Clinical trial NCT02972658
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease Dementia Brain Diseases Neurodegenerative Diseases Central Nervous System Diseases Nervous System Diseases Mental Disorders Delirium, Dementia, Amnestic, Cognitive Disorders Tauopathies Memory Amyloid
Sponsor: AstraZeneca
Start date: 2017-03-15; Completion date: 2018-10-02
Enrollment: 421 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is an extension of study I8D-MC-AZES (NCT02245737), the AMARANTH study. The purpose of this study is to evaluate the effectiveness of the study drug lanabecestat in participants with early Alzheimer's disease dementia at the time of entry into study I8D-MC-AZES.

Detailed description:
Study AZFD was designed to be integrated with 104-week study AZES to form a Delayed-Start study (Study AZES-FD). Study AZES-FD was to be used to test the hypothesis that participants originally randomized to receive placebo in the double-blind feeder study AZES and switched to LY3314814 at the start of study AZFD did not "catch up" on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) at Week 26 of study AZFD to participants originally randomized to receive LY3314814 in the double-blind feeder study.

Arms: arm 1: Participants who received Lanabecestat 20 mg in the feeder study (AZES) were randomized to receive Lanabecestat 20 mg. arm 2: Participants who received Lanabecestat 50 mg in the feeder study (AZES) were randomized to receive Lanabecestat 50 mg. arm 3: Participants who received placebo in the feeder study (AZES) were randomized to receive Lanabecestat 20 mg. arm 4: Participants who received placebo in the feeder study (AZES) were randomized to receive Lanabecestat 50 mg.
Interventions: intervention 1: Lanabecestat
Intervention descriptions: intervention 1: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol I8D-MC-AZFD(a)
A Randomized, Double-Blind, Delayed-Start Study of LY3314814 (AZD3293) in Early Alzheimer’s 
Disease Dementia (Extension of Study AZES, The AMARANTH Study)
NCT02972658
Approval Date: 06-Feb-2018


I8D-MC-AZFD(a) Clinical Protocol
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LY3314814
Protocol I8D-MC-AZFD(a)
A Randomized, Double-Blind, Delayed-Start Study of 
LY3314814 (AZD3293) in Early Alzheimer’s Disease Dementia 
(Extension of Study AZES, The AMARANTH Study)
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3314814, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3314814 (Lanabecestat)
Study AZFD is a Phase 3 study designed to test whether LY3314814 will slow disease 
progression in patients with early Alzheimer’s Disease randomized in Study AZES.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 06-Feb-2018 GMT


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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................13
3.1.
Study Rationale............................................................................................................13
3.2.
Background..................................................................................................................13
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................15
5.
Study Design.....................................................................................................................16
5.1.
Overall Design .............................................................................................................16
5.2.
Number of Participants.................................................................................................17
5.3.
End of Study Definition ...............................................................................................17
5.4.
Scientific Rationale for Study Design...........................................................................18
5.5.
Justification for Dose ...................................................................................................18
6.
Study Population...............................................................................................................19
6.1.
Inclusion Criteria..........................................................................................................19
6.2.
Exclusion Criteria ........................................................................................................20
6.3.
Lifestyle Restrictions....................................................................................................20
6.4.
Screen Failures.............................................................................................................21
6.5.
Study Partner ...............................................................................................................21
7.
Treatments........................................................................................................................22
7.1.
Treatments Administered .............................................................................................22
7.1.1.
Packaging and Labeling .......................................................................................22
7.2.
Method of Treatment Assignment ................................................................................23
7.2.1.
Selection and Timing of Doses.............................................................................23
7.3.
Blinding .......................................................................................................................23
7.4.
Dosage Modification....................................................................................................24
7.5.
Preparation/Handling/Storage/Accountability...............................................................24
7.6.
Treatment Compliance .................................................................................................24
7.7.
Concomitant Therapy...................................................................................................25
7.7.1.
Initiation of Post-Randomization Symptomatic AD 
Treatments ...........................................................................................................25
7.7.2.
Other Medication Considerations Post-Randomization.........................................25
7.8.
Treatment after the End of the Study............................................................................26
7.8.1.
Study Extensions..................................................................................................26
7.8.2.
Continued Access.................................................................................................26


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8.
Discontinuation Criteria ....................................................................................................27
8.1.
Discontinuation from Study Treatment.........................................................................27
8.1.1.
Discontinuation from Study Treatment.................................................................27
8.1.2.
Temporary Discontinuation from Study Treatment...............................................28
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................28
8.2.
Discontinuation from the Study....................................................................................28
8.3.
Lost to Follow-Up........................................................................................................29
9.
Study Assessments and Procedures ...................................................................................30
9.1.
Efficacy Assessments...................................................................................................30
9.1.1.
Primary Outcome Efficacy Assessment................................................................30
9.1.2.
Secondary Efficacy Assessments..........................................................................30
9.1.3.
Other/Exploratory Assessments............................................................................32
9.1.4.
Appropriateness of Assessments ..........................................................................34
9.1.5.
Order of Efficacy Assessments and Rater Qualifications ......................................34
Order of Efficacy Assessments .......................................................................34
9.1.5.1.
Rater Qualifications and Blinding...................................................................35
9.1.5.2.
9.2.
Adverse Events ............................................................................................................36
9.2.1.
Serious Adverse Events........................................................................................37
Suspected Unexpected Serious Adverse Reactions..........................................37
9.2.1.1.
9.2.2.
Complaint Handling.............................................................................................38
9.3.
Treatment of Overdose.................................................................................................38
9.4.
Safety...........................................................................................................................38
9.4.1.
Vasogenic Edema.................................................................................................38
9.4.2.
Rash.....................................................................................................................38
9.4.3.
Depression ...........................................................................................................39
9.4.4.
Disease Progression .............................................................................................39
9.4.5.
Laboratory Safety Assessment .............................................................................39
9.4.6.
Hepatic Monitoring ..............................................................................................39
9.4.7.
Physical and Neurological Examinations..............................................................40
9.4.8.
Electrocardiograms ..............................................................................................40
9.4.9.
Vital Signs ...........................................................................................................41
Pulse Rate and Blood Pressure........................................................................41
9.4.9.1.
Body Weight ..................................................................................................41
9.4.9.2.
9.4.10.
Other Safety Assessments ....................................................................................41
Eye and Skin Examinations ............................................................................41
9.4.10.1.
C-SSRS..........................................................................................................42
9.4.10.2.
Magnetic Resonance Imaging (Safety)............................................................43
9.4.10.3.
Safety Areas of Special Interest ......................................................................43
9.4.10.4.


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IDMC.............................................................................................................44
9.4.10.5.
9.5.
Pharmacokinetics .........................................................................................................44
9.6.
Pharmacodynamics ......................................................................................................44
9.7.
Genetics .......................................................................................................................45
9.7.1.
Whole Blood Samples for Exploratory DNA and RNA 
Research ..............................................................................................................45
9.8.
Biomarkers and Imaging ..............................................................................................45
9.8.1.
Florbetapir PET (Positron emission Tomography)................................................45
9.8.2.
Magnetic Resonance Imaging (Efficacy) ..............................................................46
9.9.
Health Economics ........................................................................................................46
10.
Statistical Considerations ..................................................................................................47
10.1. Sample Size Determination ..........................................................................................47
10.2. Populations for Analyses of AZES-FD.........................................................................48
10.3. Statistical Analyses ......................................................................................................48
10.3.1.
General Statistical Considerations ........................................................................48
10.3.2.
Treatment Group Comparability...........................................................................50
Patient Disposition..........................................................................................50
10.3.2.1.
Patient Characteristics ....................................................................................50
10.3.2.2.
Concomitant Therapy .....................................................................................50
10.3.2.3.
Treatment Compliance....................................................................................50
10.3.2.4.
10.3.3.
Efficacy Analyses ................................................................................................51
Primary Analyses ...........................................................................................51
10.3.3.1.
Multiplicity Adjustments ................................................................................51
10.3.3.2.
Secondary Analyses........................................................................................52
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................52
10.3.3.4.
10.3.4.
Safety Analyses....................................................................................................52
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................53
10.3.6.
Other Analyses.....................................................................................................53
Health Economics...........................................................................................53
10.3.6.1.
Subgroup Analyses.........................................................................................53
10.3.6.2.
10.3.7.
Interim Analyses ..................................................................................................53
11.
References ........................................................................................................................54
12.
Appendices .......................................................................................................................56


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List of Tables
Table
Page
Table 4.1.
Objectives and Endpoints...............................................................................15
Table 7.1.
Treatment Regimens......................................................................................22
Table 9.1.
Order of Test Administration for Patient and Study Partner and Rater 
Responsibilities .............................................................................................35
Table 10.1.
Treatment Regimens for Integrated Delayed-Start Study................................48


I8D-MC-AZFD(a) Clinical Protocol
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List of Figures
Figure
Page
Figure 5.1.
Illustration of study design for Clinical Protocol I8D-MC-AZFD...................17


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................57
Appendix 2.
Clinical Laboratory Tests...............................................................................62
Appendix 3.
Study Governance Considerations..................................................................63
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................66
Appendix 5.
Protocol Amendment I8D-MC-AZFD(a) Summary A Randomized, 
Double-Blind, Delayed-Start Study of LY3314814 (AZD3293) in Early 
Alzheimer’s Disease Dementia (Extension of Study AZES, The 
AMARANTH Study).....................................................................................67


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1.
Synopsis
Title of Study:
A Randomized, Double-Blind, Delayed-Start Study of LY3314814 in Early Alzheimer’s Disease Dementia 
(extension of Study AZES).
Rationale:
LY3314814 is being developed for the modification of the clinical course of Alzheimer’s disease (AD) by slowing 
disease progression in patients diagnosed with early AD, which is defined as the continuum of patients with mild 
cognitive impairment due to AD (MCI-AD) and patients diagnosed with mild AD dementia. Study AZFD 
integrated with Study AZES forms a Delayed Start study (Study AZES-FD).  Study AZES-FD will be used to test 
the hypothesis that patients originally randomized to receive placebo in the double-blind feeder Study AZES and 
switched to LY3314814 at the start of Study AZFD do not “catch up” on the Alzheimer’s Disease Assessment 
Scale-Cognitive Subscale (ADAS-Cog13) at Week 26 (Visit 7) of Study AZFD to patients originally randomized to 
receive LY3314814 in the double-blind feeder study.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

The primary analysis of Study AZES-FD is to 
evaluate disease modification as outlined in 
Liu-Seifert (2015).  This will be accomplished 
by testing the three delayed-start hypotheses 
in both doses of LY3314814 across 
Study AZES and up to Week 26 (Visit 7) of 
Study AZFD.

ADAS-Cog13
Secondary
Clinical efficacy objective:

To evaluate the disease modification of both 
doses of LY3314814 on functional and 
cognitive outcomes across Study AZES and 
up to Week 26 (Visit 7) of Study AZFD using 
the primary analysis methodology.

Functional Outcome Measures
o
ADCS-ADL score
o
FAQ

Cognitive/Functional Outcome Measures
o
iADRS score
o
CDR-SB

Cognitive Outcome Measures
o
MMSE

The delayed-start analyses as outlined above 
will also be examined through Week 104 
(Visit 15) for cognitive and functional 
outcomes.

ADAS-Cog13, ADCS-ADL, FAQ, iADRS, 
CDR-SB, MMSE
Safety Objective

Collect information in order to further 
characterize the safety and tolerability of 
LY3314814 in patients with early AD

Standard safety assessments:
o
spontaneously reported AEs
o
clinical laboratory tests
o
vital sign and body weight 


I8D-MC-AZFD(a) Clinical Protocol
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LY3314814
Objectives
Endpoints
dementia (at the time of entry into 
Study AZES)
measurements
o
12-lead ECGs
o
physical examinations including 
neurological examinations

Additional safety assessments:
o
Eye examinations
o
Skin examinations
o
Serial MRI
o
Columbia-Suicide Severity Rating 
Scale (C-SSRS)
Abbreviations:  AD = Alzheimer’s disease; ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale –
Cognitive subscale; ADCS-ADL = Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory; 
AE = adverse event; CDR-SB = Clinical Dementia Rating Sum of Boxes; ECG = electrocardiogram; FAQ = 
Functional Activities Questionnaire; iADRS = integrated Alzheimer’s Disease Rating Scale; MMSE = Mini-
Mental State Examination; MRI = magnetic resonance imaging.
Summary of Study Design:
Study I8D-MC-AZFD is a multicenter, randomized, double-blind, 104-week delayed-start study with 2 fixed doses 
of LY3314814 in patients diagnosed with early AD, which is defined as the continuum of patients with MCI-AD
and patients diagnosed with mild dementia of the Alzheimer’s type (mild AD dementia), at the time of entry into 
feeder Study AZES.
Treatment Arms and Duration:
In Study AZFD, all patients will receive treatment with LY3314814.  Patients who were randomized to LY3314814 
in feeder Study AZES will continue with the same drug dose in Study AZFD.  Patients who were randomized to 
placebo in the feeder study will be randomized, in a 1:1 ratio, to either LY3314814 20 mg or LY3314814 50 mg.
All patients will receive study drug for 104 weeks.
Number of Patients:
It is estimated that approximately 1540 patients will complete the feeder Study AZES.  Of those patients who 
complete Study AZES, it is assumed that approximately 90% (1400) of the patients will provide consent to continue 
into Study AZFD.
Statistical Analysis:
The statistical analyses outlined in this protocol pertain to the delayed-start Study AZES-FD.  Because Study AZFD 
forms the second part of a delayed-start study design when paired with Study AZES, safety and efficacy analyses of 
Study AZFD alone are difficult to interpret and are not planned a priori.


I8D-MC-AZFD(a) Clinical Protocol
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2. Schedule of Activities
Study procedurea
Delayed-Start Year 1
Delayed-Start Year 2
EDb
F/U
Visit number
V20-AZES/
V1-AZFDc
V2
V3
V4
V5
V6
V7
V8d
V9
V10
V11
V12e
V13
V14
V15
V801f
Study week
1
4
7
13
19
26
32
39
45
52
65
78
91
104
Tolerance interval for Visit 
(days)
±3
±3
±7
±7
±7
±7
±7
±7
±7
±10
±7
±7
±7
±7
Informed consent
X
Randomization
X
Prior/concomitant treatments
CO
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
NIA-AA criteria review
X
X
X
FAQ
CO
X
X
X
X
X
ADCS-ADL
CO
X
X
X
X
X
CDRg
CO
X
X
X
X
X
MMSE
CO
X
X
X
X
X
X
RBANS
X
X
X
ADAS-Cog13
CO
X
X
X
X
X
X
NPI
CO
X
X
X
X
X
Letter & Category Fluency, Digit 
Symbol-Coding tests
CO
X
X
X
X
X
EQ-5D-5L (patient)
CO
X
X
X
X
RUD-Lite
CO
X
X
X
X
MRI
CO
X
X
X
Florbetapir F18 Amyloid PETh
CO
X
Xi
Required blood samples for 
plasma biomarkersj
Xj
Xj
Xi,j
Laboratory testsk
CO
X
X
X
X
X
X
X
X
X
X
X
Physical, neurological 
examinations
CO
Xl
X
Xl
Xl
X
Xl
X
Xl
X
X
Comprehensive eye examination
CO
X
X
X
Skin examination
CO
X
X
X
X
Vital signsm
CO
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
CO
X
X
X
X
X


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Study procedurea
Delayed-Start Year 1
Delayed-Start Year 2
EDb
F/U
Visit number
V20-AZES/
V1-AZFDc
V2
V3
V4
V5
V6
V7
V8d
V9
V10
V11
V12e
V13
V14
V15
V801f
Study week
1
4
7
13
19
26
32
39
45
52
65
78
91
104
Tolerance interval for Visit 
(days)
±3
±3
±7
±7
±7
±7
±7
±7
±7
±10
±7
±7
±7
±7
12-lead ECGn
CO
X
X
X
X
X
X
X
X
X
X
C-SSRS and Self-Harm 
Supplement Formo
CO
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense drug
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess drug compliancesp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
CO
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FDG PETq
or
Flortaucipir F 18 PETq
CO
X
Xr,i
CO
X
Xr,i
Consent for optional DNA/RNA 
blood samples
X
Blood sample for DNAt
(optional)
X
Xu
Blood sample for RNAt (optional)
X
X
Xi
Abbreviations:  ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-ADL = the Alzheimer’s Disease Cooperative Study 
Activities of Daily Living Inventory; Aβ = A-beta amyloid; CDR = Clinical Dementia Rating; CO = Carryover; C-SSRS = Columbia Suicide Severity Rating 
Scale; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ED = early discontinuation; EQ-5D-5L (patient) = 5-dimensional EuroQol quality of life 
scale; FAQ = Functional Activities Questionnaire; FDG = fludeoxyglucose; F/U = follow-up; MMSE = Mini-Mental State Examination; MRI = magnetic 
resonance imaging; NIA-AA = National Institute of Aging – Alzheimer’s Association; NPI = Neuropsychiatric Inventory; PET = positron emission 
tomography; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; RNA = ribonucleic acid; RUD-Lite = Resource Utilization in 
Dementia – Lite; V = visit.
a
Every effort should be made for visits to occur on the designated study days. The overall treatment period in the protocol should be maintained (i.e., visits 
should be scheduled based on the randomization date rather than the previous visit).  Even if a patient enters into Study AZFD, it is expected that the patient 
complete all Study AZES procedures.  Any missing procedures should be completed during the maximum time window of the Study AZES follow-up period 
(6 weeks).  Studies AZES and AZFD are considered compatible studies.
b
All patients who discontinue study treatment before Visit 15 should have Early Discontinuation (ED) procedures and assessments performed as soon as 
possible.  ADCS-ADL, FAQ, CDR, MMSE, RBANS, ADAS-Cog13, NPI, and Letter & Category Fluency, Digit Symbol-Coding tests should be conducted at 
the early discontinuation visit if it has been more than 12 weeks since they were last administered.  If it has been >6 months since the last MRI, then an MRI 
is performed.  PET scans (applicable to a subset of patients) should be performed if discontinuation occurs between Visit 6 and Visit 11.


I8D-MC-AZFD(a) Clinical Protocol
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c
First dose to be administered the day after completion of Visit 1, preferably in the morning.
d
Visit 8 is conducted by telephone and may include either the patient or the study partner, or both, as appropriate. The patient or study partner may be required 
to visit the clinic if drug dispensing is needed.
e
The initiation of Visit 12 may be delayed for the patients who have completed the first year of the protocol prior to regulatory and ethics approval of the 
protocol amendment that includes the Year 2 extension.
f
Patients who complete study treatment or have early discontinuation should participate in a follow-up visit (Visit 801), 4 to 6 weeks after the last dose of 
study treatment.
g
The CDR should always be administered to the study partner first and then to the patient; the study partner and patient must be interviewed separately.  The 
assessments should be performed at approximately the same time of day at designated study visits, if possible.
h
Assessment performed only for those patients who had florbetapir F 18 PET scan at Visit 20 in Study AZES.  Patients with current participation in a research 
and/or medical protocol involving PET ligands or radioactive agents judged not to be scientifically or medically compatible with this study, with exposure to 
ionizing radiation that in combination with the planned administration of study florbetapir PET ligand would result in a cumulative exposure that exceeds 
local recommended exposure limits, or hypersensitivity to the active substance or any of the excipients of florbetapir F 18 are excluded from obtaining the 
florbetapir PET scan.
i
If discontinuation occurs after Visit 11, it is not collected or performed.
j
Blood samples for determination of plasma biomarkers (Aβ1-40, Aβ1-42) will preferably be collected 2 to 3 hours post-dose at indicated visits and failure to 
collect within this time frame will not be considered a protocol deviation.  Blood samples for other exploratory plasma biomarkers will also be collected at 
indicated visits.
k
Hematology, clinical chemistry, electrolytes, and urinalysis are included in every laboratory determination.  Thyroid-stimulating hormone, total thyroxine and 
hemoglobin A1c will be measured at Visits 11, and 15 or ED.
l
Brief physical and full neurological examinations will be performed at these visits.
m Vital signs include resting supine and standing blood pressures, pulse rates, and temperature.
n
Single safety ECGs are required.
o
The Adult C-SSRS Since Last Visit version will be administered. If, based on administration of the C-SSRS, it is determined that suicide-related behaviors 
have occurred, then the Lilly Self-Harm Follow-Up (SHFU) form will be used to collect additional information to allow for a more complete assessment of 
these behaviors.
p
The patient should be instructed to retain all empty drug kits after using up the medication in the kit and to bring the empty kits and any unused medication to 
the clinic at each visit.  During visits conducted by telephone, the patient or study partner will be questioned about compliance with study treatment.
q
Patients who participated in Study AZES FDG PET or flortaucipir F 18 PET addenda will have the option to continue in the addendum to which they were 
previously assigned, provided that they consent for these procedures in Study AZFD.
r
If the patient discontinues study treatment between Visit 6 and Visit 11, the FDG or flortaucipir F 18 addendum PET scan should be performed.
s 
Participation in this procedure is optional and consent can occur any time before blood draw.
t
Patients who participate in optional pharmacogenomics samplings will be provided a separate informed consent for the samplings.  Failure to participate in 
optional sampling will have no influence on the eligibility of the patient for the study.  Consent can be obtained any time before blood draw.
u
Blood sample should be collected at ED visit if the patient discontinues prior to Visit 7.


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3.
Introduction
3.1.
Study Rationale
Eli Lilly and Company (Lilly) and AstraZeneca (AZ) have entered into an alliance to develop 
LY3314814 (AZD3293). Throughout this document, only the Lilly compound identifier 
(LY3314814) will be used since Lilly is designated as the sponsor.  In addition, the Study code 
I8D-MC-AZFD/D5010C00030 will be referred to as Study I8D-MC-AZFD or Study AZFD 
throughout this document.
LY3314814 is being developed for the modification of the clinical course of Alzheimer’s disease 
(AD) by slowing disease progression in patients diagnosed with early AD, which is defined as 
the continuum of patients with mild cognitive impairment due to AD (MCI-AD) and patients 
diagnosed with mild dementia of the Alzheimer’s type (mild AD dementia) randomized to Study 
AZES.  Study I8D-MC-AZFD will test the hypothesis that patients originally randomized to 
receive placebo in the double-blind feeder Study AZES and switched to LY3314814 at the start 
of Study AZFD do not “catch up” on the Alzheimer’s Disease Assessment Scale-Cognitive 
Subscale (ADAS-Cog13) at Week 26 (Visit 7) of Study AZFD to patients originally randomized 
to receive LY3314814 in the double-blind feeder Study AZES.  Additionally, secondary 
delayed-start analyses will also be conducted over the entire 104 weeks of treatment.  Data 
acquired  will also be used to evaluate the long-term safety and efficacy profile of LY3314814.
3.2.
Background
Alzheimer’s disease is a progressive and fatal neurodegenerative disease manifested by cognitive 
deterioration in addition to progressive impairment of activities of daily living.  Current 
treatments are seen as minimally effective, with only minor symptomatic improvements for a 
limited duration, and they do not slow the progression of the disease.
Alzheimer’s disease pathology is characterized by the formation of amyloid plaques and 
neurofibrillary tangles.  These pathologies are associated with an inflammatory response, 
together with loss of neurons and synapses in the neocortex, hippocampus, and other subcortical 
regions of the brain.  Cleavage of amyloid precursor protein (APP) by proteases known as 
secretases (β and γ) gives rise to the group of peptide fragments known as Aβ.  They are the 
main components of the amyloid plaques.  Further, mutations or duplications of the APP gene 
constitute a genetic link to Familial AD.  BACE1 is a type I transmembrane aspartic acid 
protease related to the pepsin and retroviral aspartic protease families.  BACE1 cleaves APP at 
the β-secretase site, and APP is then cleaved by γ-secretase generating Aβ peptides.
Based on its key role in the amyloid cascade, BACE1 is considered to be a promising therapeutic 
target for slowing disease progression in AD.  BACE1 inhibitors would be expected to prevent 
the generation of Aβ peptides and, consequently, reduce the detrimental effects of Aβ toxicity 
and the progressive formation of amyloid plaques in the brain.
As a potent inhibitor of BACE1, LY3314814 is a potential disease-modifying therapy for the 
treatment of AD.  LY3314814 has been shown to reduce Aβ1-40 and Aβ1-42 in mice, rats, guinea 


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pigs, dogs, and humans.  At sufficient exposures, LY3314814 reduces Aβ levels in the brain and 
cerebrospinal fluid (CSF).
Study AZFD is the third Phase 3 study in the LY3314814 registration program.  For the purposes 
of this protocol, patients are considered eligible on the basis of early AD at the time of their 
enrollment into Study AZES, regardless of progression during their study participation.
3.3.
Benefit/Risk Assessment
To date, no safety issues have been identified that would create an unfavorable benefit-risk 
balance for LY3314814.  The potential benefits are not established but expectation for an effect 
in slowing AD progression is described above in Section 3.2.  Potential risks include but are not 
limited to elevated liver enzymes, QT-prolongation with overdose, skin or hair 
hypopigmentation, rash, retinal changes, and potential interactions with other drugs.  The 
potential risks are monitored with scheduled labs, electrocardiograms (ECGs), skin exams, eye 
exams, and restrictions on some concomitant medications.  More information about the known 
and expected benefits, risks, serious adverse events (SAEs) and reasonably anticipated adverse 
events (AEs) of LY3314814 can be found in the Investigator’s Brochure (IB).


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4.
Objectives and Endpoints
Table 4.1 shows the objectives and endpoints of the study.
Table 4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

The primary analysis of Study AZES-FD is to 
evaluate disease modification as outlined in 
Liu-Seifert (2015).  This will be accomplished 
by testing the three delayed-start hypotheses in 
both doses of LY3314814 across Study AZES 
and up to Week 26 (Visit 7) of Study AZFD.

ADAS-Cog13
Secondary
Clinical efficacy objective:

To evaluate the disease modification of both 
doses of LY3314814 on functional and 
cognitive outcomes across Study AZES and up 
to Week 26 (Visit 7) of Study AZFD using the 
primary analysis methodology.

Functional Outcome Measures
o
ADCS-ADL score
o
FAQ

Cognitive/Functional Outcome Measures
o
iADRS score
o
CDR-SB

Cognitive Outcome Measures
o
MMSE

The delayed-start analyses as outlined above 
will also be examined through Week 104 
(Visit 15) for cognitive and functional 
outcomes.

ADAS-Cog13, ADCS-ADL, FAQ, iADRS, 
CDR-SB, MMSE
Safety Objective

Collect information in order to further 
characterize the safety and tolerability of 
LY3314814 in patients with early AD dementia 
(at the time of entry into Study AZES)

Standard safety assessments:
o
spontaneously reported AEs
o
clinical laboratory tests
o
vital sign and body weight 
measurements
o
12-lead ECGs
o
physical examinations including 
neurological examinations

Additional safety assessments:
o
Eye examinations
o
Skin examinations
o
Serial MRI
o
Columbia-Suicide Severity Rating 
Scale (C-SSRS)
Abbreviations:  AD = Alzheimer’s disease; ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale –
Cognitive subscale; ADCS-ADL = Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory; 
AE = adverse event; CDR-SB = Clinical Dementia Rating Sum of Boxes; ECG = electrocardiogram; FAQ = 
Functional Activities Questionnaire; iADRS = integrated Alzheimer’s Disease Rating Scale; MMSE = Mini-
Mental State Examination; MRI = magnetic resonance imaging.


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5.
Study Design
5.1.
Overall Design
Study AZFD is a multicenter, randomized, parallel-group, double-blind, 104-week-long study of 
2 fixed dose levels of LY3314814 in patients with early AD at the time of enrollment into the 
feeder Study AZES.  The actual number of patients to be enrolled is dependent on the number of 
eligible patients completing feeder Study AZES.
The treatment period of this delayed-start extension will begin at the conclusion of Visit 20 of 
the feeder Study AZES which will also serve as Visit 1 for Study AZFD, and will continue with 
104 weeks of treatment.  Patients who were randomized in Study AZES to either 20 mg or 50 mg 
of LY3314814 will continue on the treatment allocation from the feeder study.  Patients 
randomized to placebo in Study AZES will be randomized in a blinded fashion 1:1 to 
LY3314814 20 mg or 50 mg daily (QD), administered orally.  Neither the patient nor 
investigator will be unblinded to feeder study treatment assignments.  Assessments will be made 
as indicated on the Study Schedule of Activities found in Section 2.
The study includes a longitudinal florbetapir F 18 amyloid positron emission tomography (PET)
scan for those patients who had a florbetapir F 18 PET scan at Visit 20 of Study AZES.  In 
addition, there are two longitudinal addenda of fluorodeoxyglucose (FDG) PET and 
18F-AV-1451 PET at applicable sites.  Patients who participated in these addenda in Study AZES 
are eligible to participate in the respective addenda in Study AZFD.  Figure 5.1 illustrates the 
study design.
The initiation of Visit 12 may be delayed for the patients who have completed the first year of 
the protocol prior to regulatory and ethics approval of the protocol amendment that includes the
Year 2 extension.


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Abbreviation:  LY = LY3314814.
*
At Visit 1 of Study AZFD (Visit 20 of Study AZES), patients randomized to 
placebo from Study AZES will be randomized 1:1 to LY 20 mg or LY 50 mg in 
Study AZFD.
Note:  Gray boxes after Study AZFD Visits 1, 7, 11, 13, and 15 indicate the 4-week 
symptomatic treatment initiation window for subjects with progression of symptoms.
Figure 5.1.
Illustration of study design for Clinical Protocol I8D-MC-AZFD.
5.2.
Number of Participants
It is estimated that approximately 1540 participants will complete the feeder Study AZES.  
Based on historical data, it is assumed that 90% (approximately 1400) of the participants from 
Study AZES will provide consent to continue participation in Study AZFD.  Consent for Study 
AZFD may be obtained at any time prior to performing procedures specific only for 
Study AZFD.
5.3.
End of Study Definition
The end of the study is defined as “the last visit of the last patient undergoing the study.”  This 
definition applies to the entire study and is not region specific.
The study is expected to start in Q1 of 2017 which is the scheduled date for the first completers 
of the feeder Study AZES.  The final study visit will occur approximately 110 weeks after the 
last patient completes the feeder study.
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if enrollment is slow.  The study will 
be discontinued if the Sponsor or its designee judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and GCP.


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5.4.
Scientific Rationale for Study Design
Study AZFD integrated with Study AZES forms a Delayed Start study design.  Data from 
randomization (Visit 2) in Study AZES through Visit 7 of Study AZFD will be used to test 
whether there is a treatment effect that cannot be achieved with a later start of treatment. The 
time points beyond the primary analysis at 26 weeks (Visit 7) in Study AZFD will be analyzed
upon last patient visit to determine the robustness of early treatment over the full 104-week 
delayed-start period.
5.5.
Justification for Dose
LY3314814 is administered orally at doses of 20 and 50 mg daily and the doses were selected 
based on preclinical and pharmacodynamic (PD) data. The projected therapeutic dose range is
based on levels of inhibition of BACE1 in the central nervous system as calculated from the 
multiple-ascending-dose study of CSF Aβ data. It is anticipated that 20-mg and 50-mg 
LY3314814 doses should achieve clinically relevant CSF Aβ reductions, and the projected mean 
exposures at those doses should be well within the range of exposures shown to be generally safe 
and well tolerated in the Phase 1 studies and ongoing Phase 3 studies [I8D-MC-AZES, 
I8D-MC-AZET]. From Phase 1 data, the 20-mg dose is predicted to provide >50% mean 
reduction in CSF Aβ1-42 concentrations over the dosing interval, and the 50-mg dose is predicted 
to provide approximately 75% reduction in CSF Aβ1-42 concentrations over the dosing interval.
Thus, these 2 doses are deemed sufficient to lower CSF Aβ1-42 concentrations to a level that will 
lead to a demonstration of efficacy of LY3314814 in this study based on human genetic data 
(Jonsson et al. 2012). The pharmacokinetic (PK) variability is expected to be sufficiently low to 
ensure that individual patient exposures at these doses will also not exceed the levels already 
demonstrated to be generally safe and well tolerated.


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6.
Study Population
Eligible patients will be men and women completing feeder Study AZES.  Eligible patients must 
have been randomized into Study AZES, and completed the primary protocol through Visit 20 
without permanent discontinuation of study treatment.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
General Inclusion Criteria
[1]
Provision of signed, written and dated informed consent from patient (or legal 
representative if required) and from study partner prior to any study specific 
procedures being performed.
[2]
Patients participating through Visit 20 of Study AZES and who have not permanently 
discontinued study treatment. Note:  Patients who have permanently discontinued 
study treatment prior to Visit 20 of Study AZES and have remained in Study AZES off 
treatment are not eligible for Study AZFD.
[3]
The patient must have a reliable study partner with whom he/she cohabits or has 
regular contact (combination of face-to-face visits/telephone contact acceptable).  If at 
all possible, the same study partner as for Study AZES should participate, and this 
study partner should be willing to participate throughout this study and must have 
sufficient patient interactions to be able to provide meaningful input into the rating 
scales administered in this study, where study partner input is required, in particular 
for the CDR.  As guidance, the ability for a study partner to meet his/her expected 
responsibilities for this study would normally be possible when the study partner 
spends no less than 10 hours per week with the subject, divided over multiple days.  
Evidence for adequacy of the study partner should be documented in source 
documentation.  The study partner must be cognitively able to fulfill the requirements 
of the study, in the opinion of the investigator.  Study partner must be able to read, 
write, and speak the language in which psychometric tests are provided, with 
acceptable visual and auditory acuity (corrected).
[4]
In the opinion of the investigator, the patient and study partner will be compliant with, 
and have a high probability of completing the study.
[5]
Patients who are willing to complete the diagnostic and procedural assessments as 
defined in the protocol.


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6.2.
Exclusion Criteria
General Exclusion Criteria
[6]
Patients should not have participated or currently participate in any other clinical trial 
or any other type of medical research judged not to be scientifically or medically 
compatible with this study for the duration of their participation in the current study.
[7]
Meets discontinuation criteria of feeder Study AZES at the final visit of that study.
[8]
Contradictions to continuing or starting therapy as per Study AZES protocol (that is, 
use of strong inhibitors/inducers of cytochrome P450 3A4 (CYP3A4), or use of strong 
inhibitors or inducers of P-glycoprotein (Pgp), or inhibitors of breast cancer resistance 
protein [BCRP]).
[9]
Current serious or unstable clinically important systemic illness that, in the judgment 
of the investigator, is likely to affect cognitive assessment, deteriorate, or affect the 
patient’s safety or ability to complete the study, including hepatic, renal, 
gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, or 
hematologic disorders.
[10]
Current clinically important abnormality, as determined by the investigator, in 
physical or neurological examination, vital sign, ECG, or clinical laboratory test 
results that could be detrimental to the patient or could compromise the study.
6.3.
Lifestyle Restrictions
Patients will be required to:
1.
Refrain from donating blood from the Visit 1 until 3 months after the follow-up visit.
2.
Follow restrictions regarding concomitant medications according to Section 7.7.
3.
Avoid use of tanning beds and self-tanning products.
4.
Wear a hat and appropriate clothing when exposed to sunlight; use a sunscreen with a 
sun protection factor of at least 15; and protect the lips with a lip balm containing sun 
block.
5.
Men must abstain or be willing to use barrier contraception (i.e., condoms) and not 
donate sperm during the study participation, through 3 months after study participation 
ends.  Men must also agree to abstain for 24 hours after PET scans.
6.
Avoid excessive use of alcohol during study participation.  Excessive alcohol 
consumption is defined for men as consuming an average of more than 3 drinks per 
day, or more than 21 drinks per week.  For women, excessive use of alcohol is defined 
as consuming an average of more than 2 drinks per day, or more than 14 drinks per 
week.


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6.4.
Screen Failures
Patients who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.
6.5.
Study Partner
Every patient in the study must have a study partner, who must sign an informed consent form
(ICF).  An identification number will be assigned to each study partner and recorded for each 
efficacy measure that the study partner provides input.  The study partner should be willing to 
participate in every study visit that requires their input for efficacy measures as outlined in 
Section 2.  The study partner is not required to attend all study procedures; examples include but 
are not limited to magnetic resonance imaging (MRI), PET or skin or eye examinations.  The 
study partner should either co-habit with or have regular contact with the enrolled patient.  While
every effort should be made to maintain the same study partner for a given patient throughout the 
study, and if at all possible, the same study partner who participated in Study AZES, in the event 
of an unavoidable change in study partner, the new study partner should be thoroughly oriented 
to the purpose and requirements of the study and must sign an ICF and be assigned a new 
identification number.  Demographic data, including year of birth, sex, and relationship to the 
patient, will be collected for every study partner.


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7. Treatments
7.1.
Treatments Administered
LY3314814 film-coated tablets in two different strengths (20 and 50 mg) and matching placebo 
will be manufactured and provided by AZ.
Investigational product will be dispensed as outlined in the Schedule of Activities (Section 2).  
Since the LY3314814 20 mg tablets and the LY3314814 50 mg tablets look different, the 
investigational product will be blinded using double-dummy technique (see Table 7.1).
Patients who were on placebo in the feeder Study AZES will be randomized to either 
LY3314814 20 mg or LY3314814 50 mg; blinding is maintained to prior allocation and dose 
(see Table 7.1).  Patients who were randomized to active study drug in the feeder study will 
continue on the same study drug dose.
Table 7.1.
Treatment Regimens
Regimen
AZES Dose 
AZFD Dose
Group 1
20 mg tablet
20 mg tablet
Placebo to Match 50-mg tablet
Group 2
50 mg tablet
50 mg tablet
Placebo to Match 20-mg tablet
Group 3
Group 4
Placebo 
Placebo 
20 mg tablet
Placebo to Match 50-mg tablet
50 mg tablet
Placebo to Match 20-mg tablet
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational product to the patient

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study returning all unused medication to the Sponsor, or its 
designee, unless the Sponsor and sites have agreed all unused medication is to be 
destroyed by the site, as allowed by local law
7.1.1. Packaging and Labeling
All study medication will be provided in child resistant blister packs.  The blister packs will be 
further packaged into patient compliance kits.  Each kit will have a unique kit number.  Enough 
tablets will be dispensed for daily dosing until the patient returns for the next study visit.


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Subjects randomized to the 20 mg dose group will receive a blister pack containing LY3314814
20 mg tablets and placebo tablets matching LY3314814 50 mg.  Subjects randomized to the 
50-mg dose group will receive a blister pack containing LY3314814 50 mg tablets and placebo 
tablets matching LY3314814 20 mg.  All subjects will need to take two tablets daily (one of each 
size) in a double dummy fashion in order to the guarantee blinding.
All kits will bear a label translated into local language and prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. The labels will fulfill GMP 
Annex 13 requirements for labeling.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized as the last procedure of Visit 1 
of Study AZFD (Visit 20 of Study AZES).  Assignment to treatment groups will be determined 
by a computer-generated random sequence using an interactive web- and voice-response system 
(IxRS).  The IxRS will be used to assign the kit containing double-blind investigational product
to each patient. Site personnel will confirm that they have located the correct kit by entering a 
confirmation number found on the kits into the IxRS.  Specific information concerning the use of 
the IxRS will be provided to the investigators.
To achieve between-group comparability for disease severity, the randomization will be stratified 
by disease severity at the time of randomization into Study AZES.
7.2.1. Selection and Timing of Doses
Patients will continue on Study AZES study treatment during the entire period of Visit 20 of 
Study AZES.  To ensure that patients continue on study treatment without a lapse in therapy, 
patients will take their last dose of Study AZES treatment on the day of randomization into Study 
AZFD.  Since many of the procedures and assessments will be used for both study visits, Visit 
20 of Study AZES will occur simultaneously with Visit 1 of Study AZFD.  Once all other AZES 
Visit 20 assessments and procedures have been completed, the final procedure in Study AZES is 
to assess drug compliance and collect any unused AZES study medication.  After resolving 
Study AZES drug compliance, the patient can be randomized to the Study AZFD treatment.  
Patients are to take the first dose of Study AZFD treatment on the day following randomization 
into the study.  The dose is to be taken once daily, preferably in the morning unless instructed 
otherwise.
Note:  Every attempt should be made to ensure that the transition from Study AZES to 
Study AZFD is seamless.  Any gaps in treatment should be minimized.  If a gap in treatment 
occurs, please notify your Clinical Research Associate for Study AZFD.
7.3.
Blinding
This is a double-blind study.  Both patients and site personnel will remain blind to dose 
throughout the study.
Emergency unblinding for AEs may be performed through the IxRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 


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may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All calls resulting in an unblinding event are recorded and reported by the IxRS.
If an investigator, site personnel performing assessments, or patient is unblinded prior to 
database lock for primary outcome, the patient must be discontinued from the study.  In cases 
where there are ethical reasons to have the patient remain in the study, the investigator must 
obtain specific approval from a Sponsor-designated medical monitor for the patient to continue 
in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Sponsor clinical research 
physician (CRP) prior to unblinding a patient’s treatment assignment unless this could delay 
emergency treatment of the patient.  If a patient’s treatment assignment is unblinded, the Sponsor
must be notified immediately.
7.4.
Dosage Modification
Dose adjustments are not permitted in this study.
7.5.
Preparation/Handling/Storage/Accountability
All study medication must be kept in a secure place under appropriate storage conditions.
Appropriate storage conditions are specified on the study medication label.
The study medication provided for this study will only be used as directed in the study protocol.  
The study site personnel will account for all study medications dispensed to and returned from 
the patient.
Study site personnel will account for all study medications received at the site, unused study 
medications and for appropriate destruction.  Certificates of delivery, destruction and return 
should be signed.
7.6.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit by direct questioning and 
counting returned tablets. The patient should be instructed to retain all empty drug packages 
after using up the medication in the package and to bring the empty packages and any unused 
medication to the clinic at each visit so that the clinic staff can record the amount of medication 
used since the last visit.
Compliance will be assessed at telephone visits via questioning of the patient and/or study 
partner.
Patients who consume at least 80% of the prescribed daily dose during this study will be 
considered compliant.  Similarly, a patient will be considered significantly noncompliant if he or 
she is judged by the investigator to have intentionally or repeatedly taken more than the 


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prescribed amount of medication.  Patients regarded as non-compliant may be discontinued at the 
investigator’s discretion, in consultation with the Sponsor designated medical monitor.
7.7.
Concomitant Therapy
Concomitant medications with the potential to affect cognition are permitted.  These include, but 
are not limited to, cholinesterase inhibitors, opiates, ginkgo biloba and other approved 
nootropics, anxiolytics, antidepressants, sedative-hypnotics, hormone replacement therapy, 
sleeping aids, sedating anti-allergy medications, thyroid supplements, and vitamin E and vitamin 
B12 supplements (by injection).  Maintaining consistency in testing conditions should be 
emphasized with respect to taking as-needed medications.
Patients may receive premedication for the MRI or PET assessments, but this medication should 
not be administered within 24 hours of any efficacy assessments.
After randomization, initiation, discontinuation, or dose adjustment of any therapy appropriate to 
the patient’s condition is permitted, with the exception of those listed as prohibited.  The 
Sponsor-designated medical monitor should be consulted as needed.  Concomitant medications 
taken during the study must be recorded on the electronic case report form (eCRF), along with 
the indication, daily dose, and start and stop dates of administration.  All patients will be 
questioned about concomitant medications at every study visit.
7.7.1. Initiation of Post-Randomization Symptomatic AD Treatments
Over the period of this trial patients may have progression of symptoms/disease (patients may 
progress to mild or moderate/severe stages of disease).  For patients for whom treatment 
becomes medically indicated during the trial, initiation of cholinesterase inhibitors and 
memantine (moderate stages) is permitted.  This initiation must only occur when medically 
indicated and documenting the rationale or indication for initiation will be required.  In order to 
adequately capture any decline as well as stable improvements, these symptomatic treatments 
should be initiated within approximately four weeks after the completion of cognitive testing at 
the Visit 1, Visit 7, Visit 11, Visit 13, and Visit 15 (see Figure 5.1).  Initiation at a time outside 
of these windows is discouraged, but the Sponsor-designated medical monitor should be 
contacted if a clinical need arises outside of the protocol-specified windows and will not be 
deemed a protocol violation if approved.
7.7.2. Other Medication Considerations Post-Randomization
Permitted concomitant medications should be maintained on a stable dose regimen during the 
study whenever possible.  Attempts should be made to maintain stable doses of symptomatic AD 
medication, however, changes or additions are permitted when clinically indicated and must be 
documented in the eCRF.
As there is a potential for LY3314814 to influence digoxin levels due to effects of Pgp, it is 
recommended that digoxin levels be monitored when initiating and discontinuing test drug to
avoid possible over- or under-digitalization.  Other Pgp sensitive medications with very narrow 
therapeutic margins may also require monitoring or use with caution.


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The list of excluded medications is provided in a separate Operations Manual.
The following are prohibited concomitant medications during the study:

Use of any investigational drug or device not specified in this study judged to be 
scientifically or medically incompatible with this study

Use of any drug of abuse, including but not limited to cannabis, illicit 
amphetamine, cocaine, illicit opiates, propoxyphene, methadone, methaqualone, 
phencyclidine, or illicit barbiturate

Use of depigmenting agents, such as, hydroquinone

Use of strong inhibitors or inducers of CYP3A4 (topical may be permitted)

Use of strong inhibitors of Pgp or BCRP or inducers of Pgp (topical may be 
permitted)
7.8.
Treatment after the End of the Study
7.8.1. Study Extensions
There is not currently a plan to extend the study beyond the Follow-up Visit (Visit 801).
7.8.2. Continued Access
Continued access would only be provided through a regulatory and IRB-approved protocol, 
where applicable. Safety and efficacy data may be collected during this time period.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets one of the following conditions after consultation with the 
Sponsor-designated medical monitor:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X upper 
limit of normal (ULN)

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
prothrombin time >1.5X ULN

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase elevations (ALP), if deemed of liver origin and drug-
related as follows:

ALP >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients/subjects who discontinue treatment due to a hepatic event or abnormality of liver tests 
should have further clinical and laboratory monitoring and should have additional data collected 
using the hepatic safety eCRFs (HSCRF).  The process should be initiated by the investigator in 
consultation with the sponsor-designated medical monitor.
In addition, patients must be discontinued from the investigational product in the following 
circumstances:

Patient decision.  The patient may discontinue treatment, without prejudice to further 
treatment, at any time.

Adverse event or clinically significant laboratory value, ECG result, or vital sign 
measurement of such severity that, in the opinion of the investigator or medical monitor, 
continued treatment is not in the best interest of the patient.

Severe non-compliance to the study protocol that results in a safety concern, in the 
judgment of the investigator.

The patient, for any reason, requires a treatment with an excluded therapeutic agent and 
temporary discontinuation criteria cannot be met (see Section7.7.2).


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
The patient develops a significant uncontrolled medical condition that in the opinion of 
the investigator after appropriate medical assessment, would pose an unacceptable risk to 
the patient if they were to continue receiving investigational product.
The study may be paused or stopped for safety by the Sponsor at any time.
Patients who discontinue the investigational product early will have early discontinuation (ED) 
procedures and follow-up visit performed as shown in the Schedule of Activities (Section 2).  
The follow-up visit should be performed within 4 to 6 weeks of discontinuing treatment.
8.1.2. Temporary Discontinuation from Study Treatment
Treatment suspension and re-dosing of study drug can be considered based on the Principal
Investigator’s judgment (examples include short-term treatment using a prohibited drug, 
uncertain adverse event, hospitalization).  The maximum cumulative permissible treatment 
suspension during the course of Study AZFD is 3 weeks per study year over the duration of the 
study. Temporary treatment discontinuation and restarting needs to be documented.  If 
temporary discontinuation is due to an AE, it should be reported to the Sponsor-designated 
medical monitor.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the Sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Sponsor-designated medical monitor
and the investigator to determine if the patient may continue in the study.  If both agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Sponsor-designated medical monitor to allow the inadvertently enrolled patient to continue in the 
study.
8.2.
Discontinuation from the Study
Some possible reasons that may lead to permanent discontinuation include:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and GCP.

Investigator decision:  the investigator decides that the patient should be discontinued
from the study.

Patient or study partner decision:  requests to be withdrawn from the study.

An individual patient enrolled in the study may be discontinued based on a specific AE 
profile, as recommended by the Independent Data Monitoring Committee (IDMC), the 
medical monitor, and/or the sponsor Global Study Physician, in discussions with the 
Principal Investigator.


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Patients who discontinue the study early (for any reason, including early study termination as 
determined by the Sponsor and/or IDMC) will have ED procedures and follow-up procedures 
performed as shown in the Schedule of Activities (Section 2).  Note:  Follow-up procedures are 
performed 4 to 6 weeks after last dose of investigational product.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she fails to return for scheduled visits and 
is unable to be contacted by the study site.  Site personnel are expected to make diligent attempts 
to contact patients who fail to return for a scheduled visit or were otherwise unable to be 
followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the patient 
within legal and ethical boundaries for all patients randomized, including those who did not get 
investigational product.  Public sources may be searched for vital status information.  If vital 
status is determined, this will be documented and the patient will not be considered lost to 
follow-up.
Sponsor personnel will not be involved in any attempts to collect vital status information.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Outcome Efficacy Assessment
Alzheimer’s Disease Assessment Scale—Cognitive subscale (ADAS-Cog; Rosen et al. 1984).  
Cognitive function will be assessed by using a 13-item version of ADAS-Cog.  This version is 
composed of the original 11-item ADAS-Cog as well as Delayed Recall and Digit Cancellation 
items.  Both items have been shown to be reliable and sensitive to a broad range of dementia 
severity and, therefore, provide a useful addition to the 11-item ADAS-Cog (Mohs et al. 1997).  
The maximum score for the ADAS-Cog13 is 85 points, with a lower score indicating better 
performance.
The ADAS-Cog has been designed specifically for the evaluation of the severity of major 
dysfunctions in the cognitive behavior characteristics of patients with AD. It has frequently been 
used in clinical studies in AD of mild-to-moderate severity and is recognized by regulatory 
authorities as a valid endpoint.
Administration of the ADAS-Cog13 will be audio-recorded for quality-control and training 
purposes.  Audio recordings will be centrally reviewed and monitored where permitted by local 
law.
9.1.2. Secondary Efficacy Assessments
Secondary efficacy variables in this study are the changes from baseline in Study AZES to Week 
26 (Visit 7) in Study AZFD in FAQ score, Alzheimer’s Disease Cooperative Study Activities of 
Daily Living Inventory (ADCS-ADL), integrated Alzheimer’s Disease Rating Scale (iADRS), 
CDR-SB, and Mini-Mental State Examination (MMSE).
Functional Assessment Questionnaire (FAQ; Pfeffer et al. 1982).  The FAQ measures 
complex functional activities that may be impaired in AD (such as, ability to shop, cook, and pay 
bills).  The FAQ is a study partner/ informant rating of the performance changes in 10 complex 
activities of daily living and has an overall score range of 0 to 30, with the higher score 
indicating greater impairment.
The 10 complex activities include:  1) manage finances, 2) complete forms, 3) shop, 4) perform 
games of skill or hobbies, 5) prepare hot beverages, 6) prepare a balanced meal, 7) follow current 


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events, 8) attend to television programs, books or magazines, 9) remember appointments, and 
10) travel out of the neighborhood.
Administration of the FAQ will be audio-recorded for quality-control and training purposes.  
Audio recordings will be centrally reviewed and monitored where permitted by local law.
Alzheimer’s Disease Cooperative Study—Activities of Daily Living Inventory (ADCS-ADL;
Galasko et al. 1997, 2004).  The ADCS-ADL measures 6 basic and 17 instrumental activities of 
daily living and was specifically developed as a sensitive tool to track changes in functional 
performance in AD over time.  The basic activities include self-care tasks such as eating, 
walking, toileting, bathing, and grooming.  The instrumental activities are more complex skills 
that are required to successfully live independently and include shopping, keeping appointments, 
traveling outside of home, making a meal or snack, reading, and writing.  These instrumental 
skills are often compromised in early AD.
For each activity on the ADCS-ADL, the score ranges from 0 to 78, with lower scores indicating 
greater impairment.  The maximum basic items score (sum of individual basic item scores) is 19, 
and the maximum instrumental items score (sum of individual instrumental item scores) is 
59 (Galasko et al. 2004).
Administration of the ADCS-ADL will be audio-recorded for quality-control and training 
purposes.  Audio recordings will be centrally reviewed and monitored where permitted by local 
law.
Integrated Alzheimer’s Disease Rating Scale (iADRS; Wessels et al. 2015) [calculated 
assessment, not a separately administered scale] is a composite that measures both cognition 
and function. The iADRS is a simple linear combination of scores from two well-established, 
therapeutically sensitive, widely accepted measures in AD, the ADAS-Cog13 and the 
instrumental activities within the ADCS-ADL (ADCS-iADL), measuring the core domains of 
AD. All items of these two scales are included without additional weighting of items, yielding 
face validity and ease of interpretation of the composite relative to its components.
The iADRS provides an overall measure of AD impairment (total score) and can also provide 
individual subscores for cognition and function based on standard, accepted instruments. The 
iADRS demonstrated acceptable psychometric properties (established through principal 
component analysis, estimation of the contributions of domain scores to the iADRS total score, 
and estimation of the contributions of individual item scores to the iADRS total score) and was
effective in capturing disease progression and treatment effects (both beneficial and detrimental) 
across a broad range of the symptomatic disease spectrum – MCI/prodromal, mild AD dementia, 
and moderate AD dementia populations.
The iADRS score ranges from 0 to 144; with higher scores indicating greater impairment.
Mini-Mental State Examination (MMSE; Folstein 1975) is a brief test used to screen for 
cognitive impairment.  It is routinely used for estimating the severity of cognitive impairment 
and tracking cognitive changes in an individual over time.  The MMSE assesses orientation to
time and place, immediate and delayed recall of words, attention and calculation, language 


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(naming, comprehension and repetition), and spatial ability (copying a figure).  The maximum 
total score is 30, with a higher score indicating better cognitive performance.
Administration of the MMSE will be audio-recorded for quality-control and training purposes.  
Audio recordings will be centrally reviewed and monitored where permitted by local law.
Clinical Dementia Rating (CDR; Hughes et al. 1982) is a global rating system widely used in 
clinical studies of AD as a measure of dementia severity and disease progression.  The CDR 
ratings are based on a semi-structured and in-depth interview with both the patient and the 
patient’s study partner.  The CDR rates decline in cognition and its impact on functioning 
relative to the patient’s own premorbid ability levels.
The CDR includes assessment of 6 independent domains (Memory, Orientation, Judgment and 
Problem Solving, Community Affairs, Home and Hobbies, and Personal Care).  These domain 
ratings are also known as “box” scores and the Sum of Boxes (SB) score is derived by adding the 
individual box scores at a given time point.  The CDR-SB is assessed on a scale from 0 to 18, 
with higher scores indicating greater impairment.  The CDR global score is a composite score 
calculated using the Washington University CDR-assignment algorithm applied to the 6 
individual domain box scores (Morris 1993).  The memory domain is considered the primary 
category that drives the CDR global outcome, and all other domains are secondary.  The CDR 
global score ranges from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild 
dementia, 2 = moderate dementia, 3 = severe dementia).
Administration of the CDR will be audio-recorded for quality-control and training purposes.  
Audio recordings will be centrally reviewed and monitored where permitted by local law.
9.1.3. Other/Exploratory Assessments
Letter Fluency, Category Fluency, and Digit Symbol-Coding tests.  The Letter Fluency test is 
a measure of phonemic verbal fluency and executive functioning.  The test consists of 3 trials.  
For each trial, the patient is asked to name as many words that start with a specific letter as 
he/she can in 60 seconds.  Each trial is scored for the number of words correctly generated and 
number of errors.  The total number of correct words and total errors are derived by summing the 
scores across the 3 trials.
The Category Fluency test is a measure of semantic verbal fluency and executive functioning.  
The patient is asked to name as many animals as he/she can in 60 seconds.  The test yields scores 
for the number of correct animal names generated and the number of errors.
The Digit Symbol-Coding test from the Wechsler Adult Intelligence Scale-III (Wechsler 1997) 
engages multiple cognitive abilities, including attention, psychomotor speed, complex scanning, 
visual tracking, and immediate memory.  The test instrument is composed of 140 small blank 
squares presented in 7 rows.  Each blank square is randomly paired with a number (1 to 9) 
printed directly above it.  A key printed above the rows of blank squares pairs each number with 
an unfamiliar symbol.  After completing 7 practice items, the patient must use the key to fill in 
the blank squares in order (working left to right across the rows) with the symbol that is paired 


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with the number above it, working as quickly as possible within the time limit of 90 seconds.  
The test score is the number of blank squares filled in correctly within the time limit.
The Letter Fluency, Category Fluency, and Digit Symbol-Coding assessment results will be 
recorded on worksheets.  Item-level scores from the worksheets will be transcribed into the 
eCRF.
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; Randolph et 
al. 1998; Duff et al. 2008).  The RBANS is a collection of 12 subtests representing 5 
neurocognitive domains:  Immediate Memory, Visuospatial/Constructional, Language, 
Attention, and Delayed Memory.  The raw scores from each subtest within a domain are 
converted to a summary score, or Index Score, for the domain by consulting normative data 
tables. The RBANS also provides an overall Index Score that summarizes the patient’s overall 
level of performance on this measure.
Administration of the RBANS will be audio-recorded for quality-control and training purposes.  
Audio recordings will be centrally reviewed and monitored where permitted by local law.
EuroQoL-5D (EQ-5D; Kind 1996). The EQ-5D-5L (patient) provides a single index value for 
health status and is relevant to a wide range of health conditions and treatments.  It is 
administered to the patient in only a few minutes and consists of 2 pages:  the EQ-5D-5L 
descriptive system and the EQ Visual Analogue scale (EQ VAS).  The descriptive system covers 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) each 
rated on 5 levels:  no problems, slight problems, moderate problems, severe problems, and 
extreme problems.
The EQ VAS records the patient’s estimation of his/her health on a visual analogue scale with 
endpoints labeled “the best health you can imagine” and “the worst health you can imagine.”  
This information can be used as a quantitative measure of patient health.  The EQ-5D-5L asks 
the patient to mark an “X” on the scale to indicate his/her current health status.
Resource Utilization in Dementia—Lite questionnaire (RUD-Lite; Wimo et al. 1998).  The 
RUD-Lite is designed to assess the healthcare resource utilization of patients and their caregivers 
and to determine the level of formal and informal care attributable to AD.  The data are collected 
through a structured interview.  Information on both caregivers (caregiving time, work status) 
and patients (accommodation and healthcare resource utilization) is gathered from the baseline 
and final assessment interviews.  Caregivers will be asked to provide data on time spent assisting 
patients’ basic ADLs such as using the toilet, eating, dressing, grooming, walking, and bathing; 
assisting patients’ instrumental ADLs such as shopping, cooking, housekeeping, laundry, 
transportation, taking medication, and managing finances; and providing supervision.  The 
resource utilization quantified by the RUD-Lite can be used for calculating cost offsets and in 
cost-effectiveness models.
Neuropsychiatric Inventory (NPI) is a well-validated clinical rating instrument designed 
specifically to assess a wide range of abnormal behaviors encountered in dementia patients 
(Cummings 1997; Cummings et al. 1994).  The NPI is an informant-based interview that utilizes 


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scripted questions to explore 12 different symptom domains:  delusions, hallucinations, 
agitation/aggression, dysphoria/depression, anxiety, euphoria, apathy, disinhibition, 
irritability/lability, aberrant motor activity, night-time behavioral disturbances, and appetite and 
eating abnormalities.  For each domain, the study partner is asked a screening question to 
determine whether the abnormal behavior has been present within the previous 4 weeks and 
represents a change in the patient since the onset of illness.  If the behavior has been present, 
then a series of sub-questions are asked to obtain more detailed information about the specific 
features of the behavioral disturbance.  The total NPI score has a possible range of 0 to 144, with 
higher scores indicating a greater degree of symptomatology.
The NPI also contains a Caregiver Distress Scale (NPI-D) that was designed to quantitate the 
distress experienced by caregivers as it relates specifically to the individual symptoms assessed 
in the patient by the NPI with a maximum score of 60.
9.1.4. Appropriateness of Assessments
The ADAS-Cog is a widely accepted, validated clinical outcome measure.  The scale reflects 
domains and abilities that are central to the characterization of an AD patient’s deficits in a 
clinical setting and its items are linked to meaningful aspects of the lives of patients and 
caregivers.  Furthermore, the scale has demonstrated its ability to detect treatment differences in 
the span of MCI and mild AD dementia (Aronson et al. 2009; Orgogozo et al. 2004; Salloway 
2004).
9.1.5. Order of Efficacy Assessments and Rater Qualifications
Order of Efficacy Assessments
9.1.5.1.
Assessments administered to the patient are the MMSE; RBANS; ADAS-Cog13; Letter Fluency, 
Category Fluency, and Digit Symbol-Coding tests; EQ-5D-5L; and CDR.  Assessments 
administered to the study partner include the FAQ, ADCS-ADL, CDR, NPI, and RUD-Lite.  
Refer to Table 9.1 for the relative sequencing of tests for both patient and study partner.  It is 
recommended that efficacy assessments be performed as the first activity of the study visits.  
Additionally, it is recommended that, during these visits, cognitive and functional tests are 
performed in the sequence shown in Table 9.1.  The CDR should always be administered to the 
study partner first and then to the patient; the study partner and patient must be interviewed 
separately.
It is important to maintain the same test sequence at each visit for each patient throughout the 
study.  Assessments should be scheduled to allow the cognitive testing to be performed at 
approximately the same time of the day at all the visits to avoid the known circadian variation of 
cognitive performance (Higuchi et al 2000).
It is strongly recommended that patients and study partners be assessed separately, because the 
presence of the other person may potentially contaminate the results of an assessment.  When 
necessary, patients should be allowed a rest break between cognitive tests.  Based on rater 
judgment, other non-stressful study procedures may be conducted during these breaks.


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Where there are multiple raters, i.e., a psychometric rater and a global rater, the recommended 
sequence of tests allows for simultaneous testing.  Table 9.1 describes the testing flow and 
respective rater responsibilities in this situation.
Table 9.1.
Order of Test Administration for Patient and Study Partner and 
Rater Responsibilities
Psychometric rater
Global rater
Patient
Study partner
1) MMSE
2) RBANS
1) FAQ
3) ADAS-Cog13
2) ADCS-ADL
4) Letter & Category Fluency tests
3) CDRa
5) Digit Symbol-Coding test
6) EQ-5D-5L
Study partner
Patient
4) NPI
7) CDRa
5) RUD-Lite
All tests may not be administered at each visit; the relative order of tests is maintained for any tests that are 
administered at the same visit.
a
The CDR must always be administered to the study partner first and then to the patient.  It is recommended that 
both sections be administered on the same day.
Abbreviations:  ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale - Cognitive subscale; ADCS-ADL =
The Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory; CDR = Clinical Dementia 
Rating; FAQ = Functional Activities Questionnaire; MMSE = Mini-mental State Examination; NPI =
Neuropsychiatric Inventory; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; 
RUD = Resource Utilization in Dementia.
Rater Qualifications and Blinding
9.1.5.2.
Raters will be selected based on experience appropriate for the measures and will be trained so 
that variability in ratings is minimized.  Two separate types of trained and qualified raters will 
administer the cognitive/functional and functional/global scales unless a single rater is approved 
by the sponsor.  A psychometric rater will administer measures such as the MMSE, RBANS, 
ADAS-Cog13, NPI, EQ-5D-5L, and RUD-Lite (see Table 9.1).  A separate, global rater will 
administer the FAQ, the ADCS-ADL, and the CDR.  If possible, the CDR should be 
administered by the same rater for a given patient.  It is preferred that the same rater who 
administered the test in the feeder study also administer the tests for a given patient in Study 
AZFD.
Every effort should be made to prevent the CDR rater from becoming aware of any AEs the 
patient may experience during the study.  Clinical Dementia Rating raters should, as much as 
possible, not have access to this information and should instruct patients and their study partners 
not to discuss AEs during the CDR interview.  The rater should sign a statement to this effect on 


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the CDR worksheet.  Site personnel who are involved in reviewing medical data or who may 
have access to AE information must refrain from discussing this information with the CDR rater.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patients.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect or expected clinical progression is not an AE in clinical studies, because the 
purpose of the clinical study is to establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure and/or investigational product(s), via 
eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known, and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
If deterioration in a laboratory value or vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result or vital sign 
will be considered as additional information.  Wherever possible the reporting investigator uses 
the clinical, rather than the laboratory, term (e.g., anemia versus low hemoglobin value).  In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-protocol-
mandated laboratory tests, vital sign measurements, ECG results, and other safety assessments 
should be reported as AE(s).  Any new or aggravated, clinically relevant abnormal medical 
finding at a physical examination as compared with the baseline assessment will be reported as 
an AE.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, PET tracers, or a study procedure taking into account the 
disease, concomitant treatment(s), or concurrent pathologies/conditions.


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A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, PET tracers and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to the Sponsor or its designee via eCRF clarifying the circumstances leading to 
discontinuation of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason:  important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.
Study site personnel must alert the Sponsor or its designee of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method.  If alerts are issued via 
telephone, they are to be immediately followed with official notification on study-specific SAE 
forms.  This 24-hour notification requirement refers to the initial SAE information and all 
follow-up SAE information.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process and subject should be consented to collect data on the 
outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the final disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify the Sponsor or its 
designee.
Suspected Unexpected Serious Adverse Reactions
9.2.1.1.
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or study 


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procedure.  United States 21 CFR 312.32 and European Union Clinical Trial Directive 
2001/20/EC and the associated detailed guidances or national regulatory requirements in 
participating countries require the reporting of SUSARs.  The Sponsor has procedures that will 
be followed for the recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Complaint Handling
The Sponsor collects product complaints on investigational products and drug delivery systems 
used in clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Additional details regarding treatment of overdose are provided in the IB. 
9.4.
Safety
9.4.1. Vasogenic Edema
If a patient develops symptoms believed to be suggestive of vasogenic edema, such as headache, 
confusion, gait disturbance, or visual disturbance, these should be recorded as AEs and an MRI 
should be obtained, unless contraindicated.  Study treatment should be discontinued if clinically 
significant symptomatic vasogenic edema occurs.  Temporary discontinuation may be considered 
and study medication restarted if stable (see Section 8.1 for discontinuation from study treatment 
or Section 8.1.2 for temporary discontinuation).  Temporary discontinuation of treatment may be 
considered if clinically significant symptomatic superficial siderosis or clinically significant 
symptomatic incident microhemorrhage is observed (Section 8.1.2 for temporary 
discontinuation).  Following the study treatment discontinuation, the MRI scan should be 
repeated within 4 weeks to evaluate the status of the finding and then performed every 4 to 6 
weeks (or as clinically indicated) until the finding resolves or stabilizes.  Treatment with high-
dose dexamethasone is to be considered, should symptoms be severe.
9.4.2. Rash
In the event a patient experiences a suspected drug-induced rash, the following procedures 
should be followed:

The patient should be referred to a dermatologist for an expert opinion.

A photograph of the rash may be obtained at the discretion of the dermatologist.

A blood sample should be drawn for PK analysis (Section 9.5).

A punch biopsy may be obtained at the discretion of the dermatologist.


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If treatment is discontinued due to a suspected drug-induced rash, the Sponsor-designated 
medical monitor should be notified as soon as possible, even if the rash did not meet the 
definition of an SAE.
9.4.3. Depression
In the event a patient experiences a clinically significant worsening of depression or a new onset 
major depression, the following procedures should be followed:

The investigator or another qualified study physician should assess the patient clinically 
as soon as it is possible, and any appropriate emergency measures should be undertaken.

Assuming an evaluation by a psychiatric emergency service is not required, the patient 
should be referred to a psychiatrist for an expert opinion. 

The investigator may initiate psychiatric management, including the use of psychiatric 
medication, as clinically needed.

If study treatment is discontinued due to depression, the medical monitor should be 
notified as soon as possible, even if the event did not meet the definition of an SAE.
9.4.4. Disease Progression
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease.  Gradual 
deterioration of cognition and/or function consistent with the usual course of AD should be 
considered as disease progression and not an AE.  Events that are unequivocally due to disease 
progression should not be reported as AEs during the study.
9.4.5. Laboratory Safety Assessment
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2).
Scheduled laboratory tests are performed by a central vendor.  Any clinically significant findings 
from laboratory tests that result in a diagnosis should be reported to the Sponsor or its designee 
as an AE vie eCRF per Section 9.2.
9.4.6. Hepatic Monitoring
If a patient experiences AST or ALT ≥3X ULN, total bilirubin ≥2X ULN, or ALP ≥2X ULN, the 
investigator is to repeat relevant hepatic lab testing within 3 to 5 days, including ALT, AST, T. 
BIL, D. BIL, ALP, GGT, and CK, and to consult with the sponsor-designated medical monitor 
regarding collection of specific recommended clinical information via the HSCRFs and further
follow-up laboratory tests.


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Additionally, safety data should also be collected via the HSCRFs if the patient experiences a 
hepatic event considered to be a SAE.  The process should be initiated by the investigator in 
consultation with the Sponsor-designated medical monitor. See Appendix 4.
9.4.7. Physical and Neurological Examinations
Complete physical examinations will be performed at baseline, and Visits 5, 11, 13, and 15  and 
at the ED visits indicated in the Schedule of Activities (see Section 2).  Brief physical 
examinations will be performed at Visits 3, 7, 9, 12, and 14.  The complete physical examination 
will include assessment of the following:  general appearance; skin, head and neck; lymph nodes; 
thyroid; abdomen (bowel sounds, liver and spleen palpation); back (costovertebral angle 
tenderness); and musculoskeletal, cardiovascular, and respiratory systems.  The brief physical 
examination will include assessments of the skin, lungs, cardiovascular system, and abdomen 
(bowel sounds, liver and spleen palpation).
Complete neurological examinations will be performed as indicated in the Schedule of Activities
(see Section 2).  The examinations will include a thorough assessment of gait, balance, 
coordination, cranial nerves, sensory and motor systems, and reflexes.
See Section 9.2 for information regarding the recording of AEs based on examinations.
9.4.8. Electrocardiograms
Digital 12-lead ECG files will be collected using continuous 12-lead digital recorders at the 
times indicated in the Schedule of Activities (see Table 2) after the patient has been resting in 
supine position for at least 10 minutes.
The 12-lead ECG equipment will be supplied and supported by the ECG central vendor.  
Electrocardiograms should be performed according to the study specific recommendations 
included in the ECG central vendor’s Manual of Operations.
For each ECG time point shown in the Schedule of Activities, a 90-second continuous 12-lead 
digital ECG file will be collected.  A 12-lead safety ECG will be printed at the site and the digital 
data will be transmitted to the ECG central vendor.  The safety ECG data will be reviewed for 
quality and alerts by the central vendor, and this information will be transmitted back to the 
study site.
From the 90-second continuous ECG recording, the site will print a safety ECG that will be 
evaluated for heart rate and PR, RR, QRS, QT and QTcF intervals, and the investigator will 
judge the overall interpretation as normal or abnormal.  Electrocardiograms will initially be 
interpreted by a qualified physician (the investigator or qualified designee) at the site as soon 
after the time of ECG collection as possible, and ideally while the patient is still present, for 
immediate patient management, should any clinically relevant findings be identified. The 
recording date and time and the investigator interpretation (normal, abnormal clinically 
significant, abnormal not clinically significant) and the paper printouts will be stored as source 
documents.  The investigator (or delegate) will evaluate the printout of the ECG in real time, 
with particular attention to the effects of clinical importance on the QRS and QTcF intervals.


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The investigator may add and print extra 12-lead ECG safety assessments if there are any 
abnormal findings or if the investigator considers it is required for any other safety reason.  In 
this event, concurrent blood samples may be collected for PK and electrolyte analyses.  
Additional ECGs may also be performed, at the discretion of the investigator, whenever a 
significant change in the patient’s clinical status occurs (e.g., significant deterioration in cardiac, 
renal, or liver function or salt-water balance).
Safety ECG results should be reviewed by the investigator (or delegate) for potential clinical 
significance, and the clinical significance should be determined by the investigator in 
consultation with the cardiologist at the central vendor, if necessary.  Note that new findings on 
ECG after enrollment that do not meet entry criteria do not automatically indicate that subject 
should be discontinued.  In many cases discontinuation will not be necessary and will depend on 
clinical significance and implications (e.g., QTcF > 470 ms).  See Section 9.2 for information 
regarding the recording of AEs based on ECG results.
9.4.9. Vital Signs
Vital signs, including supine and standing blood pressures and pulse rates, and temperature will 
be recorded at each in-clinic study visit (see the Schedule of Activities in Section 2).
See Section 9.2 for information regarding the recording of AEs based on tests and examinations.
Pulse Rate and Blood Pressure
9.4.9.1.
Supine blood pressure and pulse rate should be taken after at least 5 minutes of supine rest.  
Standing blood pressure and pulse rate should be taken after the respective supine measurements, 
approximately 2 and 5 minutes after patient achieves a standing position.
Body Weight
9.4.9.2.
Body weight will be measured in kilograms.  Measurements should be taken without shoes and, 
when possible, the same scale should be used for all measurements.
9.4.10. Other Safety Assessments
Eye and Skin Examinations
9.4.10.1.
The principal investigator will make all final determinations of AEs in consultation with the 
dermatologist or optometrist/ophthalmologist.  Any clinically significant findings that result in a 
diagnosis should be reported to the Sponsor or its designee as a pre-existing condition or AE via 
eCRF.
Eye examination
A comprehensive eye examination, to include corrected visual acuity, intraocular pressure, a slit 
lamp examination, and a dilated fundus examination, will be performed at the times shown in the 
Schedule of Activities (Section 2).  Note, patients with acute angle closure glaucoma or other 
contraindications to dilation should have a fundoscopic exam without dilation.  The eye 
examinations must be supervised and reviewed and/or performed by an ophthalmologist or 
optometrist where permitted by local law.


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Skin examination
A complete skin examination will be performed at the times shown in the Schedule of Activities 
(Section 2).
All skin examinations must be supervised and reviewed and/or performed by a dermatologist.
The skin examinations will preferably be completed for a given patient by the same 
dermatologist who will inspect the patient’s unclothed full body using a UV lamp.
At each examination, abnormal hypopigmentation will be assessed by location, percentage of 
body surface area involvement, degree (partial/decreased pigmentation to complete 
depigmentation), and other findings in or around the hypopigmentation area (e.g., redness or 
induration).  A static physician’s global assessment will be used to determine the patient’s 
overall hypopigmentation severity at a given time point using a visual analog scale (VAS) 
ranging from 0 to 100.  In addition, patients noted to have evidence of hypopigmentation will be 
asked to record how bothersome they find the hypopigmentation to be on a VAS ranging from 0 
to 100.  Skin photographs may be taken as appropriate for generating supporting documentation, 
but not for the purpose of primary clinical dermatologic evaluation or for data generation or 
analysis.  A punch biopsy may be obtained at the discretion of the dermatologist.
Data management and evaluation
Data from both the eye and skin examinations will be recorded on worksheets and then entered 
into the electronic data capture system at the primary study site in order to enable ongoing 
cumulative review and signal detection.
The ophthalmologist/optometrist or dermatologist will not make any determinations regarding 
whether the findings observed represent AEs or are causally related to the study medication and 
will not make decisions regarding whether the patient should discontinue study treatment.  
Instead, all information gathered by the ophthalmologist/optometrist or dermatologist should be 
reviewed by the site investigator, who will decide if an AE is present and who should take 
action, as appropriate.
See Section 9.2 for information regarding the recording of AEs based on examinations.
C-SSRS
9.4.10.2.
The Columbia Suicide Severity Rating Scale (C-SSRS) will be performed to determine the 
presence of suicidality.  The assessment schedule is indicated in the Schedule of Activities (see
Section 2).
The C-SSRS is a unique, simple and short method of assessing both behavior and ideation that 
tracks all suicidal events and provides a summary of suicidality.  It assesses the lethality of 
attempts and other features of ideation (frequency, duration, controllability, reasons for ideation 
and deterrents), all of which are significantly predictive of completed suicide.
If, during the performance of the C-SSRS assessment, the patient makes a statement indicating 
acute risk of suicide, the rater will immediately alert the site physician, and will stay with the 


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patient until the site physician is physically present.  The site physician will then make a 
complete risk assessment and refer to or initiate treatment as required.
The Lilly Self-Harm Supplement should be completed every time the C-SSRS is administered.
If, based on administration of the C-SSRS, it is determined that suicide-related behaviors have
occurred, then the Lilly Self-Harm Follow-Up form will be used to collect additional information
to allow for a more complete assessment of these behaviors.
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. If an event is serious or leads to 
discontinuation, this is an exception where the SAE and/or AE leading to discontinuation should 
be included on the AE form and the process for reporting SAEs should be followed.
Magnetic Resonance Imaging (Safety)
9.4.10.3.
Magnetic resonance imaging will be used to monitor patients for amyloid-related imaging 
abnormalities (ARIA) evaluation (see Section 2).
Magnetic resonance imaging scanning will be conducted under the management of a central 
imaging vendor.  The MRI scans will be acquired at imaging sites using a standardized protocol.  
Completion of the scheduled MRIs is required, unless a patient develops a contraindication to the 
MRI during the study.
The scans will be reviewed by the investigator or qualified designee for immediate patient 
management.  Results of centrally read MRIs regarding patient care/safety will be reported back 
to the sites even though there was a local read.  See Section 9.2 for information regarding the 
recording of AEs based on tests and examinations.
Safety Areas of Special Interest
9.4.10.4.
Specific safety topics of interest for this study include, but are not limited to, the following:

Adverse eye effects (see Section 9.4.10.1).

Adverse skin effects including rash and hypopigmentation (see Sections 9.4.2 and
9.4.10.1).

Peripheral nervous system, central nervous system and muscle effects (see Section 9.4.7).

Liver toxicity (see Section 9.4.6).

Cardiovascular (CV) -type events (including, but not limited to, orthostatic hypotension 
and QT prolongation; see Sections 9.4.8, 9.4.9, and 9.4.9.1).
Alzheimer’s disease occurs mainly in elderly people, who may have established CV disease or 
CV risk factors and constitute a population of patients at increased risk of CV events.  Serious 
CV events, as well as particular arrhythmic events related to QTcF prolongation, are therefore of 
potential special interest.  Serious adverse events that, according to the investigator, may be CV 
events of the major adverse CV event (MACE) type (myocardial infarction, stroke, or CV death) 
or may be potential QT prolongation-related arrhythmic events, e.g., syncope, ventricular 


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tachycardia/torsades des pointes/fibrillation or cardiac arrest will be carefully documented and 
sent for adjudication.  The events will be blindly evaluated by external independent adjudication 
consultants and adjudicated as MACE events per a separate charter.
In the long-term follow-up of Year 2, MACE adjudications will continue at least until data lock 
for assessment of the primary analysis.
The topics listed above, as well as other topics which may be subsequently determined by the 
sponsor, will be subject to enhanced surveillance activities.  Additionally, the topics above will 
be analyzed for presentation in the clinical study report (CSR) in accordance with the Statistical 
Analysis Plan (SAP).
IDMC
9.4.10.5.
The study will use an IDMC (an independent, external advisory group for this study formed to 
protect the integrity of data) to monitor data on an ongoing basis to ensure the continuing safety 
of patients enrolled in the study and to ensure the integrity of the blinded nature of the study until 
data lock for assessment of the primary analysis.  The IDMC details and structure will be laid out 
in its charter.  In the event that safety monitoring uncovers an issue that needs to be addressed by 
unblinding at the group level, additional analyses of the safety data may be conducted by the 
IDMC keeping the study team blinded.
9.5.
Pharmacokinetics
Unscheduled venous blood samples to determine the plasma concentration of LY3314814 may 
occur in the event of rash, as part of the assessment of hepatic laboratory abnormalities, if 
abnormal findings are identified during ECG safety assessments, or as determined to be 
warranted by the sponsor.  The date and time of the last dose of LY3314814 prior to PK 
collection should be recorded in the eCRF.
Drug concentration information that may unblind the study will not be reported to investigative
sites or blinded personnel.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.  During this time, samples 
remaining after the bioanalyses may be used for exploratory analyses such as metabolism and/or 
protein binding work.
9.6.
Pharmacodynamics
The peripheral dose-dependent PD activity of LY3314814 will be evaluated by analysis of 
plasma Aβ1-40 and Aβ1-42 as measured using validated immunoassays.  These plasma based
biomarkers will provide an assessment of target engagement, as an exploratory objective 
endpoint.
Samples collected to measure Aβ1-40 and Aβ1-42 will be identified by the patient number (coded) 
and will be destroyed within 60 days of receipt of confirmed test results.  Tests are run and 
confirmed promptly whenever scientifically appropriate.  When scientific circumstances warrant, 
however, it is acceptable to retain samples to batch the test run, or to retain the samples until the 


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end of the study to confirm that the results are valid.  Samples may be retained for a longer 
period, if necessary, to comply with applicable laws, regulations, or laboratory certification 
standards. 
9.7.
Genetics
9.7.1. Whole Blood Samples for Exploratory DNA and RNA Research
As part of an optional separate addendum, whole blood samples will be collected from consented 
patients for deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) analysis as specified in 
the Schedule of Activities (Section 2) and separate addendum, where local regulations allow, as 
an exploratory objective endpoint.
9.8.
Biomarkers and Imaging
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements.
Plasma samples for non-pharmacogenetic biomarker research will be collected at the times
specified in the Schedule of Activities (Section 2) where local regulations allow.  Additionally, 
as part of optional separate addenda, FDG and flortaucipir F 18 will be performed on consented 
patients as indicated in the Schedule of Activities.
Samples and images will be used for exploratory research on the drug target, disease process, 
variable response to LY3314814, pathways associated with AD and neurodegeneration, 
mechanism of action of LY3314814, and/or research method or in validating diagnostic tools or 
assay(s) related to AD and neurodegeneration.
All samples and images will be coded with the patient number.  These samples and images and 
any data generated can be linked back to the patient only by the investigator site personnel.
Samples and images will be retained for a maximum 15 years after the last patient visit for the 
study, or for a shorter period if local regulations and ethical review boards (ERBs) impose 
shorter time limits, at a facility selected by the Sponsor or its designee.  This retention period 
enables use of new technologies, response to regulatory questions, and investigation of variable 
response that may not be observed until later in the development of LY3314814 or after 
LY3314814 becomes commercially available.
9.8.1. Florbetapir PET (Positron Emission Tomography)
This study includes a longitudinal florbetapir F 18 amyloid PET scan for those patients who had 
a florbetapir F 18 PET scan at Visit 20 of Study AZES.  Florbetapir F 18 amyloid PET will be 
used to evaluate changes in amyloid binding from baseline of Study AZES to the end of Year 1 
of Study AZFD (Visit 11).  See Schedule of Activities (Section 2).  The number of florbetapir F 
18 PET scans performed at Visit 11 may by limited at Sponsor discretion.


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Florbetapir F 18 amyloid PET scanning will be conducted under the management of a central 
PET vendor.  To meet the longitudinal florbetapir PET objective for Study AZFD, the central 
PET imaging vendor will quantitatively analyze the florbetapir F 18 scan obtained as part of 
Study AZFD by comparing it to the eligibility and follow up scans obtained as part of Study 
AZES.
The details of patient preparation, florbetapir dose ordering and injection, patient positioning, 
image acquisition, and scan submission will be documented in the central PET vendor’s 
technical operations manual.  The details of scanner qualification, image acquisition and 
reconstruction, analysis and reader training will be documented in the central PET vendor’s 
image review charter.
The details of data and images to be transferred are specified in the respective data and image 
transfer agreements.
9.8.2. Magnetic Resonance Imaging (Efficacy)
Magnetic resonance imaging scans will be obtained as described in Section 9.4.10.3 under the 
management of the central imaging vendor and transferred to the vendor for volumetric analysis.
The following volumetric measures will be derived from the MRI scans using automated 
methods:  hippocampus volume, hippocampus atrophy, whole brain volume, whole brain 
atrophy, ventricular volume, ventricular enlargement, entorhinal cortex volume, entorhinal 
cortex atrophy, temporal lobe volumes, and temporal lobe atrophy.
Details of the qualification, imaging, processing and analysis will be contained in the MRI 
vendor technical operations manual.
9.9.
Health Economics
The self-reported questionnaires will be administered according to the Schedule of Activities
(Section 2) in countries where the questionnaires have been translated into the native language of 
the region and linguistically validated.
Health economic and outcomes data capture will focus on the assessment of resource utilization
and health-related quality of life. Resource utilization associated with direct medical resources,
caregiver informal care and patient social care will be collected via the RUD-Lite questionnaire 
(Wimo et al. 1998).  In addition, health-related quality of life will be captured with the 
EQ-5D-5L.  See Sections 9.1 and 9.1.3 for full scale descriptions.
The results of analyses of these variables may not be included in the CSR, but may be described 
in supplementary reports as appropriate.


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10. Statistical Considerations
10.1. Sample Size Determination
It is estimated that approximately 1540 patients will complete Study AZES.  Approximately 90%
of these patients are expected to enroll in Study AZFD for an estimated total of approximately 
1400 patients.
Study AZFD integrated with Study AZES forms a Delayed Start study (Study AZES-FD).  Using 
the three stage hypothesis testing approach to delayed-start analysis as outlined in Liu-Seifert 
and colleagues (2015) and assuming a 5% ED rate in the first 6 months of Study AZFD and 10% 
ED rate in the first 12 months of Study AZFD, this sample size will provide approximately 81% 
power for the noninferiority test (i.e., 3rd hypothesis) for each dose when all patients have the 
opportunity to complete the 6 month time point at a one-sided alpha level of 0.1.  At the 12
month time point of Study AZFD, this sample size will provide approximately 66% power for 
the noninferiority test.
These powering results are based on solanezumab Delayed-Start results of mild dementia, 
ApoE4 carriers (Studies LZAM, LZAN, and LZAO).  Treatment differences at the end of the 
Placebo-Controlled and Delayed-Start periods and the corresponding variance and covariance 
estimates were used to calculate the power empirically.  The 1540 patients estimated to complete 
Study AZES corresponds to an assumed ED rate of 30% from the original sample size of 2202.  
Extending to Study AZES-FD, the assumed ED rate until the 6 month time point of Study AZFD 
is 35%; until the end of the three years of Study AZES-FD, the assumed ED rate is 40%.  We 
assume an approximate 10% annual dropout over the course of Study AZFD.  These ED
assumptions were used to adjust the randomized sample sizes using the following formula:
Effective Sample Size = (Randomized Sample Size) * (1 – 0.50*ED)
The effective sample size assumes that ED patients will contribute half the information that 
completing patients contribute.  The effective sample sizes for the 6 month power calculation 
were 606 and 303, early-start arm and delayed-start arm, respectively; for 12 months, 588 and 
294, early-start arm and delayed-start arm, respectively.
The R package “pwr” and accompanying function “pwr.t2n.test” were used to calculate the 
power estimates.  To be consistent with Liu-Seifert and colleagues (2015), sig.level was set equal 
to 0.1 and alternative was set equal to “greater”.


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10.2. Populations for Analyses of AZES-FD
For purposes of analysis, the following populations are defined:
Population
Description
Entered
All participants who sign informed consent in study AZES
Randomized
All entered patients who are randomized to treatment in Study AZES.
Evaluable (Intention-to-treat 
[ITT] analysis)
All randomized patients with an AZES baseline and at least one post-baseline 
scale result.
The ITT principle asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their 
compliance to the planned course of treatment.
Safety
All AZES randomized participants who take at least 1 dose of double-blind 
study treatment. Participants will be analyzed according to the treatment group 
they were randomized to. 
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of the Sponsor.
Study AZES-FD offers the ability to assess disease modification of LY3314814 20 mg and
LY3314814 50 mg.  In order to present the integrated data, there will be four treatment regimens 
(see Table 10.1).  The estimand of interest is to compare the disease progression across Study 
AZES-FD in all AZES randomized participants after 130 weeks attributable to randomized 
treatment.
Table 10.1.
Treatment Regimens for Integrated Delayed-Start Study
Treatment Regimen
AZES Treatment
AZFD Treatment
1
LY 20 mg
LY 20 mg
2
LY 50 mg
LY 50 mg
3
Placebo
LY 20 mg
4
Placebo
LY 50 mg
Abbreviation:  LY = LY3314814.
All Study AZES-FD analyses will follow the intent-to-treat (ITT) principle unless otherwise 
specified.  Unless otherwise defined, a baseline measure is the last non-missing observation 
collected during Visits 1 and 2 of Study AZES.  End point is the last non-missing post-baseline 
measurement in the Study AZES-FD.  Efficacy analyses will be conducted on the Evaluable 
analysis set.


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For mixed-model repeated-measures (MMRM) models, observations collected at nonscheduled
visits will not be included in the analyses (Andersen and Millen 2013).  For analyses using last 
observation carried forward (LOCF), the last nonmissing post-baseline observation (scheduled or 
unscheduled) will be used to calculate change from baseline.
If any of the individual items for ADAS-Cog or ADCS-ADL are missing or unknown, every 
effort will be made to obtain the score for the missing item or items.
For ADAS-Cog13, if <30% (4 or fewer of a total of 13) of the items are missing, the total score 
(maximum = 85) will be imputed as follows:  The total from remaining items will be multiplied 
by a factor that includes the maximum score for the missing items.  For example, if the first item, 
“Word-Recall Task,” which ranges from a score of 0 through 10 (maximum = 10), is missing, 
and the second item “Commands,” which ranges from a score of 0 to 5 (maximum = 5), is 
missing, then the multiplication factor = 85/(85 - [10 + 5]) = 85/70 = 1.21.  Thus, the total score 
for this example will be the sum of the remaining 11 items multiplied by 1.21.  The imputed 
number will be rounded up to the nearest integer.  If more than 4 items are missing, the total 
score for ADAS-Cog13 at that visit will be considered missing.
For the ADCS-iADL, if <30% of the items are missing, the total score will be imputed.  The sum 
of the nonmissing items will be prorated to the sum of total items.  The imputed number will be 
rounded up to the nearest integer.  If the nearest integer is greater than the maximum possible 
score, the imputed score will be equal to the maximum score.  If >30% of the items are missing, 
the total score for ADCS-iADL at that visit will be considered missing.
The same imputation technique will be applied to the ADCS-ADL total score.  Note that, 
depending on the specific item responses that are missing, it is possible to have an imputed total 
score for both the ADCS-iADL and the ADCS-ADL, an imputed total score for one but not the 
other, or both total scores missing.
The same imputation technique will be applied to the CDR-SB.  If only 1 box (of 6) of the CDR 
is missing, the sum of the boxes will be imputed by prorating the sum from the other 5 boxes.  If 
the score from more than 1 box is not available, the CDR-SB at that visit will be considered 
missing.
For all other scales, if any item is missing, any total or sum involving that item will be 
considered missing.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP and the CSR.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
The IxRS will be used to assign a dosing regimen to each patient.  Site personnel will confirm 
that they have located the correct package by entering a confirmation number found on the label 
into the IxRS.


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10.3.2. Treatment Group Comparability
Patient Disposition
10.3.2.1.
All patients who discontinue from the AZES-FD study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will be 
given.
As is typical for most studies, the following analyses of patient disposition will be conducted.  
The reasons for discontinuation will be collected when the patient’s participation in the study 
ends and will be summarized by treatment group for all randomized subjects from each study.  
The percentage of subjects discontinuing from each treatment group will be compared between 
groups using Fisher’s exact test.  The median time to discontinuation for these reasons will also 
be compared between treatment groups using the Kaplan-Meier product limit estimator.  The 
comparisons using both the Fisher’s exact test and the Kaplan-Meier product limit estimator will 
be done for the overall percentage of patients who discontinue and also for select specific 
reasons for discontinuation.
The percentage of subjects discontinuing from each treatment group will be compared by reason 
for discontinuation using Fisher’s exact test.
Patient Characteristics
10.3.2.2.
Baseline characteristics will be summarized for the randomized populations by Study AZES-FD 
treatment group and overall. Summaries will include descriptive statistics for continuous and
categorical measures. Fisher’s exact test or Pearson’s chi-square test will be used for treatment
group comparisons of categorical data. For continuous data, analysis of variance (ANOVA),
with independent factors for treatment and investigator, will be used.
Concomitant Therapy
10.3.2.3.
Concomitant medications are defined as those being taken on or after randomization (Visit 2
Study AZES). A summary of concomitant medications will be presented as frequencies and 
percentages for each treatment group in Study AZES-FD. Fisher’s exact test will be used to test 
for treatment differences between groups.  If the start or stop dates of therapies are missing or 
partial to the degree that determination cannot be made of whether the therapy is prior or 
concomitant, the therapy will be deemed concomitant.
Prior and concomitant medications will be listed.
Summary tables will also be provided for concomitant anticholinergics that affect cognitive
function and AChEI/memantine medications.  Medications will be coded using the World Health 
Organization drug dictionary.
Treatment Compliance
10.3.2.4.
The proportion of Study AZES-FD patients who are significantly noncompliant as noted in
Section 7.6 of this protocol will be summarized and compared among all treatment groups using 
Fisher’s exact test.


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10.3.3. Efficacy Analyses
Primary Analyses
10.3.3.1.
The primary analysis of Study AZES-FD is to test the delayed-start hypothesis to evaluate 
disease modification by LY3314814 as assessed by the ADAS-Cog13. Comparisons are made by 
dose level between early-start patients (at the beginning of Study AZES) and delayed-start 
patients. Each comparison will evaluate three specific hypotheses described in the subsequent 
paragraph.
In the following description, the difference between an active arm and placebo at the end of 
Study AZES will be denoted Δ₁; the difference between delayed start and early start at the time 
point of interest in Study AZFD will be denoted Δ2.  Note that Δ₁ is the effect obtained from the 
primary analysis of Study AZES.  The primary efficacy measure will be analyzed using 
estimates from MMRM models, in which three specific hypotheses are tested:
Test 1. Δ₁ is statistically significantly greater than 0.
Test 2. Δ2 is statistically significantly greater than 0.
Test 3. 90% one-sided confidence limit of Δ2 – 50% Δ₁ is greater than 0.
The change from baseline (prior to the initiation of treatment in Study AZES) at each visit during 
Study AZES-FD (at the visits when the ADAS-Cog13 is assessed) will be the dependent variable.
The model for the fixed effects will include terms for:  baseline ADAS-Cog13, treatment, visit, 
treatment-by-visit interaction, baseline ADAS-Cog13 score-by-visit interaction, disease status at 
baseline (MCI due to AD or mild AD dementia), APOE4 status (carrier versus non-carrier), 
concomitant AChEI use at baseline (yes/no), age at baseline, and country.  Visit will be 
considered a categorical variable with values equal to the visit numbers at which the scales were 
assessed.
The first hypothesis will be tested using an estimate of Δ₁ obtained from an MMRM model fit 
using data from all randomized subjects through week 104 (the end of Study AZES).  The 
second hypothesis will be tested using an estimate of Δ2 obtained from an MMRM including data 
from all randomized subjects through week 130 (26 week time point of Study AZFD).
The noninferiority margin for this hypothesis is specified as 50% of the treatment difference 
observed at the end of Study AZES.  Using the same MMRM model used to test Δ2, the 
hypothesis will be tested by constructing a 90% one-sided CI of the difference in least-squares 
means at the 26 week visit in Study AZFD (Visit 7).  If the lower limit of the CI rules out the 
difference which would have been obtained if 50% of the observed difference had been lost, this 
study has provided evidence for modification of the course of AD beyond any short term 
symptomatic effects.
Multiplicity Adjustments
10.3.3.2.
When testing the primary endpoint and each of the key secondary endpoints, Test 1 and Test 2
listed in the primary analysis section (Section 10.3.3.1) will be tested at the α level specified in 
the Study AZES multiplicity graph in a sequential approach.  


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All other pairwise tests of treatment effects will be conducted at a 2-sided alpha level of 0.025; 
2-sided confidence intervals (CIs) will be displayed with a 97.5% CI. All tests of interactions 
between treatments and other factors will be conducted at an alpha level of 0.025.
Missing Data
A likelihood-based mixed effects model for repeated measures will be used to handle missing 
data.  The model parameters are simultaneously estimated using restricted likelihood estimation 
incorporating all of the observed data.  Estimates have been shown to be unbiased when the 
missing data are missing at random and when there is ignorable non-random missing data.
Repeated measures analyses will only use data from visits where the data was scheduled to be 
collected (see Andersen and Millen 2013).  When subjects discontinue from the study early, 
there may be efficacy or safety data measurements at visits where the variables were not 
scheduled to be collected.  These data will be used in all other analyses.
Secondary Analyses
10.3.3.3.
Similar to the primary analysis, each of the key secondary efficacy outcomes (ADL, FAQ, 
MMSE, CDR-SB, and iADRS) will be assessed using the primary analysis and assessed up to 
26 weeks (Visit 7).  The model for each of these secondary analyses will include terms for:  
baseline efficacy score, treatment, visit, treatment-by-visit interaction, baseline efficacy score-
by-visit interaction, disease status at baseline (MCI due to AD or mild AD dementia), APOE4 
status (carrier versus non-carrier), concomitant AChEI use at baseline (yes/no), age at baseline, 
and country.  The change from baseline (prior to the initiation of treatment in Study AZES) at 
each visit during Study AZES-FD (at the visits when the scale being analyzed is assessed) will 
be the dependent variable.
In addition, the Delayed-Start methodology will be used to analyze the ADAS-Cog13, ADL, 
FAQ, MMSE, CDR-SB, and iADRS at the last scheduled visit (up to Week 104 [Visit 15] of 
Study AZFD) to evaluate the durability of the treatment effect.
Tertiary/Exploratory Analyses
10.3.3.4.
Tertiary and exploratory analyses will be detailed in the SAP.
10.3.4. Safety Analyses
Safety will be assessed by summarizing and analyzing AEs, laboratory analytes, vital signs, MRI 
scans, skin and eye examinations, and ECGs for the Study AZES-FD.
For analysis comparing proportion of treatment-emergent abnormalities between treatment 
groups for laboratory analytes, vital signs, weight, MRI scans, skin and eye examinations, and 
ECGs, only patients who have both a baseline observation and a postbaseline observation will be 
included in the analysis for each analyte or parameter, respectively.
Suicide-related thoughts and behaviors, based on the C-SSRS, will be listed by patient and visit.  
Only patients that show suicidal ideation/behavior will be displayed (that is, if a patient’s
answers are all “no” for the C-SSRS, then that patient will not be displayed).  However, if a 


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patient reported any ideation or behavior at any time point, then all their ideation and behavior 
will be displayed, even if not positive.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Plasma LY3314814 concentrations are not routinely measured in this study; there are no pre-
specified analyses planned.  If PK samples are collected due to the observation of an AE or 
abnormal finding (see Section 9.5), the relationship between the observation and LY3314814 
plasma concentration may be explored.
10.3.6. Other Analyses
Health Economics
10.3.6.1.
Precise statistical analyses to support health economics’ objectives will be detailed in the SAP.
Subgroup Analyses
10.3.6.2.
To assess the effects of various demographic and baseline characteristics, subgroup analyses will 
be performed based on disease severity at Study AZES baseline (mild AD dementia vs. MCI).  
All subgroup analyses will be considered exploratory.
10.3.7. Interim Analyses
While no formal interim analyses for efficacy and/or futility are planned for this study, if 
Study AZES and/or Study AZET are successful and a regulatory submission is created, available 
data from up to 26 weeks from this study will be analyzed and included in the submission.


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11.
References
Andersen SW, Millen BA: On the practical application of mixed effects models for repeated 
measures to clinical trial data. Pharm Stat. 2013;12:7-16.
Aronson S, Van Baelen B, Kavanagh S, Schwalen S. Optimal dosing of galantamine in patients 
with mild or moderate Alzheimer’s disease: post hoc analysis of a randomized, double-blind, 
placebo-controlled trial. Drugs Aging. 2009;26(3):231-239.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. 
Neurology. 1994;44(12):2308-2314.
Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. 
Neurology. 1997;48(5 suppl 6):S10-16.
Duff K, Humphreys Clark JD, O’Bryant SE, Mold JW, Schiffer RB, Sutker PB. Utility of the 
RBANS in detecting cognitive impairment associated with Alzheimer’s disease: sensitivity, 
specificity, and positive and negative predictive powers. Arch Clin Neuropsychol. 
2008;23(5):603-612.
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(13):189-198.
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, Ferris S. An inventory to 
assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s 
Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S33-S39.
Galasko D, Kershaw PR, Schneider L, Zhu Y, Tariot PN. Galantamine maintains ability to 
perform activities of daily living in patients with Alzheimer’s disease. J Am Geriat Soc. 
2004;52(7):1070-1076.
Higuchi S, Liu Y, Yuasa T, Maeda A, Motohashi Y. Diurnal variation in the P300 component of 
human cognitive event-related potential. Chronobio Int. 2000;17(5):669-678.
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of 
dementia. Br J Psychiatry. 1982;140:566-572.
Jonsson T, Atwal JK, Steinberg S, et al. A mutation in APP protects against Alzheimer’s disease 
and age-related cognitive decline. Nature. 2012;488:96-99.  
Kind P. The EuroQol instrument: an index of health-related quality of life. In: Spilker B, editor. 
Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. Philadelphia, PA: 
Lippincott-Raven; 1996:191-201.
Liu-Seifert H, Andersen SW, Lipkovich I, Holdridge KC, Siemers E. A novel approach to 
delayed-start analyses for demonstrating disease-modifying effects in Alzheimer’s disease. 
PLoS ONE. 2015;10(3):Article No: e0119632.
Mohs RC, Knopmann D, Petersen RC, Ferris SH, Ernesto C, Grundman M, Sano M, 
Bieliauskas L, Geldmacher D, Clark C, Thal LJ. Development of cognitive instruments for use 
in clinical trials of antidementia drugs: additions to the Alzheimer’s Disease Assessment Scale 
that broaden its scope. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc 
Disord. 1997;11(suppl 2):S13-S21.


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Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 
1993;43(11):2412-2414.
Orgogozo JM, Small GW, Hammond G, Van Baelen B, Schwalen S. Effects of galantamine in 
patients with mild Alzheimer’s disease. Curr Med Res Opin. 2004;20(11):1815-1820.
Pfeffer RI, Kurosaki TT, Harrach CH Jr, Chance JM, Filos S. Measurement of functional 
activities in older adults in the community. J Gerontol. 1982;37(3):323-329.
Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): preliminary clinical validity. J Clinical Exp
Neuropsychol. 1998;20(3):310-319.
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 
1984;141(11):1356-1364.
Salloway S, Ferris S, Kluger A, Goldman R, Griesing T, Kumar D, Richardson S; Donepezil 401 
Study Group. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-
controlled trial. Neurology. 2004;63(4):651-657.
Wechsler Adult Intelligence Scale. 3rd ed. San Antonio, Texas: Psychological Corporation;
1997.
Wessels AM, Siemers ER, Yu P, Andersen SW, Holdridge KC, Sims, JR, Sundell K, Stern Y,
Rentz DM, Dubois, B, Jones RW, Cummings J, Aisen PS. A Combined Measure of Cognition 
and Function for Clinical Trials: The Integrated Alzheimer’s Disease Rating Scale (iADRS). J 
Prev Alz Dis. 2015;2(4):227-241.
Wimo A, Wetterholm AL, Mastey V, Winblad B. Evaluation of resource utilization and 
caregiver time in anti-dementia drug trials—a quantitative battery. In: Wimo A, Jonsson B,  
Karlsson G, Winblad B, editors. The Health Economics of Dementia. London: John Wiley & 
Sons; 1998:465-499.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
Aβ
amyloid beta peptide
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-Cog13
13-item Alzheimer’s Disease Assessment Scale-Cognition
ADCS-ADL
ADCS-iADL
Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory
Instrumental activities of the ADCS-ADL
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
ApoE4
apolipoprotein E4
APP
amyloid precursor protein
ARIA
amyloid-related imaging abnormality
AST
aspartate aminotransferase
AV
atrioventricular
BACE
Beta-site amyloid precursor protein cleaving enzyme
BCRP
breast cancer resistance protein
blinding
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
CDR/CDR-SB
Clinical Dementia Rating/ Clinical Dementia Rating–Sum of Boxes
CI
confidence interval


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CIOMS
Council for International Organizations of Medical Sciences
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
CRF
Case report form (sometimes referred to as clinical report form).  A printed or electronic 
form for recording study patients’ data during a clinical study, as required by the 
protocol.
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CSF
cerebrospinal fluid
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CV
cardiovascular
CYP3A4
cytochrome P450 3A4
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form (see CRF)
ED
early discontinuation
efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result under 
controlled conditions.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EQ-5D-5L™
A standardized instrument for use as a measure of health outcome (EuroQol Group; 
Rotterdam, The Netherlands)
ERB
Ethical Review Board
FAQ
Functional Activities Questionnaire
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose


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florbetapir
[18F]-AV-45 (chemical name (E)-4-(2-(6-(2-(2-(2-[18F]fluoroethoxy)ethoxy) 
ethoxy)pyridin-3-yl)vinyl)-N-methylbenzenamine)
GCP
good clinical practice
GMP
Good Manufacturing Practice
HSCRF
Hepatic Safety Case Report Form
iADRS
integrated Alzheimer’s Disease Rating Scale
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IgG/IgM
immunoglobulin G/immunoglobulin M
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IRB/ERB
Institutional Review Board/Ethical Review Board:  a board or committee (institutional, 
regional, or national) composed of medical professional and nonmedical members 
whose responsibility is to verify that the safety, welfare, and human rights of the 
patients participating in a clinical study are protected.
ITT
intent to treat: The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a patient (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
patients allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IxRS
interactive voice-response system (IVRS) and interactive web-response system (IWRS)


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legal representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
Lilly
Eli Lilly and Company
LOCF
last observation carried forward
MACE
major adverse CV event
MCI
mild cognitive impairment
MMRM
mixed-model repeated-measures
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NIA-AA
National Institute on Aging (NIA) and the Alzheimer’s Association (AA)
NPI
Neuropsychiatric Inventory
PCR
polymerase chain reaction
PET
positron emission tomography
Pgp
P-glycoprotein
PK/PD
pharmacokinetics/pharmacodynamics
QTcF
QT interval adjusted for heart rate using the Fridericia formula
RBANS
Repeatable Battery for the Assessment of Neuropsychological Status
RBC
red blood cells
RNA
ribonucleic acid
RUD-Lite
Resource Utilization in Dementia-Lite
SAE
serious adverse event
SAP
statistical analysis plan
Screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
SHFU
Self-Harm Follow-Up
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin level
ULN
upper limit of normal


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VAS
visual analog scale
vMRI
volumetric magnetic resonance imaging
WBC
white blood cells


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Variables
Hematology(blood)
Clinical Chemistry (serum)
Hematocrit
Alanine aminotransferase (ALT)
Hemoglobin
Albumin
Leukocytes (WBC) count
Absolute leukocyte differential count (neutrophils, 
basophils, monocytes, eosinophils and lymphocytes)
Alkaline phosphatase
Aspartate aminotransferase (AST)
Bilirubin, total
Platelet count
Blood urea nitrogen (BUN)
Calcium, total
Electrolytes (serum)
C-reactive protein
Bicarbonate
Creatine kinase (CK)
Chloride
Creatinine
Phosphate
Potassium
Glucose (random)
Sodium
Endocrinology
Thyroid-stimulating hormonea
Urinalysis
Total thyroxinea
Blood
Color
Other
Glucose
Hemoglobin A1c (HbA1c)a
Ketones
Leukocyte esterase
pH
Protein
Specific gravity
Abbreviation:  WBC = white blood cells.
a
At Visit 11, and Visit 15 or ED only.
Note:  Laboratory values outside the reference limit suspected to be of any clinical significance 
will be repeated.  Patients for whom suspected clinical significance is confirmed will be followed 
until normalization or for as long as the investigator considers necessary.  Additional laboratory 
tests may be performed for safety reasons if judged appropriate by the investigator.  See 
Section 9.4.5 for information regarding the recording of AEs based on laboratory tests.  All 
laboratory samples will be analyzed using routine methods per the central laboratory, as 
referenced in the Laboratory Manual for this study.


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Appendix 3.
Study Governance Considerations
Appendix 3.1.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for ensuring:

that the patient and study partner understands the potential risks and benefits 
of participating in the study

that informed consent is given by each patient or legal representative and their 
study partner.  This includes obtaining the appropriate signatures and dates on 
the informed consent form (ICF) prior to the performance of any protocol 
procedures and prior to the administration of investigational product.

answering any questions the patient and study partner may have throughout 
the study and sharing in a timely manner any new information that may be 
relevant to the patient’s willingness to continue his or her participation in the 
trial.

As used in this protocol, the term “informed consent” includes all consent and 
assent given by patient or their legal representatives and by study partner.
Appendix 3.1.2.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council
for Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to the Sponsor
before the study may begin at the investigative site(s).  The Sponsor or its representatives must 
approve the ICF, including any changes made by the ERBs, before it is used at the investigative 
site(s). All ICFs must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator Brochure (IB) and updates during the course of the 
study

informed consent and Assent Form

relevant curricula vitae
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:


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
consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party.
Appendix 3.1.4.
Investigator Information
Physicians with expertise in neurology, geriatrics, or psychiatry who have clearly documented 
extensive experience in AD trials will participate as investigators in this clinical study.  In 
addition, licensed clinicians who have clearly documented experience in AD trials may 
participate as investigators in this clinical study upon approval by the Sponsor.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Sponsor representative or designee.
Appendix 3.1.6.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the CRFs, and 
study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax


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
review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, the Sponsor or its representatives will periodically check a sample of the patient and 
study partner data recorded against source documents at the study site.  The study may be 
audited by the Sponsor or its representatives, and/or regulatory agencies at any time.  
Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data collected by a third-party will be encoded by the third-party and stored 
electronically in the third-party’s database system.  Validated data will subsequently be 
transferred to the Lilly data warehouse, using standard Lilly file transfer processes.
Data managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central vendor’s database system.  Data will subsequently be transferred 
from the central vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if the Sponsor or its designee, the investigator, or 
the ERB of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Eosinophils
Basophils
Cytomegalovirus antibody, IgG and IgM
Epstein-Barr virus VCA antibody, IgG and IgMc
Hepatitis A antibody, total
Platelets
Hepatitis A antibody, IgM
Hepatitis B surface antigen
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis C RNA PCR 
Direct bilirubin
Hepatitis E antibody, IgG and IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
PK for LY3314814
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Type I anti-liver kidney microsomal antibodies
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; PCR = polymerase chain reaction; RBC = red blood cells; RNA = ribonucleic acid; WBC = white blood 
cells; VCA = viral capsid antigen.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.
C
If EBV VCA antibody unavailable, obtain heterophile antibody of monospot testing.


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Appendix 5.
Protocol Amendment I8D-MC-AZFD(a)
Summary A Randomized, Double-Blind, Delayed-Start 
Study of LY3314814 (AZD3293) in Early Alzheimer’s 
Disease Dementia (Extension of Study AZES, The 
AMARANTH Study)
Overview
Protocol I8D-MC-AZFD A Randomized, Double-Blind, Delayed-Start Study of LY3314814 
(AZD3293) in Early Alzheimer’s Disease Dementia (Extension of Study AZES, The 
AMARANTH Study) has been amended.  The new protocol is indicated by amendment (a) and 
will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:


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Amendment Summary for Protocol I8D-MC-AZFD Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Section 1. Synopsis 
Added in Year 2 extension time points to include 
the delayed-start analyses in the Objective/Endpoint 
table, Summary of Study Design, and Treatment 
Arms and Duration Sections
Extending the study 1 additional year from original 
protocol
Section 1. Synopsis
Section 4. Objectives and Endpoints
Added CDR-SB and updated functional score to 
ADCS-ADL as secondary endpoints
Moving CDR-SB from an exploratory to secondary 
endpoint and including all ADCS-ADL score items, 
not just instrumental items (iADL)
Section 2. Schedule of Activities
Added in Year 2 to Schedule of Activities and 
updated footnotes accordingly
Extending the study 1 additional year from original 
protocol
Section 2. Schedule of Activities
Added footnote e
Clarification that there might be a delay in starting 
Visit 12 for patients who complete the first year of 
the protocol before the amendment is approved
Section 2. Schedule of Activities
Added footnote i
Clarification of early discontinuation procedures for 
certain measures
Section 3.1 Study Rationale
Added in Year 2 time points of the delayed-start 
analyses
Extending the study 1 additional year from original 
protocol
Section 4. Objectives and Endpoints
Added in Year 2 extension time points to include 
the delayed-start analyses
Extending the study 1 additional year from original 
protocol
Section 5.1. Overall Design
Added in statement regarding the Visit 12 initation 
window to be consistent with new footnote e in the 
Schedule of Activities
Clarification that there might be a delay in starting
Visit 12 for patients who complete the first year of 
the protocol before the amendment is approved
Section 5.1. Overall Design
Updated Study Design figure to include Year 2 and 
the symptomatic treatment windows
Extending the study 1 additional year from original 
protocol
Section 5.2 Number of Participants
Added statement about consent
Clarification that consent for Study AZFD may be 
obtained any time prior to performing procedures 
specific to this study.
Section 5.3 End of Study Definition
Added that final study visit will occur 
approximately 110 weeks after the last patient 
completes the feeder study
Extending the study 1 additional year from original 
protocol, plus approximately 6 weeks of follow-up
Section 5.4 Scientific Rationale for Study Design
Added in Year 2 extension time point
Extending the study 1 additional year from original 
protocol
Section 6.1 Inclusion Criteria
Updated wording of Inclusion Criteria #2 
Clarification of which patients who participate 


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through Visit 20 of Study AZES are eligible to 
enroll in Study AZFD
Section 7.2.1 Selection and Timing of Doses
Added a note regarding transition from Study 
AZES to Study AZFD
Want to minimize gaps in treatment
Section 7.7.1 Initiation of Post-Randomization 
Symptomatic AD Treatments
Added in Year 2 time points to be consistent with 
updated Study Design figure
Extending the study 1 additional year from original 
protocol
Section 7.8.2 Continued Access
Updated wording related to continued access
Clarification that continued access can only be
provided within an approved protocol.
Section 8.1.2 Temporary Discontinuation from 
Study Treatment
Added in “per study year”
Clarification that the maximum cumulative 
permissible treatment suspension is 3 weeks per 
year
Section 8.2 Discontinuation from the Study
Added reasons for discontinuation
Clarification that patients who discontinue the 
study early, for any reasons including early study 
termination as determined by the Sponsor and/or 
IDMC, will have ED procedures performed
9.1.2 Secondary Efficacy Assessments
Added CDR-SB and updated functional score to 
ADCS-ADL as secondary endpoints
Moving CDR-SB from an exploratory to secondary 
endpoint and including all ADCS-ADL score items, 
not just instrumental items (iADL)
9.1.2 Secondary Efficacy Assessments
Updated maximum score values for ADCS-bADL, 
ADCS-iADL, and iADRS
Change in classification of questions 6a and 6b of 
ADCS-ADL between basic and instrumental items.
9.4.1 Vasogenic edema
Added wording to vasogenic edema safety section
Clarification of when temporary discontinuation 
would be considered due to vasogenic edema
9.4.7 Physical and Neurological Examinations
Added in Year 2 time points for these measures 
Extending the study 1 additional year from original 
protocol
Section 9.4.10.4 Safety Areas of Special Interest
Added wording that MACE adjudications will 
continue at least until data lock for assessment of 
the primary analysis
Clarification of long-term follow-up when 
extending the study 1 additional year from the 
original protocol
Section 9.8.1 Florbetapir PET
Added wording regarding the number and timing of 
florbetapir F 18 PET scans performed
Clarification that florbetapir F 18 PET scans will 
not be conducted in the extension Year 2 
Section 10.1 Sample Size Determination 
Added wording regarding the estimated 
discontinuation rate
Clarification that the estimated annual 
discontinuation rate is approximately 10%
Section 10.3.3.2 Multiplicity Adjustments
Updated wording to minimize redundancy from 
other sections
Clarification of statistical methods for multiplicity 
adjustments
Section 10.3.3.3 Secondary Analyses
Added in Year 2 time points of the delayed-start 
analyses; added CDR-SB and updated functional 
Extending the study 1 additional year from original 
protocol; consistency with new objectives/endpoint 


I8D-MC-AZFD(a) Clinical Protocol
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score to ADCS-ADL as secondary endpoints
table.
Appendix 2. Clinical Laboratory Tests
Updated timing to clinical laboratory testing 
Updated the collection times for total thyroxine, 
thyroid stimulating hormone, and hemoglobin A1c 
to include assessments at Visits 15.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1.
Synopsis
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

The primary analysis of Study AZES-FD is to 
evaluate disease modification as outlined in 
Liu-Seifert (2015).  This will be accomplished 
by testing the three delayed-start hypotheses 
in both doses of LY3314814 across 
Study AZES and up to Week 26 (Visit 7) of 
Study AZFD.

ADAS-Cog13
Secondary
Clinical efficacy objective:

To evaluate the disease modification of both 
doses of LY3314814 on functional and 
cognitive outcomes across Study AZES and 
up to Week 26 (Visit 7) of Study AZFD using 
the primary analysis methodology.

Functional Outcome Measures
o
ADCS-iADL score
o
FAQ

Cognitive/Functional Outcome Measures
o
iADRS score
o
CDR-SB

Cognitive Outcome Measures
o
MMSE

The delayed-start analyses as outlined above 
will also be examined through Week 104 
(Visit 15) for cognitive and functional 
outcomes.

ADAS-Cog13, ADCS-iADL, FAQ, iADRS, 
CDR-SB, MMSE
Safety Objective

Collect information in order to further 
characterize the safety and tolerability of 
LY3314814 in patients with early AD
dementia (at the time of entry into 
Study AZES)

Standard safety assessments:
o
spontaneously reported AEs
o
clinical laboratory tests
o
vital sign and body weight 
measurements
o
12-lead ECGs
o
physical examinations including 
neurological examinations

Additional safety assessments:
o
Eye examinations
o
Skin examinations
o
Serial MRI
o
Columbia-Suicide Severity Rating 
Scale (C-SSRS)


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Abbreviations:  AD = Alzheimer’s disease; ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale –
Cognitive subscale; ADCS-iADL = Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory
instrumental items score; AE = adverse event; CDR-SB = Clinical Dementia Rating Sum of Boxes; ECG = 
electrocardiogram; FAQ = Functional Activities Questionnaire; iADRS = integrated Alzheimer’s Disease Rating 
Scale; CDR-Global Score = Clinical Dementia Rating Global Score; NPI = Neuropsychiatric Inventory; MMSE 
= Mini-Mental State Examination; MRI = magnetic resonance imaging.
Summary of Study Design:
Study I8D-MC-AZFD is a multicenter, randomized, double-blind, 52104-week delayed-start study with 2 fixed 
doses of LY3314814 in patients diagnosed with early AD, which is defined as the continuum of patients with MCI-
AD and patients diagnosed with mild dementia of the Alzheimer’s type (mild AD dementia), at the time of entry 
into feeder Study AZES.
Treatment Arms and Duration:
In Study AZFD, all patients will receive treatment with LY3314814.  Patients who were randomized to LY3314814 
in feeder Study AZES will continue with the same drug dose in Study AZFD.  Patients who were randomized to 
placebo in the feeder study will be randomized, in a 1:1 ratio, to either LY3314814 20 mg or LY3314814 50 mg.
All patients will receive study drug for 52 104 weeks.
...
2.
Schedule of Activities


I8D-MC-AZFD(a) Clinical Protocol
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Study procedurea
EDc
F/U
Visit number
V20-
AZES/
V1-
AZFDb
V2
V3
V4
V5
V6
V7
V8d
V9
V10
V11
V801 e
Study week
1
4
7
13
19
26
32
39
45
52
Tolerance interval for Visit (days)
±3
±3
±7
±7
±7
±7
±7
±7
±7
±10
Informed consent
X
Randomization
X
Prior/concomitant treatments
CO
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
NIA-AA criteria review
X
X
FAQ
CO
X
X
X
ADCS-ADL
CO
X
X
X
CDRf
CO
X
X
X
MMSE
CO
X
X
X
X
RBANS
X
X
ADAS-Cog13
CO
X
X
X
X
NPI
CO
X
X
X
Letter & Category Fluency, Digit 
Symbol-Coding tests
CO
X
X
X
EQ-5D-5L (patient)
CO
X
X
X
RUD-Lite
CO
X
X
X
MRI
CO
X
X
Florbetapir F18 Amyloid PETg
CO
X
X g
Required blood samples for plasma 
biomarkersh
Xh
Xh
Xh
Laboratory testsi
CO
X
X
X
X
X
X
X
Physical, neurological examinations
CO
Xj
X
Xj
Xj
X
X
Comprehensive eye examination
CO
X
X
Skin examination
CO
X
X
X
Vital signsk
CO
X
X
X
X
X
X
X
X
X
X
X
Body weight
CO
X
X
X
X
12-lead ECGl
CO
X
X
X
X
X
X
X
X


I8D-MC-AZFD(a) Clinical Protocol
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Study procedurea
EDc
F/U
Visit number
V20-
AZES/
V1-
AZFDb
V2
V3
V4
V5
V6
V7
V8d
V9
V10
V11
V801 e
Study week
1
4
7
13
19
26
32
39
45
52
Tolerance interval for Visit (days)
±3
±3
±7
±7
±7
±7
±7
±7
±7
±10
C-SSRS and Self-Harm Supplement 
Formm
CO
X
X
X
X
X
X
X
X
X
X
X
Dispense drug
X
X
X
X
X
X
X
X
X
Assess drug compliancesn
X
X
X
X
X
X
Xn
X
X
X
X
Adverse events
CO
X
X
X
X
X
X
X
X
X
X
X
X
Optional Addenda (site and patient specific)
Fluorodeoxyglucose (FDG) PETo
or
Flortaucipir F 18 (18F-AV-1451) 
PETo
CO
X
Xp
CO
X
Xp
Consent for optional DNA/RNA 
blood sampleq
Xq
Blood sample for DNAr (optional)
X
Xs
Blood sample for RNAr (optional)
X
X
Xs


I8D-MC-AZFD(a) Clinical Protocol
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Study procedurea
Delayed-Start Year 1
Delayed-Start Year 2
EDcb
F/U
Visit number
V20-
AZES/
V1-
AZFDbc
V2
V3
V4
V5
V6
V7
V8d
V9
V10
V11
V12e
V13
V14
V15
V801ef
Study week
1
4
7
13
19
26
32
39
45
52
65
78
91
104
Tolerance interval for Visit (days)
±3
±3
±7
±7
±7
±7
±7
±7
±7
±10
±7
±7
±7
±7
Informed consent
X
Randomization
X
Prior/concomitant treatments
CO
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
NIA-AA criteria review
X
X
X
FAQ
CO
X
X
X
X
X
ADCS-ADL
CO
X
X
X
X
X
CDRfg
CO
X
X
X
X
X
MMSE
CO
X
X
X
X
X
X
RBANS
X
X
X
ADAS-Cog13
CO
X
X
X
X
X
X
NPI
CO
X
X
X
X
X
Letter & Category Fluency, Digit Symbol-
Coding tests
CO
X
X
X
X
X
EQ-5D-5L (patient)
CO
X
X
X
X
RUD-Lite
CO
X
X
X
X
MRI
CO
X
X
X
Florbetapir F18 Amyloid PETgh
CO
X
X gi
Required blood samples for plasma 
biomarkershj
Xhj
Xhj
Xhi,j
Laboratory testsik
CO
X
X
X
X
X
X
X
X
X
X
X
Physical, neurological examinations
CO
Xjl
X
Xjl
Xjl
X
Xjl
X
Xjl
X
X
Comprehensive eye examination
CO
X
X
X
Skin examination
CO
X
X
X
X
Vital signskm
CO
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
CO
X
X
X
X
X
12-lead ECGln
CO
X
X
X
X
X
X
X
X
X
X
C-SSRS and Self-Harm Supplement Formmo
CO
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


I8D-MC-AZFD(a) Clinical Protocol
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Study procedurea
Delayed-Start Year 1
Delayed-Start Year 2
EDcb
F/U
Visit number
V20-
AZES/
V1-
AZFDbc
V2
V3
V4
V5
V6
V7
V8d
V9
V10
V11
V12e
V13
V14
V15
V801ef
Study week
1
4
7
13
19
26
32
39
45
52
65
78
91
104
Tolerance interval for Visit (days)
±3
±3
±7
±7
±7
±7
±7
±7
±7
±10
±7
±7
±7
±7
Dispense drug
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess drug compliancesnp
X
X
X
X
X
X
Xn
X
X
X
X
X
X
X
X
Adverse events
CO
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fluorodeoxyglucose (FDG) PEToq
or
Flortaucipir F 18 (18F-AV-1451) PEToq
CO
X
Xpr,i
CO
X
Xpr,i
Consent for optional DNA/RNA blood sampleqs
Xqs
Blood sample for DNArt (optional)
X
Xsu
Blood sample for RNArt (optional)
X
X
Xsi
Abbreviations:  ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognition; ADCS-ADL = The Alzheimer’s Disease Cooperative Study Activities of Daily 
Living Inventory; Aβ = A-beta amyloid; CDR = Clinical Dementia Rating; CO = Carryover; CSF = Cerebrospinal fluid; C-SSRS = Columbia Suicide 
Severity Rating Scale; DNA= deoxyribonucleic acid; DSM-V = Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; ECG = 
electrocardiogram; ED = early discontinuation; EQ-5D-5L (patient) = 5-dimensional EuroQol quality of life scale; FAQ = Functional Activities 
Questionnaire; FDG = fludeoxyglucose; F/U = follow-up; MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging; NIA-AA = 
National Institute of Aging – Alzheimer’s Association; NPI = Neuropsychiatric Inventory; PET = positron emission tomography; RBANS = Repeatable 
Battery for the Assessment of Neuropsychological Status; RNA = ribonucleic acid; RUD-Lite = Resource Utilization in Dementia-Lite; V = visit.
a
Every effort should be made for visits to occur on the designated study days. The overall treatment period in the protocol should be maintained (i.e., visits 
should be scheduled based on the randomization date rather than the previous visit).  Even if a patient enters into Study AZFD, it is expected that the patient 
complete all Study AZES procedures.  Any missing procedures should be completed during the maximum time window of the Study AZES follow-up period 
(6 weeks). Studies AZES and AZFD are considered compatible studies.
b
First dose to be administered the day after completion of Visit 1, preferably in the morning.
cb All patients who discontinue study treatment before Visit 11 15 should have Early Discontinuation (ED) procedures and assessments performed as soon as 
possible.  ADCS-ADL, FAQ, CDR, MMSE, RBANS, ADAS-Cog13, NPI, and Letter & Category Fluency, Digit Symbol-Coding tests should be conducted at 
the early discontinuation visit if it has been more than 12 weeks since they were last administered.  Imaging assessments such asIf it has been >6 months since 
the last MRI, then should havean MRI is performed. during the ED visit. and PET scans (applicable to a subset of patients) should be performed if 
discontinuation occurs between after Visit 6 and Visit 11.
bc First dose to be administered the day after completion of Visit 1, preferably in the morning.


I8D-MC-AZFD(a) Clinical Protocol
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d
Visit 8 is conducted by telephone and may include either the patient or the study partner, or both, as appropriate. The patient or study partner may be required 
to visit the clinic if drug dispensing is needed.
e
The initiation of Visit 12 may be delayed for the patients who have completed the first year of the protocol prior to regulatory and ethics approval of the 
protocol amendment that includes the Year 2 extension.
ef Patients who complete study treatment at Visit 11 or have early discontinuation should participate in a follow-up visit (Visit 801), 4 to 6 weeks after the last 
dose of study treatment.
fg The CDR should always be administered to the study partner first and then to the patient; the study partner and patient must be interviewed separately.  The 
assessments should be performed at approximately the same time of day at designated study visits, if possible.
gh Assessment performed only for those patients who had florbetapir F 18 PET scan at Visit 20 in Study AZES.  Patients with current participation in a research 
and/or medical protocol involving PET ligands or radioactive agents judged not to be scientifically or medically compatible with this study, with exposure to 
ionizing radiation that in combination with the planned administration of study florbetapir PET ligand would result in a cumulative exposure that exceeds 
local recommended exposure limits, or hypersensitivity to the active substance or any of the excipients of florbetapir F 18 are excluded from obtaining the 
florbetapir PET scan.
i
If discontinuation occurs after Visit 11, it is not collected or performed.
hj Blood samples for determination of plasma biomarkers (Aβ1-40, Aβ1-42) will preferably be collected 2 to 3 hours post-dose at indicated visits and failure to 
collect within this time frame will not be considered a protocol deviation.  Blood samples for other exploratory plasma biomarkers will also be collected at 
indicated visits.
ik Hematology, clinical chemistry, electrolytes, and urinalysis are included in every laboratory determination.  Thyroid-stimulating hormone, total thyroxine and 
hemoglobin A1c will be measured at Visits 11, and 1511 or ED.
jl
Brief physical and full neurological examinations will be performed at these visits.
km Vital signs include resting supine and standing blood pressures, pulse rates, and temperature.
ln Single safety ECGs are required.
mo The Adult C-SSRS Since Last Visit version will be administered. If, based on administration of the C-SSRS, it is determined that suicide-related behaviors 
have occurred, then the Lilly Self-Harm Follow-Up (SHFU) form will be used to collect additional information to allow for a more complete assessment of 
these behaviors.
np The patient should be instructed to retain all empty drug kits after using up the medication in the kit and to bring the empty kits and any unused medication to 
the clinic at each visit.  During visits conducted by telephone, the patient or study partner will be questioned about compliance with study treatment.
oq Patients who participated in Study AZES FDG PET or flortaucipir F 18 PET addenda will have the option to continue in the addendum to which they were 
previously assigned, provided that they consent for these procedures in Study AZFD.
pr If the patient discontinues study treatment betweenafter Visit 6 and Visit 11, the FDG or flortaucipir F 18 addendum PET scan should be performed.
qs Participation in this procedure is optional and consent can occur any time before blood draw.
rt
Patients who participate in optional pharmacogenomics samplings will be provided a separate informed consent for the samplings.  Failure to participate in 
optional sampling will have no influence on the eligibility of the patient for the study.  Consent can be obtained any time before blood draw.
su Blood sample should be collected at ED visit if the patient discontinues prior to Visit 7.


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3. Introduction
3.1.  Study Rationale
…
LY3314814 is being developed for the modification of the clinical course of Alzheimer’s disease 
(AD) by slowing disease progression in patients diagnosed with early AD, which is defined as 
the continuum of patients with mild cognitive impairment due to AD (MCI-AD) and patients 
diagnosed with mild dementia of the Alzheimer’s type (mild AD dementia) randomized to Study 
AZES.  Study I8D-MC-AZFD will test the hypothesis that patients originally randomized to 
receive placebo in the double-blind feeder Study AZES and switched to LY3314814 at the start 
of Study AZFD do not “catch up” on the Alzheimer’s Disease Assessment Scale-Cognitive 
Subscale (ADAS-Cog13) at Week 26 (Visit 7) of Study AZFD to patients originally randomized 
to receive LY3314814 in the double-blind feeder Study AZES.  Additionally, secondary 
delayed-start analyses will also be conducted over the entire 104 weeks of treatment.  Data 
acquired will also be used to evaluate the long-term safety and efficacy profile of LY3314814.
…
4.
Objectives and Endpoints
Table 4.1 shows the objectives and endpoints of the study.
Table 4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

The primary analysis of Study AZES-FD is to 
evaluate disease modification as outlined in 
Liu-Seifert (2015).  This will be accomplished 
by testing the three delayed-start hypotheses 
in both doses of LY3314814 across 
Study AZES and up to Week 26 (Visit 7) of 
Study AZFD.

ADAS-Cog13
Secondary
Clinical efficacy objective:

To evaluate the disease modification of both 
doses of LY3314814 on functional and 
cognitive outcomes across Study AZES and 
up to Week 26 (Visit 7) of Study AZFD using 
the primary analysis methodology.

Functional Outcome Measures
o
ADCS-iADL score
o
FAQ

Cognitive/Functional Outcome Measures
o
iADRS score
o
CDR-SB

Cognitive Outcome Measures
o
MMSE

The delayed-start analyses as outlined above 
will also be examined through Week 104 
(Visit 15) for cognitive and functional 
outcomes.

ADAS-Cog13, ADCS-iADL, FAQ, iADRS, 
CDR-SB, MMSE


I8D-MC-AZFD(a) Clinical Protocol
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Objectives
Endpoints
Safety Objective

Collect information in order to further 
characterize the safety and tolerability of 
LY3314814 in patients with early AD
dementia (at the time of entry into 
Study AZES)

Standard safety assessments:
o
spontaneously reported AEs
o
clinical laboratory tests
o
vital sign and body weight 
measurements
o
12-lead ECGs
o
physical examinations including 
neurological examinations

Additional safety assessments:
o
Eye examinations
o
Skin examinations
o
Serial MRI
o
Columbia-Suicide Severity Rating 
Scale (C-SSRS)
Abbreviations:  AD = Alzheimer’s disease; ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale –
Cognitive subscale; ADCS-iADL = Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory
instrumental items score; AE = adverse event; CDR-SB = Clinical Dementia Rating Sum of Boxes; ECG = 
electrocardiogram; FAQ = Functional Activities Questionnaire; iADRS = integrated Alzheimer’s Disease Rating 
Scale; CDR-Global Score = Clinical Dementia Rating Global Score; NPI = Neuropsychiatric Inventory; MMSE 
= Mini-Mental State Examination; MRI = magnetic resonance imaging.
5.
Study Design
5.1.
Overall Design
Study AZFD is a multicenter, randomized, parallel-group, double-blind, 52104-week-long study 
of 2 fixed dose levels of LY3314814 in patients with early AD at the time of enrollment into the 
feeder Study AZES.  The actual number of patients to be enrolled is dependent on the number of 
eligible patients completing feeder Study AZES.
The treatment period of this delayed-start extension will begin at the conclusion of Visit 20 of 
the feeder Study AZES which will also serve as Visit 1 for Study AZFD, and will continue with 
10452 weeks of treatment.  Patients who were randomized in Study AZES to either 20 mg or 50 
mg of LY3314814 will continue on the treatment allocation from the feeder study.  Patients 
randomized to placebo in Study AZES will be randomized in a blinded fashion 1:1 to 
LY3314814 20 mg or 50 mg daily (QD), administered orally.  Neither the patient nor 
investigator will be unblinded to feeder study treatment assignments.  Assessments will be made 
as indicated on the Study Schedule of Activities found in Section 2.
The study includes a longitudinal florbetapir F 18 amyloid positron emission tomography (PET)
scan for those patients who had a florbetapir F 18 PET scan at Visit 20 of Study AZES.  In 
addition, there are two longitudinal addenda of fluorodeoxyglucose (FDG) PET and 18F-AV-
1451 PET at applicable sites.  Patients who participated in these addenda in Study AZES are 
eligible to participate in the respective addenda in Study AZFD.  Figure 5.1 illustrates the study 
design.


I8D-MC-AZFD(a) Clinical Protocol
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LY3314814
The initiation of Visit 12 may be delayed for the patients who have completed the first year of 
the protocol prior to regulatory and ethics approval of the protocol amendment that includes the
Year 2 extension.
Abbreviation:  LY = LY3314814.
*
At Visit 1 of Study AZFD (Visit 20 of Study AZES), patients randomized to 
placebo from Study AZES will be randomized 1:1 to LY 20 mg or LY 50 mg in 
Study AZFD.
Note:  Gray boxes after Study AZFD Visits 1, 7, and 11, 13, and 15 indicate the 4-week 
symptomatic treatment initiation window for subjects with progression of symptoms.
Figure 5.1.
Illustration of study design for Clinical Protocol I8D-MC-AZFD.
LY 20 mg
LY 50 mg
AZFD: Week 1/Visit 1*
AZES: Week 104/Visit 20
AZES: Visit 2
Study AZES (Feeder)
Placebo-Controlled Study
Visit 2 to Visit 20
Study AZFD
Delayed-Start Study
Visit 1 to Follow-up
LY 20 mg
LY 50 mg
LY 50 mg
LY 20 mg
Week 52
Visit 11
Placebo
Placebo 
Week 26
Visit 7
Follow-up 
Visit 801


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5.2.  Number of Participants
It is estimated that approximately 1540 participants will complete the feeder Study AZES.  
Based on historical data, it is assumed that 90% (approximately 1400) of the participants from 
Study AZES will provide consent to continue participation in Study AZFD.  Consent for Study 
AZFD may be obtained at any time prior to performing procedures specific only for Study 
AZFD.
5.3.  End of Study Definition
The end of the study is defined as “the last visit of the last patient undergoing the study.”  This 
definition applies to the entire study and is not region specific.
The study is expected to start in Q1 of 2017 which is the scheduled date for the first completers 
of the feeder Study AZES.  The final study visit will occur approximately 110 58 weeks after the 
last patient completes the feeder study.
5.4. Scientific Rationale for Study Design
Study AZFD integrated with Study AZES forms a Delayed Start study design.  Data from 
randomization (Visit 2) in Study AZES through Visit 7 of Study AZFD will be used to test 
whether there is a treatment effect that cannot be achieved with a later start of treatment. The 
time points beyond the primary analysis at 26 weeks (Visit 7) in Study AZFD will be analyzed
upon last patient visit to determine the robustness of early treatment over the full 10452-week 
delayed-start period.
…
6.
Study Population
6.1.
Inclusion Criteria
General Inclusion Criteria
[1]
Provision of signed, written and dated informed consent from patient (or legal 
representative if required) and from study partner prior to any study specific 
procedures being performed.
[2]
Patients completingparticipating through Visit 20 of Study AZES and who have not 
permanently discontinued study treatment.  Note: Patients who have permanently 
discontinued study treatment prior to Visit 20 of Study AZES and have remained in 
Study AZES off treatment are not eligible for Study AZFD.
…
7.
Treatments
…
7.1.1. Packaging and LabellingLabeling


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…
All kits will bear a label translated into local language and prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines.  The labels will fulfill GMP 
Annex 13 requirements for labellinglabeling.
…
7.2.1. Selection and Timing of Doses
Patients will continue on Study AZES study treatment during the entire period of Visit 20 of 
Study AZES.  To ensure that patients continue on study treatment without a lapse in therapy, 
patients will take their last dose of Study AZES treatment on the day of randomization into Study 
AZFD.  Since many of the procedures and assessments will be used for both study visits, Visit 
20 of Study AZES will occur simultaneously with Visit 1 of Study AZFD.  Once all other AZES 
Visit 20 assessments and procedures have been completed, the final procedure in Study AZES is 
to assess drug compliance and collect any unused AZES study medication.  After resolving 
Study AZES drug compliance, the patient can be randomized to the Study AZFD treatment.  
Patients are to take the first dose of Study AZFD treatment on the day following randomization 
into the study.  The dose is to be taken once daily, preferably in the morning unless instructed 
otherwise. 
Note: Every attempt should be made to ensure that the transition from Study AZES to 
Study AZFD is seamless.  Any gaps in treatment should be minimized.  If a gap in treatment 
occurs, please notify your Clinical Research Associate for Study AZFD.
…
7.7.1. Initiation of Post-Randomization Symptomatic AD Treatments
Over the period of this trial patients may have progression of symptoms/disease (patients may 
progress to mild or moderate/severe stages of disease).  For patients for whom treatment 
becomes medically indicated during the trial, initiation of cholinesterase inhibitors and 
memantine (moderate stages) is permitted.  This initiation must only occur when medically 
indicated and documenting the rationale or indication for initiation will be required.  In order to 
adequately capture any decline as well as stable improvements, these symptomatic treatments 
should be initiated within approximately four weeks after the completion of cognitive testing at 
the Visit 1, Visit 7, and Visit 11, Visit 13, and Visit 15 (see Figure 5.1).  Initiation at a time 
outside of these windows is discouraged, but the Sponsor-designated medical monitor should be 
contacted if a clinical need arises outside of the protocol-specified windows and will not be 
deemed a protocol violation if approved.
…
7.8.2. Continued Access
LY3314814 may be made available to patients who have completed the study and are still 
receiving benefit from study treatment until LY3314814 becomes commercially available in the 


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host country of the patient.  Continued access would only be provided through a regulatory and 
IRB-approved protocol, where applicable. Safety and efficacy data may be collected during this 
time period.
8.
Discontinuation Criteria
…
8.1.2. Temporary Discontinuation from Study Treatment
Treatment suspension and re-dosing of study drug can be considered based on the Principal
Investigator’s judgment (examples include short-term treatment using a prohibited drug, 
uncertain adverse event, hospitalization).  The maximum cumulative permissible treatment 
suspension during the course of Study AZFD is 3 weeks per study year over the duration of the 
study. Temporary treatment discontinuation and restarting needs to be documented.  If 
temporary discontinuation is due to an AE, it should be reported to the Sponsor-designated 
medical monitor.
8.2.
Discontinuation from the Study
...
Patients who discontinue the study early (for any reason, including early study termination as 
determined by the Sponsor and/or IDMC) will have ED procedures and follow-up procedures 
performed as shown in the Schedule of Activities (Section 2).  Note:  Follow-up procedures are 
performed 4 to 6 weeks after last dose of investigational product.
…
9.
Study Assessments and Procedures
…
9.1.2. Secondary Efficacy Assessments
Secondary efficacy variables in this study are the changes from baseline in Study AZES to Week 
26 (Visit 7) in Study AZFD in FAQ score, Alzheimer’s Disease Cooperative Study Activities of 
Daily Living Inventory instrumental items score (ADCS-iADL), integrated Alzheimer’s Disease 
Rating Scale (iADRS), CDR-SB, and Mini-Mental State Examination (MMSE).
…
Alzheimer’s Disease Cooperative Study—Activities of Daily Living Inventory (ADCS-ADL;
Galasko et al. 1997, 2004).  The ADCS-ADL measures 6 basic and 17 instrumental activities of 
daily living and was specifically developed as a sensitive tool to track changes in functional 
performance in AD over time.  The basic activities include self-care tasks such as eating, 
walking, toileting, bathing, and grooming.  The instrumental activities are more complex skills 
that are required to successfully live independently and include shopping, keeping appointments, 
traveling outside of home, making a meal or snack, reading, and writing.  These instrumental 
skills are often compromised in early AD.


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For each activity on the ADCS-ADL, the score ranges from 0 to 78, with lower scores indicating 
greater impairment.  The maximum basic items score (sum of individual basic item scores) is 
2219, and the maximum instrumental items score (sum of individual instrumental item scores) is 
56 59 (Galasko et al. 2004).
…
Integrated Alzheimer’s Disease Rating Scale (iADRS; Wessels et al. 2015) [calculated 
assessment, not a separately administered scale] is a composite that measures both cognition 
and function. The iADRS is a simple linear combination of scores from two well-established, 
therapeutically sensitive, widely accepted measures in AD, the ADAS-Cog13 and the 
instrumental activities within the ADCS-ADL (ADCS-iADL), measuring the core domains of 
AD. All items of these two scales are included without additional weighting of items, yielding 
face validity and ease of interpretation of the composite relative to its components.
The iADRS provides an overall measure of AD impairment (total score) and can also provide 
individual subscores for cognition and function based on standard, accepted instruments. The 
iADRS demonstrated acceptable psychometric properties (established through principal 
component analysis, estimation of the contributions of domain scores to the iADRS total score, 
and estimation of the contributions of individual item scores to the iADRS total score) and was
effective in capturing disease progression and treatment effects (both beneficial and detrimental) 
across a broad range of the symptomatic disease spectrum – MCI/prodromal, mild AD dementia, 
and moderate AD dementia populations.
The iADRS score ranges from 0 to 141144; with higher scores indicating greater impairment.
…
Clinical Dementia Rating (CDR; Hughes et al. 1982) is a global rating system widely used in 
clinical studies of AD as a measure of dementia severity and disease progression.  The CDR 
ratings are based on a semi-structured and in-depth interview with both the patient and the 
patient’s study partner.  The CDR rates decline in cognition and its impact on functioning 
relative to the patient’s own premorbid ability levels.
The CDR includes assessment of 6 independent domains (Memory, Orientation, Judgment and 
Problem Solving, Community Affairs, Home and Hobbies, and Personal Care).  These domain 
ratings are also known as “box” scores and the Sum of Boxes (SB) score is derived by adding the 
individual box scores at a given time point.  The CDR-SB is assessed on a scale from 0 to 18, 
with higher scores indicating greater impairment.  The CDR global score is a composite score 
calculated using the Washington University CDR-assignment algorithm applied to the 6 
individual domain box scores (Morris 1993).  The memory domain is considered the primary 
category that drives the CDR global outcome, and all other domains are secondary.  The CDR 
global score ranges from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild 
dementia, 2 = moderate dementia, 3 = severe dementia).
Administration of the CDR will be audio-recorded for quality-control and training purposes.  
Audio recordings will be centrally reviewed and monitored where permitted by local law.


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9.1.3. Other/Exploratory Assessments
…
Clinical Dementia Rating (CDR; Hughes et al. 1982) is a global rating system widely used in 
clinical studies of AD as a measure of dementia severity and disease progression.  The CDR 
ratings are based on a semi-structured and in-depth interview with both the patient and the 
patient’s study partner.  The CDR rates decline in cognition and its impact on functioning 
relative to the patient’s own premorbid ability levels.
The CDR includes assessment of 6 independent domains (Memory, Orientation, Judgment and 
Problem Solving, Community Affairs, Home and Hobbies, and Personal Care).  These domain 
ratings are also known as “box” scores and the Sum of Boxes (SB) score is derived by adding the 
individual box scores at a given time point.  The CDR-SB is assessed on a scale from 0 to 18, 
with higher scores indicating greater impairment.  The CDR global score is a composite score 
calculated using the Washington University CDR-assignment algorithm applied to the 6 
individual domain box scores (Morris 1993).  The memory domain is considered the primary 
category that drives the CDR global outcome, and all other domains are secondary.  The CDR 
global score ranges from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild 
dementia, 2 = moderate dementia, 3 = severe dementia).
Administration of the CDR will be audio-recorded for quality-control and training purposes.  
Audio recordings will be centrally reviewed and monitored where permitted by local law.
…
9.4.1. Vasogenic Edema
If a patient develops symptoms believed to be suggestive of vasogenic edema, such as headache, 
confusion, gait disturbance, or visual disturbance, these should be recorded as AEs and an MRI 
should be obtained, unless contraindicated.  Study treatment should be discontinued if clinically 
significant symptomatic vasogenic edema occurs.  Temporary discontinuation may be considered 
and study medication restarted if stable (see Section 8.1 for discontinuation from study treatment 
or Section 8.1.2 for temporary discontinuation).  Temporary discontinuation of treatment may be 
considered if clinically significant symptomatic superficial siderosis, or clinically significant 
symptomatic incident microhemorrhage is seenobserved (see Section 8.1 for discontinuation 
from study treatmentSection 8.1.2 for temporary discontinuation).  Following the study treatment 
discontinuation, the MRI scan should be repeated within 4 weeks to evaluate the status of the 
finding and then performed every 4 to 6 weeks (or as clinically indicated) until the finding 
resolves or stabilizes.  Treatment with high-dose dexamethasone is to be considered, should 
symptoms be severe.
…
9.4.7. Physical and Neurological Examinations
Complete physical examinations will be performed at baseline, and Visits 5 and, 11, 13, and 15, 
and at the ED visits indicated in the Schedule of Activities (see Section 2).  Brief physical 


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examinations will be performed at Visits 3, 7, and 9, 12, and 14.  The complete physical 
examination will include assessment of the following:  general appearance; skin, head and neck; 
lymph nodes; thyroid; abdomen (bowel sounds, liver and spleen palpation); back (costovertebral 
angle tenderness); and musculoskeletal, cardiovascular, and respiratory systems.  The brief 
physical examination will include assessments of the skin, lungs, cardiovascular system, and 
abdomen (bowel sounds, liver and spleen palpation).
…
9.4.10.4.
Safety Areas of Special Interest
…
Alzheimer’s disease occurs mainly in elderly people, who may have established CV disease or 
CV risk factors and constitute a population of patients at increased risk of CV events.  Serious 
CV events, as well as particular arrhythmic events related to QTcF prolongation, are therefore of 
potential special interest.  Serious adverse events that, according to the investigator, may be CV 
events of the major adverse CV event (MACE) type (myocardial infarction, stroke, or CV death) 
or may be potential QT prolongation-related arrhythmic events, e.g., syncope, ventricular 
tachycardia/torsades des pointes/fibrillation or cardiac arrest will be carefully documented and 
sent for adjudication.  The events will be blindly evaluated by external independent adjudication 
consultants and adjudicated as MACE events per a separate charter.
In the long-term follow-up of Year 2, MACE adjudications will continue at least until data lock 
for assessment of the primary analysis.
…
9.8.1. Florbetapir PET (Positron Emission Tomography)
This study includes a longitudinal florbetapir F 18 amyloid PET scan for those patients who had 
a florbetapir F 18 PET scan at Visit 20 of Study AZES. Florbetapir F 18 amyloid PET will be 
used to evaluate changes in amyloid binding from baseline of Study AZES to the end of
treatment.Year 1 of Study AZFD (Visit 11).  See Schedule of Activities (Section 2).  The number 
of florbetapir F 18 PET scans performed at Visit 11 may by limited at Sponsor discretion.
…
10.
Statistical Considerations
10.1.
Sample Size Determination
…
Study AZFD integrated with Study AZES forms a Delayed Start study (Study AZES-FD).  Using 
the three stage hypothesis testing approach to delayed-start analysis as outlined in Liu-Seifert 
and colleagues (2015) and assuming a 5% ED rate in the first 6 months of Study AZFD and 10% 
ED rate in the entire first 12 months of Study AZFD, this sample size will provide approximately 
81% power for the noninferiority test (i.e., 3rd hypothesis) for each dose when all patients have 


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the opportunity to complete the 6 month time point at a one-sided alpha level of 0.1.  At the 12
month time point of Study AZFD, this sample size will provide approximately 66% power for 
the noninferiority test.
These powering results are based on solanezumab Delayed-Start results of mild dementia, 
ApoE4 carriers (Studies LZAM, LZAN, and LZAO).  Treatment differences at the end of the 
Placebo-Controlled and Delayed-Start periods and the corresponding variance and covariance 
estimates were used to calculate the power empirically.  The 1540 patients estimated to complete 
Study AZES corresponds to an assumed ED rate of 30% from the original sample size of 2202.  
Extending to Study AZES-FD, the assumed ED rate until the 6 month time point of Study AZFD 
is 35%; until the end of the three years of Study AZES-FD, the assumed ED rate is 40%.  We 
assume an approximate 10% annual dropout over the course of Study AZFD.  These ED
assumptions were used to adjust the randomized sample sizes using the following formula:
…
10.3.1. General Statistical Considerations
…
Unless otherwise noted, all pairwise tests of treatment effects will be conducted at a 2-sided 
alpha level of 0.025; 2-sided confidence intervals (CIs) will be displayed with a 97.5% CI.  All 
tests of interactions between treatments and other factors will be conducted at an alpha level of 
0.025.  For mixed-model repeated-measures (MMRM) models, observations collected at 
nonscheduled visits will not be included in the analyses (Andersen and Millen 2013).  For 
analyses using last observation carried forward (LOCF), the last nonmissing post-baseline 
observation (scheduled or unscheduled) will be used to calculate change from baseline.
Investigators with fewer than 6 evaluable patients will be pooled for statistical analysis purposes.  
All investigative sites with fewer than 6 evaluable patients on the primary endpoint measure will 
be pooled together within each country and considered a single site for analysis.  If this results in 
a pooled site still having fewer than 6 evaluable patients, this site will be pooled together with 
the next smallest investigative site, if one exists, in that country; otherwise, no further pooling is 
needed.  These pooled investigative sites will be used for any analysis that has investigative site 
as a fixed effect in the model.  The actual investigative site numbers will be included in the 
listings.
…
10.3.3.1.
Primary Analyses
…
In the following description, the difference between an active arm and placebo at the end of 
Study AZES will be denoted Δ₁; the difference between delayed start and early start at the time 
point of interest in Study AZFD will be denoted Δ2.  Note that Δ₁ is the effect obtained from the 
primary analysis of Study AZES.  The primary efficacy measure will be analyzed using 
estimates from MMRM models, in which three specific hypotheses are tested:


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Test 1. Δ₁ is statistically significantly greater than 0.
Test 2. Δ2 is statistically significantly greater than 0.
Test 3. 90% one-sided confidence limit of Δ2 – 50% Δ₁ is greater than 0.
…
10.3.3.2.
Multiplicity Adjustments
When testing the primary endpoint and each of the key secondary endpoints, the first twoTest 1 
and Test 2 hypotheses listed in the primary analysis section above (Section 10.3.3.1) will be 
tested at the α level specified in the Study AZES multiplicity graph= .025 for each dose in a 
sequential approach.  The three hypotheses in the primary analyses will be tested using a 
gatekeeping, sequential approach:
1.
Δ₁ is statistically significantly greater than 0.
2.
Δ2 is statistically significantly greater than 0.
3.
90% one-sided confidence limit of Δ2 – 50% Δ₁ is greater than 0.
All other pairwise tests of treatment effects will be conducted at a 2-sided alpha level of 0.025; 
2-sided confidence intervals (CIs) will be displayed with a 97.5% CI.  All tests of interactions 
between treatments and other factors will be conducted at an alpha level of 0.025.  No other 
adjustments for multiplicity are planned.
…
10.3.3.3.
Secondary Analyses
Similar to the primary analysis, each of the key secondary efficacy outcomes (iADL, FAQ, 
MMSE, CDR-SB, and iADRS) will be assessed using the primary analysis and assessed up to 26 
weeks (Visit 7).  The model for each of these secondary analyses will include terms for:  baseline 
efficacy score, treatment, visit, treatment-by-visit interaction, baseline efficacy score-by-visit 
interaction, disease status at baseline (MCI due to AD or mild AD dementia), APOE4 status 
(carrier versus non-carrier), concomitant AChEI use at baseline (yes/no), age at baseline, and 
country.  The change from baseline (prior to the initiation of treatment in Study AZES) at each 
visit during Study AZES-FD (at the visits when the scale being analyzed is assessed) will be the 
dependent variable.
In addition, the Delayed-Start methodology will be used to analyze the ADAS-Cog13, iADL, 
FAQ, MMSE, CDR-SB, and iADRS at the last scheduled visit (up to Week 52 104 [Visit 1115] 
of Study AZFD) to evaluate the durability of the treatment effect.
…
Appendix 1.
Abbreviations and Definitions


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Term
Definition
Aβ
amyloid beta peptide
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-Cog13
13-item Alzheimer’s Disease Assessment Scale-Cognition
ADCS-ADL
ADCS-iADL
Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory
Instrumental activities of the ADCS-ADL
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
ApoE4
apolipoprotein E4
APP
amyloid precursor protein
ARIA
amyloid-related imaging abnormality
AST
aspartate aminotransferase
AV
atrioventricular
BACE
Beta-site amyloid precursor protein cleaving enzyme
BCRP
breast cancer resistance protein
blinding
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
CDR/CDR-SB
Clinical Dementia Rating/ Clinical Dementia Rating–Sum of Boxes
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences


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complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
CRF
Case report form (sometimes referred to as clinical report form).  A printed or electronic 
form for recording study patients’ data during a clinical study, as required by the 
protocol.
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CSF
cerebrospinal fluid
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CV
cardiovascular
CYP3A4
cytochrome P450 3A4
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCOA
Electronic Clinical Outcome Assessments
eCRF
electronic case report form (see CRF)
ED
early discontinuation
efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result under 
controlled conditions.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EQ-5D-5L™
A standardized instrument for use as a measure of health outcome (EuroQol Group; 
Rotterdam, The Netherlands)
ERB
Ethical Review Board
FAQ
Functional Activities Questionnaire
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose


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florbetapir
[18F]-AV-45 (chemical name (E)-4-(2-(6-(2-(2-(2-[18F]fluoroethoxy)ethoxy) 
ethoxy)pyridin-3-yl)vinyl)-N-methylbenzenamine)
GCP
good clinical practice
GMP
Good Manufacturing Practice
HSCRF
Hepatic Safety Case Report Form
iADRS
integrated Alzheimer’s Disease Rating Scale
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference onCouncil for Harmonisation
IDMC
Independent Data Monitoring Committee
IgG/IgM
immunoglobulin G/immunoglobulin M
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IRB/ERB
Institutional Review Board/Ethical Review Board:  a board or committee (institutional, 
regional, or national) composed of medical professional and nonmedical members 
whose responsibility is to verify that the safety, welfare, and human rights of the 
patients participating in a clinical study are protected.
ITT
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IxRS
interactive voice-response system (IVRS) and interactive web-response system (IWRS)


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legal representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
Lilly
Eli Lilly and Company
LOCF
last observation carried forward
MACE
major adverse CV event
MCI
mild cognitive impairment
MMRM
mixed-model repeated-measures
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NIA-AA
National Institute on Aging (NIA) and the Alzheimer’s Association (AA)
NPI
Neuropsychiatric Inventory
PCR
polymerase chain reaction
PET
positron emission tomography
Pgp
P-glycoprotein
PK/PD
pharmacokinetics/pharmacodynamics
QTcF
QT interval adjusted for heart rate using the Fridericia formula
RBANS
Repeatable Battery for the Assessment of Neuropsychological Status
RBC
red blood cells
RNA
ribonucleic acid
RUD-Lite
Resource Utilization in Dementia-Lite
SAE
serious adverse event
SAP
statistical analysis plan
Screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
SHFU
Self-Harm Follow-Up
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin level
ULN
upper limit of normal


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VAS
visual analog scale
vMRI
volumetric magnetic resonance imaging
WBC
white blood cells
Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Variables
Hematology(blood)
Clinical Chemistry (serum)
Hematocrit
Alanine aminotransferase (ALT)
Hemoglobin
Albumin
Leukocytes (WBC) count
Absolute leukocyte differential count (neutrophils, 
basophils, monocytes, eosinophils and lymphocytes)
Alkaline phosphatase
Aspartate aminotransferase (AST)
Bilirubin, total
Platelet count
Blood urea nitrogen (BUN)
Calcium, total
Electrolytes (serum)
C-reactive protein
Bicarbonate
Creatine kinase (CK)
Chloride
Creatinine
Phosphate
Potassium
Glucose (random)
Sodium
Endocrinology
Thyroid-stimulating hormonea
Urinalysis
Total thyroxinea
Blood
Color
Other
Glucose
Hemoglobin A1c (HbA1c)a
Ketones
Leukocyte esterase
pH
Protein
Specific gravity
Abbreviation:  WBC = white blood cells.
a
At Visit 11, and Visit 15 or ED only.
…
Appendix 3.
Study Governance Considerations
Appendix 3.1.2.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International 


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Conference Council on for Harmonisation (ICH) guidelines and other applicable laws and 
regulations.


PPD
Leo Document ID = 08f5e276-f3b8-4482-8b86-d0b5f6d0c346
Approver:
Approval Date & Time: 06-Feb-2018 16:08:04 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 06-Feb-2018 22:30:18 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan I8D-MC-AZFD (Version 3)
A Randomized, Double-Blind, Delayed-Start Study of LY3314814 (AZD3293) in Early Alzheimer’s 
Disease Dementia (Extension of Study AZES, The AMARANTH Study)
NCT02972658
Approval Date: 20-Aug-2018


I8D-MC-AZFDStatistical Analysis PlanVersion 3
Page 1
LY3314814
1. Statistical Analysis Plan:
Protocol I8D-MC-AZFD–A Randomized, Double-Blind, 
Delayed-Start Study of LY3314814 (AZD3293) in Early 
Alzheimer’s Disease Dementia (Extension of Study AZES, 
The AMARANTH Study) 
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries..
LY3314814
AZFD is a Phase 3 study designed to test whether LY3314814willslow disease 
progression in patients with earlyAlzheimer’s Disease randomized in study AZES. 
Approval Date: 20-Aug-2018 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Statistical Analysis Plan version 3approved by Lilly ondateprovided below.


I8D-MC-AZFD Statistical Analysis Plan Version 3
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan: Protocol I8D-MC-AZFD – A Randomized, 
Double-Blind, Delayed-Start Study of LY3314814 (AZD3293) in 
Early Alzheimer’s Disease Dementia (Extension of Study AZES, 
The AMARANTH Study)...................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................9
4.1.
Primary Objective ..........................................................................................................9
4.2.
Secondary Objectives.....................................................................................................9
5.
Design and Sample Size....................................................................................................10
5.1.
Summary of Study Design............................................................................................10
5.2.
Determination of Sample Size ......................................................................................11
5.3.
Method of Assignment to Treatment ............................................................................12
6.
A Priori Statistical Methods ..............................................................................................13
6.1.
General Considerations ................................................................................................13
6.1.1.
Adjustments for Covariates ..................................................................................14
6.1.2.
Handling Missing Data from Subject Dropouts ....................................................14
6.1.3.
Handling Missing Items in Calculating Totals......................................................14
6.1.4.
Multicenter Studies ..............................................................................................15
6.1.5.
Multiple Comparisons/Multiplicity.......................................................................15
6.1.6.
Analysis Populations............................................................................................16
6.2.
Patient Disposition .......................................................................................................16
6.3.
Patient Characteristics ..................................................................................................16
6.4.
Concomitant Therapy...................................................................................................17
6.5.
Study Partners..............................................................................................................17
6.6.
Efficacy Analyses ........................................................................................................17
6.6.1.
Primary Outcome and Methodology.....................................................................17
6.7.
Secondary Efficacy Analyses .......................................................................................18
6.7.1.
Secondary Analyses .............................................................................................18
6.7.2.
Health Outcomes/Quality-of-Life Analyses..........................................................18
6.8.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................18
6.8.1.
Analysis of Plasma A.........................................................................................18
6.8.2.
Analyses of Amyloid PET Data............................................................................18
6.8.3.
Analyses of CSF Biomarker Data.........................................................................18
6.8.4.
Analyses of FDG PET Data..................................................................................19


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6.8.5.
Analyses of Tau PET Data ...................................................................................19
6.9.
Analyses of vMRI Data................................................................................................19
6.10. Safety Analyses............................................................................................................20
6.10.1.
Extent of Exposure...............................................................................................20
6.10.2.
Adverse Events ....................................................................................................20
6.10.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................20
6.10.4.
Clinical Laboratory Evaluation.............................................................................21
6.10.5.
Vital Signs and Other Physical Findings...............................................................22
6.10.6.
Electrocardiograms ..............................................................................................23
6.10.7.
Analyses of MRI Data..........................................................................................24
6.10.8.
Additional Safety Concerns..................................................................................24
6.10.8.1.
Columbia Suicide Severity Rating Scale.........................................................24
6.10.8.2.
Skin Examination ...........................................................................................26
6.10.8.3.
Eye Examination ............................................................................................27
6.11. Protocol Violations.......................................................................................................28
6.12. TLSR and iDMC..........................................................................................................28
6.13. Safety Follow-Up Visit ................................................................................................28
6.14. Clinical Trial Registry Analyses...................................................................................28
7.
References ........................................................................................................................30
8.
Appendices .......................................................................................................................31


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Table of Contents
Table
Page
Table AZFD.6.1.
Adverse Events of Special Interest............................................................21


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Table of Contents
Figure
Page
Figure AZFD.5.1.
Illustration of study design for Clinical Protocol I8D-MC-AZFD..............11


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Table of Contents
Appendix
Page
Appendix 1.
Complete List of AV-45 Parameters ...............................................................32
Appendix 2.
Complete List of FDG Pet Parameters ............................................................33
Appendix 3.
Potentially Clinically Significant Laboratory Values.......................................34
Appendix 4.
Potentially Clinically Significant Vital Signs and Weight ...............................35
Appendix 5.
Potentially Clinically Significant ECGs ..........................................................36


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3.
Revision History
SAP Version 1 was approved prior to the first visit of the open-label study phase.  The approval 
date was January 26, 2017.  SAP Version 2 was approved prior to first iDMC release on 
September 20, 2017.
SAP Version 3 was approved in July 2018.  See the title page for the exact approval date.  
Changes from version 2 to version 3 are:

Changed various references of the study duration from 52 weeks to 104 weeks.

Edited the objectives to align with protocol AZFD(a).

Replaced study graph to align with graph in protocol AZFD(a).

Aligned sample size section to align with protocol AZFD(a).

Adjusted analyses from summarizing delayed start hypotheses to summarizing safety and 
efficacy data during AZFD exposure.

Changed adjustments to multiplicity to align with protocol AZFD(a).

Added details on imputing missing FAQ and RBANS total scores.

Added details for pooling patients’ country if the number of patients from a country is 
small.

Clarified controlling alpha in multiple comparisons.

Clarified the analysis populations.

Dropped Kaplan-Meier analyses from disposition.

Dropped treatment compliance summary.

Added details to concomitant medications section.

Changed primary efficacy analyses.

Changed secondary efficacy analyses from delayed start analyses to MMRM analyses.

Changed other secondary efficacy analyses from delayed start analyses to MMRM 
analyses.

Changed biomarker analyses from MMRM to ANCOVA models of annualized change.

Changed vMRI analyses from MMRM to ANCOVA models of annualized change.

Changed efficacy scales included in the subgroup analyses to only include ADAS-Cog13 
and ADCS-ADL.

Updated the adverse event definition of treatment-emergent adverse events.


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
Dropped second set of analyses of adverse events that only reports events occurring in 
AZFD.

Added PCS lab summaries.

Changed categorical analysis of weight gain or loss from 4% to 7%.

Dropped analysis of BMI categories for patients changing more than 7%.

Replaced CSSRS analyses originally based on studies where no/few suicidal 
ideations/behaviors are expected to analyses where suicidal ideations/behaviors are 
anticipated.

Added description of process to handle eye exam data when patient can only count 
fingers.

Added section for protocol violations.

Added safety follow-up section.

Corrected various typographical and formatting errors.


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4.
Study Objectives
4.1.
Primary Objective
The primary analysis of study AZES-FD is to evaluate disease modification as outlined in Liu-
Seifert (2015b).  This will be accomplished by testing the three delayed-start hypotheses in both 
doses of LY3314814 across study AZES and up to week 26 (visit 7) of study AZFD with ADAS-
Cog13 as the measure under investigation.
4.2.
Secondary Objectives

To evaluate the disease modification of both doses of LY3314814 on functional and 
cognitive outcomes across Study AZES and up to Week 26 (Visit 7) of Study AZFD 
using the primary analysis methodology with the American Community Survey-
instrumental Activities of Daily Living (ACS--ADL), Functional Activities Questionnaire 
(FAQ), integrated Alzheimer’s Disease Rating Scale (iADRS), Clinical Dementia Rating 
– Sum of Boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) as the 
measures under investigation.

The delayed start analyses as outlined above will also be examined through Week 104
(Visit 15) for cognitive and functional outcomes:  Alzheimer’s Disease Assessment 
Scale-13 (ADAS-Cog13), ACS--ADL, FAQ, iADRS, CDR-SB, and MMSE.

Collect information in order to further characterize the safety and tolerability of 
LY3314814 in patients with early Alzheimer’s disease (AD) dementia (at the time of 
entry into Study AZES).


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5.
Design and Sample Size
5.1.
Summary of Study Design
Study AZFD is a multicenter, randomized, parallel-group, double-blind, 104-week-long study of 
2 fixed dose levels of LY3314814 in patients with early AD at the time of enrollment into the 
feeder Study AZES.  The actual number of patients to be enrolled depends on the number of 
eligible patients completing feeder Study AZES.
The treatment period of this delayed start extension will begin at the conclusion of Visit 20 of the 
feeder Study AZES (which will serve as Visit 1 for Study AZFD), and will continue with 104 
weeks of treatment.  Patients who were randomized in Study AZES to either 20 mg or 50 mg of 
LY3314814 will continue on the treatment allocation from the feeder study.  Patients randomized 
to placebo in Study AZES will be randomized in a blinded fashion 1:1 to LY3314814 20 mg or 
50 mg daily (QD), administered orally.  Neither the patient nor investigator will be unblinded to 
feeder study treatment assignments.  Assessments will be made as indicated on the Study 
Schedule of Activities found in Section 2 of the protocol. After the study was stopped for futility, 
all ongoing patients were asked to come in for a futility-based discontinuation visit. Patients at 
this visit followed the schedule of events for an early discontinuation visit.
The study includes a longitudinal florbetapir F 18 amyloid positron emission tomography (PET)
scan for those patients who had a florbetapir F 18 PET scan at Visit 20 of Study AZES.  In 
addition, there are two longitudinal addenda of fluorodeoxyglucose (FDG) PET and 18F-AV-
1451 PET at applicable sites.  Patients who participated in these addenda in Study AZES are 
eligible to participate in the respective addenda in Study AZFD.  Figure AZFD.5.1 illustrates the 
study design.


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Figure AZFD.5.1.
Illustration of study design for Clinical Protocol I8D-MC-AZFD.
Abbreviations:  LY = LY3314814
*At Visit 1 of Study AZFD (Visit 20 of Study AZES), patients randomized to placebo from Study AZES will be 
randomized 1:1 to LY 20 mg or LY 50 mg in Study AZFD.
Note:  Grey boxes after Study AZFD Visits 1, 7, 11, 13, and 15 indicate the 4-week symptomatic treatment initiation 
window for subjects with progression of symptoms.
5.2.
Determination of Sample Size
It is estimated that approximately 1540 patients will complete Study AZES.  Approximately 90%
of these patients are expected to enroll in Study AZFD for an estimated total of approximately 
1400 patients.
Study AZFD integrated with Study AZES forms a Delayed Start study (hereafter referred to as 
Study AZES-FD).  Using the three stage hypothesis testing approach to delayed start analysis as 
outlined in Liu-Siefert and colleagues (2015b) controlling the overall study-wide error rate at 
0.05, and assuming a 5% early discontinuation rate in the first 6 months of Study AZFD and 
10% early discontinuation rate in the first 12 months of Study AZFD, this sample size will 
provide approximately 81% power for each dose when all patients have the opportunity to 
complete the 6 month time point at an alpha level of 0.1.  At the 12 month time point of the 
Delayed-Start period, this sample size will provide approximately 66% power. 
These powering results are based on solanezumab Delayed-Start results of mild dementia, 
ApoE4 carriers (Studies LZAM, LZAN, and LZAO).  Treatment differences at the end of the 
Placebo-Controlled and Delayed-Start periods and the corresponding variance and covariance 
estimates were used to calculate the power empirically.  The 1540 patients estimated to complete 
Study AZES corresponds to an assumed ED rate of 30% from the original sample size of 2202.  
Extending to Study AZES-FD, the assumed ED rate until the 6 month time point of Study AZFD 
is 35%; until the end of the three years of Study AZES-FD, the assumed ED rate is 40%.  We 


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assume an approximate 10% annual dropout over the course of Study AZFD.    These EDC 
assumptions were used to adjust the randomized sample sizes using the following formula:
Effective Sample Size = (Randomized Sample Size) * (1 – 0.50*EDC)
The effective sample size assumes that EDC patients will contribute half the information that 
completing patients contribute.  The effective sample sizes for the 6 month power calculation 
were 606 and 303, early-start arm and delayed-start arm, respectively; for 12 months, 588 and 
294, early-start arm and delayed-start arm, respectively.
The R package ‘pwr’ and accompanying function ‘pwr.t2n.test’ were used to calculate the power 
estimates.  To be consistent with Liu-Seifert and colleagues (2015b), sig.level was set equal to 
0.1 and alternative was set equal to “greater”.
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomized as the last procedure of Visit 1 
of Study AZFD (Visit 20 of Study AZES).  Assignment to treatment groups will be determined 
by a computer-generated random sequence using an interactive web- and voice-response system 
(IxRS).  The IxRS will be used to assign the kit containing double-blind investigational product
to each patient. Site personnel will confirm that they have located the correct kit by entering a 
confirmation number found on the kits into the IxRS.  Specific information concerning the use of 
the IxRS will be provided to the investigators.
To achieve between-group comparability for disease status at baseline (MCI due to AD or mild 
AD dementia), the randomization will be stratified by disease status at baseline (MCI due to AD 
or mild AD dementia)at the time of randomization into Study AZES.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Study AZES was deemed to be futile and stopped on June 12, 2018. Because of this futility, the 
original primary analysis of evaluating disease modification of LY3314814 by summarizing both 
efficacy and safety across the placebo-controlled (study AZES) study period and delayed-start 
(study AZFD) study period became moot. Analyses of study AZFD described in this statistical 
analysis plan will summarize safety and efficacy data during patient exposure to study drug in 
study AZFD.
All analyses will follow the intention-to-treat (ITT) principle unless otherwise specified.  An ITT 
analysis is an analysis of data by the groups to which subjects are assigned by random allocation, 
even if the subject does not take the assigned treatment, does not receive the correct treatment, or 
otherwise does not follow the protocol.  The treatment groups, reflecting the randomized 
treatments from the feeder study AZES, are 20 mg LY3314814, 50 mg LY3314814, placebo / 
20 mg LY3314814, and placebo / 50 mg LY3314814 which will be referred to in short form as 
20mg, 50mg, PL/20 and PL/50 herein.  Where the ITT principle applies to random allocation, 
this refers to the randomization to the three treatment groups in AZES followed by the second 
randomization of the placebo group to one of the two LY3314814 groups in AZFD forming the 
four final randomized sequences (i.e., treatment groups) in the analyses. 
Baseline is defined as the latest measurement taken prior to first dose of AZFD study medication.  
When change from baseline is assessed, subjects will only contribute to the analysis if both a 
baseline and a post-baseline measurement are available.  Endpoint is the last non-missing post-
baseline measurement in AZFD within the time period for the given analysis. 
As the study was stopped for futility, the planned statistical tests lose their scientific validity and 
multiplicity is no longer a concern.  All reported p-values will not be adjusted for multiplicity. 
No test will be interpreted as statistically significant, and tests resulting with low p-values will 
only be considered as potential results of interest. No between treatment p-values will be 
reported because (1) all patients receive active treatment in study AZFD, and (2) previous 
treatments in study AZES were randomized at AZES baseline and do not guarantee patients 
entering study AZFD are without selection bias. Data summaries will include a total column and 
columns describing the treatments received in study AZES and AZFD: 20mg, 50mg, PL/20 and 
PL/50.
For mixed-effect model for repeated measures (MMRM) models, observations collected at 
nonscheduled visits will not be included in the analyses (Andersen and Millen 2013).  For 
analyses using last observation carried forward (LOCF), the last nonmissing post-baseline 
observation (scheduled or unscheduled) will be used to calculate change from baseline.


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6.1.1. Adjustments for Covariates
The repeated measures models will include the fixed effects for baseline ADAS-Cog13, , visit, 
baseline ADAS-Cog13 score-by-visit interaction, disease status at baseline (MCI due to AD or 
mild AD), apolipoprotein 4 (APOE4) status (carrier versus non-carrier), concomitant 
Acetylcholinesterase Inhibitor (AChEI) use at baseline (yes/no), age at baseline, and country.  
The categorical factors of the model are visit, disease status at baseline (MCI due to AD or mild 
AD), APOE4 status (carrier versus non-carrier), concomitant AChEI use at baseline (yes/no), 
and country.  The continuous covariates of the model are baseline ADAS-Cog13and age at 
baseline.
When an analysis of covariance (ANCOVA) model is used to analyze a continuous efficacy or 
safety variable, the model will contain the main effects of disease status at baseline (MCI due to 
AD or mild AD dementia), APOE4 status, and the appropriate baseline value included as a 
covariate.
6.1.2. Handling Missing Data from Subject Dropouts
A likelihood-based MMRM will be used to handle missing data.  The model parameters are 
simultaneously estimated using restricted likelihood estimation incorporating all of the observed 
data.  Estimates have been shown to be unbiased when the missing data are missing at random 
and when there is ignorable non-random missing data.
Repeated measures analyses will only use data from visits where the data was scheduled to be 
collected (see Andersen and Millen 2013).  When subjects discontinue from the study early, 
there may be efficacy or safety data measurements at visits where the variables were not 
scheduled to be collected.  These data will be used in all other analyses.
6.1.3. Handling Missing Items in Calculating Totals
All total and subscale scores for safety, efficacy, and health outcomes measures will be derived 
from individual items.  If any of the individual items are missing or unknown, every effort will 
be made to obtain the score for the missing item or items.
For ADAS-Cog13, if <30% (4 or fewer of a total of 13 items) of the items are missing, the total 
score (maximum = 85) will be imputed as follows:  The total from remaining items will be 
multiplied by a factor that includes the maximum score for the missing items.  For example, if 
the first item, “Word-Recall Task,” which ranges from a score of 0 through 10 (maximum = 10) 
is missing, and the second item “Commands,” which ranges from a score of 0-5 (maximum = 5) 
is missing then the multiplication factor = 85/(85 - [10 + 5]) = 85/70 = 1.21.  Thus, the total score 
for this example will be the sum of the remaining 11 items multiplied by 1.21.  The imputed 
number will be rounded up to the nearest integer.  If more than 4 items are missing, the total 
score for ADAS-Cog13 at that visit will be considered missing.  
For the ADCS-iADL, if <30% of the items are missing, the total score will be imputed as 
follows.  The sum of the nonmissing items will be prorated to the sum of total items.  The 
imputed number will be rounded up to the nearest integer.  If the nearest integer is greater than 


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the maximum possible score, the imputed score will be equal to the maximum score.  If >30% of 
the items are missing, the total score for ADCS-iADL at that visit will be considered missing.
The same imputation technique will be applied to the ADCS-ADL total score.  Note that, 
depending on the specific item responses that are missing, it is possible to have an imputed total 
score for both the ADCS-iADL and the ADCS-ADL, an imputed total score for one but not the 
other, or both total scores missing.
The same imputation techniques will be applied to the Functional Activities Questionnaire 
(FAQ). if <30% of the items are missing, the total score will be imputed as follows.  The sum of 
the nonmissing items will be prorated to the sum of total items.  The imputed number will be 
rounded up to the nearest integer.  If the nearest integer is greater than the maximum possible 
score, the imputed score will be equal to the maximum score.  If >30% of the items are missing, 
the total score for FAQ at that visit will be considered missing.
The same imputation technique will be applied to the Clinical Dementia Rating-Sum of Boxes
(CDR-SB).  If only 1 box (of 6) of the CDR is missing, the sum of the boxes will be imputed by 
prorating the sum from the other 5 boxes.  If the score from more than 1 box is not available, the 
CDR-SB at that visit will be considered missing.
For the RBANS, if <30% of the sub-items are missing (ie, no more than 3 of the 12 sub-items), 
the item score will be imputed. For the missing subtest, the scaled score from the other subtest 
within that index will be used to impute the missing scaled score, which is then converted to a 
raw score. If List Recognition is missing, the scaled score mean for List Recall, Story Recall, and 
Figure Recall should be used to impute the missing value. If two sub items are missing within the 
same index and/or if >30% of the sub-items are missing, the total score for the RBANS at that 
visit will be considered missing.
For all other scales, if any item is missing, any total or sum involving that item will be 
considered missing.
6.1.4. Multicenter Studies
This study will be conducted by multiple investigators at multiple sites internationally.  Country 
is a covariate of the primary and many of the secondary efficacy analyses. In the event that any 
country has an insufficient number of patients (defined as less than 20), the data from these 
countries will be pooled with the closest geographical country. A listing was presented in the 
AZES study including country, investigator site with address, number of patients enrolled 
(randomized) by each site and unique patient identifications (IDs). 
The actual investigative site numbers will be included in the listings.
6.1.5. Multiple Comparisons/Multiplicity
As the study was stopped for futility, multiplicity is no longer a concern. All reported p-values 
will not be adjusted for multiplicity. No between treatment p-values will be reported because (1) 
all patients receive active treatment in study AZFD, and (2) previous treatments in study AZES 


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were randomized at AZES baseline and do not guarantee patients entering study AZFD are 
without selection bias.
6.1.6. Analysis Populations
The AZFD evaluable efficacy dataset will group patients according to randomized treatment
assignment, even if the patient does not take the assigned treatment, does not receive the correct 
treatment, switches to a different treatment group if the assigned treatment group is dropped at an 
interim analysis, or otherwise does not follow the protocol. All patients who received at least 1 
dose of AZFD study treatment will be included in the AZFD safety analysis dataset.
6.2.
Patient Disposition
Patient disposition summarizes the reasons for patient discontinuation from study AZFD. The 
percentage of patients discontinuing from study in each treatment group will be summarized for 
the overall percentage and for each specific reason.  Patients discontinuing treatment due to the 
sponsor’s decision to end the phase 3 program, following the futility analysis, will have “sponsor 
decision” as reason for discontinuation. 
6.3.
Patient Characteristics
Baseline characteristics (captured at Visit 1 of Study AZES) will be summarized for the AZFD
randomized population.  Summaries will include descriptive statistics for continuous and 
categorical measures.  Patient characteristics to be presented include:  

disease status at baseline (MCI due to AD or mild AD dementia)

age

age group: 55 to 64, 65 to 74, and 75 to 85

gender

race

ethnicity

height

body weight

body mass index (BMI) (weight (kg) / [height (m)]^2)

region

tobacco use

alcohol use

years of education

work status

method of amyloid positivity determination (PET, Cerebrospinal Fluid [CSF], 
historical PET)

APOE4 carrier status (carrier [ε2/ε4, ε3/ε4, ε4/ε4], noncarrier [ε3/ε3, ε2/ε2, ε3/ε2])

APOE4 genotype (ε2/ε4, ε3/ε4, ε4/ε4, no ε4)

having 1 or more first degree relatives with AD

AChEI and/or memantine use at baseline


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
Baseline severity of impairment as measured by ADAS-Cog13, ADAS-Cog11, 
ADCS-ADL total score and instrumental (ADCS-iADL) and basic subscores (ADCS-
bADL), CDR Sum of Boxes, MMSE, Letter and Category Fluency tests, Symbol 
Coding test, Neuropsychiatric Inventory (NPI), Resource Utilization in Dementia
(RUD-Lite), EQ-5D Proxy, Quality of Life in Alzheimer's Disease (QoL-AD), and 
FAQ and RBANS.
Baseline characteristics will also be listed.
6.4.
Concomitant Therapy
Concomitant medications for AZFD are defined as those being taken on or after the day of the 
first administration of study drug in study AZFD.  Summaries of concomitant medications will 
be presented as frequencies and percentages. If the start or stop dates of therapies are missing or 
partial to the degree that determination cannot be made of whether the therapy is prior or 
concomitant, the therapy will be deemed concomitant. Medications will be coded using the 
World Health Organization (WHO) drug dictionary. A summary table will also be provided for 
concomitant AChEI/memantine medications. Concomitant medications will be listed.
6.5.
Study Partners
The protocol states every effort should be made to keep the same study partner through the 
duration of this trial.  However, changes may be unavoidable.  The percentage of patients with 
the same study partner will be summarized.  Additionally, study partner changes will be 
categorized (0 changes, 1 change, and more than 1 change) and summarized.
6.6.
Efficacy Analyses
6.6.1. Primary Outcome and Methodology
Study AZES was deemed to be futile and stopped on June 12, 2018. Because of this futility, the 
original primary analysis of AZES-FD to test the delayed-start hypothesis to evaluate disease 
modification by LY3314814 assessed by ADAS-Cog13 was moot. The primary analysis of Study 
AZES-FD is to summarize the ADAS-Cog13 change from AZES baseline across the AZES-FD 
visits via MMRM . The change from baseline (prior to the initiation of treatment in Study 
AZES) at each visit during Study AZES-FD when ADAS-Cog13 is assessed will be the 
dependent variable.
The model for the fixed effects will include terms for:  baseline ADAS-Cog13, visit, baseline
ADAS-Cog13 score-by-visit interaction, disease status at baseline (MCI due to AD or mild AD 
dementia), APOE4 status (carrier versus non-carrier), concomitant AChEI use at baseline 
(yes/no), age at baseline, and country.  Visit will be considered a categorical variable with values 
equal to the visit numbers at which the scales were assessed.  An unstructured covariance matrix 
will be used to model the within-patient variance-covariance errors.  If the unstructured 
covariance structure matrix results in a lack of convergence, the following tests will be used in 
sequence: heterogeneous Toeplitz covariance structure, heterogeneous autoregressive 
covariance structure, heterogeneous compound symmetry covariance structure, and compound 


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symmetry covariance structure.  The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom.
6.7.
Secondary Efficacy Analyses
6.7.1. Secondary Analyses
The efficacy measures that are aligned with the secondary objectives (ADCS-ADL, FAQ, 
MMSE, CDR-SB, and iADRS) will be analyzed using the MMRM analysis described in Section 
6.6.1.  The model for each of these secondary analyses will include terms for:  baseline efficacy 
score, visit, baseline efficacy score-by-visit interaction, disease status at baseline (MCI due to 
AD or mild AD dementia), APOE4 status (carrier versus non-carrier), concomitant AChEI use at 
baseline (yes/no), age at baseline, and country.  The change from baseline (prior to the initiation 
of treatment in Study AZES) at each visit during Study AZES-FD (at the visits when the scale 
being analyzed is assessed) will be the dependent variable.
6.7.2. Health Outcomes/Quality-of-Life Analyses
Analyses of the EQ-5D combined component scores and of the RUD-Lite will follow the same 
methods as outlined in Section 6.7.1.  These measures are assessed at week 19 instead of week 
26 and week 45 instead of week 52 so the model for these results will be adjusted accordingly.
6.8.
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Annualized change in bioanalytical biomarkers for each patient will be calculated using the 
change in CSF at the last post-baseline visit. The annualized change will be analyzed with an 
ANCOVA. The ANCOVA model will include the following independent variables: baseline 
value, age at baseline, and disease status at baseline (MCI due to AD or mild AD). 
6.8.1. Analysis of Plasma A
The plasma Aβ analytes (including assayed plasma Aβ1-40 and Aβ1-42) will be analyzed using 
the ANCOVA methods described in Section 6.8.
6.8.2. Analyses of Amyloid PET Data
The composite summary standard uptake value ratio (SUVr) of AV-45 (florbetapir F 18 PET 
scan) normalized (based on whole cerebellum and based on atlas-based white matter) will be 
analyzed using the ANCOVA methods described in Section 6.8.  The change from baseline score 
at each scheduled postbaseline visit (according to the Study Schedule) during the treatment 
period will be analyzed. 
6.8.3. Analyses of CSF Biomarker Data
The CSF biomarkers (including total CSF Aβ1-40, total CSF Aβ1-42, CSF total tau, and CSF p-
tau from lumbar puncture) will be analyzed using the ANCOVA methods described in Section 
6.8.  The change from baseline score at each scheduled postbaseline visit (according to the Study 
Schedule) during the treatment period will be analyzed.


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6.8.4. Analyses of FDG PET Data
Two composite summary standard uptake value ratios (SUVr) of FDG PET normalized to the 
pons + vermis will be assessed: (1) Composite Meta and (2) Composite Meta Automated 
Anatomical Labeling atlas (AAL). The SUVRs will be analyzed using the ANCOVA methods 
described in Section 6.8.  The change from baseline score at each scheduled postbaseline visit 
(according to the Study Schedule) during the treatment period will be analyzed.
6.8.5. Analyses of Tau PET Data
The composite summary standard uptake value ratio (SUVr) of Tau PET computed from the 
MUBADA region with the bimodal white matter serving as the reference region normalized to 
bimodal white matter will be analyzed using the ANCOVA methods described in Section 6.8.  
The change from baseline score at each scheduled postbaseline visit (according to the Study 
Schedule) during the treatment period will be analyzed.
6.9.
Analyses of vMRI Data
Analyses of the following volumetric MRI (vMRI) parameters will be conducted (right + left for 
all but whole brain volume and ventricular volume):

Hippocampal volume (mm3)

Entorhinal cortex (mm3)

Inferior parietal lobe (mm3)

Isthmus cingulate (mm3)

Lateral parietal lobe (mm3)

Medial temporal lobe (mm3)

Precuneus (mm3)

Prefrontal lobe (mm3)

Superior temporal lobe (mm3)

Atrophy of Total whole brain volume (cm3)

Enlargement of Ventricular volume (cm3)
All of the above volumes are corrected for intracranial volume. Annualized change in volumetric 
magnetic resonance imaging (vMRI) for each patient will be calculated using the change in 
vMRI at the last post-baseline visit.  The annualized change will be analyzed with an ANCOVA 
model on the full efficacy dataset.  The ANCOVA model will include fixed, categorical effects 
of disease status at baseline (MCI due to AD or mild AD) as well as the continuous effects of 
baseline vMRI value, and age at baseline.  


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6.10. Safety Analyses
6.10.1. Extent of Exposure
Days of exposure will be calculated for each patient for the AZFD period as (date of last dose –
date of first dose of the AZFD period +1). Summary statistics will be provided for the total 
number of days and patient-years of exposure. Study drug treatment assignment will be listed.
6.10.2. Adverse Events
Treatment-emergent adverse events (TEAEs) will be defined as events that first occurred or 
worsened after the randomization date (Visit 1 date).  The treatment-emergent period ends on the 
last day of treatment plus 5 days (these 5 days constitute at least 5 half-lives of lanabecestat).  
Events occurring within the study but during a period of treatment interruption will only be 
treated as treatment-emergent if they occur within 5 days of the last dose prior to the treatment 
interruption.  Should there be insufficient data for AE start date, stop date, and time to make this 
comparison, the AE will be considered treatment-emergent.
The MedDRA lower-level term (LLT) will be used in the treatment-emergent computation. The 
maximum severity for each lower-level term (LLT) during the baseline period will be used as 
baseline.   
Summaries of AEs by decreasing frequency of preferred term within system organ class will be 
provided for the following:
o
TEAEs
o
TEAEs by maximum severity
o
TEAEs occurring in greater than or equal to 2% of patients by preferred term
o
Serious adverse events (SAEs)
o
AEs reported as reason for study treatment discontinuation
These summaries will include number and percentages of patients with TEAEs.  For TEAEs by 
maximum severity, Severity =”Severe” and “More Severe” will be combined into “Severe” 
category.
6.10.3. Deaths, Other Serious Adverse Events, and Other Notable
Adverse Events
An overview of AEs, including the number and percentage of patients who died, suffered SAEs, 
discontinued due to AEs and who suffered TEAEs, will be provided.  
In addition, the proportion of patients within specific clusters of TEAEs will be summarized.  
Clusters will be created from MedDRA High Level Group Terms (Table AZFD.6.1) and 
MedDRA standardized MedDRA Queries (SMQs). 


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Table AZFD.6.1.
Adverse Events of Special Interest
AE Groups of Interest (Clusters)
MedDRA HLGT
Nervous System Disorders
Neuromuscular Disorders HLGT
Demyelination SMQ
Peripheral Neuropathy SMQ
Eye Disorders
Retinal disorders SMQ
Skin Disorders
Sub-group A:
Epidermal and Dermal Conditions HLGT (excluding sub-group B 
terms)
Sub-group B (Hypopigmentation-related events):
Hypopigmentation disorders HLT
Pigmentation changes, NEC HLT
Preferred terms: 'hair depigmented', 'eyelash discolouration', 'iris 
hypopigmentation', 'eye colour change', 'lip colour altered', 'lip 
discolouration', 'hair colour changes', 'achromotrichia aquired', 
'poliosis'
Liver Disorders
Drug related hepatic disorders - comprehensive search SMQ
Cardiovascular-type events – Arrhythmic
Arrhythmia related investigations, signs and symptoms SMQ
Cardiac arrhythmia terms (incl bradyarrhythmias and 
tachyarrhythmias) SMQ
TdP/QT prolongation SMQ
Cardiovascular-type events – Ischemic
Ischaemic heart disease SMQ
Cardiovascular-type events – Stroke
Central nervous system vascular disorders SMQ
Cardiovascular-type events – including 
orthostatic hypotension
Decreased and Nonspecific Blood Pressure Disorders and Shock 
HLGT
Abbreviations:  SMQ = standardized MedDRA Query, NEC = Not Elsewhere Classified, HLGT = High Level 
Group Term; TdP/QT = Torsades de pointes /QT interval.
6.10.4. Clinical Laboratory Evaluation
Laboratory measurements will be analyzed using continuous data (change from baseline) and 
categorical or ordinal data (proportion of treatment-emergent abnormalities) for AZFD. If there 
are multiple records of laboratory measurements at a baseline or postbaseline visit, the last 
record will be used. Summaries and analyses of continuous data (change from baseline) will be 
performed using both conventional and International System of Units (SI units).
Change from baseline to post-baseline visit at which laboratory measurements are taken will be 
analyzed using an MMRM model.  For each lab analyte, the rank-transformation will be applied 
to the change from baseline for all patients and all visits prior to analysis.  Similarly, an 
independent rank-transformation will be applied to the baseline values prior to analysis.  The 
model for the fixed effects will include terms for the following independent effects: ranked 
baseline value, visit, and disease status at baseline (MCI due to AD or mild AD).  This analysis 
will be done separately for each laboratory analyte.  


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The proportion of patients with treatment-emergent high or treatment-emergent low or treatment-
emergent abnormal laboratory values at (1) anytime and (2) each post-baseline visit will be 
summarized.  Treatment-emergent high or low laboratory abnormality will be based on SI unit.  
For each laboratory analyte, only patients who were low or normal at baseline and have at least 
one post-baseline measurement will be included in the denominator when computing the 
proportion of patients with treatment-emergent high results.  Similarly, only patients who were 
high or normal at baseline and have at least one post-baseline measurement will be included in 
the denominator when computing the proportion of patients with treatment-emergent low results.  
In addition, the proportion of patients who have normal baselines with a change to abnormal high 
or abnormal low values at any post-baseline visit will be summarized. For urinalysis parameters, 
baseline to post-baseline shifts will be summarized at each visit.  
A second categorical analysis will be conducted on laboratory analytes. This analysis is 
considered a PCS analysis and will use limits typically wider than the first categorical analysis. 
Abnormal criteria for these treatment-emergent PCS changes are presented in Appendix 3.  
For urinalysis parameters, baseline to post-baseline shifts will be summarized at each visit.  
The proportion of patients with treatment-emergent clinically significant changes from a low
value or normal value at all baseline at any time in ALT and total bilirubin will be summarized 
by treatment group.  Clinically significant changes of interest at any time are:  alanine 
transaminase (ALT) ≥ 3 x upper limit of normal (ULN) and total bilirubin ≥ 2 x ULN, aspartat 
aminotransferase (AST) ≥ 3 x ULN, ALT ≥ 5 x ULN, ALT ≥ 10 x ULN, and total bilirubin ≥ 2 x 
ULN.  Additionally, Hy’s Law analysis will be summarized with regard to the proportion of 
patients with (ALT ≥ 3 x ULN or AST ≥ 3 x ULN) and total bilirubin ≥ 2 x ULN at any time.  
When criteria are met for hepatic evaluation and completion of the hepatic safety case report 
form (CRF), investigators are required to answer a list of questions pertaining to the patient’s 
history, relevant pre-existing medical conditions, and other possible causes of liver injury. A 
listing of the information collected on the hepatic-safety CRF will be generated.
6.10.5. Vital Signs and Other Physical Findings
Vital sign measurements and weight will be analyzed using continuous data (change from 
baseline) and categorical data (proportion of potentially clinically significant changes) for 
AZFD.
If there are multiple records of vital sign or weight measurements at baseline or postbaseline 
visits, the last record will be used.  Summary statistics will be presented for observed values at 
baseline and for change from baseline results at each scheduled postbaseline visit.  Systolic and 
diastolic blood pressure and pulse (collected in sitting position), orthostatic diastolic and systolic 
blood pressures and orthostatic pulse (measurement after 5 minutes in the supine position minus 
that after 2 and 5 minutes in the standing position), temperature, and weight by treatment group 
for all patients in the safety population will be summarized.
With the large number of visits at which vital signs are scheduled to be measured, the MMRM 
model is not suitable for the change from baseline comparison of treatment groups.  Change from 


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baseline to each post-baseline visit at which vital signs are taken will be assessed using an 
ANCOVA model with baseline value and age as covariates in the model.  This analysis will be 
done separately for each vital sign parameter and weight.  
The incidence of treatment-emergent abnormal high or low vital signs and weight will be 
presented by treatment group and visit.  Treatment-emergent vital sign evaluations are those
collected after the initiation of study medication.  Abnormal criteria for post-baseline vital signs 
and weight are presented in Appendix 4.  Any vital sign or weight meeting the criteria will be 
considered abnormal.  Summaries of the proportion of patients with treatment-emergent 
abnormal high or low vital signs and weight will be assessed between treatment groups using
Fisher’s exact test at (1) any time and (2) each post-baseline visit. For each vital sign at each 
post-baseline visit, only patients who had a baseline result and had a nonmissing result at that 
post-baseline visit will be included in the denominator when computing the proportion of 
patients with treatment-emergent high, low, or abnormal values.
Summary and analyses of change from baseline in weight will be provided.  The proportion of 
patients with a weight gain or loss of greater than or equal to 7 percent of baseline body weight 
will be summarized at each visit and at any time.    
A listing of treatment-emergent abnormal vital signs and weight will also be presented.  
6.10.6. Electrocardiograms
Electrocardiograms (ECG) measurements will be analyzed using continuous data (change from 
baseline) and categorical data (proportion of treatment-emergent abnormalities) for AZFD.
The ECG measurements are derived from three 10 second readings taken every 30 seconds.  
These 3 readings are to be averaged prior to analysis.  Additionally, whenever ECG is measured
in triplicate, the average of these readings will be used in the analysis.  If there are multiple
records after averaging ECG triplicates within a visit, the last record of averages will be used.  
The analysis will be done for the following ECG measurements:  heart rate, PR, QT, QTc, and 
RR intervals and QRS duration.  All analyses of QTc will be carried out using the Fridericia 
correction (QTcF) method.  These summaries will include data from each visit at which ECG 
measurements are taken.  Change from baseline to each post-baseline visit at which ECG 
measurements are taken will be assessed using an MMRM model.  The model for the fixed 
effects will include terms for the following independent effects:  baseline ECG score, visit, and 
age at baseline.  This analysis will be done separately for each ECG parameter.  
Treatment-emergent high ECG parameters (heart rate, PR interval, QRS duration, QT and QTcF 
intervals) are the values which are low or normal at all baseline visits and fall into the high 
abnormal categories post-baseline.  Similarly, treatment-emergent low ECG parameters (heart 
rate, PR interval, QRS duration) are the values which are high or normal at all baseline visits and 
fall into the low abnormal categories above. In addition, treatment differences in the proportion 
of patients who have normal baselines with a change to abnormal high or abnormal low values at 
any post-baseline visits will be summarized. Incidence of treatment-emergent abnormal ECGs 
will be summarized at (1) any time and (2) each post-baseline visit.  For analyses of treatment-


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emergent abnormal ECGs, baseline will be considered as all visits before the initiation of drug 
dose in Study AZES. Abnormal ECG criteria and criteria for abnormal QTcF prolongation are 
presented in Appendix 5.
6.10.7. Analyses of MRI Data
The MRI analyses will apply to AZFD. Frequencies and percentages of the following amyloid-
related imaging abnormality – edema (ARIA-E, also known as vasogenic edema) and ARIA –
hemorrhage (ARIA-H, also known as microhemorrhage) parameters will be summarized:

ARIA-E:
o
Severity (mild, moderate, severe, or no presence)
o
Status compared to the previous MRI(s) (questionable, increased, unchanged, 
decreased, no longer present)

ARIA-H:
o
Number of ARIA-H (1, 2 to 5, 6 to 10, >10, or no presence), 
o
Baseline to endpoint changes (increase in size of pre-existing ARIA-H, increase 
in number of ARIA-H, no change, partial resolution, or complete resolution)  
To evaluate white matter changes over time, a shift table will be created from the following 
categories:

0 = No lesions

1 = Focal lesions

2 = Beginning confluence of lesions

3 = Diffuse involvement of entire region
A listing of MRI data will also be presented.  
6.10.8. Additional Safety Concerns
6.10.8.1. Columbia Suicide Severity Rating Scale
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent occurring 
during treatment, based on the Columbia-Suicide Severity Rating Scale (C-SSRS), will be 
summarized by treatment.  In particular, for each of the following events, the number and percent 
of patients with the event will be enumerated by treatment:  completed suicide, nonfatal suicide 
attempt, interrupted attempt, aborted attempt, preparatory acts or behavior, active suicidal 
ideation with specific plan and intent, active suicidal ideation with some intent to act without 
specific plan, active suicidal ideation with any methods (no plan) without intent to act, 
nonspecific active suicidal thoughts, wish to be dead, and self-injurious behavior without suicidal 
intent. Although not suicide-related, the number and percent of patients with non-suicidal self-
injurious behavior occurring during the treatment period will also be summarized by treatment.
In addition, the number and percent of patients who experienced at least one of various 
composite measures during treatment will be presented and compared.  These include suicidal 
behavior (completed suicide, non-fatal suicidal attempts, interrupted attempts, aborted attempts, 
and preparatory acts or behavior), suicidal ideation [active suicidal ideation with specific plan 


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and intent, active suicidal ideation with some intent to act without specific plan, active suicidal 
ideation with any methods (no plan) without intent to act, non-specific active suicidal thoughts, 
and wish to be dead], and suicidal ideation or behavior.  
The number and percent of patients who experienced at least one of various comparative
measures during treatment will be presented and compared.  These include treatment-emergent
serious suicidal ideation compared to recent history, emergence of serious suicidal ideation 
compared to recent history, improvement in suicidal ideation at endpoint compared to baseline, 
and emergence of suicidal behavior compared to all prior history (including AZES and prior to 
AZES).  
Specifically, the following outcomes are C-SSRS categories and have binary responses (yes/no).  
The categories have been re-ordered from the actual scale to facilitate the definitions of the 
composite and comparative endpoints, and to enable clarity in the presentation of the results.  
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts  
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt
Category 8 – Interrupted Attempt
Category 9 – Actual Attempt (non-fatal)
Category 10 – Completed Suicide
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not suicide-
related) and has a binary response (yes/no).  
Composite endpoints based on the above categories are defined below.

Suicidal ideation:  A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS.

Suicidal behavior:  A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS.

Suicidal ideation or behavior:  A “yes” answer at any time during treatment to any one of 
the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
The following outcome is a numerical score derived from the C-SSRS categories.  The score is 
created at each assessment for each patient and is used for determining treatment emergence.  

Suicidal Ideation Score:  The maximum suicidal ideation category (1-5 on the C-SSRS) 
present at the assessment.   Assign a score of 0 if no ideation is present.
Comparative endpoints of interest are defined below.  “Treatment emergence” is used for 
outcomes that include events that first emerge or worsen.  “Emergence” is used for outcomes that 
include events that first emerge.    

Treatment-emergent suicidal ideation compared to recent history (last visit of AZES):  


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An increase in the maximum suicidal ideation score during treatment (Visits Y1-Y2) 
from the maximum suicidal ideation category during the screening and lead-in periods
(C-SSRS scales taken at Visits X1-X2).  Recent history excludes “lifetime” scores from 
the Baseline C-SSRS scale or Baseline/Screening C-SSRS scale.

Treatment-emergent serious suicidal ideation compared to recent history (last visit of 
AZES):  An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS 
during treatment (Visits Y1-Y2) from not having serious suicidal ideation (scores of 0-3) 
during the screening and lead-in periods (C-SSRS scales taken at Visits X1-X2).  Recent 
history excludes “lifetime” scores from the Baseline C-SSRS scale or Baseline/Screening 
C-SSRS scale.

Emergence of serious suicidal ideation compared to recent history (last visit of AZES):  
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS during 
treatment (Visits Y1-Y2) from no suicidal ideation (scores of 0) during the screening and 
lead-in periods (C-SSRS scales taken at Visits X1-X2).  Recent history excludes 
“lifetime” scores from the Baseline C-SSRS scale or Baseline/Screening C-SSRS scale.

Improvement in suicidal ideation at endpoint compared to baseline (AZES visit 20):
A decrease in suicidal ideation score at endpoint (the last measurement during treatment; 
Visits Y1-Y2) from the baseline measurement (the measurement taken just prior to 
treatment; (Visit X2).  This analysis should only be performed for a non-lifetime baseline 
measurement (i.e., having improvement from the worse event over a lifetime is not 
clinically meaningful).  A specific point in time can be used instead of endpoint.    

Emergence of suicidal behavior compared to all prior history (including AZES and prior 
to AZES):  
The occurrence of suicidal behavior (Categories 6-10) during treatment (Visits Y1-Y2) 
from not having suicidal behavior (Categories 6-10) prior to treatment (Visits X1-X2). 
Prior to treatment includes “lifetime” and/or “screening” scores from the Baseline C-
SSRS scale, Screening C-SSRS scale, or Baseline/Screening C-SSRS scale, and any 
“Since Last Visit” from the Since Last Visit C-SSRS scales taken prior to treatment.
Patients who discontinued from the study with no postbaseline C-SSRS value will be considered 
unevaluable for analyses of suicide-related events.  Only evaluable patients will be considered in 
the analyses.  
6.10.8.2. Skin Examination
Skin color will be reported at baseline using Fitzpatrick Scale Rating.  The frequencies of the 
Fitzpatrick Scale Rating (I, II, III, IV, V, and VI) will be displayed by treatment group.
Frequency tables and summary statistics for continuous parameters will be given by treatment 
group.  
Any hypopigmentation will be assessed by location, percentage of body surface area 
involvement, degree (partial/decreased pigmentation to complete depigmentation), and other 
findings in or around the hypopigmentation area (e.g., redness or induration).  A static 
physician’s global assessment (sPGA) will be used to determine the patient’s overall 
hypopigmentation severity at a given timepoint using a visual analog scale (VAS) ranging from 0 


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to 100.  In addition, patients noted to have evidence of hypopigmentation will be asked to record 
how bothersome they find the hypopigmentation to be on a VAS ranging from 0 to 100.
Additionally, the percentage of patients with emergence of greater than expected hair 
hypopigmentation will be summarized for patients ‘no’ at baseline if question is available on 
worksheet.
In order to display any changes/deteriorations during treatment, the following will be reported:  
number of patients for whom no hypopigmentation was observed at baseline, but for whom at 
least once after randomization hypopigmentation was observed during the treatment period; 
summary statistics for the difference of maximum value during treatment minus baseline value 
for percentage body surface area (BSA) of hypopigmentation; shift table of baseline vs. 
maximum value during treatment for degree of overall lesion severity.  Summary statistics for 
the change in overall severity (sPGA) and “how bothered is the patient” will be reported for 
patients with emergence of hypopigmentation, increased severity of hypopigmentation, or 
increased BSA during the study.
6.10.8.3. Eye Examination
Frequency tables will be produced for all time points for performance of eye examination, visual 
acuity examination, intraocular pressure examination, and slit lamp exam status and dilated 
fundus exam status (normal, abnormal – clinically not significant, and abnormal – clinically 
significant).  Clinically significant abnormalities will be displayed together with the 
corresponding specifications of abnormalities in separate individual data listings.
Summary statistics will be produced for the following continuous parameters:  left eye total 
visual acuity score, right eye total visual acuity and both eyes score (scores expressed as 
logMAR calculated as the negative log (base 10) of the decimal scores)), as well as left eye 
intraocular pressure and  right eye intraocular pressure (both in mmHg). For visual acuity, 
"count fingers" will be given a decimal score of 0.01 and a logMAR of 2 (reference 
http://www.hicsoap.com/publications/ProperMethodforCalculating.pdf). “Light perception” and 
“no light perception” cannot be assigned decimal or LogMAR values and so are treated as 
missing in the mean change summary tables.  Visual acuities of patients with these values at any 
time during the study will be provided in a separate listing.
In order to display any changes/deteriorations during treatment, the following will be reported:  
number of patients with potentially clinically significant changes (slit lamp examination or 
dilated fundus examination) documented during treatment that was not already present at 
baseline; summary statistics for the difference of maximum value during treatment minus 
baseline value for left eye total visual acuity score, right eye total visual acuity score, left eye 
intraocular pressure (mmHg), and right eye intraocular pressure (mmHg).  Worst assessment of 
overall eye examination results during treatment with possible entries “unchanged”, “new”, 
“improved”, and “worsened”.


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6.11. Protocol Violations
Listings of patients with significant protocol violations will be provided for the Randomized 
population.  The following list of significant protocol violations will be determined from the 
clinical database and from the clinical/medical group:

Informed consent violation detected as a missing date of informed consent.

Did not have an assessment of either the ADAS-Cog at any of the visits at which the 
scales were scheduled to be assessed.

Not compliant with study drug calculated as taking less than 80% or greater than 
120% of study drug while the subject was expected to be on treatment.
The following list of significant protocol violations will be determined by clinical/medical group:

Protocol violations of inclusion/exclusion criteria.

Had a study dosing algorithm violation (such as if patients randomized to treatment A 
were given treatment B or patients randomized to treatment A never received the 
assigned study drug.)

Unqualified raters for the ADAS-Cog.
Other protocol violations reported through the monitoring process will be reviewed by the study 
team and if judged to be significant, will be added to the final reported listing.
6.12. TLSR and iDMC
The reports for the trial-level safety reviews and the independent data monitoring committee will 
summarize categorical safety data which first occurred or worsened in study AZFD using the 
AZES baseline.  Mean change from baseline reports will use the AZES baseline and only report 
changes occurring in AZFD.   
6.13. Safety Follow-Up Visit
Patients who choose to withdraw from the study upon discontinuing study treatment and after 
completing the early discontinuation visit assessments, as appropriate, should be asked to return 
for a follow-up visit (Visit 801) within 4 to 6 weeks of discontinuing treatment. Adverse events, 
concomitant medications, vital signs, and ECGs will be collected at these visits.  Separate 
summaries of adverse events, concomitant medications, C-SSRS, PCS vital signs and PCS ECGs 
will be created for the safety follow-up data from Visit 801.
6.14. Clinical Trial Registry Analyses
Analyses provided for the clinical trial registry (CTR) requirements include the following:
Summary of AEs, provided as a dataset which will be converted to an XML file.  Both SAEs
and ‘Other’ AEs are summarized:  by treatment group, by MedDRA preferred term.

An AE is considered ‘Serious’ whether or not it is a TEAE.


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
An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each Serious AE and ‘Other’ AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event - the number at risk can be different 
for different events, particularly if they are gender-specific events
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of subjects/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).


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7.
References
Andersen SW, Millen BA. On the practical application of mixed effects models for repeated 
measures to clinical trial data. Pharm Stat. 2013;12:7-16. doi: 10.1002/pst.1548.
Brannath W, Koenig F, Bauer P. Multiplicity and flexibility in clinical trials. Pharm Stat.
2007;6:205-216.
Cedarbaum JM, Jaros M, Hernandez C, Coley N, Andrieu S, Grundman M, et al. Rationale for 
use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for 
Alzheimer’s disease clinical trials. Alzheimers Dement. 2013;9(1 Suppl):S45-S55.
Diggle PD, Kenward MG. Informative dropout in longitudinal data analysis (with discussion). 
Appl Stat. 1994;43:49-93.
Liu-Seifert H, Andersen SW, Lipkovich I, Holdridge KC, Siemers E. A novel approach to 
delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease. 
PLoS ONE. 2015;10(3):Article No: e0119632.
Lyketsos CG, Breitner JCS, Rabins PV. Evidence-based proposal for the classification of 
neuropsychiatric disturbance in Alzheimer’s disease. Int J Geriatr Psychiatry. 2001a;16:1037-
1042.
Lykestos CG, Sheppard JE, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JCS. 
Neuropsychiatric disturbance in Alzheimer’s disease clusters into three groups: the Cache 
County study. Int J Geriatr Psychiatry. 2001b;16:1043-1053.
Mohs R, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil 
in AD patients. Neurology. 2001;57:481-488.
Tun S, Murman DL, Long HL, Colenda CC, von Eye, A. Predictive validity of neuropsychiatric 
subgroups on nursing home placement and survival in patients with Alzheimer Disease. Am J 
Geriatr Psychiatry. 2007;15(4):314-327.


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8.
Appendices


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Appendix 1.
Complete List of AV-45 Parameters
SUVr will be obtained for the regions listed below normalized to whole cerebellum and to 
patient-specific white matter:

composite summary 

anterior cingulate

frontal medial orbital

parietal

posterior cingulate

precuneus

temporal
The composite summary measure is an unweighted average of the 6 smaller regions listed.


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Appendix 2.
Complete List of FDG Pet Parameters
SUVr will be obtained for the regions listed below normalized to the pons, whole cortex and 
group of voxels with AD-preserved activity (Herholz et al. 2002). 
composite summary 
caudate left
caudate right
cerebellar cortex left
cerebellar cortex right
cerebellar white matter
cingulum anterior left
cingulum anterior right
cingulum posterior lefta
cingulum posterior righta
lateral frontal cortex left
lateral frontal cortex right
lateral temporal cortex left
lateral temporal cortex right
mean cerebellum gray matter
mean whole cerebellum
mesial temporal cortex left
mesial temporal cortex right
lateral occipital cortex left
lateral occipital cortex right
orbitofrontal cortex left
orbitofrontal cortex right
lateral parietal cortex left
lateral parietal cortex right
pons
putamen right
putamen left
rectus left
rectus right
subcortical white matter
temporal cortex lefta
temporal cortex righta
thalamus left
thalamus right
angular lefta
angular righta
whole cortex
region with AD-preserved 
uptake 
precuneus left
precuneus right
a Regions used in calculation of the composite summary SUVr.


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Appendix 3.
Potentially Clinically Significant Laboratory 
Values
Parameter
SI Unit
Low PCS Criteria
High PCS Criteria
Hematology (whole blood)
Hemoglobin (male)
mml/L-Fe
<6.8266
>11.1708
Hemoglobin (female)
mml/L-Fe
<6.206
>10.5502
Hematocrit
Proportion of 1.0
<0.3
>0.50 (F); >0.55 (M)
Leukocyte (WBC Count)
109/L
≤2.8
≥15
Neutrophils
109/L
≤1.5
NA
Platelet Count
109/L
≤75
≥700
Chemistry (serum or plasma)
ALT (SGPT)
U/L
NA
≥3 X ULN
AST (SGOT)
U/L
NA
≥3 X ULN
Total Bilirubin
umol/L
NA
≥1.5 ULN
BUN
mmol/L
NA
≥1.2 ULN
Creatinine Kinase (CK)
U/L
NA
≥3ULN
Sodium
mmol/L
≤125
≥155
Potassium
mmol/L
≤3.0
≥5.5
Calcium
mmol/L
≤0.7 ULN
≥1.2 ULN
Alkaline Phosphatase
U/L
NA
≥3ULN
Albumin
g/L
≤26
≥60
Chloride
mmol/L
≤85
≥120
Glucose (random)
mmol/L
≤0.3 ULN
≥1.5 ULN
Serum Creatinine
umol/L
NA
>1.5 ULN
TSH
mIU/L
below normal range
above normal range
Urinalysis
Hb/RBCs/Blood
NA
≥+ 2
Protein/Albumin
NA
≥+ 2
Glucose
NA
≥+ 2
Abbreviations:  ALT/SGPT = alanine aminotransferase/serum glutamic pyruvic; AST/SGOT = aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase; BUN = blood urea nitrogen; Hb = heart beat, PCS = 
potentially clinically significant; RBC = red blood cells; TSH = thyroid stimulating hormone; ULN = upper limit 
of normal; WBC = white blood cells.


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Appendix 4.
Potentially Clinically Significant Vital Signs 
and Weight
Potentially Clinically Significant Vital Signs and Weight
Vital Sign Parameter (Unit)
Postbaseline Low Criteria
Postbaseline High Criteria
Sitting Systolic Blood Pressure 
(mmHg)
Absolute value 90 and 20 decrease 
from baseline
Absolute value 160 and 20 increase 
from baseline
Sitting Diastolic Blood Pressure 
(mmHg)
Absolute value 50 and 10 decrease 
from baseline
Absolute value 100 and 10 increase 
from baseline
Sitting Pulse (bpm)
Absolute value <50 and 15 decrease 
from baseline
Absolute value >100 and 15 increase 
from baseline
Weight
7% decrease
7% increase
Vital Sign Parameter (Unit)
Postbaseline Criteria for Abnormality
Orthostatic Systolic Blood 
Pressure (mmHg)
20 decrease in systolic blood pressure (supine to standing) 
(ie, supine minus standing 20)
Orthostatic Diastolic Blood 
Pressure (mmHg)
10 decrease in diastolic blood pressure (supine to standing) 
(ie, supine minus standing 10)
Orthostatic Pulse (bpm)
≤ -30 decrease (supine to standing) (ie, supine minus standing ≤ -30)
Temperature
Absolute value 38.3C and 1.1C increase from baseline
(Absolute value 101F and 2F increase from baseline)
Abbreviations:  bpm=beats per minute, NA=not applicable.


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Appendix 5.
Potentially Clinically Significant ECGs
Potentially Clinically Significant ECGs
Parameter
Unit
Low PCS Criteria
High PCS Criteria
QRS Interval
msec
NA
≥120
PR Interval
msec
<100
≥220
Heart Rate
bpm
<45
≥120
QTcF
msec
<320
>500
QTcF interval: change from baseline
>60 msec at any time after randomization
Abbreviation:  PCS = potentially clinically significant.


PPD
Leo Document ID = 7b0666b3-9413-4cee-9e54-d240e0071b2e
Approver:
Approval Date & Time: 20-Aug-2018 17:09:00 GMT
Signature meaning: Approved