Follow-Up Visit 
3 months later. (revised per Amendment 01) 
HYPERSENSITIVITY REACTIONS 
Apart from infusion reactions, subjects will also be monitored for hypersensitivity reactions 
(thought to arise from Type II, III, IV, or other hypersensitivity mechanisms) by AEs, physical 
examinations, and laboratory tests.  The investigator should discuss with the sponsor’s medical 
team the clinical features or laboratory evidence associated with hypersensitivity reactions.  
Subjects who have hypersensitivity reactions with clinical features of tissue injury (eg, arthritis, 
glomerulonephritis, mononeuritis multiplex) will be discontinued from study drug but will comply 
with the Early Termination Visit (within 7 days after the last dose of study drug) and the 
Follow-Up Visit (3 months after the last dose of study drug).  (revised per Amendment 06)  In 
addition, subjects who discontinue study drug are required to return after the Early Termination 
Visit for each scheduled visit when the clinical assessments of efficacy are to be conducted per the 
Schedule of Procedures/Assessments.  At these visits, safety information (in addition to efficacy 
assessments) on concomitant medications, AEs, and SAEs will be collected.  (revised per 
Amendment 01) 
For hypersensitivity reactions in the skin, subjects may be treated with diphenhydramine 
hydrochloride 25 to 50 mg PO or IV.  Dermatologic opinion may be sought with regard to 
treatment with topical corticosteroids.  For hypersensitivity reactions in the skin, subjects need not 
be discontinued from study drug if such reactions are mild to moderate in intensity and respond to 
treatment, after discussion with sponsor medical monitor.  Otherwise the investigator should 
discontinue study drug in subjects whose skin hypersensitivity reactions are severe, or respond 
poorly to treatment, or likely to worsen with continued exposure to study drug.  (revised per 
Amendment 06)  For hypersensitivity reactions with other systemic manifestations or tissue injury, 
specialist opinion should be sought with regard to treatment.    
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VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats per 
minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained using validated methods, before and after infusions as indicated in the Schedule of 
Procedures/Assessments (Table 7 and Table 8 for the Core Study).  (revised per Amendment 08)  
All vital signs will be measured after the subject has been in a semi-supine position for 3 minutes.  
All BP measurements should be performed on the same arm, preferably by the same person.  
During Study Visits 3, 4, 5, and 6, vital signs should be obtained at least 2 hours after infusion.  If 
at those visits no untoward effects of infusions on vital signs are detected ≥2 hours after infusion 
(revised per Amendment 06), these assessments at subsequent study visits may be conducted at a 
shorter interval after infusion. 
PHYSICAL EXAMINATIONS 
A complete physical examination will be performed at Screening as described in Section 9.5.1.2.  
During the Randomization Phase, routine physical examinations will take place as shown in the 
Schedule of Procedures/Assessments (Table 8).  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. 
ELECTROCARDIOGRAMS 
Single ECGs will be obtained as designated on the Schedule of Procedures/Assessments Table 7 
and Table 8 for the Core Study).  (revised per Amendment 08)  An ECG abnormality may meet 
the criteria of an AE as described in this protocol (see Adverse Events and Other Events of Interest 
[Section 9.5.1.5]) and the eCRF 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 for an SAE (see Serious Adverse Events and Other Events 
of Interest [Section 9.5.1.5]), the site must fax or email the SAE report including the ECG report 
to the sponsor using the SAE form (see Reporting of Serious Adverse Events [Section 9.5.4.1]). 
If QTc is found to be out of range, 2 additional ECGs will be done to allow evaluation of triplicate 
ECGs.  The subject should be withdrawn if (1) the absolute value of the QTc becomes greater than 
500 ms absolute value or (2) if the QTc increases by more than 60 ms from baseline and the QTc 
is greater than 450 msec. 
BRAIN MRI 
During the Screening Period (Day –60 to Day –31), and during the Randomization Phase as shown 
in the Schedule of Assessments (Table 7 and Table 8 for the Core Study).  (revised per Amendment 
08), all subjects will undergo noncontrast MRI.  MRI may be conducted at any time following the 
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immediately preceding visit and prior to each of the designated study visits during treatment phase 
as shown in the Schedule of Assessments.  In all cases, the safety MRI must be reviewed by the 
imaging vendor and a local reader, with agreement that none of the abnormalities on MRI which 
require discontinuation of study drug are present, prior to a subject receiving the next dose of study 
drug.  (revised per Amendment 06)  In the event of an unscheduled visit, the investigator in 
consultation with the study medical monitor will determine whether or not a safety MRI should be 
conducted.  If an Early Termination Visit takes place, regardless of reason, an MRI is to be 
conducted if not performed within the last 90 days.  Sedation will be permitted prior to MRI.  A 
sufficient interval should be allowed between sedation and designated study visits during which 
psychometric testing takes place, such that there is no carryover of sedative effects which would 
interfere with testing. 
MRI imaging will include FLAIR, GRE, 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 (AV) 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 MR images 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) DICOM 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 IAG.  MRI acquisition and interpretation will be organized centrally to ensure reproducibility 
and consistency between units involved.  (revised per Amendment 01) 
At any time during the treatment period, subjects will be withdrawn from further dosing 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 events must be reported on 
the SAE form with the same reporting requirements as an SAE, but these events are not 
automatically considered SAEs, except for intracerebral hemorrhages >1 cm, which should always 
be classified as an important medical event and reported as an SAE even if they do not meet other 
serious criteria.  (revised per Amendments 06 and 20)  These subjects will undergo an Early 
Termination Visit within 7 days after discontinuation and a Follow-Up Visit 3 months after the 
last dose of treatment.  During this interval, they 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 90 days after the final dose of study drug.  In addition, subjects who discontinue 
study drug are required to return after the Early Termination Visit for each scheduled visit when 
the clinical assessments of efficacy are to be conducted per the Schedule of 
Procedures/Assessments.  (revised per Amendment 06)  At these visits, safety information (in 
addition to efficacy assessments)  on concomitant medications, AEs, and SAEs will be collected.  
(revised per Amendment 01) 
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Also, at any time during the treatment period, subjects who have nonsymptomatic, 
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 30 days 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.   
ANTI-BAN2401 ANTIBODY ASSESSMENT 
Blood for anti-BAN2401 antibody assessment will be collected predose in a blinded fashion from 
all subjects during the treatment period at Visits 3, 9, 16, 22, 29, 35, and 42 and at the Early 
Termination Visit (if applicable) and the Follow-Up Visit, as specified in the Schedule of 
Assessments (Table 8) (revised per Amendments 01 and 08).  Anti-BAN2401 antibodies will be 
processed in an ongoing basis.  The PI is required to evaluate whether a subject has any infusion 
reactions or hypersensitivity to the study medication based solely on clinical findings and 
laboratory results from hematology, biochemistry and urinalysis, and to decide if the subject 
should be withdrawn from treatment or receive prophylactic medications prior to the next infusion 
based on these clinical assessments as outlined in the protocol. 
PREGNANCY TEST 
During the Randomization Phase, at study visits specified in Table 7 and Table 8 for the Core 
Study (revised per Amendment 08), urine samples for pregnancy tests will be taken from females 
of childbearing potential as defined in Section 9.3.1, Inclusion Criterion 12.  Additionally, on the 
days on which PET scans take place, urine samples will be obtained from these subjects. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Subjects will be assessed for suicidal ideation and suicidal behavior using the C-SSRS according 
to the designed time points on the Schedule of Procedures/Assessments (Table 7, Table 8).  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 sponsor’s medical team.  The types of C-SSRS forms will be specified in the 
eCRF or a separate manual to the protocol.   
9.5.1.6 Other Assessments 
AMYLOID PET AND CSF Aβ(1-42) ASSESSMENT  (REVISED PER AMENDMENT 06) 
Amyloid PET imaging or CSF Aβ(1-42) assessment will be used to confirm that all subjects with 
EAD have amyloid deposition in the brain.  This criterion will allow for the definition of subjects 
with MCI due to AD – intermediate likelihood and will confirm amyloid pathology in mild 
Alzheimer’s disease dementia subjects.  Florbetapir, flutemetamol, florbetaben, or any approved 
agent may be used in Canada, the EU, or any other region in which the study is conducted.  For 
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screening purposes, the imaging agent of choice will be florbetapir at study sites in the US, while 
in other regions the choice of imaging agent will depend on local availability of imaging agent, 
thus allowing for use of florbetaben or flutemetamol as well as florbetapir.  (revised per 
Amendment 07) While florbetapir is the preferred agent in the US, flutemetamol, florbetaben, or 
any approved agent may be used in the US if needed.  For the longitudinal amyloid PET substudy 
in the Core Study, only florbetapir will be used in the US, while in other regions the choice of 
imaging agent will depend on local availability of the imaging agent, but the same tracer must be 
used across all PET assessments per subject.  (revised per Amendment 07) Florbetapir, 
flutemetamol, florbetaben, or any approved agent may be used in Canada, the EU, or any other 
region in which the study is conducted (revised per Amendments 02 and 06). Certification of PET 
scanners, quality control, and analysis of the PET images will be performed by a central vendor.  
To determine eligibility at Baseline during the Prerandomization Phase, within 20 days after the 
Baseline Visit, each subject will undergo CSF Aβ(1-42) assessment or amyloid PET imaging with 
1 of the aforementioned imaging agents.  Eligibility will be based on a binary read (normal or 
abnormal) for PET, or a specified cut-off for CSF Aβ(1-42).  (revised per Amendment 06)  
Subjects may consent to both the PET and CSF assessments, but only need a positive amyloid 
result in only one of the 2 procedures to confirm eligibility (ie, even if one of the 2 results does not 
meet its respective eligibility criterion).  Subjects who initially consent for only one of the amyloid 
screening assessments will only be allowed to subsequently consent for the second assessment 
should the first assessment result be positive or they have not yet been informed of the results of 
the first assessment (revised per Amendments 06 and 07).  To determine eligibility for the study 
according to CSF Aβ(1-42) levels, a cutoff value for CSF Aβ(1-42) collected using single LP 
during the Baseline Visit will be applied.  Subjects with CSF Aβ(1-42) levels less than this value 
will be eligible for the study.  (revised per Amendment 06) 
To determine whether or not the PET scan results allow the subject to remain eligible for the study, 
uptake patterns will be categorized as "normal" (ie, absence of amyloid deposition) or "abnormal" 
(ie, presence of amyloid deposition) by 2 independent readers, who will be blinded to each other's 
observations.  Each reader will perform a qualitative visual read of the PET scans and will 
separately categorize subjects as having either “normal” or “abnormal” uptake on the basis of the 
PET image pattern.  Readers will have been trained and certified to recognize brain PET images 
with abnormal or normal patterns of uptake.  Inter rater and intra rater reliability will be assessed 
at regular intervals throughout the study.  
Each subject's MRI scan will be warped into a template space and the same parameters will be 
applied to the subject’s PET scan, resulting in alignment of the MRI and amyloid PET to the 
template.  The template regions of interest will be then used to sample the warped PET images.  
Quantification of amyloid levels will be derived using an automated algorithm based on the 
standard uptake value ratio (SUVR) in the region of interest from 5 to 6 regions for each subject, 
including the precuneus, anterior cingulate gyrus, frontal lobe, parietal lobe, temporal lobe and the 
occipital lobe at Baseline and at 12 and 18 months of treatment.  A weighted average from these 
regions in addition to regional values will be derived at baseline and longitudinal assessments. 
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Subjects who consent to participate in the imaging subgroup (n=306 total who complete 12 months 
of treatment in the Core Study) will undergo amyloid PET scans at Visits 29 and 42 (12 and 
18 months).  Duration of the PET scan and its timing relative to injection of the imaging agent will 
as per the imaging agent manufacturer's guidance (revised per Amendments 02 and 07).  Subjects 
who participate in the imaging subgroup must undergo a baseline PET scan in this study (ie, 
historic PET scans are not allowed as baseline scans for the imaging subgroup).   
Baseline CSF samples will be used for eligibility and for establishing the subject’s baseline for the 
longitudinal assessment.  CSF will be drawn via LP 2 to 4 days after the scheduled study Visit 29 
(12 months).  CSF samples should be collected predose on the day of the Visit 41 infusion.  For 
those subjects who also consent to both CSF assessment and to amyloid PET, CSF should be 
collected 2 to 4 days after study drug infusion at Visit 29, and the amyloid PET procedure should 
be scheduled to take place on a separate day within 10 days of Visit 29 but after CSF collection.  
(revised per Amendment 06)  
FUNCTIONAL ASSESSMENTS QUESTIONNAIRE (FAQ) (REVISED PER AMENDMENT 01)  
On the basis of interviews with caregivers/informants or qualified partners, subjects will be rated 
for ability to carry out ten complex activities of daily living:  1) manage finances, 2) complete 
forms, 3) shop, 4) perform games of skill or hobbies, 5) prepare hot beverages, 6) prepare balanced 
meal, 7) follow current events, 8) attend to television programs, books, and magazines, 9) 
remember appointments, and 10) travel out of the neighborhood.35  Each activity will be rated as 
0 (normal, does without difficulty), 1 (has difficulty but does by self), 2 (requires assistance), or 3 
(dependent).  Scores will be summed across items to provide a total disability score (higher scores 
= greater impairment; maximum score = 30).  If an activity was never or very rarely performed 
premorbidly, it will be marked as “Not Applicable” and will not be included in the score.  A 
proportional score will be derived for subjects who mark any activity as ‘Not Applicable’ as 
follows (achieved score / (30 – 3 times the number of activities marked ‘Not Applicable’) 
MEDICAL CLAIMS SUBSTUDY (REVISED PER AMENDMENT 16)  
An optional medical claims substudy will be undertaken in the US only.  The purpose of this 
substudy is to use medical claims data to further evaluate patterns of resource utilization and 
associated costs of care for subjects with EAD and their study partners.  It will describe baseline 
characteristics of subjects with EAD for up to 5 years before study enrollment, for the duration of 
the Core Study, the duration of the period between the end of the Core Study and the Extension 
Baseline (if applicable), the duration of the Extension Phase (if applicable), and for up to 3 years 
after the end of the Core Study or Extension Phase (where applicable).  The analyses will measure 
the evolution of care and the appearance of various diagnoses as subjects progress from MCI or 
Mild AD to other diagnoses.  It will describe changes among subjects and study partners, in 
contrast to a comparison population consisting of a demographically matched cohort of non-EAD 
Medicare beneficiaries.  A survey of study partners will provide supplemental information on the 
experience of those individuals who are responsible for the care of subjects with EAD.  The survey 
data on burden to both subject and study partner health, utilization, and expenditure outcomes will 
be analyzed to explore the relationship between burden and subject/study partner health.  The 
survey will assess current burden and lost productivity, perceived changes in burden with the 
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introduction of the new medication, attitudes regarding medication safety and cost, and use of 
respite programs in which study partners may be participating.  The results of the medical claims 
substudy will be presented in a separate report.  (revised per Amendments 16 and 17) 
9.5.2 Schedule of Procedures/Assessments  
9.5.2.1 Schedule of Procedures/Assessments 
Table 7 presents the Schedule of Screening and Baseline Procedures/Assessments for the 
Prerandomization Phase.  Table 8 presents the Schedule of Procedures/Assessments for Visits 3 
through 27 (Panel A), and Visits 28 through 43, including the Follow-Up Visit (Panel B). 
Further information regarding assessments in the Extension Phase Part A and Part B are provided 
in Appendix 4 and Appendix 5, respectively. 
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Table 7 
Schedule of Screening and Baseline Procedures/Assessments (Visits 1 and 2), 
Study BAN2401-G000-201 – Core Study 
Phase 
Prerandomization 
Period 
Screening 
Baseline 
Visit 
1 
2 
Day 
-60 to -31 
-30 to -1 
Procedures/ Assessments 
 
Informed consent 
X 
 
Demographics 
X 
 
Medical history (including AD history) (revised 
per Amendment 01) 
X 
 
Inclusion/Exclusion 
X 
X 
Vital signs  
X 
X 
Height, weight, and BMIa 
X 
X 
Complete physical exam 
X 
 
Routine physical examination 
 
X 
12-lead ECG 
 
X 
Serum pregnancy testb 
X 
 
Urine pregnancy testb 
 
X 
Blood for laboratory tests 
X 
X 
Urinalysis (revised per Amendment 06) 
X 
X 
Urine drug screen 
X 
 
GDS 
X 
 
MMSE c 
X 
X 
WMS-IV LMI and LMIIc 
X 
 
CDRc 
X 
X 
ADAS-Cogc 
 
X 
FAQc 
  
X 
C-SSRS 
X 
X 
Safety MRI d 
X 
 
vMRI  (for PD)  
X 
 
Amyloid PETe 
 
X 
Blood for PGf 
 
X 
Blood for exploratory PD biomarker analysis 
 
X 
CSF sampling (for eligibility (revised per 
Amendment 06), PD and PK) ,g 
 
X 
Prior / concomitant meds including AChE 
inhibitors 
X 
X 
Adverse events 
X 
X 
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Table 7 
Schedule of Screening and Baseline Procedures/Assessments (Visits 1 and 2), 
Study BAN2401-G000-201 – Core Study 
AChE = acetylcholinesterase,  AD = Alzheimer’s disease, ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognitive subscale,  BMI = body 
mass index, CDR = Clinical Dementia Rating, CSF = cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, 
ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire, GDS = Geriatric Depression Scale, MCI = mild cognitive impairment,  
MMSE = Mini-Mental State Examination, MRI = magnetic resonance imaging, PD = pharmacodynamic, PET = positron emission tomography, 
PG = pharmacogenomic, PK = pharmacokinetic, vMRI = volumetric MRI, WMS-IV LMI= Wechsler Memory Scale-Logical Memory (subscale) I,  
WMS-IV LM II= Wechsler Memory Scale-Logical Memory (subscale) II (revised per Amendment 01) 
a: 
Height measured only at Screening.  BMI to be calculated at screening only. 
b: 
Pregnancy tests are only necessary for female subjects of childbearing potential.  For those subjects, an additional urine pregnancy test must 
be done on the day of Amyloid PET scanning. 
c: 
Clinical assessments must be administered before any other screening assessments are conducted.  These are to be completed in the morning 
whenever possible, or consistently at the same time of day.  The order of assessments for the Screening Visit is as follows:    MMSE, WMS-
IV LMI and II, and CDR. will be administered to all subjects and subjects will be diagnosed as either MCI due to AD or mild Alzheimer’s 
disease dementia as defined by the protocol after completion of MMSE, WMS-IV LMI, WMS-IV LMII, and CDR.  Once the diagnosis is 
made, the WMS-IV LMII inclusion criterion can be applied to all subjects. (revised per Amendment 06)  The WMS-IV LMII is to be 
administered 20 to 30 minutes after the completion of LMI.  Subject information should be collected in the 20 to 30 minutes between the 
WMS-IV LM1 and LMII.  Subjects who are considered ineligible for this study based on these assessments should not continue with the rest 
of the assessments for this visit.  The order of assessments for the Baseline Visit is as follows: MMSE, CDR, ADAS-Cog, and FAQ.  
Caregivers/informants need to be present at the Screening and Baseline Visits.  (revised per Amendment 01) 
d: 
For subjects who are approved for rescreening, safety MRI and vMRI need not be repeated if the date of the rescreen is <90 days from the 
date of the original screening MRI. 
e: 
Amyloid PET should be done at least 10 days before the planned randomization date.  For those subjects who consent to CSF and PET 
eligibility assessments, CSF collection should always precede amyloid PET, and the 2 assessments should be separated by at least 24 hours.  
For these subjects, a positive amyloid result is needed for only one of the procedures to confirm eligibility (ie, even if one of the 2 results 
renders the subject ineligible).  Subjects who initially consent for only one of the amyloid screening assessments will only be allowed to 
subsequently consent for the second assessment should the first assessment result be positive.  Subjects who consent to Amyloid PET or CSF 
Amyloid are not required to participate in the respective substudies.  For subjects who are approved for rescreening, the amyloid PET need 
not be repeated for eligibility if confirmed amyloid positive during the original screening procedure.  If a rescreened subject will participate 
in the longitudinal PET substudy, quantitative PET collection should be repeated if the original PET collection was done >6 months from the 
date of the original screening procedure. (revised per Amendments 06 and 07)  . 
f: 
For subjects who are approved for rescreening, pharmacogenetic testing need not be repeated if a sample was collected, processed, and 
APOE4 results issued during the previous screening procedure.  Great care must be taken to link the APOE status information with the new 
subject number.    
g: 
For those subjects who consent to the longitudinal CSF substudy, Baseline samples will be used for eligibility assessment and to establish a 
baseline measure for the longitudinal assessments.  CSF should be collected at or after the Baseline Visit, and at least 19 days (21 days for 
sites in the Asia-Pacific region) before the planned randomization date.  For those subjects who consent to both CSF and PET eligibility 
assessments, CSF collection should always precede amyloid PET, and the 2 assessments should be separated by at least 24 hours.  For these 
subjects, a positive amyloid result is needed for only one of the procedures to confirm eligibility (ie, even if one of the 2 results renders the 
subject ineligible).  For subjects who are approved for rescreening, the CSF need not be repeated for eligibility if confirmed amyloid positive 
during the original screening procedure.  If a rescreened subject will participate in the longitudinal CSF sub-study, quantitative CSF collection 
should be repeated if the original CSF collection was done > 6 months from the date of the original screening procedure.  (revised per 
Amendments 06 and 07) . 
 
 
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Table 8 
Schedule of Procedures/Assessments, Core Study BAN2401-G000-201, Panel A, Visits 3 
through 27, Weeks 1 through 49 – Core Study  
Phase 
Randomization  
Period 
Treatment 
Visita 
3
4
5 
6 
7
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Week 
1
3
5 
7 
9
11 
13 
15 
17 
19 
21 
23 
25 
27 
29 
31 
33 
35 
37 
39 
41 
43 
45 
47 
49 
Procedures/ Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X
X
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighte 
X
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Routine physical exam 
 
 
 
 
X
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
12-lead ECG 
 
 
 
 
X
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Urine pregnancy testf 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Blood for laboratory testsg 
X
X
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Urinalysis (revised per 
Amendment 06) 
X
X
 
X
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
MMSEh 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
CDRh 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
ADAS-Cogh 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
FAQh 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
C-SSRS 
 
 
X
 
X
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Safety MRIi 
 
 
 
 
X
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Volumetric MRI (for PD)j 
 
 
 
 
X
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Abbreviated MRIk 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consentl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amyloid PETm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
X
X
X
X
X
X 
X 
X 
X 
X 
Xn 
Xn 
Xn 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
Blood for serum BAN2401 
PKo 
X
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Blood for exploratory PD 
biomarker analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for serum 
anti-BAN2401p 
X
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
CSF samplingq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior / concomitant meds 
X
 
 
X
 
 
X 
 
 
X 
 
 
X 
 
 
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 
X 
X 
X 
X 
 
 
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Table 8 
Schedule of Procedures/Assessments, BAN2401-G000-201, Panel B, Visits 28 through 43, Weeks 
51 through 90 – Core Study 
Phase 
Randomization  
Period 
Treatment 
Early 
Termination 
Visitb 
Follow-Up 
Visit 
Unscheduled  
Visitc 
Visita 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
 
43 
-- 
Week
51 
53 
55 
57 
59 
61 
63 
65 
67 
69 
71 
73 
75 
77 
79 
 
90 
 
Procedures/ Assessments 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighte 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Routine physical exam 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
12-lead ECG 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Urine pregnancy testf 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
Laboratory testsg 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Urinalysis (revised per 
Amendment 06) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
MMSEh 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
CDRh 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
ADAS-Cogh 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
FAQh 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
C-SSRS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Safety MRIi 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Xi 
X 
X 
Volumetric MRI  (for PD)j 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
Abbreviated MRIk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consentl 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Amyloid PETm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
Xn 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
Xn 
Xn 
Xn 
Xn 
Xn 
X 
 
 
 
 
Blood for serum BAN2401 
PKo 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Blood for exploratory PD 
biomarker analysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood for serum 
anti-BAN2401p 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
CSF samplingq 
 
X 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
 
Prior / concomitant meds 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 8 
Schedule of Procedures/Assessments, BAN2401-G000-201, Panel B, Visits 28 through 43, Weeks 
51 through 90 – Core Study - Footnotes 
ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognitive subscale, AE = adverse event, ARIA = amyloid-related imaging abnormalities,  CDR = Clinical Dementia Rating, CSF = 
cerebrospinal fluid, C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, EU = European Union, FAQ = Functional Assessment Questionnaire, LP = lumbar puncture, 
MMSE = Mini-Mental State Examination, MRI = magnetic resonance imaging, PD = pharmacodynamic, PET = positron emission tomography, PK = pharmacokinetic. (revised per Amendment 
01) 
a: Assessments should take place on the first day of the study visit in the designated study week except as noted below (footnotes h, i, and j pertaining to imaging assessments, and footnote o 
pertaining to CSF sample collection).  A visit window of ± 8 days will be allowed for each visit, except for Visit 3.  A visit window of ± 7 days will be allowed for the Follow-Up Visit (Visit 
43).  (revised per Amendment 01) 
b: Subjects who discontinue the study or study drug early must comply with the Early Termination Visit (within 7 days after discontinuation the last dose of study drug) and the Follow-Up Visit 
(3 months after the last dose of study drug).  They may also have unscheduled visits for safety assessments.  Subjects who discontinue due to APOE status are expected to return for their 
Early Termination Visit and 3-month Follow-Up Visit (ie, 3 months after the last dose of study drug).  Subjects who discontinue due to AE (including ARIA) are not allowed to rescreen for 
Study BAN2401-G000-201 (revised per Amendment 06).  In addition, subjects who discontinue from study drug are expected to return after the Early Termination Visit for each scheduled 
visit when the clinical assessments of efficacy are to be conducted (Visits 9, 16, 22, 29, 35, and 42).  At these visits clinical efficacy assessments (MMSE, CDR, ADAS-Cog, and FAQ) will 
be conducted and information on concomitant medications, AEs, and SAEs will be collected.  Regularly scheduled clinical efficacy visits do not need to be attended if they fall within 8 days 
(visit window) of the Early Termination Visit or the 3-month Follow-Up Visit.  Subjects who discontinue 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 01) 
c: 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 assessments 
indicated under Unscheduled Visits need not always be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs. 
d: Vital signs will be measured both at predose and after infusion.  During Visits 3, 4, 5, and 6, vital signs should be recorded at least 2 hours after study drug infusion, in addition to predose. If 
at those visits no untoward effects of infusion on vital signs are detected ≥2 hours after infusion, these assessments at subsequent study visits may be conducted at a shorter interval after 
infusion.  (revised per Amendment 06)  At visits where no infusion takes place (Visits 42 and 43), vital signs will be measured once.  Vital sign measurements will consist of  systolic and 
diastolic blood pressure (mmHg) measured after at least 3 minutes in a semi supine position, pulse (beats per minute), respiratory rate (per minute), and body temperature (in centigrade). 
e: Weight will be taken in the clinic at designated visits (Visits 3, 9, 16, 22, 29, 35, and 43).  If a subject misses a clinic visit where weight is to be collected, subsequent visits should use the 
most recent, previous collected weight for infusion calculations until the next clinic visit.  Under such circumstances, weight is to be taken at the next clinic visit and entered into the IVRS 
even if the visit is not designated for weight data collection. 
f: Females of childbearing potential only 
g: Blood for laboratory tests will be taken 4 hours after the end of infusion at Visit 3 and predose at all other visits as indicated.  
h: Scales are to be completed in the morning (or, if not possible, consistently at the same time of day) in the following order on the days indicated:  MMSE, CDR, ADAS-Cog, and FAQ.  
Caregivers/informants (defined as a person able to support the subject for the duration of the study) need only to be present at visits where clinical assessment of MMSE, CDR, and ADAS-
Cog takes place.  (revised per Amendment 01) 
i: 
MRI imaging should be conducted at any time following the immediately preceding visit and prior to each of the following Visits according the Schedule of Procedures/Assessments: Visits 
7, 9, 16, 22, 29, 35, and 42 and at the Follow-Up Visit (Visit 43).  The MRI may be conducted on the same day as the immediately preceding visit, after dosing at that visit.  In all cases, the 
safety MRI must be reviewed by the imaging vendor and a local reader prior to a subject receiving the next dose of study drug. 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 Early Termination Visit takes place, an MRI is to be conducted if not already performed 
during the preceding 90 days. (revised per Amendments 04, 06, and 07) 
j: 
A volumetric MRI sequence will be collected in ALL subjects immediately following all safety MRI assessments.  Volumetric MRI data will be analyzed at the Screening Visit and at Visits 
16, 29, and 42.  
k: The Visit 6 abbreviated MRI will be conducted at EU sites only, and should be conducted at any time following the immediately preceding visit (Visit 5) and prior to dosing at Visit 6.  The 
Visit 6 MRI may be conducted on the same day as Visit 5 after subjects have been dosed.  This abbreviated MRI will be comprised of a safety MRI to detect ARIA, lasting approximately 8 to 
10 minutes.  Volumetric MRI sequences will not be conducted at this visit.  The safety MRI must be reviewed by the imaging vendor and a local reader prior to a subject receiving the next 
dose of study drug.  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 Early 
Termination Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  (revised per Amendment 07). 
l: 
Subjects can reconsent to enter the Extension Phase at this visit or any subsequent visit at which they are eligible.  Subjects must consent to the longitudinal PET substudy for the Extension 
Phase to participate in the substudy.  (revised per Amendment 11) 
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m: In the imaging subgroup only, amyloid PET imaging will be conducted on or within 10 days after the scheduled Visits 29 and 42 (12 and 18 months).  For those subjects who also consent to 
CSF assessment in addition to PET, CSF should be collected 2 to 4 days after study drug infusion at Visit 29, and the amyloid PET procedure should be scheduled to take place on a separate 
day within 10 days of Visit 29, but after CSF collection. (revised per protocol Amendment 06)  For those subjects who did not consent to the imaging substudy in the Core Study, a baseline 
scan can be taken at Visit 42 (Week 79).  Subjects who consented to the imaging subgroup in the Core Study may continue into the OLE if they reconsent. (revised per Amendments 08 and 
11). 
n: Subjects may be given the option to receive home infusions during the Core Study (per DSMB charter, if allowed and conducted according to country and local guidelines; home infusions 
will not be allowed in Germany) for study drug administration during Visits 13, 14, and 15, and Visits 17 through 21, Visits 23 through 28, Visits 30 through 34, and Visits 36 through 40, 
inclusive, provided they express no clinical features related to drug infusion during the first 4 months of the study.  Upon implementation of Amendment 07 newly enrolled subjects will not 
be offered the option for home infusions during the Core Study.  Subjects opting for home infusions before the implementation of Amendment 07 will be allowed to continue with home 
infusions for the duration of their participation in the Core Study.   (revised per Amendments 01, 03, 07, and 14)   
o: At Visit 3, blood will be taken for the BAN2401 assay approximately 4 hours after the end of infusion (before subjects leave the clinic for home).  Subjects must stay in clinic for the full 4 
hours following infusion during this first infusion visit.  Subjects must stay in clinic for at least 2 hours following infusion up through Week 13 (Visit 9).  After the Week 13 (Visit 9) Visit, 
if no untoward effects of infusion are noted, or infusion reactions can be prevented with prophylaxis, then subjects may be discharged from clinic 30 min after the end of infusion if judged 
medically stable by the investigator.  At Visits 9, 16, 22, 29, 35, and 41, blood will be taken for the BAN2401 assay both predose and at least 2 hours after the end of infusion (before 
subjects leave the clinic for home).  Subjects are required to remain in clinic for at least 2 hours following infusion at visits where PK samples are taken (except Visit 3, the first infusion 
visit).  PK samples should be taken at least 2 hours after the end of infusion.  These samples can be taken any time after those 2 hours and should generally be taken just prior to the subject 
leaving the site.  (revised per Amendment 01)  For subjects who participate in the CSF sub-study, serum PK sample should also be taken immediately following the CSF collection that is to 
take place 2 to 4 days after study drug infusion at Visit 29.  For the same CSF sub-study subjects, the CSF sample should be taken predose at Visit 41 and the predose serum PK sample at 
Visit 41 should be taken immediately after the CSF sampling. (revised per Amendments 06 and 07) 
p: Blood for the BAN2401 anti-drug antibody assay will be taken as follows: predose at Visits 3, 9, 16, 22, 29, 35, and 42, and the Follow-Up Visit (Visit 43).  Blood for the BAN2401 
anti-drug antibody assay will also be taken at the Early Termination Visit when applicable.   
q: Those subjects who consent to CSF assessments should have CSF drawn via LP 2 to 4 days after the scheduled study Visit 29 (12 months) infusion, and serum PK samples should be taken 
immediately following the CSF collection.  CSF samples should be collected predose on the day of the Visit 41 infusion.  (revised per Amendment 06) 
 
 
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9.5.2.2 Total Volume of Blood and CSF 
Table 9 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. 
Table 9 
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 
Clinical laboratory tests 
13 
2 x 12 mL 
11 x 10 mL 
134 mL 
Blood sampling for serum 
anti-BAN2401 
8 
- 
8 x 10 mL 
80 mL 
Blood sampling for serum 
BAN2401 PK 
13 
-- 
13 x3 mL 
39 mL 
APOE4 
pharmacogenomics 
1 
1 x 6 mL 
None 
6 mL 
Blood for exploratory 
biomarker analysis 
3 
1 x 6 mL 
2 x 6 mL 
18 mL 
All blood samples, total volume collected 
277 mL 
CSF sampling 
3 
1 x up to 12 mL 
2 x up to 12 mL 
Up to 36 mL 
APOE4 = apolipoprotein є4 variant, CSF = cerebrospinal fluid, PG = pharmacogenomic, PK = pharmacokinetic 
9.5.3 Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of Alzheimer’s 
disease.  The appropriateness of the Composite Clinical Score as an efficacy assessment is 
explained in Section 7.2.1. 
Standard safety assessments incorporated into this protocol include vital signs, clinical laboratory 
assessments, physical examinations, ECG measurements, and reports of AEs.  Amyloid-related 
imaging abnormalities (ARIAs) that have been associated with related therapeutic interventions in 
AD are readily detected by MRI as planned for this study, in accordance with FDA guidelines.   
The anti-BAN2401 assay was developed under the FDA guidance for detecting ADAs, and criteria 
for evaluating human samples have been developed using a preclinical (rabbit) positive control.  
The assay is run under GLP. 
The C-SSRS has been endorsed by the FDA as a measure of potential suicidality.36  
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9.5.4 Reporting of Serious Adverse Events, Pregnancy, and Other Events of Interest 
9.5.4.1 Reporting of Serious Adverse Events 
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, must 
be reported on a completed SAE form by email or fax as soon as possible but no later than 
24 hours after 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. 
Serious adverse events, 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.  This includes those subjects 
who discontinue from study drug and who return for regularly scheduled visits where clinical 
efficacy assessments are conducted.  Imaging center personnel should promptly report to the 
investigator any SAEs which occur while the subject is at the imaging center.  (revised per 
Amendment 01) 
For subjects who transition to commercial BAN2401 (including the postmarketing section in 
Japan), all AEs (including SAEs) will be followed until the end of the study, which will be the date 
of the last study evaluation prior to transitioning to commercial BAN2401 and at which time  all 
assessments included in Week 261/Early Termination Visit (Part A) and Early Termination Visit 
(Part B) are to be performed according to the Schedule of Assessments of Part A and Part B, 
respectively.  (revised per Amendment 18 and 19) 
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  Any SAE 
judged by the investigator to be related to the study treatment should be reported to the sponsor 
regardless of the length of time that has passed since study completion. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study File. 
For urgent safety issues call:  1-310-728-5684 (24/7 number).  For urgent safety issues, please 
ensure all appropriate medical care is administered to the subject and contact the appropriate study 
team member listed in the Investigator Study File. 
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. 
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The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if required 
by their institution.  A copy of this communication must be forwarded to the sponsor or its designee 
to be filed in the sponsor’s Trial Master File.   
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9.5.4.2 Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or within 
3 months of last study treatment or any exposure to study drug through breastfeeding during study 
treatment or within 3 months of last study treatment must be reported.  (revised per 
Amendment 01) 
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.  
Any pregnancy in which the estimated conception date is after using commercial BAN2401, 
reporting is not required as these events are collected separately as a spontaneous report.  (revised 
per Amendment 18) 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Reporting of Serious Adverse Events [Section 9.5.4.1]). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or email as 
soon as possible but no later than 1 business day from the date the investigator becomes aware of 
the pregnancy.  The contact information for the reporting of pregnancies and exposure to study 
drug through breastfeeding is provided in the Investigator Study File.  The Pregnancy Report Form 
must be used for reporting.  All pregnancies must be followed to outcome.  The outcome of the 
pregnancy must be reported as soon as possible but no later than 1 business day from the date the 
investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3 Reporting of Other Events of Interest 
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, MISUSE, 
ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol.  Overdose, 
misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose  
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the protocol  
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event  that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site 
personnel or the subject.   
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All AEs associated with an overdose should be captured on the Adverse Event eCRF.  Adverse 
events associated with overdose, misuse, abuse, or medication error should be reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1) even if the AEs do 
not meet serious criteria.  Abuse is always to be captured as an AE.  If the AE associated with an 
overdose, 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. 
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. 
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 (Serious Adverse Events and Other Events of Interest) 
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.  
REPORTING OF STUDY-SPECIFIC EVENTS 
Study-specific events, including pregnancy, any treatment-emergent significant laboratory 
abnormality, and vasogenic edema (ARIA-E), macrohemorrhages, superficial siderosis, or new 
cerebral microhemorrhages on brain MRI, infusion reactions (any grade of severity as per 
NCI-CTCAE criteria), skin rash considered to be due to study drug, other hypersensitivity 
reactions, or a “yes” response to C-SSRS suicidal ideation type 4 or 5, an increase in body 
temperature to greater than 38ºC within 24 hours postdose, or AEs associated with study drug 
overdose, or medication error, 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.  (revised per Amendment 08)  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 and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within specific time 
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frames).  For this reason, it is imperative that sites provide complete SAE information in the 
manner described above. 
9.5.4.5 Breaking the Blind 
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code for an 
individual subject.  In all such cases, the AE necessitating the emergency blind break will be 
handled as an SAE in accordance with the procedures indicated above.  Any broken code will be 
clearly justified and documented.  The medical monitor must be notified immediately of the blind 
break. 
9.5.4.6 Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor or a third party acting on behalf of the sponsor to 
regulatory authorities in compliance with local and regional law and established guidance.  The 
format of these reports will be dictated by the local and regional requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All suspected 
unexpected serious adverse reactions (SUSARs) will be reported, as required, to the competent 
authorities of all involved European member states. 
9.5.5 Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason.  Subjects who discontinue 
the study or study drug early must comply with the Early Termination Visit (within 7 days after 
the last dose of study drug) and the Follow-Up Visit (3 months after the last dose of study drug).  
They may also have unscheduled visits for safety assessments.  Subjects who discontinued the 
Core Study due to APOE status are expected to return for their Early Termination Visit and 
3-month Follow-Up Visit (ie, 3 months after the last dose of study drug).  In addition, subjects 
who discontinue from study drug are expected to return after the Early Termination Visit for each 
scheduled visit when the clinical assessments of efficacy are to be conducted (Visits 9, 16, 22, 29, 
35, and 42) per the Schedule of Procedures/Assessments (Table 8).  At these visits, clinical 
efficacy assessments (MMSE, CDR, ADAS-Cog, and FAQ) will be completed and information 
on concomitant medications, AEs, and SAEs will be collected from these subjects.  Regularly 
scheduled clinical efficacy visits do not need to be attended if they fall within 8 days after the Early 
Termination Visit or within ±8 days of the 3-month Follow-Up Visit.  Subjects who complete the 
Core Study may elect to continue into the Extension Phase Part A if the criterion is met (see 
Appendix 4).  Subjects who discontinue study drug in the Extension Phase will not be required to 
return after the Early Termination Visit for each scheduled visit when clinical efficacy assessments 
are conducted.  Subjects in the Extension Phase who discontinue the study or study drug early are 
requested to undertake the Early Termination Visit (within 7 days after the last dose of study drug) 
and the Follow-Up Visit (3 months after the last dose of study drug).  The 3-month Follow-Up 
Visit is not required for any subject who transitions directly from the Extension Phase Part A or 
Part B (including the postmarketing section in Japan) of the study to commercial BAN2401 
(revised per Amendments 08, 11, 17, and 18).  Upon approval of BAN2401 in Japan, subjects who 
meet the approved indication and dosage of BAN2401 will continue in Extension Phase Part A or 
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B of this study as a postmarketing part in Japan.  Treatment will continue until BAN2401 is 
commercially available for individual subjects at each study site, at which time the subjects will 
switch to commercial BAN2401.  For those subjects who transition to commercial BAN2401 
(including the postmarketing section in Japan), the end of the study will be the date of the last 
study evaluation prior to transitioning to commercial BAN2401 and at which time, all assessments 
included in Week 261/Early Termination Visit (Part A) and Early Termination Visit (Part B) are 
to be performed according to the Schedule of Assessments of Part A and Part B, respectively.  
(revised per Amendments 18 and 19) 
Subjects who discontinue 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 due to AE will not be allowed to rescreen for the BAN2401-G000-201 
study.  Subjects who discontinue due to ARIA will be unblinded by the sponsor.  (revised per 
Amendments 06 and 11)   
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.  This 
information will be recorded in the eCRF. 
Subjects who discontinue early from the study will be discontinued for 1 of these primary reasons: 
AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study terminated by 
sponsor, or other.  In addition to the primary reason, the subject may indicate 1 or more of 
secondary reasons 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 
Not applicable.  The study drug is to be administered by study site personnel. 
9.5.7 Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects to inform site personnel when they are planning to receive 
medical care by another physician.  At each visit, the investigator will ask the subject whether 
he/she has received medical care by another physician since the last visit or is planning to do so in 
the future.  When the subject is going to receive medical care by another physician, the 
investigator, with the consent of the subject, will inform the other physician that the subject is 
participating in the clinical study. 
9.6 
DATA QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines.  Site 
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audits will be conducted 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, which constitute into a validated 
data management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the eCRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject. 
Data collection on the eCRF must follow the instructions described in the CRF Completion 
Guidelines.  All activities, including remote assessments, must be documented with a clear 
description of how this is related to the COVID-19 pandemic (or other extenuating circumstances).  
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.  
(revised per Amendment 15) 
Completed eCRF case books are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 
9.6.2 Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All data, 
both CRF and external data (eg, laboratory data), will be entered into a clinical system. 
9.7 
STATISTICAL METHODS 
All statistical analyses will be performed by the sponsor or designee after the database is locked 
and released for unblinding.  (revised per Amendment 07)  At each IA of the primary endpoint, a 
snapshot of the data will obtained and released for analysis.  A copy of this snapshot will be 
archived.  This process will also be followed for the safety data that will be used for analysis for 
the DSMB.  Statistical analyses will be performed using SAS software or other validated statistical 
software as required.  All statistical tests will be based on the 10% level of significance, except for 
the Bayesian methods on the primary endpoint (revised per Amendments 09 and 10).  Details of 
the statistical analyses will be included in a separate statistical analysis plan (SAP). 
9.7.1 Statistical and Analytical Plans 
The statistical analyses of the BAN2401-G000-201 study data are described in this section.  
Further details of the analysis plan will be provided in the SAP, which will be finalized before the 
first IA. 
In this Phase 2 dose-finding study of BAN2401 for the treatment of EAD, response adaptive 
randomization will be used to allocate subjects to placebo control or 1 of the 5 active doses with 
the goal of characterizing the dose response.  The study will be monitored for early success and 
early futility.  The sponsor intends that the futility rule for stopping will be binding.  If the study 
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continues to randomize subjects after futility is declared, it will be considered a failed study.  
(revised per Amendment 01) 
9.7.1.1 Study Endpoints 
PRIMARY ENDPOINT: 
 Change from baseline in the ADCOMS at 12 months 
KEY SECONDARY ENDPOINTS:  (revised per Amendments 09 and 10) 
 Change from baseline at 18 months in brain amyloid pathophysiology as measured by 
amyloid PET  (revised per Amendments 09 and 10) 
 Change from baseline in the ADCOMS at 18 months  (revised per Amendment 09) 
 Change from baseline in CDR-SB at 18 months  (revised per Amendments 09 and 10) 
 Change from baseline in ADAS-Cog at 18 months  (revised per Amendments 09 and 10) 
 Change from baseline in CSF biomarkers (Aβ[1-42], t-tau, and p-tau) at 18 months  
(revised per Amendment 10) 
 Change from baseline in total hippocampal volume at 18 months using vMRI  (revised per 
Amendments 09 and 10) 
SECONDARY ENDPOINTS:  (revised per Amendments 09 and 10) 
 Change from baseline at 12 months in brain amyloid pathophysiology as measured by 
amyloid PET  (revised per Amendments 09 and 10) 
 Change from baseline at 12 months on clinical status for the following assessments: 
ADCOMS, CDR-SB, and ADAS-Cog  (revised per Amendment 10) 
 Change from baseline in CSF biomarkers (Aβ[1-42], t-tau, and p-tau) at 12 months (revised 
per Amendment 10) 
 Change from baseline in total hippocampal at 6 and 12 months, and in left and right 
hippocampus, whole brain, and total ventricular volume as measured by vMRI at 6, 12, 
and 18 months  (revised per Amendment 10)  
EXPLORATORY ENDPOINTS: 
 Change from baseline in clinical status at time points not analyzed in Key Secondary and 
Secondary sections for each of the following:  ADCOMS, ADAS-Cog, CDR-SB, MMSE, 
and FAQ  (revised per Amendment 10) 
9.7.1.2 Definitions of Analysis Sets 
The Randomized Set is the group of subjects who are randomized to study drug. 
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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 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 PK Analysis Set is the group of subjects with at least 1 quantifiable BAN2401 serum 
concentration with a documented dosing history. 
The PD Analysis Set is the group of subjects who have sufficient PD data to derive at least 1 PD 
parameter. 
The Per Protocol (PP) Analysis Set is the subset of subjects in the Full Analysis Set who 
sufficiently complied with the protocol.  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 SAP. 
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/exclusion criteria, AE, lost to follow-up, withdrawal consent, and other, will be 
presented. 
Study Completion:  the number (percent) of randomized and treated subjects who completed the 
study and who discontinued from the study will be summarized according to the primary reason 
for discontinuation and secondary reason(s) for discontinuation, based on data reported on the 
Subject Disposition (Study Phase) CRF.  The number (percent) will be presented by treatment 
group and total for subjects; randomized, not treated, treated, who completed the study, and 
discontinued from the study.  The primary reasons for discontinuation from the study are; AE, lost 
to follow-up, subject choice, withdrawal 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 treatment and who discontinued from study treatment will be summarized 
according to the primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on both the Subject Disposition (Study Phase) eCRF and 
Early Discontinuation from Study Drug eCRF.  The number (percent) will be presented by 
treatment group and total for subjects; randomized, not treated, treated, who completed study 
treatment, and discontinued from study treatment.  The primary reasons for discontinuation from 
the study treatment are:  AE, lost to follow-up, subject choice, withdrawal of consent, pregnancy, 
study terminated by sponsor, inadequate therapeutic response, and other (revised per 
Amendment 01).  The secondary reasons for discontinuation from the study are:  AE, subject 
choice, and other. 
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9.7.1.4 Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics for the Safety Analysis set and Full Analysis set will be 
summarized for each treatment group using descriptive statistics.  Continuous demographic and 
baseline variables include age, WMS-IV LMII, Geriatric Depression scale, MMSE; categorical 
variables include age ≤65 years, age >65 years, sex, race, ethnicity, CDR score, memory box score 
of the CDR, positive amyloid load, APOE4 genotype and clinical subgroup (MCI due to AD – 
intermediate likelihood or mild Alzheimer’s disease dementia).  
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.  The number (percentage) of subjects who 
took prior and concomitant medications will be summarized on the Safety Analysis Set by 
treatment group, Anatomical Therapeutic Chemical (ATC), and the World Health Organization 
Drug Dictionary preferred term.  Prior medications are defined as medications that stopped before 
the first dose of study drug.  Concomitant medications are defined as medications that (1) started 
before the first dose of study drug and were continuing at the time of the first dose of study drug, 
or (2) started on or after the date of the first dose of study drug and continued up to the last dose. 
9.7.1.6  Efficacy Analyses 
ADAPTIVE TRIAL DEFINITIONS  
Clinically Significant Difference (CSD):  The CSD used in the adaptive model relative to the 
change from baseline over time for placebo in the ADCOMS.  The CSD for this study represents 
an approximate 25% reduction compared to placebo in the progression of AD as measured by the 
ADCOMS. 
Maximum Effective Dose (dMax):  The dose that achieves the greatest treatment effect  
ED90:  The ‘simplest’ dose regimen that achieves at least 90% of the dMax treatment effect.  The 
term ‘simplest’ reflects the preference for dosing frequency and amount when considering the 
treatment arms for the study and while taking efficacy into account (monthly administration is 
preferred over biweekly administration and lower doses are preferred over higher doses, with 
priority placed on frequency of administration).  Thus, the rank order of prioritized doses 
(beginning with the simplest) is:  5 mg/kg Q4wk, 10 mg/kg Q4wk, 2.5 mg/kg Q2wk, 5 mg/kg 
Q2wk, and 10 mg/kg Q2wk. 
Early Success:  The study meets early success criteria if the probability that the ED90 is better than 
the placebo by the CSD is at least 0.95.  Early success is achieved before all subjects complete 
12 months of treatment and can only be determined once ≥350 subjects are randomized.  If early 
success is declared prior to full enrollment, randomization of new subjects will stop, outside Japan.  
Sites in Japan will randomize up to 40 Japanese subjects even if early success is declared or the 
study achieves 800 subjects randomized.  All randomized Japanese subjects in the study will 
receive up to 18 months of treatment in the Core Study and are eligible to participate in the 
Extension Phase if implemented.  (revised per Amendments 07, 08, and 11) 
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Futility:  The study meets statistical futility criteria if the probability that the ED90 is better than 
the placebo by the CSD is less than 0.05 (with ≤300 subjects randomized) or 0.075 (with 
≥350 subjects randomized) at 12 months of treatment.  If the study meets statistical futility criteria, 
the sponsor will make the final decision pertaining to study futility after reviewing 
recommendations by the DSMB.  Based on the sponsor's final decision, if the study continues after 
statistical futility criteria are met, it will be considered a failed study.  (revised per Amendment 01) 
The study will be considered a success if either of the following criteria are met: 
1. The study meets early success criteria 
2. The study reaches complete randomization and the Bayesian analysis at completion of 
12 months of treatment results in an ED90 with at least an 80% probability of being better 
than the placebo by the CSD  (revised per Amendment 09) 
ANALYSIS OF PRIMARY EFFICACY ENDPOINT (REVISED PER AMENDMENT 09) 
The primary analysis will be based on subjects from the Full Analysis Set with the prespecified 
censoring rules applied.  Japanese subjects who are randomized after early success is declared or 
the study achieves 800 subjects randomized will not be included in the primary analysis.  (revised 
per Amendment 07)  The primary endpoint is the change from baseline to 12 months in the 
ADCOMS.  The ADCOMS is a weighted linear combination of 12 items from the 3 existing 
clinical scales, the ADAS-Cog, the MMSE, and the CDR.  These 12 items consist of the predictive 
variables A4, A7, A8, A11, M1, M7, C1, C2, C3, C4, C5, and C6, which have been selected from 
the clinical scales, the ADAS-Cog, the MMSE, and the CDR.  The names of these item and the 
corresponding scale names are described in Table 10.  
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Table 10 
Predictive Variables for the ADCOMS 
Scale 
Item ID 
Item Name 
PLS weight 
ADAS-Cog 
A4 
Delayed Word Recall 
0.00847483 
A7 
Orientation 
0.017088 
A8 
Word Recognition 
0.003732761 
A11 
Word Finding 
0.016211 
MMSE 
M1 
Orientation Time 
0.041567 
M7 
Drawing 
0.038238 
CDR 
C1 
Personal Care 
0.054321 
C2 
Community Affairs 
0.1091 
C3 
Home and Hobbies 
0.089039 
C4 
Judgment and Problem Solving 
0.069493 
C5 
Memory 
0.058724 
C6 
Orientation 
0.078152 
ADAS-Cog = Alzheimer’s Disease Assessment Scale, cognitive subscale, CDR = Clinical Dementia Rating, ID = identification,
MMSE = Mini-Mental State Examination, PLS = Partial Least Squares. 
The maximum ADCOMS is achieved when each item is assigned the maximum score.  This 
maximum composite score is 1.97.  The range of this new composite score is therefore between 0 
and 1.97. 
The primary endpoint is the change from baseline to 12 months in the ADCOMS.  The dose 
response of the primary endpoint is modeled with a 2-dimensional 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 the CSD compared to the placebo arm.  At each Bayesian analysis, 3 Bayesian 
probabilities will be summarized for each active dose:  the probability of being the ED90 dose, the 
probability of being statistically superior to placebo, and the probability of being statistically 
superior to placebo by the CSD.  The study will be considered a success in the Bayesian analysis 
at the completion of 12 months of treatment if there is at least an 80% probability that the ED90 
achieves the CSD from placebo.  (revised per Amendment 09) 
For the clinical efficacy data (ie, derived Clinical Composite Score, MMSE, CDR-SB, 
ADAS-Cog, and FAQ), subjects will be censored at the time of initiation of new AChEIs or 
memantine treatment regimens if they were not on AChEIs or memantine at randomization, and 
will be censored at the time of dose adjustment of AChEIs or memantine if they were already on 
stable treatment with AChEIs or memantine at randomization.  The value of the primary endpoint 
for censored subjects will be imputed using data up to the censoring time and the Bayesian 
imputation method. 
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:  (revised per Amendment 01) 
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 The primary endpoint will be analyzed regardless of initiation of new AChEIs or 
memantine or dose adjustment of stable AChEIs or memantine, using the same Bayesian 
analysis method as in the primary analysis.  (revised per Amendment 01) 
 In case of early success, the primary analysis as well as the above sensitivity analyses will 
be repeated after all subjects have either completed 12 months follow up or are lost to 
follow-up.  (revised per Amendment 01) 
Statistical methods for the conventional analyses of primary efficacy endpoint will use a mixed 
effects model with repeated measures (MMRM) comparing placebo to the identified ED90 dose 
from the Bayesian analysis (revised per Amendment 09).  The model will include randomization 
of stratification variables, clinical subgroup (MCI due to AD, mild AD), the presence or absence 
of ongoing AD treatment (ie, AChEIs or memantine or both), APOE4 status (positive, negative), 
and baseline Composite Clinical Score as covariates.  These analyses will be performed on the 
Full Analysis Set as well as the PP set based on the ITT principle.  In case of early success, the 
conventional analyses will also be performed using the data collected prior to the IA.  (revised per 
Amendment 01) 
ANALYSIS OF KEY SECONDARY EFFICACY ENDPOINTS (REVISED PER AMENDMENTS 09 AND 10) 
Key Secondary endpoints were ordered to reflect the most recent FDA Draft Guidance and EMA 
Guideline that prioritizes effects on pathophysiology in early AD, as measured by biomarkers 
(February, 2018).  Conventional analysis will be performed using all available data at the time of 
success (if applicable), and at 18 months of treatment, regardless of success.  An MMRM will be 
used to compare the combined 10 mg dose group (including biweekly and monthly regimens) with 
placebo for the key secondary endpoints (revised per Amendments 09 and 10).  The rationale for 
combining the two 10-mg dose regimens is to account for the loss of subjects positive for APOE4 
in the 10 mg/kg biweekly dose group and the inability to randomize APOE4 carriers to the 
10 mg/kg biweekly group following a Regulatory request by European Health Authorities in July, 
2014.  The key Secondary endpoint based on clinical status (ADCOMS, CDR-SB, and 
ADAS-Cog) will be analyzed in subjects with EAD as well as separately within subjects with MCI 
and mild AD dementia.  (revised per Amendment 10)   
In addition, as sensitivity analysis, MMRM analysis will be performed for the following treatment 
comparisons:  (revised per Amendment 10) 
 Combining 2 high doses (10 mg biweekly + 10 mg monthly), 2 middle doses (5 mg 
biweekly + 5 mg monthly), and the 2.5 mg biweekly dose, resulting in 3 treatment 
comparisons with placebo (for dose response)  (revised per Amendment 10) 
 ED90 dose of BAN2401 versus placebo, where the ED90 dose of BAN2401 will be 
established by Bayesian analysis at 18 months as described in the next paragraph  
(revised per Amendment 10) 
 By treatment regimen (10 mg biweekly, 10 mg monthly, 5 mg biweekly, 5 mg monthly, 
2.5 mg biweekly, placebo)  (revised per Amendment 10) 
 Combining the top 3 doses (10 mg biweekly, 10 mg monthly, and 5 mg biweekly) versus 
placebo  (revised per Amendment 10) 
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Change from baseline in the ADCOMS at 18 months will be analyzed, as a sensitivity analysis to 
the conventional analysis, using the same Bayesian methodology as that for analysis of change 
from baseline in the ADCOMS at 12 months, but using the full 18 months of efficacy data with 
the model projecting to 18 months of treatment.  The Bayesian analysis of change from baseline 
in the ADCOMS at 18 months is positive if the analysis results in an ED90 dose with at least an 
80% probability of being better than the placebo by the CSD.  The ED90 dose will be identified 
based on change from baseline in the ADCOMS at the 18 month Bayesian analysis and will be 
used to compare ED90 dose of BAN2401 and placebo in the above sensitivity analyses for all key 
secondary endpoint analyses.  (revised per Amendments 09 and 10) 
ANALYSIS FOR OTHER SECONDARY EFFICACY ENDPOINTS 
The same analysis described above for key secondary endpoints will be performed for other 
secondary endpoints.  (revised per Amendment 10) 
EXPLORATORY EFFICACY ANALYSES 
The same analysis described above for key secondary endpoints will be performed for exploratory 
endpoints.  (revised per Amendment 10) 
The effect of baseline brain amyloid pathopohysiology as measured by amyloid PET on change 
from baseline in clinical status at 12 and 18 months of treatment will be explored using correlation 
analysis and evaluated using statistical models as appropriate.  (revised per Amendment 10) 
The relationship between change from baseline in clinical status and change from baseline in brain 
amyloid pathopohysiology at 12 and 18 months of treatment as measured by amyloid PET will be 
explored by correlation analysis.  (revised per Amendment 10) 
Change in ADCOMS and its components, ADAS-Cog, CDR-SB, and MMSE across all clinical 
assessment time points between BAN2401 and placebo in Japanese subjects will be evaluated 
using the descriptive statistics within Japanese subjects as well as with the overall population.  
(revised per Amendments 07 and 10)  
9.7.1.7 Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic Analyses 
PHARMACOKINETIC ANALYSES 
The Safety Analysis Set will be used for individual BAN2401 serum and CSF concentration 
listings.  The PK Analysis Set will be used for summaries of BAN2401 serum and CSF 
concentrations.  
A population PK approach will be used to characterize the PK of BAN2401.  The effect of 
covariates (ie, demographics) on BAN2401 PK will be evaluated.  The PK model will be 
parameterized for clearance (CL) and volumes of distribution.  Derived exposure parameters such 
as AUC will be calculated from the model using the individual posterior estimate of CL and dosing 
history.   
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PHARMACODYNAMIC ANALYSES 
The PD Analysis Set will be used for the summaries and analyses of CSF biomarkers.  CSF 
Aβ(1-42), t-tau, and p-tau will be assessed and data 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-PHARMACODYNAMIC ANALYSES 
The PK/PD relationship between CSF biomarker levels and serum PK parameters or CSF 
concentrations of BAN2401 will be explored graphically and any emergent relationship will be 
explored through population PK/PD modeling.  These serum PK parameters include SS, Cmax and 
AUC(0-t) derived from the population PK model.  The PK/PD relationship between serum PK 
parameters and CSF concentrations of BAN2401 with other biomarkers may also be explored 
using similar methods. 
Additionally, the relationship between various serum PK parameters (eg, Cmax) or CSF 
concentrations of BAN2401 (Core Study only) and the ADCOMS at 12, 18, 30, and 42 months, 
and the relationship between various serum PK exposure parameters or CSF concentrations of 
BAN2401 and the change from Baseline for 12, 18, 30, and 42 months in the ADAS-Cog, the 
CDR-SB, and the MMSE, will be explored graphically (revised per Amendments 08 and 11).  Any 
emergent relationships will be explored through population PK/PD modeling. 
The relationship between exposure to BAN2401 and most frequent AEs will also be explored. 
PHARMACOGENOMIC/PHARMACOGENETIC ANALYSES 
APOE4 genotypes or other important genomic/genetic findings will be used in the statistical 
analysis to determine the effects on treatment response and safety.  
Exploratory PG and biomarker analyses may be performed and reported separately.  Details of 
these analyses may be described in a separate analysis plan.  (revised per Amendment 01) 
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 examination), out-of-normal-range laboratory safety 
test variables, abnormal ECG findings, anti-BAN2401 antibody titers, and out-of-range vital signs, 
suicidality (C-SSRS), along with change from baseline in laboratory safety test variables, ECGs, 
safety MRI, and vital sign measurements, will be summarized by treatment group using descriptive 
statistics.  The safety analysis will be also be summarized by the following safety subgroups:  age 
(≤65 years, >65 years), sex (male, female), race (white, black, Asian, other), APOE4 status, and 
clinical subgroup (MCI due to AD – intermediate likelihood or mild Alzheimer’s disease 
dementia).  (revised per Amendment 07) 
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EXTENT OF EXPOSURE 
Extent of exposure to study drug will be summarized as cumulative extent of exposure from Day 1 
to Week 6 initially, and at 3 months intervals thereafter.  The number and percent of subjects will 
be presented by treatment group.  Duration of exposure will be summarized using descriptive 
statistics and by duration categories; Day 1 to 6 weeks, 6 weeks to 3 months, and 3-month intervals 
thereafter.  The number and percent of subjects will be presented by each duration category and 
treatment group. 
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 15.0 or higher) lower level 
term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) will also be captured in the database. 
A treatment-emergent AE (TEAE) is defined as an AE that emerged during treatment or any time 
prior to the last study visit following the last dose of study drug, having been absent at pretreatment 
(Baseline) or:  
 
Reemerged during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
 
Worsened in severity during treatment relative to the pretreatment state, when the AE 
was continuous. 
Treatment-emergent AEs (TEAEs) and AEs will be followed for the entire duration of the study.  
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. 
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 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 (possibly related, 
probably related, and not related). 
Adverse events will be summarized by the following subgroups:  age (≤65 years, >65 years), sex 
(male, female), race (white, black, other), clinical subgroup (MCI due to AD – intermediate 
likelihood and mild Alzheimer’s disease dementia), the presence or absence of ongoing AD 
treatment (ie, AChEIs or memantine or both), and APOE4 genotype. 
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. 
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The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT for each treatment.  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.  A subject data listing of all AEs 
leading to discontinuation from study drug will be provided. 
ANTI-DRUG (BAN2401) ANTIBODIES  
The number (percentage) of subjects with positive and negative ADA, ADA titer categories (>0, 5, 
25, 125, etc.), and neutralizing antibodies by visit and treatment group will be summarized (revised 
per Amendment 08).  In addition, the correlation between ADA titer and PK profile or the 
correlation between ADA titer and efficacy will be evaluated using descriptive statistics and 
summary plots.  
LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.  Safety Assessments (Laboratory 
Measurements), the actual value and the change from baseline to each 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 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 post-baseline 
results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 tables 
(shift tables) that compare the baseline LNH classification to the LNH classification at each 
postbaseline visit and at the end of treatment.  Similar shift tables will be used to compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during the 
treatment period. 
The Sponsor’s Grading for Laboratory Values (Appendix 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 postbaseline value with an 
increase from baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each 
subject will be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.  
VITAL SIGNS 
Descriptive statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
respiration rate, temperature, weight and changes from baseline) will be presented by visit and 
treatment group. 
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ELECTROCARDIOGRAMS 
(revised per Amendment 01)   
Abnormal ECG findings will be presented as shifts from baseline (normal/abnormal clinically 
significant/abnormal not clinically significant) to postbaseline (normal/abnormal clinically 
significant/abnormal not clinically significant) visits.  The number and percent of subjects will be 
presented.  
9.7.1.9 Determination of Sample Size 
The sample size and design characteristics to test the hypothesis under the primary objective based 
on the primary endpoint, the Composite Clinical score at 12 months, were determined by means 
of simulations.  Extensive trial simulations have shown that a total of 800 subjects will be sufficient 
to demonstrate that the most likely ED90 dose achieves a CSD from placebo with a probability of 
at least 95% in the IA and greater than 80% in the final analysis if the trial does not stop for early 
success.  There is at least 80% probability of study success for the dose response scenarios where 
the treatment was considered to have clinically meaningful treatment effect.  Simulations have also 
shown that if there is no efficacy at all for any dose, then the probability of falsely claiming 
superiority to placebo is no more than 10.0% assuming a 20% dropout rate.  
For each of the 6 treatment groups (5 active dose regimens and placebo) the final number of 
subjects per group will differ depending on the observed interim treatment responses.  The 
simulation plan will be described in the appendix section of the Statistical Analysis Plan, which 
will present further details. 
VMRI 
The null hypothesis is that there is no difference between active dose and placebo.  There are 5 null 
hypotheses corresponding to 5 active dose regimens.  The alternative hypothesis is that at least 1 
null hypothesis is false (1-sided).  The null hypotheses will be tested using Dunnett 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 to placebo would be 15%, 20%, 25%, 15%, and 20% corresponding to the 
5 dose regimens (2.5, 5, and 10 mg/kg biweekly, 5 and 10 mg/kg 4-week interval), respectively.  
The estimated power for actual planned study sample size is 0.764 at 12 months and 0.694 at 
18 months, assuming an attrition rate of 20% at 12 months and an exponential dropout model.  
Under a stronger dose-response assumption (ie, the percent reduction in change from baseline of 
total hippocampal volume compared to placebo is twice as much as that in the moderate 
dose-response assumption), the estimated power is at least 99% at both 12 and 18 months.  
AMYLOID PET (IMAGING SUBGROUP) 
The null and alternative hypotheses and statistical test are the same as that for vMRI.  To estimate 
the sample size for amyloid PET imaging subgroup at 18 months, a common standard deviation 
of change from baseline was estimated as 0.4 and a reasonable mean difference between treatment 
and placebo was estimated as 0.25 (SUVR).  The corresponding standard deviation and mean 
difference at 12 months were estimated as 0.27 and 0.17, respectively.  Assuming a moderate 
dose-response that the best dose regimen would achieve a difference of 0.25 (SUVR), and that the 
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2 middle and 2 low dose regimens would achieve a difference of 0.2 and 0.15 (SUVR), 
respectively, it would require a total 230 subjects from all 6 arms at 18 months to achieve an 80% 
power.  This sample size took into account possible unequal number of subjects per arm.  Under 
the same attrition rate assumption as that for vMRI, a total sample size of 306 at 12 months is 
sufficient to obtain 230 subjects at 18 months.  The estimated power with 306 subjects at 12 months 
is approximately 85%.  The postbaseline amyloid PET in the imaging subgroup will be planned 
for the first 306 subjects who have consented and who are still on treatment at 12 months.  (revised 
per Amendments 02 and 07) 
9.7.2 Interim Analysis 
An unblinded independent Interim Monitoring Committee (IMC) will provide oversight to ensure 
that the response adaptive randomization process and IA perform as expected.  An independent 
data analysis group will perform all of the IA and will provide the results to the IMC. 
Randomization to placebo or 1 of 5 dose arms of BAN2401 will be fixed for the first 196 subjects 
randomized in the study (4:2:2:2:2:2; placebo [4] to each of the active arms [2 each]).  After this 
initial burn-in, adaptive randomization will begin.  Randomization probabilities to each arm will 
be updated at each IA such that the randomization probability will be increased for the placebo 
arm and arms that represent the potential target dose (ED90), and simultaneously decreased for 
other active arms.  Subjects who are confirmed APOE4 positive (APOE4 hetero- or homozygous) 
will not be randomized to the 10 mg/kg, biweekly dose (revised per Amendments 04 and 05).  
After each IA, the randomization probability vector will be split between APOE4+ and APOE4- 
strata to ensure no APOE4 positive subjects are enrolled on the 10 mg/kg biweekly dose.  The 
overall probabilities as suggested by RAR will still be preserved (revised per Amendments 05 and 
07).  Details of the estimation of the randomization probabilities will be presented in the Statistical 
Analysis Plan. 
The study will be monitored for early success and early futility (see definitions in Study 
Definitions).  The first IA will be conducted when 196 subjects are randomized, again when 
250 subjects are randomized and again after each additional 50 subjects until 800 subjects are 
randomized.  Sites in Japan will randomize at least 40 Japanese subjects, even if early success is 
declared or the study achieves 800 subjects randomized.  In these circumstances, subjects in Japan 
will be allocated treatment according to the latest (or last) allocation schedule.  If the study reaches 
its maximum of 800 randomized subjects, additional IA will be conducted every 3 months until all 
subjects complete 12 months of treatment.  Only those subjects who were randomized before the 
target of 800 was met will contribute to these additional IA, except for the full 12 and 18 month 
Bayesian analyses.  The study will be monitored for futility at each IA and for success starting at 
the 350 subject IA, until the full 12 months of treatment have been completed.  (revised per 
Amendment 09)  Each IA will be conducted on data for the derived Clinical Composite Score.  If 
the efficacy or futility boundary is reached, the IMC will communicate directly with the DSMB 
members.  (revised per Amendment 07) 
The study may be stopped for safety reasons at any time. 
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9.7.3 Other Statistical/Analytical Issues 
Not applicable. 
9.7.4 Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the revision 
impacts the study and how the revision should be implemented.  The details of the revision will be 
documented and described in the clinical study report. 
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10 REFERENCE LIST 
1. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM.  Forecasting the global burden of 
Alzheimer’s Disease. Alzheimer Dement. 2007;3:186-91. 
2.  Alzheimer’s Association.  Alzheimer’s Association report.  2010 Alzheimer’s disease facts 
and figures  Alzheimer Dement. 2010;6:158-94. 
3. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the U.S. 
population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119-1122. 
4. Doraiswamy PM, Leon J, Cummings JL, Marin D, Neumann PJ. Prevalence and impact of 
medical comorbidity in Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 2002;57(3):M173-
M177. 
5. Kalaria RN, Ballard C.  Overlap between pathology of Alzheimer disease and vascular 
dementia.  Alzheimer Dis Assoc Disord. 1999;13 Suppl 3:S115-23. 
6. Dodort J-C and May P.  Overview on rodent models of Alzheimer’s disease.  Curr Protocols 
Neurosci. 2005;9.22-1-9.22-6. 
7. Englund H, Sehlin D, Johansson AS, Nilsson LN, Gellerfors P, Paulie S, et al.  Sensitive 
ELISA detection of amyloid-β protofibrils in biological samples.  J Neurochem. 2007;103:334-
45. 
8. Gotz J, Streffer JR, David D, Schild A, Hoerndli F, Pennanen L, et al.  Transgenic animal 
models of Alzheimer’s disease and related disorders:  histopathology, behavior and therapy.  
Mol Psychiat. 2004;9:664-83. 
9. Broich K, Weiergraber M, Hampel H.  Biomarkers in clinical trials for neurodegenerative 
diseases:  Regulatory perspectives and requirements.  Prog Neurobiol. 2011;95:498-500. 
10. Hampel H, Frank R, Broich K, Teipel SJ, Katz R, Hardy J, et al.  Biomarkers for Alzheimer’s 
disease:  academic, industry and regulatory perspectives.  Nat Rev Drug Discov. 2010;9:560-
74. 
11. 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.  Alzheimer Dement. May;7(3):270-9. Epub 2011 Apr 21. 
12. 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. 2011;76:280–
286. 
13. McKahnn 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.  Ahzheimer Dement. 2011;7:263-9. 
14. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, et al. Frequent 
amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 
2008;65:1509–17. 
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15. Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, et al. Two-year 
follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 2006;129:2856–
66.  
16. Mathis CA, Price JC, Klunk WE, Weissfield L, McNamee R, Wolk DA, et al. Longitudinal 
PIB measures in control, MCI, and AD subjects. J Nucl Med. 2008;49:35P. 
17. Villemagne V, Pike  K, Chetelat G, Ellis KA, Mulligan RS, Bourgeat P, et al. Longitudinal 
Assessment of Abeta and cognition in Aging and Alzheimer Disease. Ann Neurol. 
2011;69:181-192. 
18. Drzezga A, Grimmer T, Henriksen G, Muhlau M, Perneczky R, Miederer I, et al.  Effect of 
APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease.  
Neurology. 2009;72:1487-94. 
19. Moromino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, Miller BL, et al.  Episodic 
memory loss is related to hippocampal-mediated beta amyloid deposition in elderly subjects.  
Brain. 2009;132:1310-23. 
20. Vandenberghe R, Van Laere K, Ivanoiu A, Salmon E, Bastin C, Triau E et al.  
18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment.  A 
Phase 2 trial.  Ann Neurol. 2010;68:319-29. 
21. 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;48:668–81.  
22. 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;51:63-75. 
23. 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;50:516–23.  
24. 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;30:2766-88.  
25. 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 A{beta}1-42. 2010.  Cereb 
Cortex. 2010;20:2069-79. 
26. 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;30:2088–101. 
27. 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;133:3336-48.  
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28. DeSouza LC, Chupina M, Lamarie F, Jardela C, Leclercq D, Colliota O, et al.  CSF tau markers 
are correlated with hippocampal volume in Alzheimer’s disease.  Neurobiol Aging. 
2012;33:1253-7. 
29. Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R,  et al.  Effect of 
immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with 
mild to moderate Alzheimer’s disease.  Arch Neurol. 2012;69:1002-010. 
30. 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. 
31. Drozdick LW, Holdnack JA, Hilsabeck RC.  Essentials of WMS-IV Assessment.  John Wiley 
and Sons, 2011. 
32. Berg L, Miller JP, Storandt M, Duchek J, Morris JC, Rubin EH, et al.  Mild senile dementia of 
the Alzheimer type:  2.  Longitudinal assessment.  Ann Neurol. 1988;23:477-84. 
33. Sheikh JI, Yesavage JA.  Geriatric depression scale (GDS):  Recent evidence and development 
of a shorter version.  Clin Gerontol. 1986;23:477-84. 
34. Rosen WG, Mohs RC, Davis KL  A new rating scale for Alzheimer’s disease.  Am J Psychiatry. 
1984;141:1356-64. 
35. Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S.  Measurement of functional 
activities in older adults in the community. J Gerontol. 1982;37:323-9. 
36. 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. 
37. Swanson, CJ, Zhang, Y, Dhadda, S, et al.  A randomized, double-blind, phase 2b proof-of-
concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril 
antibody.  Alz Res Therapy. 2021; 13:80.  (revised per Amendment 17) 
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) 
11.1 CHANGES TO THE PROTOCOL 
Any change to the protocol requires a written protocol amendment or administrative change that 
must be approved by the sponsor before implementation.  Amendments specifically affecting the 
safety of subjects, the scope of the investigation, or the scientific quality of the study require 
submission to health or regulatory authorities as well as additional approval by the applicable 
IRBs/IECs.  These requirements should in no way prevent any immediate action from being taken 
by the investigator, or by the sponsor, in the interest of preserving the safety of all subjects included 
in the study.  If the investigator determines that an immediate change to or deviation from the 
protocol is necessary for safety reasons to eliminate an immediate hazard to the subjects, the 
sponsor’s medical monitor [and the IRB/IEC for the site must be notified immediately.  The 
sponsor must notify the health or regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory authority 
and IRB/IEC (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/CRO’s CRA will maintain contact with the investigator and designated staff by 
telephone, letter, or email between study visits.  Monitoring visits to each site will be conducted 
by the assigned CRA as described in the monitoring plan.  The investigator (or if regionally 
required, the head of the medical institution) will allow the CRO 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 IRB/IEC review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to the 
following: 
 
Clinic, office, or hospital charts 
 
Copies or transcribed health care provider notes which have been certified for accuracy 
after production 
 
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computed tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, electroencephalograms, polysomnographs, 
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pulmonary function tests) regardless of how these images are stored, including 
microfiche and photographic negatives 
 
Pain, quality of life, or medical history questionnaires completed by subjects 
 
Records of telephone contacts 
 
Diaries or evaluation checklists 
 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks) 
 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs 
 
eCRF components (eg, questionnaires) that are completed directly by subjects and serve 
as their own source 
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 eCRFs must reflect the corresponding source documents.   
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).  In addition, the sponsor will send a list of treatment 
codes by study subject to the investigator after the clinical database for this study has been locked.  
The site should plan to retain study documents, as directed by the sponsor, for at least 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. 
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In Japan, the site should plan to retain all study documentation for postmarketing part in Japan in 
the same manner as the clinical study.  (revised per Amendment 18) 
11.7 AUDITING PROCEDURES AND INSPECTION 
In addition to the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s SOPs 
to evaluate compliance with the principles of ICH GCP and all applicable local regulations.  If a 
government regulatory authority requests an inspection during the study or after its completion, 
the investigator must inform the sponsor immediately. 
11.8 HANDLING OF STUDY DRUG 
All study drug will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug supplies 
must be kept in an appropriate secure area (eg, locked cabinet) and stored according to the 
conditions specified on the drug labels.  The investigator (or a designated pharmacist) must 
maintain an accurate record of the shipment and dispensing of the study drug in a drug 
accountability ledger, a copy of which must be given to the sponsor at the end of the study.  An 
accurate record of the date and amount of study drug administered 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 study drug, 
drug containers, drug labels, and a copy of the completed drug disposition form to the an Eisai 
designated facility. 
11.9 PUBLICATION OF RESULTS 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study must 
be reviewed and approved in writing by the sponsor in advance of submission pursuant to the terms 
and conditions set forth in the executed Clinical Trial Agreement between the sponsor/CRO and 
the institution/investigator.  The review is aimed at protecting the sponsor's proprietary 
information existing either at the date of the commencement of the study or generated during the 
study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement between 
each investigator and the sponsor or CRO, as appropriate. 
11.10  DISCLOSURE AND CONFIDENTIALITY 
The contents of this protocol and any amendments and results obtained during the study should be 
kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and will not be 
disclosed in whole or in part to others, or used for any purpose other than reviewing or performing 
the study, without the written consent of the sponsor.  No data collected as part of this study will 
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be used in any written work, including publications, without the written consent of the sponsor.  
These obligations of confidentiality and non-use shall in no way diminish such obligations as set 
forth in either the Confidentiality Agreement or Clinical Trial Agreement executed between the 
sponsor/CRO and the institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO. 
11.11  DISCONTINUATION OF STUDY 
The sponsor reserves the right to discontinue the study for medical reasons or any other reason at 
any time.  If a study is prematurely terminated or suspended, the sponsor will promptly inform the 
investigators/institutions and regulatory authorities of the termination or suspension and the 
reason(s) for the termination or suspension.  The IRB/IEC will also be informed promptly and 
provided the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so dictate.  If 
the investigator terminates or suspends a study without prior agreement of the sponsor, the 
investigator should inform the institution where applicable, and the investigator/institution should 
promptly inform the sponsor and the IRB/IEC and provide the sponsor and the IRB/IEC with a 
detailed written explanation of the termination or suspension.  Study records must be retained as 
noted above. 
11.12  SUBJECT INSURANCE AND INDEMNITY 
The sponsor will provide insurance for any subjects participating in the study in accordance with 
all applicable laws and regulations. 
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12 APPENDICES 
Appendix 1 
Sponsor’s Grading for Laboratory Values 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
< LLN – 10.0 g/dL 
< LLN – 100 g/L 
< LLN – 6.2 mmol/L 
< 10.0 – 8.0 g/dL 
< 100 – 80 g/L 
< 6.2 – 4.9 mmol/L  
< 8.0 g/dL 
< 80 g/L 
< 4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC) 
< LLN – 3.0 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 
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 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium, serum-high (hypernatremia) 
> ULN – 150 mmol/L 
> 150 – 155 mmol/L 
> 155 – 160 mmol/L 
hospitalization indicated
> 160 mmol/L 
life-threatening 
consequences 
Sodium, serum-low (hyponatremia) 
< LLN – 130 mmol/L 
N/A 
< 130 – 120 mmol/L 
< 120 mmol/L 
life-threatening 
consequences 
Triglyceride, serum-high 
(hypertriglyceridemia)  
150 – 300 mg/dL 
1.71 – 3.42 mmol/L 
> 300 – 500 mg/dL 
> 3.42 – 5.7 mmol/L  
> 500 – 1000 mg/dL 
>5.7 – 11.4 mmol/L 
> 1000 mg/dL 
> 11.4 mmol/L 
life-threatening 
consequences  
Uric acid, serum-high (hyperuricemia) 
> ULN – 10 mg/dL  
≤ 0.59 mmol/L without 
physiologic 
consequences  
N/A 
> ULN – 10 mg/dL  
≤ 0.59 mmol/L with 
physiologic 
consequences  
> 10 mg/dL 
> 0.59 mmol/L  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010). 
 
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Appendix 2 
List of Permitted and Prohibited Prior/Concomitant Medications  
Restricted medications are listed in Listing #1.  Medications that are permitted with restrictions 
are listed in Listings #2, #3, and #4.  (revised per Amendment 12) 
These listings of restricted and permitted medications 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 BAN2401-A001-201 study.  (revised per Amendment 12) 
Antibiotics, analgesics and anti-inflammatory drugs intended for short courses of treatment are 
permitted and do not need to follow the restrictions of Listing #4 for a stable dose of 4 weeks prior 
to 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. 
 
 
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Postrandomization, subjects who require anticoagulant treatment as prophylaxis for <4 weeks need 
not be withdrawn if during this period study drug treatment is suspended, after discussion with 
sponsor medical monitor.  See Listing 1 below for a list of restricted medications.  (revised per 
Amendments 01, 06, and 12) 
 
Listing 1 
Restricted Medications Within 4 Weeks Prior to Extension Baseline 
(Extension Screening Visit) Until Follow-Up Visit  
Generic Name 
Trade Name 
Anticoagulants (See Appendix 4 for Anticoagulant use during Extension Phase) 
Warfarin 
Coumadin®, Jantoven 
Dabigatran 
Pradaxa 
Enoxaparin 
Lovenox 
Dalteparin 
Fragmin 
Anisindione 
Miradon 
Tinzaparin 
Innohep 
Andeparin sodium 
Normiflo 
Heparin Sodium 
Hemochron 
Bivalirudin 
Angiomax 
Argatroban 
 
Rivaroxaban 
Xarelto 
Apixaban 
Eliquis 
Endoxaban 
Savaysa 
Lepirudin 
Refludan 
Fondaparinux  
Arixtra® 
Antithrombin III 
ATryn, Thrombate III 
Thrombolytics are permitted; however, treatment with study drug should be temporarily 
suspended during thrombolytic therapy until stabilization or resolution of the medical 
condition that required thrombolytic drug treatment (thrombolytic examples below).  
Streptokinase 
Streptase 
Reteplase 
Retavase, Retevase 
Tenecteplase 
TNKase 
Urokinase 
Abbokinase, Kinlytic 
Alteplase, tPA 
Activase, Cathflo Activase 
Antiplatelet drugs are permitted but the subject should be on a stable dose for 4 weeks 
before Extension Baseline (Extension Screening Visit).  
Aspirin or clopidogrel is permitted in all 
subjects.  Aspirin and clopidogrel in 
combination is permitted in subjects who 
are not to undergo lumbar puncture. 
Aspirin and Plavix 
(only in subjects undertaking LP in biomarker 
subgroup) 
 
 
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Listing 1 (cont’d) 
Prohibited Medications Within 6 Months Prior to Baseline Until Follow-Up Visit 
 
Systemic Biologic Immunosuppressants, Monoclonal Antibodies Targeting Immune 
Function, & Immunoglobulin therapya (revised per Amendment 17) 
Generic Name 
Trade Name 
Denosumab 
Prolia, Xgeva 
Bevacizumab 
Avastin  
Ranibizumab 
Lucentis 
Infliximab 
Remicade  
Evolocumab  
Repatha  
Etanercept 
Enbrel 
Sarilumab 
Kevzara 
Adalimumab  
Humira  
Omalizumab 
Xolair 
Efalizumab 
Raptiva 
Immunoglobulin (IV or SC) 
Carimune, Flebogamma, Gamimune N, 
Gammagard, Gamunex, Gammar-P IV, Iveegam, 
Octagam, Panglobulin, Vigam, Polygam S/D, 
Privigen, Sandoglobulin, Venoglobulin-S 
Other monoclonal antibodies or biologics not listed here 
a Permitted in the Extension Phase after consultation with the Medical Monitor 
 
Listing 2 
Medications Expected To Be on a Stable Dose for 12 Weeks Prior to Baseline 
 
Cognitive Enhancers 
Donepezil 
Aricept 
Rivastigmine 
Exelon 
Galantamine 
Reminyl 
Memantine 
Namenda 
Donepezil and Memantine combination 
(revised per Amendment 06) 
Donamem  
(revised per Amendment 06) 
Any other drug approved in the subject’s country for treatment of cognitive impairment
 
Listing 2.1 
Prohibited Medications if Used Any Time Until Follow-Up Visit  (revised per 
Amendment 17) 
 
Amyloid-Targeting AD Treatments  
Generic Name 
Trade Name 
Aducanumab 
Aduhelm 
AD = Alzheimer’s Disease 
Any amyloid-targeting AD treatment approved in the subject’s country 
This listing may not be exhaustive, if new therapies are approved. 
 
 
 
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Listing 3 
Permitted Medications Used on PRN Basis Which Are Not To Be Used 
Within 72 Hours of Cognitive Testing  
 
Examples are shown below; this list is not exhaustive. 
 
Generic Name 
Trade Name 
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 & 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, anti-psychotics and other drugs which are used on PRN basis as 
sedatives 
 
 
 
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If the following permitted medications are used on a PRN basis, see restrictions in Listing 3.  If 
they are used chronically, they are required to be on a stable dose for at least 4 weeks prior to 
baseline (Core Baseline or Extension Baseline [Extension Screening Visit]).  Changes in dose or 
initiation of new concomitant medications for chronic use (not PRN use) is permitted during the 
study but if these medications may affect cognitive function, no cognitive testing should be 
conducted until the dose has been stable for 4 weeks.  Examples are given below: 
 
Listing 4 
Permitted Medications 
Generic Name 
Trade Name 
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  
Mood Stabilizers 
Fluoxetine; Olanzapine 
Symbyax 
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 
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Listing 4 
Permitted Medications 
Generic Name 
Trade Name 
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 
 
Zopidem 
 
 
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Appendix 3 
Pharmacogenomic and Biomarker Bioanalysis 
Subjects enrolled in this clinical study will have blood and CSF (if consented) samples collected 
for PG and biomarker analysis.  The aim of this research is to identify factors that may influence 
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 treatment and to explore the role of genetic variability 
in response.  Blood samples may be analyzed to determine 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 pharmacokinetics or therapeutic 
response.  Similarly, biomarker discovery and validation may be performed along with samples 
from AD subjects, to identify blood and genetic biomarkers which may be useful to predict subject 
PK/PD response to BAN2401. 
Collection of the samples for PG and biomarker analysis will be bound by the sample principles 
and processes outlined in the main study protocol.  
Sample collection and handling 
The PG and biomarker samples will be collected according to the study flow chart.  If for 
operational or medical reasons the blood samples for PG and biomarker analysis cannot be 
obtained at the pre-specified 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, including DNA extraction and 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.   
Pharmacogenomic and biomarker samples will only be used for the purposes described in this 
protocol by the Sponsor.  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. 
Pharmacogenomic and biomarker samples may be stored for up to 15 years after the completion 
of the study (defined as submission of the CSR to appropriate regulatory agencies).  (revised per 
Amendment 01)  At the end of the storage period, samples will be destroyed.  Samples may be 
stored for 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.   
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, samples collected will be single or 
double coded (according to the ICH15 guidelines) in order to maintain subject privacy.   
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Right to withdraw 
If during the time the PG and biomarker samples are stored a participant would like to withdraw 
their consent for participation in this research, Eisai will destroy the samples, if they can still be 
identified (not anonymized).  Once samples have been anonymized, it will not be possible to 
identify which samples have come from a particular individual.  Therefore, it will not be possible 
to destroy subject samples after anonymization.  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 samples.  Samples that are processed for analysis (DNA/RNA extracted) 
may be double coded.  Double coding involves removing the initial code 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) as long as the initial tube does not carry any personal identifiers 
or the random code assigned by the central laboratory or biorepository.  Laboratory personnel 
performing genetic analysis will not have access to the “key”.  Laboratory personnel performing 
the 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 insure 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, its representatives and agents, may share anonymized data with persons and 
organizations involved in the conduct or oversight of this research.  These include: 
 Clinical research organizations retained by the Sponsor 
 Independent ethics committees or institutional review boards 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 anonymized 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. 
All subjects must provide blood for APOE4 for genotyping.  Individual data will not be returned 
to subjects unless specifically required by law.  (revised per Amendment 01) 
In countries where local law requires the return of  PG or biomarker data to subjects, no exploratory 
PG or biomarker analysis will be conducted on biosamples from subjects in that jurisdiction.  
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Additionally, no additional biosamples will be taken for exploratory PG or biomarker analysis 
from subjects in that jurisdiction.  (revised per Amendment 01) 
 
 
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Appendix 4 
EXTENSION PHASE PART A (revised per Amendments 11, 16, 17, 18, and 
19) 
PRIMARY OBJECTIVE 
To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD 
SECONDARY OBJECTIVE 
To assess if the treatment benefit in brain amyloid levels (as measured by amyloid PET) at the end 
of the Core Study will be maintained over time in the Extension Phase Part A in subjects with 
EAD  
EXPLORATORY OBJECTIVES 
1. To evaluate the clinical effects of BAN2401 in subjects with EAD on the ADCOMS, 
CDR-SB, ADAS-Cog, and MMSE over time during the Extension Phase Part A 
2. To assess time to disease progression as evaluated CDR global score during the Extension 
Phase Part A  (revised per Amendment 12) 
3. To explore the long-term effects of BAN2401 in subjects with EAD on total hippocampal 
volume and other biomarkers (eg, plasma biomarkers) annually in the Extension Phase 
Part A  (revised per Amendment 15)  
4. To characterize population PK of BAN2401 in subjects enrolled in the Extension Phase 
Part A of the study 
5. To evaluate patterns of resource utilization and associated costs of care for subjects with 
EAD and their study partners, using medical claims data  (revised per Amendment 16) 
Objectives for the Dosing Regimen Substudy (revised per Amendment 17) 
1. To assess whether amyloid levels are maintained over time at less frequent dosing regimens 
as measured by positron emission tomography standard uptake value ratio (PET SUVR) 
2. To assess the effect of less frequent dosing regimens on the changes in plasma biomarkers  
3. To explore the clinical effects of less frequent dosing regimens in subjects with EAD on 
ADCOMS, CDR-SB, ADAS-Cog, and MMSE over time  
4. To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD at less 
frequent dosing regimens 
5. To characterize population PK and PK/PD (biomarker and PET SUVR [when available]) of 
BAN2401 in subjects enrolled in the Dosing Regimen substudy of the study 
ELIGIBILITY CRITERIA (revised per Amendment 12) 
 
Inclusion: 
1. Subjects who have completed Visit 42 (Week 79) of the Core Study or who discontinued 
study drug during the Core Study due to any of the following reasons:  
a. ARIA-E 
b. amyloid related imaging abnormality hemorrhage (ARIA-H) (superficial siderosis, 
macrohemorrhage, or symptomatic microhemorrhage) 
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c. Prohibited or restricted medications that were prohibited during Core Study 
conduct but are no longer prohibited in the Extension Phase  
d. Subjects who were APOE4 positive and receiving treatment with BAN2401 
10 mg/kg biweekly  
e. Any reason for discontinuation not related to prohibited medications, including any 
AE that was considered not related to study drug, and that was not severe or 
life-threatening  
2. 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 
3. Provide written informed consent.  If a subject lacks capacity to consent in the 
investigator's opinion, the subject's assent should be obtained, if required in accordance 
with local laws, regulations and customs, plus the written informed consent of a legal 
representative should be obtained (capacity to consent and definition of legal 
representative should be determined in accordance with applicable local laws and 
regulations).   
4. Must be able to physically attend clinic visits and be willing and able to comply with all 
aspects of the protocol 
Exclusion: 
1. Subjects who discontinued from the study drug or from the Core Study for reasons other 
than the following: 
a. ARIA-E 
b. ARIA-H 
(superficial 
siderosis, 
macrohemorrhage, 
or 
symptomatic 
microhemorrhage) 
c. Prohibited or restricted medications that were prohibited during Core Study 
conduct but are no longer prohibited in the Extension Phase  
d. Subjects who were APOE4 positive and receiving treatment with BAN2401 
10 mg/kg biweekly 
e. AE that was considered not related to study drug, and that was not severe or 
life-threatening  
2. Females who are breastfeeding or pregnant at Extension Phase Baseline (Extension 
Screening Visit, as documented by a positive β-hCG assay).  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. 
3. Females of childbearing potential who:  
 Had unprotected sexual intercourse within 30 days before Extension Phase Baseline 
and 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 
period and for 28 days after study drug discontinuation.  
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 Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from becoming sexually active during the study period 
or for 28 days after study drug discontinuation.   
 Are who are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do not 
agree to use the same contraceptive during the study and for 28 days after study 
drug discontinuation. 
(NOTE:  All females will be considered to be of childbearing potential unless they 
are postmenopausal [amenorrheic for at least 12 consecutive months, in the 
appropriate age group, and without other known or suspected cause] or have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]). 
4. Subjects who develop the following conditions from the time of completion of the Core 
Study to the start of the Extension Phase:  
a. Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, 
ferromagnetic metal implants (eg, in skull and cardiac devices other than those 
approved as safe for use in MRI scanners) 
b. Other significant pathological findings on brain MRI at Extension Phase Baseline 
(Extension Screening Visit), including but not limited to:  any macro-hemorrhage 
(greater than 10 mm at greatest diameter), which is currently symptomatic or 
worsened since the Core Study; any area of superficial siderosis, which is currently 
symptomatic or worsened since the Core Study; evidence of vasogenic edema, 
which is severe or symptomatic; aneurysms, vascular malformations, infective 
lesions, evidence of multiple lacunar infarcts or stroke involving a major vascular 
territory, severe small vessel, or white matter disease or space occupying lesions or 
brain tumors (however lesions diagnosed as meningiomas or arachnoid cysts and 
<1cm at their greatest diameter need not be exclusionary)  
c. Any immunological disease which is not adequately controlled, or which requires 
treatment with biologic drugs during the study  
d. Bleeding disorder that is not under adequate control (including a platelet count 
<50,000 or INR >1.5) 
e. Receiving treatment with anticoagulant therapy but anticoagulation control is not 
optimized and is stable for at least 4 weeks before Extension Phase Baseline 
(Extension Screening Visit) 
f. Any other clinically significant abnormalities in physical examination, vital signs, 
laboratory tests or ECG at Extension Phase Baseline (Extension Screening Visit) 
which in the opinion of the PI, require further investigation or treatment or which 
may interfere with study procedures or safety 
g. Malignant neoplasms within 3 years of Extension Phase Baseline (Extension 
Screening Visit) (except for basal or squamous cell carcinoma in situ of the skin, 
or localized prostate cancer in male subjects).  Subjects who had malignant 
neoplasms but who have had at least 3 years of documented uninterrupted remission 
before Extension Screening Visit need not be excluded 
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h. Known or suspected history of drug or alcohol abuse or dependence within 2 years 
before Extension Phase Baseline (Extension Screening Visit) or a positive urine 
drug test at Extension Screening Visit.  Subjects who test positive for 
benzodiazepines or opioids in urine drug testing 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 and not due to drug abuse 
i. Any other medical conditions (eg, cardiac, respiratory, gastrointestinal, renal 
disease) which 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 
j. Subjects who are taking prohibited or restricted medications  
k. Participation in a clinical study involving any therapeutic monoclonal antibody, 
protein derived from a monoclonal antibody, immunoglobulin therapy, or vaccine 
during the time between the Core Study and Extension Phase Baseline (Extension 
Screening Visit) 
l. Participation in a clinical study involving any new chemical entities for AD during 
the time between the Core Study and Extension Phase Baseline (Extension 
Screening Visit) 
m. Participation in any other investigational medication or device study during the time 
between the Core Study and Extension Phase Baseline (Extension Screening Visit) 
n. Planned surgery which 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 day case without inpatient stay postoperatively 
need not result in exclusion if in the opinion of the PI this operation does not 
interfere with study procedures and subject safety 
 
5. Severe visual or hearing impairment that would prevent the subject from performing 
psychometric tests accurately 
STUDY DESIGN AND PLAN 
The Extension Phase Part A will be initiated following Core Study to allow subjects to receive 
open-label BAN2401 10 mg/kg biweekly (or if the subject chooses to enter the Dosing Regimen 
substudy, 1 of the 2 alternative dosing regimens [either BAN2401 10 mg/kg once every 4 weeks 
(Q4W) or BAN2401 10 mg/kg once every 3 months (Q3M)] as described below) 
All subjects who are ongoing in the Extension Phase Part A and who have completed at least 
18 months of treatment in the Extension Phase Part A may take part in an optional Dosing Regimen 
substudy to evaluate the effects on safety, pharmacokinetic (PK) exposure, biomarker, and clinical 
efficacy of alternate dosing regimens for maintenance dosing of BAN2401.  Subjects may choose 
to enter this substudy at any study visit according to their prior biweekly schedule of assessments.  
Subjects who choose to participate in this substudy will be randomized to 1 of 2 intravenous dosing 
regimens; either BAN2401 10 mg/kg Q4W or BAN2401 10 mg/kg Q3M.  Subjects will adopt a 
new schedule of assessments specific to the Dosing Regimen substudy.  At any point during the 
Dosing Regimen substudy, a subject can withdraw consent from the substudy and revert back to 
open label BAN2401 10 mg/kg biweekly administration. 
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All infusions will take place in the clinic; however, if approved by the Sponsor and allowable and 
conducted according to country and local guidelines, subjects will be offered the option of home 
infusions for approved visits.  Home infusions are being implemented as a result of the Coronavirus 
Disease 2019 (COVID-19) pandemic to allow subjects who cannot visit clinical sites for various 
reasons to continue receiving treatment.  Home infusions will be allowed per Sponsor approval 
according to country and local guidelines during the COVID-19 pandemic and following its 
resolution, where permitted.  (revised per Amendment 14)   
Any subject who completed Visit 42 (Week 79) of the Core Study will have the option to 
participate in the Extension Phase Part A.  Subjects who previously completed the Core Study 
(through the Follow-Up Visit; Visit 43) at any time before implementation of the Extension Phase 
Part A, and/or fulfill the Extension Phase Part A inclusion and exclusion criteria, will also be 
eligible to participate in the Extension Phase Part A.  Subjects who discontinued the Core Study 
will be eligible to participate in the Extension Phase Part A, provided they meet the inclusion and 
exclusion criteria for the Extension Phase Part A.  Subjects in Extension Phase Part A will 
transition to commercial supplies upon availability for individual subjects at each study site.  All 
subjects ongoing in Extension Part A upon implementation of Protocol Amendment 19 will 
transition to Extension Part B.  Extension Phase Part A and Part B combined will continue for up 
to 60 months (5 years), or until BAN2401 is commercially available for individual subjects at each 
study site, at which time the subjects will switch to commercial BAN2401, or in the cases where 
drug is not yet commercially available, treatment will continue until the benefit to risk ratio from 
treatment with BAN2401 is no longer considered favorable, whichever comes first.  (revised per 
Amendments 12, 15, 17, and 19)  Extension Phase Part A will continue for up to 60 months (5 
years), or until BAN2401 is commercially available for individual subjects at each study site, at 
which time the subjects will switch to commercial BAN2401, or until implementation of Protocol 
Amendment 19, or in the cases where drug is not yet commercially available, treatment will 
continue until the benefit to risk ratio from treatment with BAN2401 is no longer considered 
favorable, whichever comes first.  (revised per Amendment 19)  
Upon approval of BAN2401 in Japan, subjects who meet the approved indication and dosage of 
BAN2401 will continue in this study as a postmarketing study.  Treatment will continue until 
BAN2401 is commercially available for individual subjects at each study site, at which time the 
subjects will switch to commercial BAN2401.  For those subjects who seamlessly transition to 
commercial BAN2401 (including postmarketing part in Japan), the end of the study will be the 
date of the last study evaluation prior to transitioning to commercial BAN2401 and at which time, 
all assessments included in Week 261/Early Termination Visit are to be performed.  (revised per 
Amendment 18)  The Follow-up Visit will take place 3 months after the last dose of study drug.  
The 3-month Follow-up Visit is not required for any subject who transitions directly from the 
Extension Phase (including postmarketing part in Japan) of the study to commercial BAN2401.  
(revised per Amendments 18 and 19)   
For those subjects who transition to commercial BAN2401 (including the postmarketing part in 
Japan), the end of the study will be the date of the last study evaluation prior to transitioning to 
commercial BAN2401.  At that time, all assessments included in Week 261/Early Termination 
Visit are to be performed according to the Schedule of Assessments.  (revised per Amendment 19).   
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All subjects who underwent amyloid PET for inclusion in the Core Study should receive a baseline 
amyloid PET scan before dosing in the Extension Phase Part A.  The baseline amyloid PET scan 
must be conducted with the same imaging tracer that was used for inclusion at the baseline visit 
for the Core Study.  In addition, qualified subjects located in the US and Japan will have the option 
to participate in the longitudinal PET substudy.  Florbetapir will be used in the US and 
flutemetamol will be used in Japan in this imaging substudy, and only subjects who consent to the 
longitudinal assessments per the Extension Phase Part A Schedule of Procedures/Assessments 
(Table 13) will be allowed to participate in this imaging substudy.  (revised per Amendment 12 
and 19) 
Subjects may discontinue from study drug for any reason.  Subjects who discontinue the study or 
study drug are requested to undertake the Early Termination Visit (within 7 days after the last dose 
of study drug) and the Follow-Up Visit (3 months after the last dose of study drug).  (revised per 
Amendment 17) 
Dosing Regimen Substudy (revised per Amendment 17 and 19)  
All subjects who are ongoing in the Extension Phase Part A and who have completed at least 
18 months of treatment in the Extension Phase Part A may take part in an optional Dosing Regimen 
substudy to evaluate the effects on safety, PK exposure, biomarker, and clinical efficacy of 
alternate dosing regimens for maintenance dosing of BAN2401.  Subjects may choose to enter this 
substudy at any study visit according to their prior biweekly schedule of assessments.  Subjects 
who participate in this substudy will be randomized to 1 of 2 intravenous dosing regimens; either 
BAN2401 10 mg/kg Q4W or BAN2401 10 mg/kg once Q3M.  Subjects will adopt a new schedule 
of assessments specific to the Dosing Regimen substudy (Table 14and Table 15).  Subjects will 
undertake a baseline plasma blood draw upon entry to the substudy and will attend site visits Q4W, 
regardless of dosing regimen for the 1st year of the Dosing Regimen substudy.  Blood will be 
drawn at each Dosing Regimen substudy visit for plasma biomarker monitoring to assess that 
baseline levels (at substudy entry) are maintained over the course of treatment at each dosing 
regimen.  The sponsor will assess the plasma biomarker responses periodically, and if an optimal 
regimen is established, that regimen will be administered to all subjects in the substudy.  For those 
subjects who undergo an optional amyloid PET assessment, a Dosing Regimen substudy baseline 
amyloid PET assessment should be conducted before substudy Visit 1 (Week 1), unless it has been 
conducted within 3 months of the Dosing Regimen substudy Visit 1.  Subjects may participate in 
home infusions with sponsor and medical monitor approval, and in accordance with local 
guidelines.  (revised per Amendments 17 and 19).   
EXTENSION PHASE ASSESSMENTS 
All subjects will provide informed consent and subjects will be assessed for eligibility for the 
Extension Phase Part A.  Current medical history will be assessed at the Extension Baseline visit 
(Extension Screening Visit) to ensure safety in continued study participation.  A complete physical 
examination will be performed at Extension baseline (Extension Screening Visit).  Safety 
assessments will be performed and all AEs and SAEs recorded.  Vital signs will be assessed when 
study drug is administered both at predose and after infusion.  During Visits 44, 45, 46, and 47, 
vital signs should be obtained at least 2 hours after infusion.  (revised per Amendment 19) 
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Hematology, blood chemistry assessments, and urinalysis will be performed at Extension Baseline 
(Extension Screening Visit), at Extension Phase Weeks 3, 7, 13, 19, 27 (Visits 45, 47, 50, 53, and 
57), and every 6 months thereafter.  Safety and vMRIs will be performed at Extension Baseline 
(Extension Screening Visit), at Extension Phase Weeks 9, 13, 27, and every 6 months thereafter.   
Clinical assessments will be administered at baseline (Extension Screening Visit) and every 
6 months in the morning (whenever possible) in the following order:  MMSE, CDR, and the 
ADAS-Cog.   
Florbetapir will be used in the US and flutemetamol will be used in Japan for longitudinal amyloid 
PET analysis in qualified subjects who participate in the longitudinal imaging substudy (US and 
Japan only).  (revised per Amendment 12)  At the Extension Screening Visit, subjects who 
consented to the longitudinal imaging substudy will be stratified into 2 cohorts based on their 
treatment allocation during the Core Study.  Cohort 1 will have amyloid PET assessments 
performed at baseline (Extension Screening Visit), Visit 50 (Extension Week 13), Extension Phase 
Visit 70 [Extension Week 53], and annually thereafter; Cohort 2 will have amyloid PET 
assessments performed at baseline (Extension Screening Visit), Visit 57 (Extension Week 27), at 
Extension Phase Visit 70 [Extension Week 53], and annually thereafter.  In Japan, those who 
consented to the longitudinal imaging substudy will only undergo amyloid PET at Extension Phase 
Visit 70 [Extension Week 53], and annually thereafter.  (revised per Amendments 12 and 15) 
Blood for serum PK and anti-BAN2401 for PK and anti-BAN2401 antibodies will be collected at 
Extension Phase Week 1 (Visit 44), Extension Weeks 3, 9, 13, 27, 39, 53, and every 24 to 26 weeks 
thereafter, through to Extension Week 261, and the Follow-Up Visit.  These samples should not 
be taken from the same arm as that in which the study drug is infused, and subjects must stay in 
clinic for at least 2 hours following infusion up through Visit 50.  After this visit, if no untoward 
effects of infusion are noted, or if infusion reactions can be prevented with prophylaxis as per 
Section 9.5.1.5, subjects may be discharged from clinic 30 minutes after the end of infusion if 
judged medically stable by the investigator.  Any ECG abnormality that the investigator considers 
as an AE should be reported as such.  If a corrected QT interval (QTc) interval is found to be out 
of range, triplicate ECGs are mandatory.  The Fridericia formula will be used for the determination 
of QTc (corrected QT interval by Fredericia, QTcF).  The ECG out-of-range criterion, which 
would need to be met to obtain 2 additional ECGs, is a QTcF of more than 450 ms (ie, QTcF >450 
ms).  Abnormal QTcF measurements, if not otherwise considered part of a clinical symptom that 
is being reported as an AE, should be considered an AE if (1) the QTcF interval is >450 ms and 
there is an increase of >60 ms from baseline, or (2) the QTcF interval is >500 ms. (revised per 
Amendments 15 and 17) 
For all subjects in the Extension Phase Part A, safety assessments will be performed and all adverse 
events (AEs) and serious adverse events (SAEs) 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 (Follow-Up Visit, as 
shown in Table 13).  For subjects who transition to commercial BAN2401 (including the 
postmarketing section in Japan), all AEs (including SAEs) will be followed until the end of the 
study, which will be the date of the last study evaluation prior to transitioning to commercial 
BAN2401 and at which time all assessments included in Week 261/Early Termination Visit are to 
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be performed according to the Schedule of Assessments of Part A.  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:  ARIA-E, ARIA-H, infusion 
reaction, skin rash considered to be related to study drug, other hypersensitivity reactions, and a 
“yes” answer to Type 4 or 5 suicidal ideation, or a “yes” response to any suicidal behavior on the 
C-SSRS.  It is the responsibility of the investigator to review the results of the C-SSRS and 
determine if any result constitutes an AE.  These AEs do not need to be reported as SAEs unless 
they meet the criteria for Reporting of Serious Adverse Events (Section 9.5.4.1).  Intracerebral 
hemorrhages >1 cm should always be classified as an important medical event and reported as an 
SAE even if they do not meet other serious criteria.  (revised per Amendments 15, 18, 19, and 20) 
In the US only, subjects and study partners who have participated in any phase of the study (Core 
Study or Extension Phase) will have the option to participate in an optional medical claims 
substudy.  The purpose of this substudy is to use medical claims data to further understand patterns 
of resource utilization and associated costs of care for subjects with EAD and their study partners.  
Additionally, study partners will have the option to participate in a survey, which will provide 
supplemental information on the experience of those individuals who are responsible for the care 
of subjects with EAD.  This medical claims substudy will require a separate consent.  Medical 
claims data for subjects and study partners who consent to this substudy will be collected for up to 
5 years before study enrollment, for the duration of the Core Study, the duration of the period 
between the end of the Core Study and the Extension Baseline (if applicable), the duration of the 
Extension Phase (if applicable), and for up to 3 years after the end of the Core Study or Extension 
Phase (where applicable).  The results of the medical claims substudy will be presented in a 
separate report.  (revised per Amendments 16 and 17) 
During the Extension Phase, subjects who develop asymptomatic ARIA-H, will continue on the 
study uninterrupted per the Schedule of Assessments and do not require additional MRI follow-up 
outside the regularly scheduled assessments.  Subjects who develop multiple (>10) asymptomatic 
cerebral microhemorrhages, superficial siderosis, or a single macrohemorrhage (greater than 10 
mm at greatest diameter; also referred to within this protocol as intracerebral hemorrhage >1 cm), 
will continue on the study uninterrupted per the Schedule of Assessments, and will undertake an 
unscheduled safety visit (with MRI) at approximately 30 days after the MRI features 
(asymptomatic ARIA-H) were first identified.  Thereafter, all subjects who develop these events 
will have further safety visits (with MRI) at approximately every 30 days (which may be an 
unscheduled or a scheduled visit) until the asymptomatic ARIA-H has stabilized radiographically.  
Subjects who develop symptomatic ARIA-H (including symptomatic microhemorrhages, 
symptomatic superficial siderosis, symptomatic macrohemorrhage) on MRI will have study drug 
administration temporarily stopped.  All subjects who develop these events will undertake an 
unscheduled safety visit (with MRI) at approximately 30 days after the MRI features (ARIA-H) 
were first identified.  Thereafter they will have further safety visits (with MRI) at approximately 
every 30 days (which may be unscheduled or scheduled visit) until the ARIA-H has stabilized and 
is no longer symptomatic.  During treatment interruption, time will elapse on the Schedule of 
Assessments when the scheduled visit would otherwise occur.  They may then resume treatment 
for the study duration and study assessments remaining on the Schedule of Assessments.  
Resumption of treatment following symptomatic ARIA-H can only occur twice, after which the 
subject must be discontinued from the study.  (revised per Amendment 12) 
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Subjects who develop asymptomatic, radiographically mild or moderate Amyloid-Related 
Imaging Abnormality–Edema/Effusion (ARIA-E) on MRI will continue on the study 
uninterrupted per the Schedule of Assessments.  They will undertake an unscheduled safety visit 
(with MRI) at approximately 30 days and another safety visit (with MRI) at approximately 90 days 
(which may be unscheduled or scheduled visit) after the MRI features were first identified.  They 
will continue with study drug treatment if their ARIA-E does not become severe radiologically 
and remains asymptomatic.   
Those subjects who develop symptomatic or radiographically severe treatment emergent ARIA-E 
will be temporarily stopped from study drug administration until the ARIA-E resolves 
radiographically, and will be followed up to resolution of the event (including symptoms, if any).  
They will undertake an unscheduled safety visit (with MRI) at approximately 30 days and another 
safety visit (with MRI) at approximately 90 days (which may be unscheduled or scheduled visit) 
after the symptomatic or severe ARIA-E was first identified.  Thereafter, these subjects will have 
a safety visit (with MRI) at approximately 30 days (which may be an unscheduled or a scheduled 
visit) until the ARIA-E has resolved both radiologically and clinically.  During treatment 
interruption, time will elapse on the Schedule of Assessments when the scheduled visit would 
otherwise occur.  Once the ARIA-E has resolved both radiologically and clinically, they may then 
resume treatment for the study duration and study assessments on the Schedule of Assessments.  
Resumption of treatment following symptomatic ARIA-E can only occur twice, after which the 
subject must be discontinued from the study.  (revised per Amendment 12) 
In Japan only, subjects who develop asymptomatic, radiographically mild ARIA-E on MRI will 
continue on the study uninterrupted per the Schedule of Assessments.  They will undertake an 
unscheduled safety visit (with MRI) at approximately 30 days and another safety visit (with MRI) 
at approximately 90 days (which may be unscheduled or scheduled visit) after the MRI features 
were first identified.  They will continue with study drug treatment if their ARIA-E does not 
become moderate or severe radiologically and remains asymptomatic.  Those subjects who 
develop symptomatic or radiographically moderate or severe treatment emergent ARIA-E will be 
temporarily stopped from study drug administration until the ARIA-E resolves radiographically, 
and will be followed up to resolution of the event (including symptoms, if any).  They will 
undertake an unscheduled safety visit (with MRI) at approximately 30 days and another safety 
visit (with MRI) at approximately 90 days (which may be unscheduled or scheduled visit) after 
the symptomatic or moderate or severe ARIA-E was first identified.  Thereafter, these subjects 
will have a safety visit (with MRI) at approximately 30 days (which may be an unscheduled or a 
scheduled visit) until the ARIA-E has resolved both radiologically and clinically.  During 
treatment interruption, time will elapse on the Schedule of Assessments when the scheduled visit 
would otherwise occur.  Once the ARIA-E has resolved both radiologically and clinically, they 
may then resume treatment for the study duration and study assessments on the Schedule of 
Assessments.  Resumption of treatment following symptomatic and/or radiographically moderate 
or severe ARIA-E can only occur twice, after which the subject must be discontinued from the 
study.  (revised per Amendment 13) 
Radiographic severity is defined as follows:  (revised per Amendment 12) 
No ARIA-E present:  No signs of ARIA-E. 
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Questionable ARIA-E:  Subtle sulcal or cortical fluid-attenuated inversion recovery (FLAIR) 
hyperintensity, most likely artifactual. 
Mild ARIA-E:  Mild FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white 
matter (with or without gyral swelling and sulcal effacement), which affects an area of less 
than 5 cm in a single greatest dimension.  Only a single region of involvement detected. 
Moderate ARIA-E:  Moderate involvement (area of FLAIR hyperintensity measuring 
5 - 10 cm in single greatest dimensions), or more than one site of involvement, each measuring 
less than 10 cm in a single greatest dimension. 
Severe ARIA-E:  Severe involvement (area of FLAIR hyperintensity measuring greater than 
10 cm in single greatest dimension [white matter and/or sulcal involvement with associated 
gyral swelling and sulcal effacement)).  One or more separate/independent sites of involvement 
may be noted. 
Should a subject discontinue from study treatment from one of these events, such subjects will 
undergo the Early Termination Visit within 7 days of discontinuation and will undergo the 3 month 
Follow-Up Visit per protocol.  These subjects will continue to be followed with safety MRIs on a 
monthly basis thereafter, until the finding has either resolved or stabilized.  
An end-of-study assessment will be performed for subject who complete treatment in the 
Extension Phase Part A (Visit 174).  Subjects may discontinue from study drug for any reason in 
the Extension Phase Part A.  Subjects who discontinue study drug early are requested to undertake 
the Early Termination Visit (within 7 days after the last dose of study drug) during which end-of-
study assessments will be performed.  Any subjects who consent to participation in the PET 
subtudy will have those assessments performed at the Early Termination visit.  Subjects who 
discontinue study drug early may also have unscheduled visits for safety assessments as needed.  
The Follow-Up Visit will take place 3 months after the last dose of study drug for all subjects.  The 
3-month Follow-Up Visit is not required for any subject who transitions directly from the 
Extension Phase Part A (including the postmarketing section in Japan) of the study to commercial 
BAN2401.  For those subjects who transition to commercial BAN2401 (including the 
postmarketing section in Japan), the end of the study will be the date of the last study evaluation 
prior to transitioning to commercial BAN2401 and at which time, all assessments included in 
Week 261/Early Termination Visit are to be performed.  (revised per Amendments 15, 17, 18, and 
19) 
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Dosing Regimen Substudy Assessments (revised per Amendment 17) 
Subjects entering the substudy will follow the substudy-specific schedule of assessments (Table 14 
and Table 15).  Consenting subjects may enter the Dosing Regimen substudy at any time during 
the Extension Phase Part A after they have completed 18 months in the Extension Phase Part A.  
Subjects may choose to enter this substudy at any study visit according to their prior biweekly 
schedule of assessments.  (revised per Amendments 17 and 19) 
Conduct of the Extension Phase During the Coronavirus Disease 2019 (COVID-19) 
Pandemic and Other Extenuating Circumstances  (revised per Amendment 15) 
All study assessment and visit information affected by any extenuating circumstances (eg, the 
COVID-19 pandemic) will be collected on the case report forms (CRFs).  These include but are 
not limited to any visits or assessments that are missed or not done, any assessments that are 
performed remotely/offsite or in person/onsite, and any home infusions offered and completed.   
During the COVID-19 pandemic and under other extenuating circumstances, every attempt should 
be made to have Visits 57, 70, 83, 96, 109, 122, 135, 148, 161, End of Study Visit (Visit 174, or 
Early Termination Visit), and the Follow-Up Visit (visits with clinical assessments) conducted at 
the study site.  However, if this is not feasible under these extenuating circumstances, home 
infusion at applicable visits may be permitted, only with sponsor approval and only where 
permitted according to country and local guidelines.  During these visits, the clinical assessments, 
MMSE, CDR, ADAS-Cog14, and C-SSRS, may be conducted remotely via a sponsor-approved 
telehealth system, following sponsor approval.  Where feasible, raters for these assessments should 
remain unchanged for each subject.  Every effort should be made to have the End of Study Visit 
(Visit 174 or Early Termination Visit) and the Follow-Up CDR assessment performed at the study 
site.  
COVID-19 vaccines and booster shots may be administered during the Extension Phase, but 
vaccination should be timed such that it will be administered at least 7 days after the previous 
infusion and at least 7 days before the next infusion.  The duration between COVID-19 vaccination 
and study drug infusions may be reduced to less than 7 days according to the clinical judgement 
of the investigator, following discussion with the medical monitor.  (revised per Amendment 17) 
During the Extension Phase, if subjects cannot return to clinical sites due to extenuating 
circumstances (ie, the COVID-19 pandemic) and home infusion is not an option, the 
investigator/designee will instruct the subjects to contact the site promptly if there are changes in 
their medical condition including new adverse events and changes in medication.  The investigator  
should maintain close contact with the subjects (eg, via telephone or via a sponsor approved 
telehealth system) to ensure medical and safety oversight at least every 6 weeks.  During this 
contact, the investigator/designee will collect, at minimum, all AEs and concomitant medication 
information.  Additionally, with sponsor approval, remote clinical assessments for the CDR and 
C-SSRS will be performed as per protocol Schedule of Assessments.  (revised per Amendment 17) 
If for any reason, study drug dosing is interrupted (due to the COVID-19 pandemic or other 
extenuating circumstances), every effort should be made to have all missed safety and efficacy 
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assessments performed as soon as possible during a scheduled or unscheduled visit, unless the next 
scheduled assessment(s) is (are) expected to occur within 30 days.  For subjects missing 3 or more 
consecutive doses, and who have not had any safety assessments performed either in-clinic or at 
the home infusion visit(s) during the period of dose interruption, the following safety assessments 
must be performed (either at the study site or during a home infusion visit) before resuming study 
drug dosing:  AE and concomitant medication assessments, vital signs, weight, routine physical 
(where feasible) or symptom directed physical (if routine physical is not feasible), clinical 
laboratory assessments, C-SSRS, and ECG.  Study drug dosing may resume on the same day as 
these assessments (ie, before receipt of the clinical laboratory assessments results) based on the 
clinical judgement of the investigator.  All laboratory results should be promptly evaluated by the 
investigator before the subsequent visit to ensure safety of continued study drug dosing.  If ECG 
or clinical laboratory assessments cannot be conducted before restarting study drug dosing, study 
drug dosing may resume based on the clinical judgement of the investigator.  However, these 
assessments must be performed as soon as possible and results should be promptly evaluated by 
the investigator before subsequent visits to ensure safety of continued study drug dosing.   
Subjects who discontinue the study or study drug early are requested to undertake the Early 
Termination Visit (within 7 days after the discontinuation of study drug) and the Follow-Up Visit 
(3 months after the last dose of study drug).  The 3-month Follow-Up Visit is not required for any 
subject who transitions directly from the Extension Phase (including the postmarketing section in 
Japan) of the study to commercial BAN2401.  (revised per Amendments 18 and 19)   
Every effort should be made to have the Early Termination Visit and Follow-Up Visit, conducted 
at the study site.  However, with approval from the sponsor, subjects who cannot visit clinical sites 
for various reasons may have these visits performed by the home infusion staff.  (revised per 
Amendment 17) 
For those subjects who are taking part in the Dosing Regimen substudy, subjects are to contact 
sites between their scheduled clinic visits if there are any changes in their medical condition 
including new AEs and changes in medication.  If for any reason study reasons are missed, the 
investigator should maintain close contact with the subjects (eg, via telephone) to ensure medical 
and safety oversight, at least every 6 weeks.  (revised per Amendment 17) 
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Table 11 
Summary of Blood Sample Volumes in the Extension Phase Part A  
(revised per Amendment 15 and 19) 
Assessment 
Total 
Number of 
Collection 
Timepoints 
Sample Volume, Number of Timepoints x 
Volume per Collection (ml) 
Total Volume (ml) 
Extension Phase Treatment and Follow-
Up Periods 
 
Clinical laboratory tests 
16 
16 x 10 mL 
160 
Blood sampling for serum 
anti-BAN2401 
16 
16 x 10 mL 
160 
Blood sampling for serum 
BAN2401 PK 
29 
29 x 3 mL 
87 
Blood for exploratory 
biomarker analysis 
12 
12 x 6 mL 
72 
All blood samples, total volume collected 
479 
PK = pharmacokinetic. 
 
Table 12 
Summary of Blood Sample Volumes in the Extension Phase Part A Dosing 
Regimen Substudy (revised per Amendments 17 and 19) 
Assessment 
Total 
Number of 
Collection 
Timepoints 
Sample Volume, Number of Timepoints x 
Volume per Collection (ml) 
Total Volume (ml) 
Extension Phase Treatment and Follow-
Up Periods 
 
Clinical laboratory tests 
7 
7 x 10 mL 
70 
Blood sampling for serum 
anti-BAN2401 
22 
22 x 4 mL 
88 
Blood sampling for serum 
BAN2401 PK 
22 
22 x 3 mL 
66 
Blood for exploratory 
biomarker analysis 
22 
22 x 10 mL 
220 
All blood samples, total volume collected 
444 
PK = pharmacokinetic. 
STUDY DRUG SUPPLIES  
All subjects will be administered the BAN2401 10 mg/kg biweekly dose.  For subjects who 
previously participated in the dosing regimen substudy, BAN2401 10 mg/kg will be administered 
either at the biweekly dose or they may continue with their prior dose of Q4W or Q3M intervals 
until the end of the study.  BAN2401 will be administered in normal saline as 60 minute 
intravenous (IV) infusions.  An infusion system containing a terminal 0.22-µm in-line filter is 
required for administration of BAN2401 drug product.  (revised per Amendment 17)  
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Removal of Subjects From Therapy or Assessment 
Subjects who discontinue from treatment during the Extension Phase will have a Follow-Up 
Visit 3 months after the last dose of study drug.  The 3-month Follow-Up Visit is not required for 
any subject who transitions directly from the Extension Phase (including the postmarketing part in 
Japan) of the study to commercial BAN2401.   
Safety-related criteria for discontinuation of study drug are as follows: 
 Infusion reactions associated with administration of study drug, of Grade 3 severity or 
above (as defined in the NCI-CTCAE) that do not lessen or resolve with treatment  
 Clinical features which indicate meningoencephalitis (eg, combination of 1 or more of the 
following: headache, worsening confusion, neck stiffness, impaired consciousness, focal 
neurological signs) 
 Hypersensitivity reactions with clinical features of tissue injury (eg, arthritis, 
glomerulonephritis, mononeuritis multiplex)     
Note:  Out-of-range ECGs are not included as safety-related criteria for study drug discontinuation, 
as the clinical significance in these cases should be assessed by the investigator.  (revised per 
Amendment 17) 
Treatment Administered and Identity of Investigational Product(s) 
All subjects will receive BAN2401 10 mg/kg biweekly dose during the Extension Phase.  For 
subjects participating in the dosing regimen substudy, BAN2401 10 mg/kg will be administered at 
either Q4W or Q3M intervals until the end of the study.  (revised per Amendment 17)  
BAN2401 is a humanized IgG1 monoclonal antibody that binds to soluble Aβ aggregates.  
BAN2401 is manufactured at Patheon Ltd, United Kingdom (UK) and at Biogen, RTP, under 
contract to Eisai.  It is currently supplied as a sterile clear solution for injection containing 
10 mg/mL, in a single use 10-mL vial (total 100 mg/vial).  The drug product is formulated in 
25 mM sodium citrate, 125 mM sodium chloride, 0.02% (w/v) polysorbate 80 and has a pH of 5.7.  
This current formulation of the drug product may be progressively phased out as stocks near the 
end of their shelf life and replaced by a newer formulation containing 100 mg/mL BAN2401.  The 
newer formulation (100 mg/mL BAN2401) was developed to reduce the number of vials of drug 
product required per dose and to reduce demand for storage space in a pharmacy.  The newer 
(100 mg/mL BAN2401) formulation is supplied as a sterile aqueous solution containing 
100 mg/mL BAN2401, 50 mmol/L citric acid, 0.05% (w/v) polysorbate 80, 350 mmol/L arginine, 
at pH 5.0, in glass vials containing 5 mL solution.  The phasing out of the older formulation will 
only occur after appropriate regulatory authority approval for the newer formulation has been 
obtained, and adequate training of any pharmacy staff involved in the preparation of the final drug 
product for infusion has been completed.  The appearance of the 2 different formulations after 
dilution in normal saline is identical. 
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Study drug will be packaged such that there is 1 vial per dispenser (10 mg/mL) and 4 vials per 
dispenser (100 mg/mL), and will be dispensed by a pharmacist at each site according to the 
Interactive Voice Response System (IVRS).  At the time that the study drug is dispensed for 
administration to the subject, the tear-off label on the dispenser must be removed and placed in the 
study drug accountability log at the time of dispensing.  (revised per Amendment 15) 
All study drug will be administered in the clinic; however, if approved by the Sponsor and 
allowable and conducted according to country and local guidelines, subjects will be offered the 
option of home infusions for approved visits.  Home infusions are being implemented as a result 
of the COVID-19 pandemic to allow subjects who cannot visit clinical sites for various reasons to 
continue receiving treatment.  Home infusions will be allowed per Sponsor approval according to 
country and local guidelines during the COVID-19 pandemic and following its resolution, where 
permitted.  (revised per Amendment 14) 
Rationale For Dosing Regimen Alterations (revised per Amendment 17) 
BAN2401 demonstrated a dose-dependent, time-dependent, and statistically significant amyloid 
reduction across all doses vs placebo in Study 201 Core37 , where amyloid status by visual read 
was converted from positive to negative in more than 65% of subjects at 12 months and in more 
than 81% of subjects at 18 months for those in the 10 mg/kg biweekly group.  The mean amyloid 
PET SUVr for 10 mg/kg biweekly at 18 months was below the SUVr for amyloid negativity of 
1.17 (based on Florbetapir).  Overall, these results indicate that BAN2401 treatment significantly 
clears amyloid from the brain.  (revised per Amendment 17) 
Exposure-response modeling data has shown that less frequent dosing regimens are expected to 
keep amyloid levels below the threshold for amyloid positivity based on PET SUVr.  As shown 
below in Figure 3, discontinuation of BAN2401 10 mg/kg biweekly treatment following 
18 months results in a slow re-accumulation of amyloid over time.  In contrast, continuation of 
treatment with 10 mg/kg biweekly beyond 18 months of treatment results in further reduction of 
brain amyloid.  In these analyses, a switch to less frequent dosing regimens (monthly, every 
3 and 6 months) following treatment with 10 mg/kg biweekly for 18 months is predicted to 
maintain amyloid levels at or below the SUVr amyloid negativity level of 1.17 for the full 
24 months of simulated treatment.  (revised per Amendment 17) 
Fluid biomarker changes in plasma Aβ42/40 ratio and plasma p-tau181 have been shown to 
mirror (inverse for Aβ42/40 ratio) changes in brain amyloid as measured by PET SUVr37.  
Exposure-response modeling indicates that for alternate dosing regimens, at 18 months 10 mg/kg 
biweekly treatment followed by less frequent dosing (10 mg/kg for Q4W and Q3M), the plasma 
A42/40 ratio (Figure 4) is predicted to decrease gradually, at a slightly lower rate compared to 
when lecanemab 10 mg/kg Q2W is discontinued after 18 months.  Similarly, p-tau181 PK/PD 
modeling shows that for alternate less frequent dosing, plasma p-tau181 (Figure 5) increases 
gradually, at a slightly lower rate compared to when lecanemab treatment 10 mg/kg biweekly is 
discontinued after 18 months.  (revised per Amendment 17) 
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Figure 3 
Model-Predicted PET SUVr after Various Dosing Regimens (revised 
per Amendment 17) 
Solid line and shaded area show predicted median and 95% CI, respectively.  Black dotted line represents 
PET SUVr = 1.17, indicating amyloid negative line. 
PET = positron emission tomography, SUVr = standard uptake value ratio, Q2W = every 2 weeks, Q4W = every 4 
weeks, Q3M = every 3 months, Q6M = every 6 months 
 
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Figure 4 
Model-Predicted Plasma Aβ42/40 Ratio after Various Dosing 
Regimens (revised per Amendment 17) 
Solid line and shaded area show predicted median and 95% CI, respectively. 
Aβ = amyloid beta, Q2W = every 2 weeks; Q4W = every 4 weeks, Q3M = every 3 months 
Source:  CPMS-BAN2401-002R-ADD2-v1 Figure 8 
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Figure 5 
Model-Predicted Plasma p-tau181 After Various Dosing 
Regimens (revised per Amendment 17) 
Solid line and shaded area show predicted median and 95% CI, respectively. 
p-tau181 = human tau protein phosphorylated at threonine in position 181, Q2W = every 2 weeks, Q4W = every 4 weeks, 
Q3M = every 3 months 
Source:  CPMS-BAN2401-002R-ADD3-v1 Figure 7 
Concomitant Therapies and Drugs  (revised per Amendment 17) 
A list of restricted and permitted drugs is provided in Appendix 2. 
 
During the course of the Extension Phase, immunoglobulin therapy may be allowed, if 
clinically indicated and after a documented discussion with the medical monitoring team.  
In this case, an interval of 30 days between study drug infusion and immunoglobulin 
therapy should be observed.  (revised per Amendment 17)  Subjects who require 
treatment with thrombolytic drugs do not have to be discontinued from the study, but 
study drug will be temporarily suspended for these subjects during thrombolytic therapy 
until stabilization or resolution of the medical condition that required thrombolytic drug 
treatment. 
 
Flu, shingles, pneumococcal, hepatitis B, COVID-19 (including the booster shot), and 
other vaccines can be administered during the treatment period, but vaccination should be 
timed such that it will be administered at least 7 days after the previous infusion and at 
least 7 days before the next infusion.  The duration between COVID-19 vaccination and 
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study drug infusions may be reduced to less than 7 days according to the clinical 
judgement of the investigator.  (revised per Amendment 17) 
 
Subjects who are on anticoagulants at Extension Baseline (Extension Screening Visit) are 
required to have their anticoagulation status optimized and stable for at least 4 weeks 
before Extension Screening Visit.   
 
Subjects who initiate AD treatment or who adjust their AD dosing regimen while on 
study will continue to study completion.  However, if aducanumab (or other approved 
amyloid-targeting AD treatments) is started during the study, then subjects are required to 
immediately discontinue from study drug.  (revised per Amendment 17) 
The following requirements apply to all other medications: 
 
Subjects must be on a stable dose for at least 4 weeks prior to Extension Screening Visit, 
except for medications which are administered as short courses of treatment (eg, 
anti-infectives) or which are to be used as needed (PRN). 
 
Medications which are used on a PRN basis or as a short course of treatment, and which 
are CNS active and may affect cognitive function are not permitted during a period of 
72 hours prior to cognitive testing. 
 
Subjects may receive PRN prophylactic medications prior to infusion of study drug 
(outlined in the protocol) to minimize the risk of immunologic reaction or infusion 
reaction during or shortly after the infusion. 
 
Subjects who initiate treatment or undertake dose adjustment with drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the PI this adjustment will not interfere with study procedures or subject safety 
and are not prohibited above. 
 
SCHEDULE OF PROCEDURES/ASSESSMENTS 
Table 13 to Table 15 presents the Schedule of Procedures/Assessments for Extension Phase Part A.  
(revised per Amendment 19) 
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Table 13 
Schedule of Procedures/Assessments for Study BAN2401-G000-201:  Extension Phase Part A (revised per Amendments 
12, 14, 15, 17, 18, and 19) 
Phase 
 
Extension (Visit 44 through Visit 75, Extension Phase Week 1 through Extension Phase Week 63)  
Period 
Screen 
Treatment 
Visit(s)a 
Scrn 
44 
45 
46 
47 
48 
49 
50 
51,52 
53 
54, 
55, 56 
57 
58, 59 
60 
61, 62 
63 
64, 65 
66 
67, 
68, 69 
70 
71, 72 
73 
74, 75 
Extension Phase Week(s) 
0 
1 
3 
5 
7 
9 
11 
13 
15,17 
19 
21, 
23, 25 
27 
29, 31 
33 
35, 37 
39 
41, 43 
45 
47, 
49, 51 
53 
55, 57 
59 
61, 63 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weightc 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Routine physical exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
12-lead ECGd 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Serum pregnancy teste 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy teste 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Blood for laboratory testsf 
Xn 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis  
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMSEg 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
CDRg 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
ADAS-Cogg 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Safety MRIh 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Volumetric MRIi 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Amyloid PETj 
X 
 
 
 
 
 
 
Xo 
 
 
 
Xo 
 
 
 
 
 
 
 
X 
 
 
 
Study drug administrationk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for serum BAN2401 PKl 
 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Blood for exploratory PD 
biomarker analysis 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Blood for serum 
anti-BAN2401m 
 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Prior/concomitant meds 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
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Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Phase 
Extension (Visit 76 through Visit 111, Extension Phase Week 65 through Extension Phase Week 135)  
Period 
Treatment 
Visit(s)a 
76 
77, 
78 
79 
80, 
81, 
82 
83 
84, 
85 
86 
87, 
88 
89 
90, 91 
92 
93, 
94, 95 
96 
97, 98 
99 
100, 101 
102 
103, 
104 
105 
106, 
107, 
108 
109 
110 , 
111 
Extension Phase Week(s) 
65 
67, 
69 
71 
73, 
75, 
77 
79 
81, 
83 
85 
87, 
89 
91 
93, 95 
97 
99, 
101, 
103 
105 
107, 
109 
111 
113, 115 
117 
119, 
121 
123 
125, 
127, 
129 
131 
133, 
135 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weightc 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Routine physical exam 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
12-lead ECGd 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Urine pregnancy teste 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Blood for laboratory testsf 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Urinalysis  
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
MMSEg 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
CDRg 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
ADAS-Cogg 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
C-SSRS 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Safety MRIh 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Volumetric MRIi 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Amyloid PETj 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study drug administrationk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for serum BAN2401 PKl 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Blood for exploratory PD 
biomarker analysis 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Blood for serum 
anti-BAN2401m 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Prior/concomitant meds 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
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 
X 
Phase 
Extension (Visit 112 through Visit 147, Extension Phase Week 137 through Extension Phase Week 207)  
Period 
Treatment 
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Visit(s)a 
112 
113, 
114 
115 
116, 
117 
118 
119, 
120, 
121 
122 
123, 
124 
125 
126, 
127 
128 
129, 
130 
131 
132, 
133, 
134 
135 
136, 
137 
138 
139, 
140 
141 
142, 
143 
144 
145, 
146, 147 
Extension Phase Week(s) 
137 
139, 
141 
143 
145, 
147 
149 
151, 
153, 
155 
157 
159, 
161 
163 
165, 
167 
169 
171, 
173 
175 
177, 
179, 
181 
183 
185, 
187 
189 
191, 
193 
195 
197, 
199 
201 
203, 
205, 207 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weightc 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Routine physical exam 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
12-lead ECGd 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Urine pregnancy teste 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Blood for laboratory testsf 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Urinalysis  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
MMSEg 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
CDRg 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
ADAS-Cogg 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
C-SSRS 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Safety MRIh 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Volumetric MRIi 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Amyloid PETj 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administrationk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for serum BAN2401 PKl 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Blood for exploratory PD 
biomarker analysis 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Blood for serum anti-BAN2401m 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Prior/concomitant meds 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
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 
X 
 
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Phase 
 
 
Extension (Visit 148 through Follow-Up Visit, Extension Phase Week 209 through Follow-Up Visit)  
Period 
Treatment 
 
 
Visit(s)a 
148 
149, 
150 
151 
152, 
153 
154 
155, 
156 
157 
158, 
159, 
160 
161 
162, 
163 
164 
165, 
166 
167 
168, 
169 
170 
171, 
172 
173 
174 
Early
Termination 
Visitp 
Follow-
Upr 
Unscheduled 
Visitq 
Extension Phase Week(s) 
209 
211, 
213 
215 
217, 
219 
221 
223, 
225 
227 
229, 
231, 
233 
235 
237, 
239 
241 
243, 
245 
247 
249, 
251 
253 
255, 
257 
259 
261 
 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weightc 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Routine physical exam 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
12-lead ECGd 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Urine pregnancy teste 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
  
X 
Blood for laboratory testsf 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Urinalysis  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
MMSEg 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
CDRg 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
ADAS-Cogg 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
C-SSRS 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Safety MRIh 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Volumetric MRIi 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Amyloid PETj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Study drug administrationk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Blood for serum BAN2401 
PKl 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Blood for exploratory PD 
biomarker analysis 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
Blood for serum 
anti-BAN2401m 
X 
 
 
 
 
 
 
 
X 
  
  
  
  
  
  
  
 
X 
X 
X 
X 
Prior/concomitant meds 
X 
 
X 
 
X 
 
X 
 
X 
  
X 
  
X 
  
X 
  
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 
ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognitive subscale, CDR = Clinical Dementia Rating, CDR-SB = Clinical Dementia Rating – Sum of Boxes, C-SSRS = Columbia Suicide Severity Rating Scale, 
ECG = electrocardiogram, FAQ = Functional Assessment Questionnaire, IVRS = Interactive Voice Response System, MMSE = Mini-Mental State Examination, MRI = magnetic resonance imaging, PD = pharmacodynamic, 
PET = positron emission tomography, PK = pharmacokinetic.   
a 
Visit 3 should be conducted no more than 10 days after completion of the Screening Visit and confirmation of eligibility to continue in the study. Assessments should take place on the first day of the study visit in the 
designated study week except as noted below (footnotes h, i, and j pertaining to imaging assessments).  If required, and with prior sponsor approval, visits where clinical assessments are conducted may be split such that 
clinical assessments are performed in order on the 1st day and that the subject and caregiver agree to return to the clinical site on the next consecutive day for study dosing.  The remaining assessments can be done on 
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CONFIDENTIAL 
 
 
either the 1st or the 2nd day before study drug administration.  A visit window of ±8 days will be allowed for each visit.  A visit window of ± 7 days will be allowed for the Follow-Up Visit.  (revised per Amendments 
15 and 17) 
b 
Vital signs will be measured both at predose and after infusion.  During Visits 44, 45, 46, and 47, vital signs should be recorded at least 2 hours after study drug infusion, in addition to predose. If at those visits no 
untoward effects of infusion on vital signs are detected ≥2 hours after infusion, these assessments at subsequent study visits may be conducted at a shorter interval after infusion.  Vital sign measurements will consist of  
systolic and diastolic blood pressure (mmHg) measured after at least 3 minutes in a semi supine position, pulse (beats per minute), respiratory rate (per minute), and body temperature (in centigrade).  
c 
Weight will be taken in the clinic at designated visits.  If a subject misses a clinic visit where weight is to be collected subsequent visits should use the most recent, previous collected weight for infusion calculations until 
the next clinic visit.  Under such circumstances, weight is to be taken at the next clinic visit and entered into the IVRS even if the visit is not designated for weight data collection.  If the subject is receiving home 
infusions, weight measure will be collected one visit before the protocol-specified scheduled weight measurement during the scheduled home infusion. For subjects with weight measurement collected one visit before 
the protocol-specified schedule, weight measurement will not be needed at the protocol-specified scheduled visit.  (revised per Amendment 17) 
d 
If corrected QT interval by Fredericia (QTcF) is found to be out of range, triplicate ECGs are mandatory.  (revised per Amendment 17) 
e 
Females of childbearing potential only.  For all females of childbearing potential, an additional urine pregnancy test must be done on the day of amyloid PET scanning. 
f 
Blood for laboratory tests will be taken predose at all visits as indicated.  
g 
Scales are to be completed in the morning (or, if not possible, consistently at the same time of day) in the following order on the days indicated:  MMSE, CDR (including CDR-Global and CDR-SB), and ADAS-Cog.  
Caregivers/informants (defined as a person able to support the subject for the duration of the study) need only to be present at visits where clinical assessments take place.  If required, and with prior sponsor approval, 
visits where clinical assessments are conducted may be split such that clinical assessments are performed in order on the 1st day and that the subject and caregiver agree to return to the clinical site on the next consecutive 
day for study dosing.  The remaining assessments can be done on either the 1st or the 2nd day.  (revised per Amendment 15) 
h 
MRI imaging must be completed within the Screening Period and before the first dose of study drug in the Extension Phase. During the Treatment Period, MRI imaging will be conducted on separate days from the 
scheduled visits.  MRI imaging should be conducted at any time following the immediately preceding visit and prior to each of the following Visits for ALL subjects according to the Schedule of Procedures/Assessments.  
In all cases, the safety MRI must be reviewed by the imaging vendor and a local reader prior to a subject receiving the next dose of study drug.  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 Early Termination Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  (revised per 
Amendment 12) 
i 
A volumetric MRI sequence will be collected in ALL subjects immediately following all safety MRI assessments.   
j 
Before dosing in the Extension Phase, all subjects who underwent amyloid PET for inclusion in the Core Study should receive a baseline amyloid PET scan.  In Japan, those who consented to the longitudinal imaging 
substudy will only undergo amyloid PET at Extension Phase Visit 70 [Extension Week 53], and annually thereafter.  The baseline amyloid PET scan must be conducted with the same imaging tracer that was used for 
inclusion at the baseline visit for the Core Study.  During Screening, amyloid PET imaging will be conducted within 10 days before the first dose of study drug in the Extension Phase for qualified subjects. During the 
Treatment Period,  Amyloid PET imaging will be conducted on or within 10 days after the scheduled 3 month (Cohort 1 only), 6 month (Cohort 2 only), 12 month (all subjects in the PET substudy), and annually thereafter 
(all subjects in the PET substudy) in the Extension Phase (Visit 50 [Week 13; Cohort 1 only]; Visit 57 [Week 27; Cohort 2 only], Visit 70 [Week 53; all subjects in the PET substudy], and annually thereafter [all subjects 
in the PET substudy], and at the Early Termination Visit [all subjects in the PET substudy]).  (revised per Amendments 12 and 15) 
k 
If approved by the Sponsor, and allowable and conducted according to country and local guidelines, subjects may be offered the option of home infusions for approved visits.  If home infusion occurs at Visits 45 through 
Visit 50, subjects must be observed for at least 2 hours following infusion by the infusion staff.  After Visit 50, if no untoward effects of infusion are noted, or infusion reactions can be prevented with prophylaxis, then 
subjects will be observed 30 minutes after the end of infusion if judged medically stable by the investigator.  Additionally, if home infusion occurs at visits where PK samples are taken, blood will be taken for the 
BAN2401 assay both predose and at least 2 hours after the end of infusion (revised per Amendment 14) 
l 
At Visit 44, blood will be taken for the BAN2401 assay approximately 4 hours after the end of infusion (before subjects leave the clinic for home).  Subjects must stay in clinic for the full 4 hours following infusion 
during this first infusion visit.  Subjects must stay in clinic for at least 2 hours following infusion up through Visit 50.  After Visit 50, if no untoward effects of infusion are noted, or infusion reactions can be prevented 
with prophylaxis, then subjects may be discharged from clinic 30 minutes after the end of infusion if judged medically stable by the investigator.  Blood will be taken for the BAN2401 assay both predose and at least 
2 hours after the end of infusion (before subjects leave the clinic for home).  Subjects are required to remain in clinic for at least 2 hours following infusion at visits where PK samples are taken (except Visit 44, the first 
infusion visit).  PK samples should be taken at least 2 hours after the end of infusion.  These samples can be taken any time after those 2 hours and should generally be taken just prior to the subject leaving the site.  A 
single blood sample for PK will be taken at any time at both Visit 174 (or Early Termination) and the Follow-Up Visit.  (revised per Amendment 15) 
m 
Blood for the BAN2401 anti-drug antibody assay will be taken predose at the specified Visits.  Blood for the BAN2401 anti-drug antibody assay will also be taken at the Early Termination Visit when applicable.  At 
Visit 174 (or Early Termination) and the Follow-Up Visit, the sample can be taken at any time.  (revised per Amendment 15) 
n 
Clotting screen (prothrombin time [PT, INR], activated partial thromboplastin time [APTT]) will be performed at the Screening Visit.  
o 
Subjects will have PET amyloid testing at Visit 50 (Extension Week 13) or Visit 57 (Extension Week 27) based on stratification. Cohort 1 will have amyloid PET assessments performed at Visit 50 (Extension Week 13); 
Cohort 2 will have amyloid PET assessments performed at Visit 57 (Extension Week 27). 
p 
Subjects who discontinue the study or study drug early are requested to undertake the Early Termination Visit (within 7 days after discontinuation the last dose of study drug) and the Follow-Up Visit (3 months after the 
last dose of study drug).  They may also have unscheduled visits for safety assessments.  (revised per Amendment 17) 
q 
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 assessments indicated under Unscheduled 
Visits need not always be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs. 
r 
The 3-month Follow-Up visit is not required for any subject who transitions directly from the Extension Phase Part A or Part B (including the postmarketing section in Japan) of the study to commercial BAN2401.  
(revised per Amendment 18)
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Amendment 20 
BAN2401-G000-201
 
 
Eisai 
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Page 217 of 235 
CONFIDENTIAL 
 
 
Table 14 
Dosing Regimen Substudy Schedule of Assessments (Visits 1 through 25, Weeks 1 through 97)  (revised per 
Amendment 17) 
Phase 
Dosing Regimen Substudy 
Period 
Treatment 
Visit(s)a 
1b 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
Substudy Week(s) 
1 
5 
9 
13 
17 
21 
25 
29 
33 
37 
41 
45 
49 
53 
57 
61 
65 
69 
73 
77 
81 
85 
89 
93 
97 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weightf 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
Routine physical exam 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
12-lead ECGg 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Urine pregnancy testh 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
Blood for laboratory testsi 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
MMSEj 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
CDRj 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
ADAS-Cogj 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
C-SSRS 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Safety MRIk 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Volumetric MRIl 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Amyloid PETm 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration Q4Wn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration Q3Mn 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Blood for serum BAN2401 PKo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Blood for exploratory PD biomarker analysisp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Blood for serum anti-BAN2401q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Prior/concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
a 
Assessments should take place on the first day of the study visit in the designated study week except as noted below (footnotes k, l, and m pertaining to imaging assessments).  A visit window of ±8 days will be 
allowed for each visit.  If required, and with prior sponsor approval, visits where clinical assessments are conducted may be split such that clinical assessments are performed in order on the 1st day and that the subject 
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Amendment 20 
BAN2401-G000-201
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 218 of 235 
CONFIDENTIAL 
 
 
and caregiver agree to return to the clinical site on the next consecutive day for study dosing.  The remaining assessments can be done on either the 1st or the 2nd day before study drug administration.  A visit window 
of ± 7 days will be allowed for the Follow-Up Visit.   
b 
Subjects who are already in OLE and participating in the Dosing Regimen substudy do not need to undertake a baseline amyloid PET scan if they had amyloid PET within 3 months of substudy entry.  
c 
Subjects who discontinue the Dosing Regimen substudy or discontinue study drug early are requested to undertake the Early Termination Visit (within 7 days after discontinuation the last dose of study drug) and the 
Follow-Up Visit (3 months after the last dose of study drug).  They may also have unscheduled visits for safety assessments.   
d 
Unscheduled visits may be conducted at any time when safety or MRI data indicates it to be necessary, per protocol or as clinically indicated in the judgment of the investigator.  Note that assessments indicated under 
Unscheduled Visits need not always be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs. 
e 
Vital signs will be measured both at predose and after infusion.  Vital signs should be recorded at least 2 hours after study drug infusion, in addition to predose; however, if at previous Extension Phase visits, no 
untoward effects of infusion on vital signs are detected ≥2 hours after infusion, these assessments at subsequent study visits may be conducted at a shorter interval after infusion.  Vital sign measurements will consist 
of systolic and diastolic blood pressure (mmHg) measured after at least 3 minutes in a semi supine position, pulse (beats per minute), respiratory rate (per minute), and body temperature (in centigrade) 
f 
Weight will be taken in the clinic at designated visits.  If a subject misses a clinic visit where weight is to be collected, subsequent visits should use the most recent, previous collected weight for infusion calculations 
until the next clinic visit.  Under such circumstances, weight is to be taken at the next clinic visit and entered into the IVRS even if the visit is not designated for weight data collection.  If the subject is receiving home 
infusions, weight measure will be collected one visit before the protocol-specified scheduled weight measurement during the scheduled home infusion.  For subjects with weight measurement collected one visit before 
the protocol-specified schedule, weight measurement will not be needed at the protocol-specified scheduled visit. 
g 
If QTcF is found to be out of range, triplicate ECGs are mandatory.   
h 
Females of childbearing potential only.  For all females of childbearing potential, an additional urine pregnancy test must be done on the day of amyloid PET scanning. 
i 
Blood for laboratory tests will be taken predose at all visits as indicated.    
j 
Scales are to be completed in the morning (or, if not possible, consistently at the same time of day) in the following order on the days indicated:  MMSE, CDR (including CDR-Global and CDR-SB), and ADAS-Cog.  
Caregivers/informants (defined as a person able to support the subject for the duration of the study) need only to be present at visits where clinical assessments take place.  If required, and with prior sponsor approval, 
visits where clinical assessments are conducted may be split such that clinical assessments are performed in order on the 1st day and that the subject and caregiver agree to return to the clinical site on the next 
consecutive day for study dosing.  The remaining assessments can be done on either the 1st or the 2nd day.   Subjects who are already in the OLE and who are participating in the Dosing Regimen substudy do not 
need to undertake these baseline assessments if they have undertaken them within 3 months of substudy entry.   
k 
MRI imaging should be conducted at any time following the immediately preceding visit and prior to each of the following Visits for ALL subjects according to the Schedule of Procedures/Assessments.  In all cases, 
the safety MRI must be reviewed by the imaging vendor and a local reader prior to a subject receiving the next dose of study drug.  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 Early Termination Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.  Subjects who 
are already in the OLE and who are participating in the Dosing Regimen substudy do not need to undertake a baseline MRI if they have had one within 3 months of substudy entry.   
l 
A volumetric MRI sequence will be collected in ALL subjects immediately following all safety MRI assessments.  Subjects who are already in the OLE and who are participating in the Dosing Regimen substudy do 
not need to undertake a baseline MRI if they have had one within 3 months of substudy entry. 
m 
PET in this substudy is optional, but encouraged - A Dosing Regimen substudy baseline amyloid PET assessment should be conducted before substudy Visit 1 (Week 1).  Those who are already participating in OLE 
amyloid PET substudy need not to undertake a baseline PET if they had amyloid PET with in last 3 months as a part of extension phase (at entry). 
n 
If approved by the Sponsor, and allowable and conducted according to country and local guidelines, subjects may be offered the option of home infusions for approved visits.  If a subject begins home infusion during 
the Dosing Regimen substudy, subjects must be observed for at least 2 hours following the first and second home infusion by the infusion staff.  After the third infusion, if no untoward effects of infusion are noted, 
or infusion reactions can be prevented with prophylaxis, then subjects will be observed 30 minutes after the end of infusion if judged medically stable by the infusion staff.   
o 
If home infusion occurs at visits where PK samples are taken, blood will be taken for the BAN2401 assay only at predose. 
p 
Blood for serum PD should be taken predose at specified visits. 
q 
Blood for the BAN2401 anti-drug antibody assay will also be taken at the Early Termination Visit when applicable.  At Early Termination and the Follow-Up Visit, the sample can be taken at any time.   
r 
For Subjects on the Q3M (3 monthly) dosing regimen, subjects do not need to attend any visits after Visit 14 (Week 53) where only Vital Signs, Prior/Concomitant Medication, and Adverse Events are scheduled.  
 
 
 
 
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Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 219 of 235 
CONFIDENTIAL 
 
 
 
 
Table 15 
Dosing Regimen Substudy Schedule of Assessments – (Visits 26 through Follow-Up, Weeks 101 through 
157) (revised per Amendment 17) 
 
 
Phase 
Dosing Regimen Substudy 
 
Period 
Treatment 
 
Visit(s)a 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
Early 
Termination 
Visitb 
Follo
w-Up 
Unscheduled 
Visitc 
 
Substudy Week(s) 
10
1 
10
5 
10
9 
11
3 
11
7 
12
1 
12
5 
12
9 
13
3 
137 
141 
145 
149 
153 
157 
 
 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weighte 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Routine physical exam 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
12-lead ECGf 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Urine pregnancy testg 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
Blood for laboratory testsh 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Urinalysis  
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
MMSEi 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
CDRi 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
ADAS-Cogi 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
C-SSRS 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Safety MRIj 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Volumetric MRIk 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Amyloid PETl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Study drug administration Q4wm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Study drug administration Q3Mm, n 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Blood for serum BAN2401 PKo 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood for exploratory PD biomarker 
analysisp 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Blood for serum anti-BAN2401q 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
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Amendment 20 
BAN2401-G000-201
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
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CONFIDENTIAL 
 
 
Prior/concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognitive subscale, C-SSRS = Columbia Suicide Severity Rating Scale, CDR = Clinical Dementia Rating, CDR-SB = Clinical Dementia Rating – Sum of 
Boxes, ECG = electrocardiogram, IVRS = Interactive Voice Response System, MMSE = Mini-Mental State Examination, MRI = magnetic resonance imaging, OLE = open-label Extension, PET = positron 
emission tomography, PD = pharmacodynamic, PK = pharmacokinetic, Q3M = every 3 months, Q4W = every 4 weeks, QTcF = corrected QT interval by Fredericia. 
 
a 
Assessments should take place on the first day of the study visit in the designated study week except as noted below (footnotes j,k,and l pertaining to imaging assessments).  A visit window of ±8 days 
will be allowed for each visit.  If required, and with prior sponsor approval, visits where clinical assessments are conducted may be split such that clinical assessments are performed in order on the 1st 
day and that the subject and caregiver agree to return to the clinical site on the next consecutive day for study dosing.  The remaining assessments can be done on either the 1st or the 2nd day before study 
drug administration.  A visit window of ±7 days will be allowed for the Follow-Up Visit.   
b 
Subjects who discontinue the Dosing Regimen substudy or discontinue study drug early are requested to undertake the Early Termination Visit (within 7 days after discontinuation the last dose of study 
drug) and the Follow-Up Visit (3 months after the last dose of study drug).  They may also have unscheduled visits for safety assessments.   
c 
Unscheduled visits may be conducted at any time when safety or MRI data indicates it to be necessary, per protocol or as clinically indicated in the judgment of the investigator.  Note that assessments 
indicated under Unscheduled Visits need not always be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs. 
d 
Vital signs will be measured both at predose and after infusion.  Vital signs should be recorded at least 2 hours after study drug infusion, in addition to predose; however, if at previous Extension Phase 
visits, no untoward effects of infusion on vital signs are detected ≥2 hours after infusion, these assessments at subsequent study visits may be conducted at a shorter interval after infusion.  Vital sign 
measurements will consist of systolic and diastolic blood pressure (mmHg) measured after at least 3 minutes in a semi supine position, pulse (beats per minute), respiratory rate (per minute), and body 
temperature (in centigrade) 
e 
Weight will be taken in the clinic at designated visits.  If a subject misses a clinic visit where weight is to be collected, subsequent visits should use the most recent, previous collected weight for infusion 
calculations until the next clinic visit.  Under such circumstances, weight is to be taken at the next clinic visit and entered into the IVRS even if the visit is not designated for weight data collection.  If the 
subject is receiving home infusions, weight measure will be collected one visit before the protocol-specified scheduled weight measurement during the scheduled home infusion.  For subjects with weight 
measurement collected one visit before the protocol-specified schedule, weight measurement will not be needed at the protocol-specified scheduled visit 
f 
If QTcF is found to be out of range, triplicate ECGs are mandatory.   
g 
Females of childbearing potential only.  For all females of childbearing potential, an additional urine pregnancy test must be done on the day of amyloid PET scanning. 
h 
Blood for laboratory tests will be taken predose at all visits as indicated.    
i 
Scales are to be completed in the morning (or, if not possible, consistently at the same time of day) in the following order on the days indicated:  MMSE, CDR (including CDR-Global and CDR-SB), and 
ADAS-Cog.  Caregivers/informants (defined as a person able to support the subject for the duration of the study) need only to be present at visits where clinical assessments take place.  If required, and 
with prior sponsor approval, visits where clinical assessments are conducted may be split such that clinical assessments are performed in order on the 1st day and that the subject and caregiver agree to 
return to the clinical site on the next consecutive day for study dosing.  The remaining assessments can be done on either the 1st or the 2nd day.    
j 
MRI imaging should be conducted at any time following the immediately preceding visit and prior to each of the following Visits for ALL subjects according to the Schedule of Procedures/Assessments.  
In all cases, the safety MRI must be reviewed by the imaging vendor and a local reader prior to a subject receiving the next dose of study drug.  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 Early Termination Visit takes place, an MRI is to be conducted if not already performed during the 
preceding 90 days.   
k 
A volumetric MRI sequence will be collected in ALL subjects immediately following all safety MRI assessments. 
l 
PET in this substudy is optional, but encouraged - A Dosing Regimen substudy baseline amyloid PET assessment should be conducted before substudy Visit 1 (Week 1).   Those who are already 
participating in OLE amyloid PET substudy need not to undertake a baseline PET if they had amyloid PET with in last 3 months as a part of extension phase (at entry). 
m 
If approved by the Sponsor, and allowable and conducted according to country and local guidelines, subjects may be offered the option of home infusions for approved visits.  If a subject begins home 
infusion during the Dosing Regimen substudy, subjects must be observed for at least 2 hours following the first and second home infusion by the infusion staff.  After the third infusion, if no untoward 
effects of infusion are noted, or infusion reactions can be prevented with prophylaxis, then subjects will be observed 30 minutes after the end of infusion if judged medically stable by the infusion staff.   
n 
Subjects on the Q3M (3 monthly) dosing regimen do not need to attend any visits after Visit 14 (Week 53) where only Vital Signs, Prior/Concomitant Medication, and Adverse Events are scheduled. 
o 
If home infusion occurs at visits where PK samples are taken, blood will be taken for the BAN2401 assay only at predose. 
p 
Blood for serum PD should be taken predose at specified visits. 
q 
Blood for the BAN2401 anti-drug antibody assay will also be taken at the Early Termination Visit when applicable.  At Early Termination and the Follow-Up Visit, the sample can be taken at any time. 
 
 
 
Page 221 of 5021

Clinical Study Protocol 
Amendment 20 
BAN2401-G000-201
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 221 of 235 
CONFIDENTIAL 
 
 
STATISTICAL METHODS (revised per Amendments 11, 15, 16, 17, and 19) 
Primary Endpoint 
 Safety assessments will be based on medical review of AE reports and the results of vital 
sign measurements, ECG, physical examinations, clinical laboratory tests, anti-drug 
antibody (ADA) test results, and any relevant test of cognitive function to evaluate decline.  
Additionally, MRI assessments of microhemorrhage, vasogenic edema, and other clinically 
significant abnormalities will be evaluated. 
Secondary Endpoints 
 Change from baselines in brain amyloid levels as measured by amyloid PET at 3 months 
(Visit 50 [Extension Week 13], Cohort 1) or 6 months (Visit 57 [Extension Week 27], 
Cohort 2), 12 months and annually thereafter in the Extension Phase  (revised per 
Amendment 15) 
 Change from end of Core Study in brain amyloid levels as measured by amyloid PET at 
the baseline of Extension Phase 
 Proportion of amyloid positive subjects over time 
Exploratory Endpoints 
 Change from baselines in ADCOMS, CDR-SB, ADAS-Cog, and MMSE at each visit 
assessed 
 Time to worsening of CDR global scores, eg, the worsening of global CDR score is 
defined as an increase from baseline by at least 0.5 points on the global CDR scale on 
2 consecutive scheduled visits at which global CDR is measured 
 Change from baselines in total hippocampal volume and other biomarkers annually in the 
Extension Phase (revised per Amendment 15) 
 Describe the characteristics, comorbidities, treatments, associated costs for subjects with 
EAD, and study partner burden up to 5 years before study enrollment, for the duration of 
the Core Study, the duration of the period between the end of the Core Study and the 
Extension Baseline (if applicable), the duration of the Extension Phase (if applicable), and 
for up to 3 years after the end of the Core Study or Extension Phase (where applicable) 
(revised per Amendment 16) 
 
Dosing Regimen Substudy Endpoints (revised per Amendment 17)  
 Change from substudy baseline in brain amyloid levels as measured by amyloid PET  
 
Change from substudy baseline in plasma Aβ42/40 ratio and plasma p-tau181 
 
Change from substudy baseline in ADCOMS, CDR-SB, ADAS-Cog, and MMSE at each 
visit assessed 
 
Safety assessments including, but not limited to, AEs, vital signs, ECG, physical 
examinations, clinical laboratory tests, anti-drug antibody (ADA).  MRI assessments of 
microhemorrhage, vasogenic edema, and other clinically significant abnormalities  
 
Population PK parameters of BAN2401 in serum, including but not limited, to AUC, Cav, 
Correlation of PK exposure with biomarkers, safety parameters, and efficacy 
Page 222 of 5021

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Amendment 20 
BAN2401-G000-201
 
 
Eisai 
FINAL (v23.0):  24 Sep 2023 
Page 222 of 235 
CONFIDENTIAL 
 
 
ANALYSIS SETS 
 
The OLE Full Analysis Set (OLE-FAS) is the group of subjects who receive at least 
1 dose of study drug during the Extension Phase and who have a baseline assessment and 
at least 1 postdose efficacy measurement during the Extension Phase Part A.  The 
baseline assessment is defined as the last measurement prior to first dose of BAN2401 in 
the Extension Phase Part A.  (revised per Amendments 17 and 19) 
 
The OLE Safety Analysis Set is the group of subjects who receive at least 1 dose of 
study drug during the Extension Phase Part A.  This analysis set is the analysis population 
used for all safety analyses which will be based on the as-treated principle.  (revised per 
Amendments 17 and 19) 
 
The OLE PK Analysis Set is the group of subjects with at least 1 quantifiable BAN2401 
serum concentration with a documented dosing history during the Extension Phase Part 
A.  (revised per Amendment 19) 
 
The OLE PD Analysis Set is the group of subjects who have sufficient PD data to derive 
at least 1 PD parameter during the Extension Phase Part A.  (revised per Amendment 19) 
Similar analysis sets will be defined for the Dosing Regimen substudy.  The details will be included 
in the SAP.  (revised per Amendment 17) 
EFFICACY ANALYSES 
An MMRM will be used to analyze the change from baseline secondary efficacy endpoints.  
Proportion of amyloid positive subjects over time will be summarized.   
An MMRM will also be used to analyze the following exploratory endpoints (revised per 
Amendment 17): 
 
Change from baseline in the ADCOMS, CDR-SB, ADAS-Cog score, and MMSE score  
For each endpoint at a scheduled visit in the Extension Phase, a 90% 1-sided confidence interval 
will be constructed to test the null hypothesis that the treatment difference between subjects who 
took placebo in Core Study and those who took 10 mg/kg biweekly in the Core Study is no more 
than 50% of the treatment difference at the end of Core Study.  If the lower limit of this confidence 
interval is greater than 0, the null hypothesis is rejected.  In addition, comparisons between subjects 
who took placebo at Core Study and those who took 10 mg/kg biweekly in the Core Study will be 
performed for each endpoint at scheduled visits in the Extension Phase.  
Time to worsening of CDR global scores will be analyzed on the FAS using Cox regression model.  
Time to worsening of CDR global score is defined as time from the first treatment in the Extension 
Phase to worsening of the CDR score (ie, the first worsening in 2 consecutive scheduled visits).  
For subjects whose CDR scores have not worsened by the end of study, the time to worsening of 
the CDR score will be censored at the date of last CDR assessment for these subjects. 
Change from baseline in total hippocampal volume and other biomarkers will be summarized using 
descriptive statistics at scheduled visits in the Extension Phase. 
Biomarker and efficacy analysis in the Dosing Regimen substudy will also be performed similarly 
by dosing regimen.  The details will be included in SAP.  (revised per Amendment 17) 
Additional analyses and summaries will be performed as appropriate. 
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SAFETY ANALYSES 
Safety analysis will be performed similarly to the Core Study.  All safety analyses will be based 
on Safety Analysis Set of the Extension Phase.  The incidence of TEAE, laboratory test variables, 
ECG findings, vital signs, brain MRI, ADAs will be summarized using the descriptive statistics.  
(See Section 9.7.1.8) 
Safety analysis in the Dosing Regimen substudy will also be performed similarly by dosing 
regimen.  The details will be included in SAP.  (revised per Amendment 17) 
EXPLORATORY ANALYSES 
No hypothesis testing will be performed for efficacy variables.  Descriptive summary statistics 
will be generated for the efficacy endpoints as follows:  
Continuous variables will be summarized by number, mean, median, maximum, and 
minimum  
Categorical variables will be summarized by number and percentage 
Additional summary/analyses will be performed using appropriate statistical methodologies if 
deemed necessary. 
SAMPLE SIZE RATIONALE 
There is no sample size calculation for the Extension Phase Part A.  (revised per Amendment 19) 
 
 
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Appendix 5 
EXTENSION PHASE PART B  (revised per Amendment 19) 
PRIMARY OBJECTIVE: 
To evaluate the long-term safety and tolerability of BAN2401 in subjects with EAD 
ELIGIBILITY CRITERIA  
Must be currently enrolled in Extension Phase Part A.  
STUDY DESIGN AND PLAN 
All subjects ongoing in Extension Part A upon implementation of Protocol Amendment 19 will 
transition to Extension Part B.  Extension Phase Part A and Part B combined will continue for up 
to 60 months (5 years), or until BAN2401 is commercially available for individual subjects at each 
study site, at which time the subjects will switch to commercial BAN2401, or in the cases where 
drug is not yet commercially available, treatment will continue until the benefit to risk ratio from 
treatment with BAN2401 is no longer considered favorable, whichever comes first.  Upon 
transition to Extension Phase Part B, Dosing Regimen substudy subjects will be given the option 
to remain on their current dosing regimen or transition back to BAN2401 10 mg/kg biweekly 
infusions.   
Subjects in Extension Phase Part B will have procedures and assessments including periodic safety 
assessments at approximately 6 monthly intervals (±4 weeks) or as unscheduled assessments, 
when required.   
All infusions will take place in the clinic; however, if approved by the Sponsor and allowable and 
conducted according to country and local guidelines, subjects will be offered the option of home 
infusions for approved visits.  Home infusions are being implemented as a result of the Coronavirus 
Disease 2019 (COVID-19) pandemic to allow subjects who cannot visit clinical sites for various 
reasons to continue receiving treatment.  Home infusions will be allowed per Sponsor approval 
according to country and local guidelines during the COVID-19 pandemic and following its 
resolution, where permitted.     
Subjects will continue in Extension Phase B for a maximum combined (Part A and Part B) 
open-label treatment duration of up to 60 months (5 years), or until BAN2401 is commercially 
available for individual subjects at each study site, at which time the subjects will switch to 
commercial BAN2401, or in the cases where drug is not yet commercially available, treatment 
will continue until the benefit to risk ratio from treatment with BAN2401 is no longer considered 
favorable, whichever comes first.   
Upon approval of BAN2401 in Japan, subjects who meet the approved indication and dosage of 
BAN2401 will continue in Extension Phase Part B of this study as a postmarketing part in Japan.   
The Follow-Up Visit will take place 3 months after the last dose of study drug.  Subjects may 
discontinue from study drug for any reason.  Subjects who discontinue the study drug are requested 
to undertake the Early Termination Visit (within 7 days after the last dose of study drug) and the 
Follow-Up Visit (3 months after the last dose of study drug).  The 3-month Follow-Up visit is not 
required for any subject who transitions directly (including the postmarketing part in Japan) to 
commercial BAN2401.   
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For those subjects who transition to commercial BAN2401 (including the postmarketing part in 
Japan), the end of the study will be the date of the last study evaluation prior to transitioning to 
commercial BAN2401.  At that time, all assessments included in the Early Termination Visit are 
to be performed.     
EXTENSION PHASE PART B ASSESSMENTS 
Safety assessments will be performed and all adverse events (AEs) and SAEs will be recorded.  
Vital signs will be assessed when study drug is administered both at predose and after infusion.  
Safety MRIs will be performed every 6 months.  Intracerebral hemorrhages >1 cm should always 
be classified as an important medical event and reported as an SAE even if they do not meet other 
serious criteria.  (revised per Amendment 20) 
Subjects who develop asymptomatic ARIA-H, will continue on the study uninterrupted per the 
Schedule of Assessments and do not require additional magnetic resonance imaging (MRI) 
follow up outside the regularly scheduled assessments.  Subjects who develop multiple (>10) 
asymptomatic cerebral microhemorrhages, superficial siderosis, or a single macrohemorrhage 
(greater than 10 mm at greatest diameter also referred to within this protocol as intracerebral 
hemorrhage >1 cm), will continue on the study uninterrupted per the Schedule of Assessments, 
and will undertake an unscheduled safety visit (with MRI) at approximately 30 days after the MRI 
features (asymptomatic ARIA-H) were first identified.  Thereafter, all subjects who develop these 
events will have further safety visits (with MRI) at approximately every 30 days (which may be 
an unscheduled or a scheduled visit) until the asymptomatic ARIA-H has stabilized 
radiographically.  Subjects who develop symptomatic ARIA-H (including symptomatic 
microhemorrhages, symptomatic superficial siderosis, symptomatic macrohemorrhage) on MRI 
will have study drug administration temporarily stopped.  All subjects who develop these events 
will undertake an unscheduled safety visit (with MRI) at approximately 30 days after the MRI 
features (ARIA-H) were first identified.  Thereafter they will have further safety visits (with MRI) 
at approximately every 30 days (which may be unscheduled or scheduled visit) until the ARIA-H 
has stabilized and is no longer symptomatic.  During treatment interruption, time will elapse on 
the Schedule of Assessments when the scheduled visit would otherwise occur.  They may then 
resume treatment for the study duration and study assessments remaining on the Schedule of 
Assessments.  Resumption of treatment following symptomatic ARIA-H can only occur twice, 
after which the subject must be discontinued from the study.  (revised per Amendment 20) 
Subjects who develop asymptomatic, radiographically mild or moderate Amyloid-Related 
Imaging Abnormality–Edema/Effusion (ARIA-E) on MRI will continue on the study 
uninterrupted per the Schedule of Assessments.  They will undertake an unscheduled safety visit 
(with MRI) at approximately 30 days and another safety visit (with MRI) at approximately 90 days 
(which may be unscheduled or scheduled visit) after the MRI features were first identified.  They 
will continue with study drug treatment if their ARIA-E does not become severe radiologically 
and remains asymptomatic.   
Those subjects who develop symptomatic or radiographically severe treatment emergent ARIA-E 
will be temporarily stopped from study drug administration until the ARIA-E resolves 
radiographically, and will be followed up to resolution of the event (including symptoms, if any).  
They will undertake an unscheduled safety visit (with MRI) at approximately 30 days and another 
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safety visit (with MRI) at approximately 90 days (which may be unscheduled or scheduled visit) 
after the symptomatic or severe ARIA-E was first identified.  Thereafter, these subjects will have 
a safety visit (with MRI) at approximately 30 days (which may be an unscheduled or a scheduled 
visit) until the ARIA-E has resolved both radiologically and clinically.  During treatment 
interruption, time will elapse on the Schedule of Assessments when the scheduled visit would 
otherwise occur.  Once the ARIA-E has resolved both radiologically and clinically, they may then 
resume treatment for the study duration and study assessments on the Schedule of Assessments.  
Resumption of treatment following symptomatic ARIA-E can only occur twice, after which the 
subject must be discontinued from the study.   
In Japan only, subjects who develop asymptomatic, radiographically mild ARIA-E on MRI will 
continue on the study uninterrupted per the Schedule of Assessments.  They will undertake an 
unscheduled safety visit (with MRI) at approximately 30 days and another safety visit (with MRI) 
at approximately 90 days (which may be unscheduled or scheduled visit) after the MRI features 
were first identified.  They will continue with study drug treatment if their ARIA-E does not 
become moderate or severe radiologically and remains asymptomatic.  Those subjects who 
develop symptomatic or radiographically moderate or severe treatment emergent ARIA-E will be 
temporarily stopped from study drug administration until the ARIA-E resolves radiographically, 
and will be followed up to resolution of the event (including symptoms, if any).  They will 
undertake an unscheduled safety visit (with MRI) at approximately 30 days and another safety 
visit (with MRI) at approximately 90 days (which may be unscheduled or scheduled visit) after 
the symptomatic or moderate or severe ARIA-E was first identified.  Thereafter, these subjects 
will have a safety visit (with MRI) at approximately 30 days (which may be an unscheduled or a 
scheduled visit) until the ARIA-E has resolved both radiologically and clinically.  During 
treatment interruption, time will elapse on the Schedule of Assessments when the scheduled visit 
would otherwise occur.  Once the ARIA-E has resolved both radiologically and clinically, they 
may then resume treatment for the study duration and study assessments on the Schedule of 
Assessments.  Resumption of treatment following symptomatic and/or radiographically moderate 
or severe ARIA-E can only occur twice, after which the subject must be discontinued from the 
study.   
Radiographic severity is defined as follows:   
No ARIA-E present:  No signs of ARIA-E. 
Questionable ARIA-E:  Subtle sulcal or cortical fluid-attenuated inversion recovery (FLAIR) 
hyperintensity, most likely artifactual. 
Mild ARIA-E:  Mild FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white 
matter (with or without gyral swelling and sulcal effacement), which affects an area of less 
than 5 cm in a single greatest dimension.  Only a single region of involvement detected. 
Moderate ARIA-E:  Moderate involvement (area of FLAIR hyperintensity measuring 
5 - 10 cm in single greatest dimensions), or more than one site of involvement, each measuring 
less than 10 cm in a single greatest dimension. 
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Severe ARIA-E:  Severe involvement (area of FLAIR hyperintensity measuring greater than 
10 cm in single greatest dimension [white matter and/or sulcal involvement with associated 
gyral swelling and sulcal effacement).  One or more separate/independent sites of involvement 
may be noted. 
Should a subject discontinue from study treatment from one of these events, such subjects will 
undergo the Early Termination Visit within 7 days of discontinuation and will undergo the 3 month 
Follow-Up Visit per protocol.  These subjects will continue to be followed with safety MRIs on a 
monthly basis thereafter, until the finding has either resolved or stabilized.  
STUDY DRUG SUPPLIES  
All subjects will be administered the BAN2401 10 mg/kg biweekly dose.  For subjects who 
previously participated in the Dosing Regimen substudy, BAN2401 10 mg/kg will be administered 
either at the biweekly dose or they may continue with their prior dose of Q4W or Q3M intervals.  
BAN2401 will be administered in normal saline as 60 minute IV infusions.  An infusion system 
containing a terminal 0.22-µm in-line filter is required for administration of BAN2401 drug 
product.   
Removal of Subjects From Therapy or Assessment 
Subjects who discontinue from treatment during the Extension Phase will have a Follow-Up Visit 
3 months after the last dose of study drug.  The 3-month Follow-Up Visit is not required for any 
subject who transitions directly from the Extension Phase (including the postmarketing part in 
Japan) of the study to commercial BAN2401.   
Safety-related criteria for discontinuation of study drug are as follows: 
 Infusion reactions associated with administration of study drug, of Grade 3 severity or 
above (as defined in the NCI-CTCAE) that do not lessen or resolve with treatment  
 Clinical features which indicate meningoencephalitis (eg, combination of one or more of 
the following: headache, worsening confusion, neck stiffness, impaired consciousness, 
focal neurological signs) 
 Hypersensitivity reactions with clinical features of tissue injury (eg, arthritis, 
glomerulonephritis, mononeuritis multiplex)     
Treatment Administered and Identity of Investigational Product(s) 
All subjects will be administered the BAN2401 10 mg/kg biweekly dose.  For subjects who 
previously participated in the Dosing Regimen substudy, BAN2401 10 mg/kg will be administered 
either at the biweekly dose or they may continue with their prior dose of Q4W or Q3M intervals.  
BAN2401 will be administered in normal saline as 60 minute IV infusions.  An infusion system 
containing a terminal 0.22-µm in-line filter is required for administration of BAN2401 drug 
product.     
BAN2401 is a humanized IgG1 monoclonal antibody that binds to soluble Aβ aggregates.  
BAN2401 is manufactured at Patheon Ltd, United Kingdom (UK) and at Biogen, RTP, under 
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contract to Eisai.  It is currently supplied as a sterile clear solution for injection containing 
10 mg/mL, in a single use 10-mL vial (total 100 mg/vial).  The drug product is formulated in 
25 mM sodium citrate, 125 mM sodium chloride, 0.02% (w/v) polysorbate 80 and has a pH of 5.7.  
This current formulation of the drug product may be progressively phased out as stocks near the 
end of their shelf life and replaced by a newer formulation containing 100 mg/mL BAN2401.  The 
newer formulation (100 mg/mL BAN2401) was developed to reduce the number of vials of drug 
product required per dose and to reduce demand for storage space in a pharmacy.  The newer 
(100 mg/mL BAN2401) formulation is supplied as a sterile aqueous solution containing 
100 mg/mL BAN2401, 50 mmol/L citric acid, 0.05% (w/v) polysorbate 80, 350 mmol/L arginine, 
at pH 5.0, in glass vials containing 5 mL solution.  The phasing out of the older formulation will 
only occur after appropriate regulatory authority approval for the newer formulation has been 
obtained, and adequate training of any pharmacy staff involved in the preparation of the final drug 
product for infusion has been completed.  The appearance of the 2 different formulations after 
dilution in normal saline is identical. 
Study drug will be packaged such that there is 1 vial per dispenser (10 mg/mL) and 4 vials per 
dispenser (100 mg/mL), and will be dispensed by a pharmacist at each site according to the 
Interactive Voice Response System (IVRS).  At the time that the study drug is dispensed for 
administration to the subject, the tear-off label on the dispenser must be removed and placed in the 
study drug accountability log at the time of dispensing.   
All study drug will be administered in the clinic; however, if approved by the Sponsor and 
allowable and conducted according to country and local guidelines, subjects will be offered the 
option of home infusions for approved visits.  Home infusions are being implemented as a result 
of the COVID-19 pandemic to allow subjects who cannot visit clinical sites for various reasons to 
continue receiving treatment.  Home infusions will be allowed per Sponsor approval according to 
country and local guidelines during the COVID-19 pandemic and following its resolution, where 
permitted.   
Concomitant Therapies and Drugs  (revised per Amendment 17) 
A list of restricted and permitted drugs is provided in Appendix 2. 
 
During the course of the Extension Phase, immunoglobulin therapy may be allowed, if 
clinically indicated and after a documented discussion with the medical monitoring team.  
In this case, an interval of 30 days between study drug infusion and immunoglobulin 
therapy should be observed.  Subjects who require treatment with thrombolytic drugs do 
not have to be discontinued from the study, but study drug will be temporarily suspended 
for these subjects during thrombolytic therapy until stabilization or resolution of the 
medical condition that required thrombolytic drug treatment. 
 
Flu, shingles, pneumococcal, hepatitis B, COVID-19 (including the booster shot), and 
other vaccines can be administered during the treatment period, but vaccination should be 
timed such that it will be administered at least 7 days after the previous infusion and at 
least 7 days before the next infusion.  The duration between COVID-19 vaccination and 
study drug infusions may be reduced to less than 7 days according to the clinical 
judgement of the investigator.   
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 
Subjects who are on anticoagulants at Extension Baseline (Extension Screening Visit) are 
required to have their anticoagulation status optimized and stable for at least 4 weeks 
before Extension Screening Visit.   
 
Subjects who initiate Alzheimer’s disease (AD) treatment or who adjust their AD dosing 
regimen while on study will continue to study completion.  However, if aducanumab (or 
other approved amyloid-targeting AD treatments) is started during the study, then 
subjects are required to immediately discontinue from study drug.   
The following requirements apply to all other medications: 
 
Subjects must be on a stable dose for at least 4 weeks prior to Extension Screening Visit, 
except for medications which are administered as short courses of treatment (eg, 
anti-infectives) or which are to be used as needed (PRN). 
 
Medications which are used on a PRN basis or as a short course of treatment, and which 
are CNS active and may affect cognitive function are not permitted during a period of 
72 hours prior to cognitive testing. 
 
Subjects may receive PRN prophylactic medications prior to infusion of study drug 
(outlined in the protocol) to minimize the risk of immunologic reaction or infusion 
reaction during or shortly after the infusion. 
 
Subjects who initiate treatment or undertake dose adjustment with drugs not intended for 
treatment of cognitive impairment during the study may continue in the study if in the 
opinion of the PI this adjustment will not interfere with study procedures or subject safety 
and are not prohibited above. 
SCHEDULE OF PROCEDURES/ASSESSMENTS 
Table 16 presents the Schedule of Assessments for Extension Phase Part B. 
 
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Table 16 
Extension Phase Part B – Schedule of Assessments (revised per Amendment 19) 
Phase 
Extension Phase Part B 
Period 
Treatment 
Visit(s)a 
Bi-weekly 
Infusion Visit 
Dosing Regimen 
Substudy Q4W 
Infusion Visitb 
Dosing Regimen 
Substudy Q3M 
Infusion Visitc 
6 Monthly 
Infusion Visit 
Early 
Termination 
Visitd 
Unscheduled 
Visite 
Follow-Up Visitf 
Procedures/Assessments 
 
 
 
 
 
 
 
Study drug 
administrationg 
X 
X 
X 
X 
 
 
 
Vital signsh 
X 
X 
X 
X 
 
X 
 
Weighti 
 
 
 
X 
 
X 
 
Urine pregnancy testj 
 
 
 
X 
 
X 
 
Routine Physical 
Examination  
 
 
 
 
 
X 
 
Blood for laboratory 
tests 
 
 
 
 
 
X 
 
Urinalysis 
 
 
 
 
 
X 
 
C-SSRSk 
 
 
 
X 
 
X 
 
12-Lead ECGl 
 
 
 
 
 
X 
 
Safety MRIm 
 
 
 
X 
X 
X 
 
Prior/concomitant meds 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
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Subjects should continue along their current Visit Schedule from Part A with assessments completed per Table 16. Eg, if a subject moves from Part A to Part B at visit 144 Extension Phase Week 
201 their first Part B 6 Monthly Infusion Visit would be at Visit 148 Extension Phase Week 209. 
C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram, IVRS = MRI = magnetic resonance imaging, Q3M = every 3 months, Q4W = every 4 weeks, QTcF = corrected QT 
interval by Fredericia 
a:  Visit window of ±8 days will be allowed for each visit. A visit window of ±7 days will be allowed for the Follow-up Visit.   
b:  Q4W visits will occur every 4 weeks and are only applicable to those in the Dosing Regimen Substudy who are on that regimen. At any point subjects may revert to Q2W (Biweekly) infusion 
visits. 
c:  Q3M visits will occur every 12 weeks and are only applicable to those in the Dosing Regimen Substudy who are on that regimen. At any point subjects may revert to Q2W (Biweekly) infusion 
visits. 
d:  Subjects who discontinue study drug early or who transitions to commercial BAN2401 are requested to undertake the Early Termination Visit (within 7 days after discontinuation the last dose 
of study drug) and the Follow-Up Visit (3 months after the last dose of study drug).  The 3-month Follow-Up visit is not required for any subject who transitions directly from the Extension 
Phase (including the postmarketing part in Japan) of the study to commercial BAN2401. 
e: Unscheduled visits may be conducted at any time when safety or MRI data indicates it to be necessary, per protocol or as clinically indicated in the judgment of the investigator.  Note that 
assessments indicated under Unscheduled Visits need not always be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs. 
f:  Subjects who completed the 5 years Extension Phase without transitioning to commercial BAN2401 are required to attend an End-of-Study Visit (Visit 174 Week 261) and a 3-month Follow-
Up Visit. 
g:  If approved by the Sponsor, and allowable and conducted according to country and local guidelines, subjects may be offered the option of home infusions for approved visits.  If a subject begins 
home infusion during the dosing regimen substudy, subjects must be observed for at least 2 hours following the first and second home infusion by the infusion staff.  After the third infusion, if 
no untoward effects of infusion are noted, or infusion reactions can be prevented with prophylaxis, then subjects will be observed 30 minutes after the end of infusion if judged medically stable 
by the infusion staff. 
h:  Vital signs will be measured both at predose and after infusion; the timing of post dose vital signs is at investigator discretion based on prior infusion visits.  Vital sign measurements will consist 
of systolic and diastolic blood pressure (mmHg) measured after at least 3 minutes in a semi supine position, pulse (beats per minute), respiratory rate (per minute), and body temperature (in 
centigrade). 
i:  Weight will be taken approximately every 6 months.  If a subject misses a clinic visit where weight is to be collected, subsequent visits should use the most recent, previous collected weight for 
infusion calculations until the next clinic visit.  Under such circumstances, weight is to be taken at the next clinic visit and entered into the IVRS even if the visit is not designated for weight 
data collection.  If the subject is receiving home infusions, weight measure will be collected one visit before the protocol-specified scheduled weight measurement during the scheduled home 
infusion.  For subjects with weight measurement collected one visit before the protocol-specified schedule, weight measurement will not be needed at the protocol-specified scheduled visit. 
j:  Females of childbearing potential only.   
k:  Since last visit (SLV) version should be used for all visits. 
l:  If QTcF is found to be out of range, triplicate ECGs are mandatory.   
m:  MRI imaging for safety should be conducted approximately every 6 months, at any time following the immediately preceding infusion visits.  In all cases, the safety MRI must be reviewed by 
the imaging vendor and a local reader prior to a subject receiving the next dose of study drug.  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 Early Termination Visit takes place, an MRI is to be conducted if not already performed during the preceding 90 days.   
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STATISTICAL METHODS  
Primary Endpoint 
 
Safety assessments will be based on medical review of AE reports and the results of vital 
sign measurements, and physical examinations.  Additionally, MRI assessments of 
microhemorrhage, vasogenic edema, and other clinically significant abnormalities will be 
evaluated. 
ANALYSIS SETS 
 The OLE Safety Analysis Set is the group of subjects who receive at least 1 dose of study 
drug during the Extension Phase Part B.  This analysis set is the analysis population used 
for all safety analyses which will be based on the as-treated principle. 
 
EFFICACY ANALYSES 
No efficacy analyses will be performed. 
SAFETY ANALYSES 
Safety analysis will be performed similarly to the Core Study.  All safety analyses will be based 
on Safety Analysis Set of the Extension Phase Part B.  The incidence of treatment emergent 
adverse events (TEAEs), vital signs, and brain MRI, will be summarized using descriptive 
statistics.  The details will be included in SAP.   
EXPLORATORY ANALYSES 
Not applicable 
SAMPLE SIZE RATIONALE 
There is no sample size calculation for the Extension Phase Part A or Part B.   
 
 
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PROTOCOL SIGNATURE PAGE 
(revised per Amendments 01 and 17) 
Study Protocol Number: BAN2401-G000-201 
Study Protocol Title: 
A Placebo-Controlled, Double-Blind, Parallel-Group, Bayesian 
Adaptive Randomization Design and Dose Regimen-finding 
Study with an Open-Label Extension Phase to Evaluate Safety, 
Tolerability and Efficacy of BAN2401 in Subjects With Early 
Alzheimer’s Disease 
Investigational Product 
Name: 
BAN2401/lecanemab (revised per Amendment 16) 
IND Number: 
105081 
EudraCT Number: 
2012-002843-11 
 
SIGNATURES (revised per Amendments 15, 17, and 19) 
 
 
Authors: 
 
 
 
 
 
 
 
 
Study Director, 
  
 
Eisai Ltd.  
European Knowledge Centre 
Mosquito Way 
Hatfield, Hertfordshire  
AL10 9SN UK. 
 
Date 
 
 
 
 
 
 
,  
Medical Monitor  
 
 
Eisai Inc. 
 
Date 
 
 
 
 
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Clinical Pharmacologist 
 
 
Eisai Inc. 
 
Date 
 
 
 
 
 
 
 
 Biostatistics 
 
Eisai Inc. 
 
 
Date 
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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
BAN2401-G000-201 
Study Protocol Title: 
A Placebo-Controlled, Double-Blind, Parallel-Group, Bayesian 
Adaptive Randomization Design and Dose Regimen-finding Study 
with an Open-Label Extension Phase to Evaluate Safety, 
Tolerability and Efficacy of BAN2401 in Subjects With Early 
Alzheimer’s Disease 
Investigational Product 
Name: 
BAN2401/lecanemab (revised per Amendment 16) 
IND Number: 
105081 
EudraCT Number: 
2012-002843-11 
I have read this protocol and agree to conduct this trial 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 
 
 
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