A 24-month, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy, Safety, Tolerability, Biomarker, and Pharmacokinetic Study of AZD3293 in Early Alzheimer's Disease (The AMARANTH Study)
Phase: PHASE2
Conditions: Alzheimer´s Disease
Sponsor: AstraZeneca

Protocol I8D-MC-AZES (Version 7.1)
A 24-month, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy, Safety, 
Tolerability, Biomarker, and Pharmacokinetic Study of AZD3293 in Early Alzheimer's Disease (The 
AMARANTH Study)
NCT02245737 
Approval Date: 17-Jul-2017

D5010C00009 (ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]
Revised Clinical Study Protocol
Drug Substance
AZD3293 [LY3314814; 
lanabecestat]
Study Code
D5010C00009 [I8D-MC-AZES]
Edition Number
7.1
Date
See approval date below
A 24-Month, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Efficacy, Safety, Tolerability, Biomarker, and 
Pharmacokinetic Study of AZD3293 in Early Alzheimer’s Disease
(The AMARANTH Study)
Sponsor:  Eli Lilly and Company, Indianapolis, IN 46285
IND number:  116,692
EudraCT number:  2014-002601-38
The following Amendment(s) and Administrative Changes have been made to this protocol since the date of 
preparation:
Amendment No.
Date of Amendment
Local Amendment No:
Date of Local Amendment
01
24 November 2014
01 (Korea)
24 February 2015
02
12 March 2015
03
12 June 2015
04
30 June 2016
5.1
See approved date below
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change
01
02 September 2014
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
AstraZeneca 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.  This document and its associated 
appendices are subject to United States Freedom of Information Act (FOIA) Exemption 4.
Approval Date: 17-Jul-2017 GMT

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AZD3293 [LY3314814]
PROTOCOL SYNOPSIS
A 24-Month, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Efficacy, Safety, Tolerability, Biomarker, and 
Pharmacokinetic Study of AZD3293in Early Alzheimer’s Disease (The 
AMARANTH Study)
International Co-ordinating Investigator
Study centersand number of patients planned
The study is expected to enroll a total of approximately 2202patients fromacross the globe.  
Study period
Phase of development
Estimated date of first patientenrolled
Q42014
Phase 2/3
Estimated date of last patientcompleted
Q32019
Objectives
Primary objective:  to test the hypothesis thatAZD3293, administered orally at doses of 20 and 
50 mg daily for 104weeks, will slow the decline of Alzheimer’s disease (AD)as compared with 
placebo in patients with earlyAD dementiaas measured by the 13-itemAlzheimer’s Disease 
Assessment Scale –Cognitive subscale (ADAS-Cog13).
PPD
  Early AD is defined as the continuum 
of patients with mild cognitive impairment (MCI)due to AD (ie, prodromal AD) and patients 
diagnosed with mild dementia of the Alzheimer’s type.

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AZD3293 [LY3314814]
Double-Blind Treatment Period
Secondary Objectives
Endpoints
Clinical efficacy objectives:

To evaluate the efficacy of AZD3293 on 
functional, clinical, and cognitive outcomes in 
patients with early AD dementia at the end of 
the Double-Blind Treatment period 
(Week 104).  

Functional Outcome Measures
o
The Alzheimer’s Disease Cooperative 
Study Activities of Daily Living Inventory 
instrumental items (ADCS-iADL) score
o
Functional Activities Questionnaire 
(FAQ) score

Cognitive/Functional Outcome Measures
o
Integrated Alzheimer’s Disease Rating 
Scale (iADRS) score 
o
Clinical Dementia Rating – Sum of Boxes 
(CDR-SB) score

Clinical Outcome Measures
o
CDR-Global Score
o
Neuropsychiatric Inventory (NPI) score

Cognitive Outcome Measures
o
Mini-Mental State Examination (MMSE)

To evaluate the relationship between treatment 
effect of AZD3293 and time (at points other 
than the end of the Double-Blind Treatment 
period [Week 104], such as Week 26, Week 52 
and Week 78).  Specific time points will vary 
by instrument. 

ADAS-Cog13, ADCS-iADL, FAQ, CDR-SB, 
and iADRS

To test the hypothesis that AZD3293 will slow 
the rate of cognitive and functional decline 
associated with AD, compared with placebo 

ADAS-Cog13, ADCS-iADL, and FAQ using a 
slope analysis from a repeated-measures model 

To evaluate the efficacy of AZD3293 to 
prolong time in the current disease state 

CDR global score

To evaluate the clinical worsening and need  
for symptomatic treatments 

AD symptomatic treatments time of initiation
Biomarker objectives:

To evaluate the effect of AZD3293 on 
cerebrospinal fluid (CSF) amyloid beta peptide 
(Aβ) pharmacodynamics (PD) markers  

CSF Aβ1-42 and Aβ1-40 concentrations

To evaluate the effect of AZD3293 on CSF 
markers of neurodegeneration

CSF total tau and phosphorylated tau 
concentrations

To evaluate the effect of AZD3293 on brain 
amyloid burden

Florbetapir amyloid scan

To evaluate the effect of AZD3293 on brain 
aggregated tau levels

18F-AV-1451 Tau PET [separate addendum] 

To evaluate the effect of AZD3293 on brain  
metabolism

Fluorodeoxyglucose (FDG) positron emission  
tomography (PET) [separate addendum]

To evaluate the effect AZD3293 on brain 
atrophy  

Brain volumes measured by magnetic 
resonance imaging (MRI) 

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AZD3293 [LY3314814]
Pharmacokinetic objective:

To assess the population PK of AZD3293 and 
metabolite AZ13569724 in patients with early 
AD dementia  

Apparent Oral Clearance of AZD3293

Central Volume of Distribution of AZD3293 
Safety Objective

To evaluate the safety and tolerability of 
AZD3293 in patients with early AD dementia

Standard safety assessments: 
o
spontaneously reported adverse events 
(AEs)
o
clinical laboratory tests
o
vital sign and body weight measurements
o
12-lead electrocardiograms (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)
Exploratory Objectives*
Endpoints*

To evaluate the efficacy of AZD3293 on 
executive function 

Changes from baseline in the Letter Fluency, 
Category Fluency, and Digit Symbol-Coding 
test scores

To evaluate the efficacy of AZD3293 on 
neuropsychological status 

Change from screening in the Repeatable 
Battery for the Assessment of 
Neuropsychological Status (RBANS) score

To explore the effects of AZD3293 on resource 
utilization and health status 

Change from baseline in the Resource 
Utilization in Dementia (RUD)-Lite and 
EQ-5D-5L score

To explore the effects of AZD3293 on 
caregiver distress 

Change from baseline in the NPI-D score

To evaluate the dose-exposure effect 
relationships for selected efficacy, safety, and 
biomarker endpoints 

Changes in scales, adverse events and blood, 
CSF and imaging biomarkers in relation to 
exposure 

To explore the genetic effects of APOE4 allele 
status (carrier or non-carrier) 

Change from baseline on selected efficacy, 
safety, and biomarker endpoints

To explore the effect of AZD3293 on gene 
expression.

Change in levels of whole blood messenger 
ribonucleic acid (mRNA) and on plasma and 
CSF micro-ribonucleic acid (miRNA) levels
and the relation to selected efficacy, safety and 
biomarker endpoints

To explore the effect of AZD3293 on 
peripheral and central nervous system protein 
expression. 

Change in CSF or peripheral protein 
biomarkers, including CSF or plasma Aβ1-42
and Aβ1-40, neurodegenerative inflammatory 
markers, and proteomic assessments and the
relation to selected efficacy, safety, and other 
biomarker endpoints

To examine AZD3293 population PK/PD 

Exposure and selected measures of efficacy 
and/or tolerability

To optionally collect and store 

Association of genetic variation with selected 

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AZD3293 [LY3314814]
deoxyribonucleic acid (DNA) for future 
exploratory research into genes/genetic 
variation that may influence response (that is, 
distribution, safety, tolerability, and efficacy) to 
AZD3293.  Genes that will be tested for 
heritable genetic (DNA) or expression (mRNA, 
miRNA) effects will be limited to those for 
which a hypothesis for involvement in the 
pharmacology of AZD3293 or in the 
pathogenesis of AD can be formulated, as 
currently understood and as directed by future 
scientific progress in the field.
endpoints (optional pharmacogenomics 
sampling)
*Note: the results of analyses that address some exploratory objectives may not form part of the Clinical Study 
Report, but may be described in supplementary reports as appropriate.
Study design
This is a multicenter, randomized, parallel-group, double-blind, placebo-controlled, international 
study of 2 fixed dose levels of AZD3293 in patients with early AD.  Patients who meet other 
study entry requirements will be required to be amyloid positive. They may undergo a 
florbetapir F 18 amyloid PET scan or a lumbar puncture for CSF sampling (but not both) at 
screening to document the presence of abnormal levels of amyloid for study inclusion.  
The study includes 2 longitudinal biomarker sub-studies:  a longitudinal florbetapir F 18 amyloid 
PET sub-study and a longitudinal CSF sub-study.  Patients who undergo a florbetapir F 18 PET 
scan at screening to document the presence of amyloid will be included in the florbetapir F 
18 PET sub-study, and patients who undergo a lumbar puncture for CSF sampling at screening 
will be included in the CSF sub-study.  However, all enrolled patients will be required to 
demonstrate amyloid positivity by PET or CSF collection at screening or by a historical amyloid 
PET scan.  In addition, there are two longitudinal sub-studies of FDG and 18F-AV-1451 PET at 
applicable sites (see addenda for details).
Target patient population
Men and women, aged 55 to 85 years, with early AD (defined as the continuum of patients with 
MCI due to AD and patients diagnosed with mild dementia of the Alzheimer’s type).  All 
enrolled patients must have an MMSE score of 20 to 30 inclusive.  For a diagnosis of mild AD, 
the patient must (1) meet the National Institute on Aging (NIA) and the Alzheimer’s Association 
(AA) (NIA-AA) criteria for probable AD and (2) have a CDR global score of 0.5 or 1, with the 
memory box score ≥0.5.  For a diagnosis of MCI due to AD, the patient must (1) meet NIA-AA 
criteria for MCI due to AD and (2) have a CDR global score of 0.5, with the memory box score 
≥0.5.
Investigational product, dosage and mode of administration
AZD3293 20 mg or 50 mg, administered as tablets orally once daily (in the morning).  
Comparator, dosage and mode of administration
Placebo matching AZD3293, administered as tablets orally once daily (in the morning).  

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AZD3293 [LY3314814]
Duration of treatment
The overall study duration will be approximately 118 weeks, including a screening period of 
approximately 8 weeks, a baseline assessment period of approximately 1 week, a double-blind 
treatment period of 104 weeks, and a follow-up period of 4 to 6 weeks.  Of note, those patients 
who complete 104 weeks of treatment in Study I8D-MC-AZES (AZES) and wish to continue 
treatment may enter a separate double-blind extension trial, Study I8D-MC-AZFD (AZFD).  
Statistical methods
General principles
A comprehensive Statistical Analysis Plan (SAP) will be prepared and finalized before the study 
data are unblinded.  An interim analysis SAP will be prepared and finalized before each interim 
analysis. 
A graphical multiplicity strategy will be used for testing key secondary hypotheses to protect 
against Type I error of falsely rejecting a null hypothesis.  The use of a prespecified analysis plan 
that employs Bretz’ graphical approach will provide strong control of the study-wise Type I error 
rate for the primary and key secondary hypotheses at level α=0.05. The order of testing of 
hypotheses and control of Type 1 error will be prespecified in the graphical analysis as stated in 
the SAP.
A separate family of biomarkers will be tested at α=0.05.  The family will include the 
biochemical biomarkers (CSF Aβ1-42, total tau, and phosphorylated tau), as well as imaging 
biomarkers (florbetapir F 18 amyloid PET and volumetric MRI).  
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be established to monitor data on an 
ongoing basis to ensure the continuing safety of patients enrolled in this study, to ensure the 
integrity of the blinded nature of the study, and to oversee the 4 planned interim analyses.  The 
IDMC will be composed of individuals external to the sponsor.  An IDMC charter will be 
developed which will specify the Committee’s responsibilities, authorities, and procedures along 
with details of the interim analysis planning, decision-making guidance, and dissemination of the 
results as well as the recommendations and decisions after the interim analyses.  Formal 
implementation and communication of IDMC recommendations will be managed by the sponsor 
Executive Committee, which will be unrelated to the AZD3293 project team.  A firewall will be 
established to ensure the maintenance of the study blind for the sponsor, the investigational site 
staff, and study patients and their study partners.
Interim analyses
Four interim analyses may be conducted during this study, overseen by the IDMC and an 
Independent Statistical Center.
Interim analysis 1
The first interim analysis (IA1) will be performed when approximately 70 patients per group 
have 13 weeks’ worth of data.  It is expected that, at IA1, approximately 500 patients will have 

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AZD3293 [LY3314814]
been randomized globally.  The objective of IA1 is to assess the viability of continuing with 
AZD3293 with regard to safety.  
One of the following IDMC recommendations will result from IA1:

Continue the study unmodified

Discontinue enrollment in 1 or both AZD3293 treatment groups for reasons of an 
unacceptable safety profile.

If 1 AZD3293 treatment group is discontinued for enrollment at IA1, the 
randomization ratio for newly enrolled patients will remain 2:1 (active:placebo).  
Patients in the discontinued AZD3293 treatment group will be switched to the other 
AZD3293 treatment group; for analysis purposes, these patients will be included in 
their originally assigned AZD3293 treatment group.

Stop the study if enrollment in both AZD3293 treatment groups is discontinued
Interim analysis 2
The second interim analysis (IA2) will be performed when approximately 80% of patients have 
been randomized.  IA2 will assess the viability of continuing AZD3293 treatment groups with 
regard to safety and will re-assess the total sample size based on the Bayesian predictive 
probability of the ADAS-Cog13, ADCS-iADL, and/or FAQ.  
One or more of the following IDMC recommendations will result from IA2:

Continue the study unmodified

If neither AZD3293 treatment group was discontinued at IA1 and, therefore, both
AZD3293 treatment groups remain in the study at IA2:

Discontinue enrollment in 1 or both AZD3293 treatment groups for reasons of an 
unacceptable safety profile.  If 1 dose is discontinued for enrollment at IA2, the 
randomization ratio for newly enrolled patients will remain 2:1 (active:placebo).  
Patients in the discontinued AZD3293 treatment group will be switched to the other 
AZD3293 treatment group; for analysis purposes, these patients will be included in 
their originally assigned AZD3293 treatment group.

Stop the study if both AZD3293 treatment groups are discontinued

If 1 AZD3293 treatment group was discontinued at IA1 and, therefore, 1 AZD3293 
treatment group remains in the study at IA2:

Discontinue enrollment in the remaining AZD3293 treatment group for reasons of an 
unacceptable safety profile

Stop the study if the remaining AZD3293 treatment group is discontinued

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AZD3293 [LY3314814]

Increase the sample size
Interim analysis 3
A third interim analysis (IA3) may be performed to calculate the futility of either dose. The 
parameters of this futility analysis will be described in the interim analysis and the end-of-study 
analysis SAPs.
Interim analysis 4
A fourth interim analysis (IA4) may be performed to assess for futility and for early stopping of 
the study for efficacy.  This interim analysis will be described in the interim analysis and end-of-
study analysis SAPs.
Efficacy analyses
All analyses will be performed in a manner that is consistent with the intent-to-treat (ITT) 
principle.  When change from baseline is assessed, patients will be included in the analysis only 
if both a baseline and a post-baseline measure are available.  
Primary analysis
The primary efficacy endpoint, change from baseline at Week 104 in ADAS-Cog13 score, will be 
analyzed using a mixed-effect repeated-measures (MMRM) model that includes the fixed effects 
of treatment, visit (categorical covariate), treatment-by-visit interaction, disease status at baseline 
(MCI due to AD or mild AD), APOE4 status (carrier versus non-carrier), baseline ADAS-Cog13 
score (continuous covariate), concomitant acetylcholinesterase inhibitors (AChEI) use at baseline 
(yes/no), age at baseline, country, and baseline ADAS-Cog13 score-by-visit interaction.  
Differences between treatment groups will be assessed using appropriate linear contrasts of the 
parameters in the MMRM model.  
Secondary analyses
When a comparison between an AZD3293 dose group and the placebo group is statistically 
significant on the primary efficacy endpoint, the secondary efficacy endpoints for the AZD3293 
dose group will be tested through a graphical approach which includes the primary efficacy 
endpoint. The order of testing and control of Type 1 error will be prespecified in the graphical 
analysis as stated in the SAP.  
Exploratory efficacy variables will be analyzed using the MMRM models described above as 
well as with descriptive statistical analyses.  These variables are listed above and in the SAP.  
Biomarkers
Changes from screening in CSF biomarkers (eg, Aβ1-42, total tau, and phosphorylated tau) will 
be analyzed using an MMRM analysis that includes the fixed effects of treatment, visit 
(categorical covariate), treatment-by-visit interaction, disease status at baseline (MCI due to AD 
versus mild AD), APOE4 status (carrier versus non-carrier), and predose biomarker value 
(continuous covariate).  

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AZD3293 [LY3314814]
Estimates of global cortical load from florbetapir F 18 amyloid PET and volumetric brain 
measures from MRI will be analyzed using the same methodology as described above for the 
CSF biomarker data.
Pharmacokinetics
Plasma and CSF AZD3293 and metabolite AZ13569724 concentrations will be summarized by 
treatment and time point using descriptive statistics.  
A population PK analysis of plasma AZD3293 and AZ13569724 concentration data will be 
performed using a nonlinear mixed effects modelling approach.  The results of the population PK 
analysis will be summarized in a separate report.
Pharmacokinetics-pharmacodynamics
A population PK/PD analysis implementing appropriate structural models will be conducted 
following completion of the study to examine the relationships between AZD3293 and/or 
AZ13569724 and selected measures of efficacy (eg, the primary efficacy endpoint) or tolerability 
(eg, AE incidence) using nonlinear mixed effects modelling.  The results of the population 
PK/PD analysis will be provided in a separate report.
Pharmacogenomics
The analysis of pharmacogenomics (DNA) outcomes will consist of an analysis of the 
association of baseline variation with chosen outcome parameters, including efficacy and 
biomarker outcomes.  The analysis of messenger ribonucleic acid (mRNA) and micro-
ribonucleic acid (miRNA) outcomes will consist of descriptive statistics regarding change from 
baseline, including stratification by endpoints.  Pharmacogenomics outcomes will be tested in a 
prioritized list of genes for which a scientific hypothesis for interaction with the pharmacology of 
AZD3293 and/or the pathophysiology of AD can be formulated, based on knowledge in the field.
Safety
The incidence and severity of treatment-emergent AEs will be summarized by treatment group.  
The results of clinical laboratory tests; 12-lead ECGs; physical, eye, skin, and neurological 
examinations; safety MRIs; suicidality evaluations (C-SSRS); body weight and body mass index; 
and vital sign measurements will be summarized with descriptive statistics, by treatment group, 
for all time points at which these variables are collected.  In addition, visual displays of the time
course of AEs will be generated, and analyses that account for time on study will be conducted.
Individual patient data for vital signs, ECG results, and laboratory test results will be assessed for 
potentially clinically significant (PCS) values according to predetermined criteria, and any PCS
values identified will be summarized by treatment group.

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AZD3293 [LY3314814]
Table of Contents
Section
Page
1.
INTRODUCTION ............................................................................................................24
1.1.
Background..................................................................................................................24
1.2.
Research hypothesis.....................................................................................................24
1.3.
Rationale for conducting this study ..............................................................................25
1.4.
Preliminary human experience .....................................................................................25
1.4.1.
Safety and adverse events.....................................................................................25
1.4.2.
Pharmacokinetics in humans ................................................................................25
1.4.3.
Pharmacodynamic effects in humans....................................................................26
1.5.
Benefit/risk and ethical assessment...............................................................................26
1.5.1.
Benefits................................................................................................................26
1.5.2.
Risks....................................................................................................................27
2.
STUDY OBJECTIVES.....................................................................................................29
2.1.
Primary objective .........................................................................................................29
2.2.
Secondary and exploratory objectives...........................................................................29
3.
STUDY PLAN AND PROCEDURES ..............................................................................32
3.1.
Overall study design and flowchart...............................................................................32
3.1.1.
Longitudinal Biomarker Sub-studies ....................................................................33
3.1.2.
PET Imaging Addenda.........................................................................................33
3.2.
Summary of study visits and assessments.....................................................................34
3.2.1.
Screening period (Visits 1&2) and Informed Consent...........................................34
3.2.2.
Screening - Imaging and Biomarkers....................................................................36
3.2.3.
Re-screening of a potential study patient ..............................................................39
3.2.4.
Study Plan............................................................................................................39
3.3.
Rationale for study design, doses and control groups....................................................44
3.4.
Role of the patient’s study partner................................................................................45
3.5.
Discontinuation of the study.........................................................................................46
4.
SUBJECT SELECTION CRITERIA.................................................................................47
4.1.
Inclusion criteria ..........................................................................................................47
4.2.
Exclusion criteria .........................................................................................................49
5.
STUDY CONDUCT.........................................................................................................53
5.1.
Restrictions during the study ........................................................................................53
5.2.
Patient enrollment and randomization...........................................................................53
5.2.1.
Procedures for enrollment ....................................................................................53
5.2.2.
Procedures for randomization...............................................................................53
5.3.
Procedures for handling subjects incorrectly enrolled or entered...................................54

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AZD3293 [LY3314814]
5.4.
Blinding and procedures for unblinding the study.........................................................54
5.4.1.
Methods for ensuring blinding..............................................................................54
5.4.2.
Methods for unblinding the study.........................................................................55
5.5.
Treatments ...................................................................................................................55
5.5.1.
Identity of study medication.................................................................................55
5.5.2.
Doses and treatment regimens..............................................................................56
5.5.3.
Labeling...............................................................................................................56
5.5.4.
Storage.................................................................................................................56
5.6.
Concomitant treatment(s).............................................................................................56
5.6.1.
Initiation of post-randomization symptomatic AD treatments...............................57
5.6.2.
Other medication considerations post-randomization............................................57
5.7.
Treatment compliance ..................................................................................................58
5.7.1.
Assessment of compliance ...................................................................................58
5.7.2.
Accountability......................................................................................................58
5.8.
Discontinuation of study treatment...............................................................................59
5.9.
Suspension of study treatment ......................................................................................60
5.10. Withdrawal from study.................................................................................................60
6.
COLLECTION OF STUDY VARIABLES.......................................................................62
6.1.
Recording of data.........................................................................................................62
6.2.
Screening assessments..................................................................................................62
6.2.1.
NIA-AA criteria review........................................................................................62
6.2.2.
APOE genotyping ................................................................................................64
6.3.
Efficacy........................................................................................................................65
6.3.1.
Primary efficacy variable .....................................................................................65
6.3.2.
Secondary efficacy variables................................................................................66
6.3.2.1.
Functional Activities Questionnaire................................................................66
6.3.2.2.
The Alzheimer’s Disease Cooperative Study Activities of 
Daily Living Inventory ...................................................................................66
6.3.2.3.
Clinical Dementia Rating Scale ......................................................................67
6.3.2.4.
Integrated Alzheimer’s Disease Rating Scale (iADRS) 
[calculated assessment, not a separately administered 
scale]..............................................................................................................68
6.3.2.5.
Mini-Mental State Examination......................................................................68
6.3.2.6.
Neuropsychiatric Inventory.............................................................................69
6.3.3.
Exploratory efficacy variables..............................................................................69
6.3.3.1.
Letter Fluency, Category Fluency, and Digit Symbol-
Coding tests....................................................................................................69
6.3.3.2.
Repeatable Battery for the Assessment of 
Neuropsychological Status..............................................................................70

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AZD3293 [LY3314814]
6.3.4.
Order of efficacy assessments and rater qualifications..........................................70
6.3.4.1.
Order of efficacy assessments.........................................................................70
6.3.4.2.
Rater qualifications and blinding ....................................................................72
6.4.
Safety...........................................................................................................................73
6.4.1.
Definition of adverse events.................................................................................73
6.4.2.
Definitions of serious adverse event .....................................................................73
6.4.3.
Recording of adverse events.................................................................................73
6.4.3.1.
Time period for collection of adverse events...................................................73
6.4.3.2.
Follow-up of unresolved adverse events .........................................................74
6.4.3.3.
Intensity of adverse events..............................................................................74
6.4.3.4.
Causality collection ........................................................................................74
6.4.3.5.
Adverse events based on signs and symptoms.................................................74
6.4.3.6.
Adverse events based on examinations and tests.............................................74
6.4.3.7.
Vasogenic edema............................................................................................75
6.4.3.8.
Rash ...............................................................................................................75
6.4.3.9.
Depression......................................................................................................75
6.4.3.10.
Disease progression........................................................................................76
6.4.4.
Reporting of serious adverse events......................................................................76
6.4.5.
Laboratory safety assessment ...............................................................................76
6.4.5.1.
Elevation in Liver Tests..................................................................................78
6.4.6.
Physical and neurological examinations ...............................................................79
6.4.7.
12-lead ECG ........................................................................................................79
6.4.8.
Vital signs............................................................................................................80
6.4.8.1.
Pulse rate and blood pressure..........................................................................81
6.4.8.2.
Height, body weight, and body temperature....................................................81
6.4.9.
Other safety assessments......................................................................................81
6.4.9.1.
Eye and skin examinations..............................................................................81
6.4.9.2.
C-SSRS..........................................................................................................82
6.4.9.3.
Magnetic resonance imaging...........................................................................82
6.4.10.
Safety areas of specific interest ............................................................................83
6.5.
Pharmacokinetics .........................................................................................................84
6.5.1.
Collection of samples...........................................................................................84
6.5.2.
Determination of drug concentration ....................................................................84
6.6.
Pharmacodynamics ......................................................................................................84
6.6.1.
Cerebrospinal fluid biomarkers ............................................................................85
6.6.2.
Imaging biomarkers .............................................................................................85
6.6.2.1.
Positron emission tomography........................................................................85
6.6.2.2.
Magnetic resonance imaging...........................................................................86

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AZD3293 [LY3314814]
6.6.3.
Plasma biomarkers ...............................................................................................87
6.7.
Pharmacogenetics.........................................................................................................87
6.8.
Pharmacogenomics ......................................................................................................87
6.9.
Health economics.........................................................................................................88
6.9.1.
RUD-Lite.............................................................................................................88
6.9.2.
EQ-5D-5L............................................................................................................88
7.
BIOLOGICAL SAMPLING PROCEDURES ...................................................................89
7.1.
Volume of blood ..........................................................................................................89
7.2.
Handling, storage and destruction of biological samples...............................................89
7.2.1.
Pharmacokinetic and/or pharmacodynamic samples.............................................89
7.2.2.
Pharmacogenetic samples.....................................................................................90
7.3.
Labeling and shipment of biohazard samples................................................................90
7.4.
Chain of custody of biological samples ........................................................................90
7.5.
Withdrawal of informed consent for donated biological samples ..................................91
8.
ETHICAL AND REGULATORY REQUIREMENTS......................................................92
8.1.
Ethical conduct of the study .........................................................................................92
8.2.
Patient data protection..................................................................................................92
8.3.
Ethics and regulatory review ........................................................................................92
8.4.
Informed consent..........................................................................................................93
8.5.
Changes to the protocol and informed consent form .....................................................93
8.6.
Audits and inspections..................................................................................................94
9.
STUDY MANAGEMENT................................................................................................95
9.1.
Pre-study activities.......................................................................................................95
9.2.
Training of study site personnel....................................................................................95
9.3.
Monitoring of the study................................................................................................96
9.3.1.
Source data ..........................................................................................................96
9.4.
Study agreements .........................................................................................................97
9.4.1.
Archiving of study documents..............................................................................97
9.5.
Study timetable and end of study..................................................................................97
10.
DATA MANAGEMENT..................................................................................................98
10.1. General principles ........................................................................................................98
10.2. Genetic data .................................................................................................................98
11.
EVALUATION AND CALCULATION OF VARIABLES ..............................................99
11.1. Calculation or derivation of efficacy variable(s) ...........................................................99
11.1.1.
ADAS-Cog13 ......................................................................................................99
11.1.2.
Clinical Dementia Rating – Sum of Boxes............................................................99
11.1.3.
Functional Activities Questionnaire......................................................................99

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AZD3293 [LY3314814]
11.1.4.
The Alzheimer’s Disease Cooperative Study Activities of 
Daily Living Inventory.........................................................................................99
11.1.5.
Neuropsychiatric Inventory..................................................................................99
11.1.6.
Mini-mental State Examination..........................................................................100
11.1.7.
iADRS cognitive/functional composite measure.................................................100
11.1.8.
Letter and Category Fluency and Digit Symbol-Coding tests..............................100
11.1.9.
Repeatable Battery for the Assessment of 
Neuropsychological Status.................................................................................100
11.2. Calculation or derivation of safety variable(s) ............................................................101
11.2.1.
Other significant adverse events (OAE)..............................................................101
11.2.2.
Laboratory tests (hematology, chemistry and urinalysis) ....................................101
11.2.3.
Vital signs..........................................................................................................101
11.2.4.
ECG results........................................................................................................101
11.2.5.
Body weight and body mass index .....................................................................102
11.2.6.
Magnetic resonance imaging ..............................................................................102
11.3. Calculation or derivation of pharmacokinetic variables ..............................................102
11.4. Calculation or derivation of pharmacodynamic variable(s) .........................................102
11.4.1.
Cerebrospinal fluid biomarkers ..........................................................................102
11.4.2.
Imaging biomarkers ...........................................................................................102
11.4.3.
Relationship between pharmacokinetic and 
pharmacodynamic variables ...............................................................................103
11.4.4.
Population analysis of pharmacokinetic/pharmacodynamic 
variables.............................................................................................................103
11.5. Calculation or derivation of pharmacogenetic variables..............................................103
11.6. Calculation or derivation of health economic variables...............................................103
12.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION........................................................................................................104
12.1. Description of analysis sets ........................................................................................104
12.1.1.
Efficacy .............................................................................................................104
12.1.2.
Safety.................................................................................................................104
12.1.3.
Pharmacokinetics ...............................................................................................104
12.2. Methods of statistical analyses ...................................................................................104
12.2.1.
General principles ..............................................................................................104
12.2.2.
Interim analyses .................................................................................................105
12.2.2.1.
Interim analysis 1 .........................................................................................105
12.2.2.2.
Interim analysis 2 .........................................................................................105
12.2.2.3.
Interim analysis 3 .........................................................................................106
12.2.2.4.
Interim analysis 4 .........................................................................................106
12.2.3.
Multiplicity adjustments.....................................................................................107

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12.2.4.
Efficacy .............................................................................................................107
12.2.4.1.
Primary analysis ...........................................................................................108
12.2.4.2.
Secondary analyses.......................................................................................108
12.2.5.
Biomarkers.........................................................................................................109
12.2.6.
Health economics...............................................................................................109
12.2.7.
Pharmacokinetics ...............................................................................................110
12.2.8.
Pharmacokinetics-pharmacodynamics................................................................110
12.2.9.
Pharmacogenomics ............................................................................................110
12.2.10. Safety.................................................................................................................110
12.3. Determination of sample size .....................................................................................111
12.3.1.
Efficacy .............................................................................................................111
12.3.2.
Biomarkers.........................................................................................................112
12.3.2.1.
CSF biomarkers............................................................................................112
12.3.2.2.
PET biomarkers............................................................................................112
12.3.2.3.
MRI biomarkers ...........................................................................................113
12.3.3.
Pharmacogenetics ..............................................................................................113
12.4. Data monitoring committee........................................................................................113
13.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY 
THE INVESTIGATOR...................................................................................................115
13.1. Medical emergencies and sponsor contacts.................................................................115
13.2. Overdose....................................................................................................................115
13.3. Pregnancy ..................................................................................................................115
13.3.1.
Maternal exposure..............................................................................................115
13.3.2.
Paternal exposure...............................................................................................116
14.
LIST OF REFERENCES ................................................................................................117

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AZD3293 [LY3314814]
List of Tables
Table
Page
Table 1.
Objectives and Endpoints...............................................................................29
Table 2.
Study Plan (D5010C00009) ...........................................................................40
Table 3.
Study Medication...........................................................................................55
Table 4.
Order of Test Administration for Patient and Study Partner and Rater 
Responsibilities .............................................................................................72
Table 5.
Safety Laboratory Variables...........................................................................77
Table 6.
Volume of Blood to be Drawn From Each Patient..........................................89
Table 7.
Effect Size and Power per Dose for Mild AD and MCI Patient 
Populations..................................................................................................112

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AZD3293 [LY3314814]
List of Figures
Figure
Page
Figure 1.
Study flow chart for Study D5010C00009. ....................................................32
Figure 2.
Schematic of flow for patients participating in the longitudinal CSF and 
amyloid PET sub-studies and PET imaging addenda......................................34
Figure 3.
Schematic of patient screening process and entry criteria. ..............................36
Figure 4.
Patient-screening workflow............................................................................38

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AZD3293 [LY3314814]
List of Appendices
Appendix
Page
Appendix A.
Signatures....................................................................................................122
Appendix B.
Additional Safety Information......................................................................123
Appendix C.
International Airline Transportation Association (IATA) 6.2 Guidance 
Document....................................................................................................126
Appendix D.
Actions Required in Cases of Combined Increase of Aminotransferase 
and Total Bilirubin - Hy’s Law ....................................................................127

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AZD3293 [LY3314814]
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Clinical Study Protocol.
Abbreviation or special 
term
Explanation
AA
Alzheimer’s Association
AChEI
Acetylcholinesterase inhibitors
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale – Cognitive subscale 
ADAS-Cog13
13-item ADAS-Cog
ADCS-ADL
The Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory
ADCS-iADL
instrumental activities of the ADCS-ADL
ADNI
The Alzheimer´s Disease Neuroimaging Initiative
AE
Adverse event (see definition in Section 6.4.1)
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
APOE
Apolipoprotein E
APP
Amyloid precursor protein
ARIA
Amyloid Related Imaging Abnormalities
AST
Aspartate aminotransferase
AUC
Area under plasma drug concentration-time curve from zero to infinity
AV
atrioventricular
AZ13569724
Metabolite of AZD3293
Aβ
Amyloid beta peptide
Aβ1-40Aβ1-42
Aβ protein fragments
BACE1
Beta-site amyloid precursor protein cleaving enzyme 1
BCRP
Breast cancer resistance protein
BUN
Blood urea nitrogen

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AZD3293 [LY3314814]
Abbreviation or special 
term
Explanation
CDR
Clinical Dementia Rating scale
CDR-SB
Clinical Dementia Rating – Sum of Boxes
CIOMS
Council for International Organizations of Medical Sciences
CNS
Central nervous system
CRF
Case Report Form
CSA
Clinical Study Agreement
CSF
Cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
Cardiovascular
CYP
Cytochrome P450
DNA
Deoxyribonucleic acid 
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DVR
Distribution volume ratio
EC
Ethics Committee, synonymous to Institutional Review Board (IRB)
ECG
Electrocardiogram
eCRF
Electronic CRF
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 (synonymous with “randomized”).
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
FSH
Follicle-stimulating hormone
FWER
Family-wise error rate
GCP
Good Clinical Practice

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AZD3293 [LY3314814]
Abbreviation or special 
term
Explanation
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HDL
High-density lipoproteins; HDL cholesterol
HIV
human immunodeficiency virus
IA
Interim analysis
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
INR
International Normalized Ratio
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating
Investigator is the Investigator co-ordinating the investigators and/or activities 
internationally. 
IRB
Institutional Review Board
ISHNE
International Society for Holter and Noninvasive Electrocardiology
ITT
Intention to treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KO
Knockout
LDL
Low-density lipoproteins
MACE
Major adverse cardiovascular event
MAD
Multiple ascending dose
MCI
Mild cognitive impairment
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
Micro-ribonucleic acid
mITT
Modified intention to treat
MMRM
Mixed-effect repeated-measures

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AZD3293 [LY3314814]
Abbreviation or special 
term
Explanation
MMSE
Mini-mental State Examination
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
NIA
National Institute on Aging
NPI
Neuropsychiatric Inventory
NPI-D
Neuropsychiatric Inventory Caregiver Distress Scale
OAE
Other Significant Adverse Event (see definition in Section 11.2.1)
PCR
Polymerase chain reaction
PCS
Potentially Clinically Significant
PD
Pharmacodynamic
PET
Positron emission tomography
Pgp
P-glycoprotein
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/pharmacodynamic
QRS
ECG interval measured from the onset of the QRS complex to the J point
QT
ECG interval measured from the onset of the QRS complex to the offset of the T 
wave
QTcF interval
QT interval adjusted for heart rate using the Fridericia formula
RBANS
Repeatable Battery for the Assessment of Neuropsychological Status
RPR
Rapid Plasma Reagin
RR
The time between corresponding points on 2 consecutive R waves on the ECG
RT-PCR
Reverse transcription polymerase chain reaction
RUD
Resource Utilization in Dementia
SAD
Single ascending dose
SAE
Serious adverse event (see definition in Section 6.4.2).
SAP
statistical analysis plan

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AZD3293 [LY3314814]
Abbreviation or special 
term
Explanation
sAPPα
Soluble amyloid precursor protein - alpha
sAPPβ
Soluble amyloid precursor protein - beta
SD
standard deviation
SUSAR
Suspected Unexpected Serious Adverse Reactions
SUVR
Standardized uptake value ratio
VAS
visual analog scale
WBDC
Web Based Data Capture
WHO
World Health Organization

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AZD3293 [LY3314814]
1. INTRODUCTION
1.1.
Background
AZD3293 (lanabecestat) is a brain-permeable inhibitor of human Beta-site amyloid precursor 
protein-cleaving enzyme 1 (BACE1/β-secretase).  It 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, defined as the continuum of patients with mild cognitive impairment 
(MCI) due to AD (ie, prodromal AD) and patients diagnosed with mild dementia of the 
Alzheimer’s type.
AD is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory 
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.  
AD 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.  AD is 
clinically expressed as a progressive loss of cognitive functions.  Cleavage of amyloid precursor 
protein (APP) by proteases known as secretases (β and γ) gives rise to the group of peptide 
fragments known as amyloid beta peptides (Aβ).  They are the main component of the amyloid 
plaques.  Further, mutations or duplications of the APP gene constitute a genetic link to Familial 
AD.  BACE1 is a novel 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 -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 formation of amyloid plaques in the brain.  
As a potent inhibitor of BACE1, AZD3293 is a potential disease-modifying therapy for the 
treatment of AD.  AZD3293 has been shown to reduce Aβ1-40 and Aβ1-42 in mice, rats, guinea 
pigs, dogs, and humans.  At sufficient exposures, AZD3293 reduces Aβ levels in the brain and 
cerebrospinal fluid (CSF).
Detailed information on the results of non-clinical studies with AZD3293 may be found in the 
Investigator’s Brochure.
Protocol D5010C00009 has been amended (edition 7.1).  The changes and rationales for changes 
are described in an amendment summary (amendment 5.1).
1.2.
Research hypothesis
This study will test the hypothesis that AZD3293 will slow the decline of AD in patients with 
early AD, defined as the continuum of patients with MCI due to AD and patients diagnosed with 
mild dementia of the Alzheimer’s type, as measured by change from baseline in the 13-item 

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AZD3293 [LY3314814]
Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog13) score at Week 104 in each of 
the 2 AZD3293 treatment groups compared with placebo.  Please see Section 12.2.4 and 12.3.1
for further details.  
1.3.
Rationale for conducting this study
The rationale for this study is based on the critical, unmet medical need for disease-modifying 
AD treatments and the potential for AZD3293 to slow the decline of cognition and function in 
patients with early AD by reducing Aβ production via BACE1 inhibition.  
Alzheimer’s disease is an insidious, progressive disorder, and accumulation of brain pathology 
and cognitive decline occur gradually over many years (Jack et al 2010, Villemagne et al 2013).  
Deficits in cognitive functioning may start to appear up to 10 years before a clinical diagnosis of 
AD is made (Amieva et al 2008).  A review of recent Phase 3 clinical studies with anti-Aβ 
monoclonal antibodies suggests that intervention with anti-amyloid therapies at the moderate 
dementia stage of AD may be too late to be effective, but that reducing Aβ in mild AD dementia 
or in earlier-stage AD patients may be beneficial (Vellas et al 2013).  
It is estimated that approximately 39 million people in the world currently have AD, based on 
2006 prevalence estimates; this number is likely to grow by an average of 1.8 million a year and 
reach 70 million by the year 2030.  Current AD treatments have only transient benefits on 
patients’ symptoms, and afflicted patients face an inexorable progressive disease that robs them 
of their identity and ultimately leads to death.  Thus, it is imperative that disease-modifying 
treatments be rapidly discovered, tested, and made available to patients.  
This study will evaluate the potential of AZD3293 to be a disease-modifying treatment for early 
AD by providing evidence of the compound’s impact on cognitive decline and on biomarkers 
relevant to AD in patients with early AD.
1.4.
Preliminary human experience
Details can be found in the Investigator Brochure.
1.4.1. Safety and adverse events
No safety or tolerability concerns were identified in the Phase 1 program up to the highest 
AZD3293 dose given (750 mg single dose; 150 mg multiple dose) to date.  Interim Analysis 1
was reviewed by the IDMC on 06 April 2016 and the committee recommended continuing the 
trial without changes. This action officially moves the study into Phase 3.
1.4.2. Pharmacokinetics in humans
Plasma AZD3293 reaches peak concentration in humans approximately 2 hours after 
administration.  The plasma drug concentration-time profile of the demethylated metabolite 
AZ13569724 (present at >10% of plasma AZD3293 concentrations) essentially parallels that of 
AZD3293.  Comparison of AZD3293 pharmacokinetic (PK) parameters under fed and fasted 
conditions showed a modest effect of food on maximum plasma drug concentration (Cmax; 

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AZD3293 [LY3314814]
reduced with food relative to fasted) but not on the area under the plasma drug concentration-
time curve from zero to infinity (AUC).  AZD3293 is predominantly metabolized by CYP3A4.  
1.4.3. Pharmacodynamic effects in humans
Following a single oral dose of 75 mg AZD3293 in the thorough QT study, which yields an 
exposure equal to the steady-state exposure observed after AZD3293 50 mg daily, the mean 
change from baseline in QTcF interval at a concentration equal to the geometric mean Cmax was 
1.245 msec. Following a single oral dose of 450 mg AZD3293, the estimated mean change from 
baseline in QTcF interval at a concentration equal to the geometric mean Cmax was 9.858 msec. 
The exposure following the 450 mg supra-therapeutic dose (approximately 3400 ng/mL) is 
approximately >3.5-fold higher than the highest Cmax value projected for patients receiving 
multiple once-daily 50-mg doses of AZD3293, even if they were taking a strong CYP3A4 
inhibitor. Therefore, clinically significant increases in QTcF interval are not expected in this 
study.
Under the 15-mg and 50-mg once-daily dosing regimens in the multiple ascending dose (MAD)
study, plasma Aβ1-40 and Aβ1-42 concentrations were reduced rapidly, remained depressed by 
>75% during dosing, and recovered to 60% by 72 hours following the last dose.  Cerebrospinal 
fluid Aβ1-40 and Aβ1-42 concentrations were reduced to approximately 50% or 80% for the 
15-mg or 50-mg dose groups, respectively, and did not appreciably recover within 24 hours 
following the last dose.  Similar results were obtained in both healthy elderly subjects and 
patients with AD.
For further information regarding preliminary human experience with AZD3293, please refer to 
the Investigator’s Brochure.
1.5.
Benefit/risk and ethical assessment
1.5.1. Benefits
There is a large unmet medical need for disease-modifying treatments for AD.  Based on the key 
involvement of BACE1 in APP processing, inhibition of BACE1 is therefore considered a 
promising therapeutic approach for AD.  BACE1 inhibitors would be expected to prevent the 
generation of Aβ peptides and consequently reduce the detrimental effects of Aβ toxicity and the 
formation of amyloid plaques in the brain.  BACE1 inhibitors in clinical development have been 
reported to reduce Aβ in human CSF and/or in plasma by up to 80% to 90% (May et al 2011, 
Forman et al 2012, Hitt et al 2010, Hu et al 2006, Hu et al 2008, Hu et al 2010, Kim et al 2011, 
Koike et al 2012, Kuhn et al 2012, Lai et al 2012).  Taking the demonstrated lowering of Aβ in 
humans into consideration, treatment with BACE1 inhibitors has the potential to be of benefit to 
AD patients.  However, it remains to be proven that BACE1 inhibitors are able to delay the onset 
or slow the progression of AD.  
This study will evaluate whether patients with early AD treated with AZD3293 will show 
evidence of disease modification.  The study will also test whether patients with MCI due to AD 

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AZD3293 [LY3314814]
and patients with mild AD will show evidence of delayed development of underlying 
pathophysiology relative to placebo treatment.  
1.5.2. Risks
A number of findings related to BACE biological function recently described in the literature 
point toward the non-redundant physiological significance of BACE enzyme.  The list of 
possible functions and processes that could be affected includes normal memory function, 
cognition and emotional processing (Ohno et al 2004, Laird et al 2005, Wang et al 2008,
Savonenko et al 2008), myelination and re-myelination upon neuronal trauma (Hu et al 2006, Hu 
et al 2008), sodium channel expression in the brain and threshold for epileptiform activity and 
neurodegeneration (Kim et al 2011, Hu et al 2010, Hitt et al 2010), axonal guidance in the 
olfactory bulb in development and perhaps also in adult organism (Rajapaksha et al 2011), 
processes of neuronal connectivity (Zhou et al 2012), adaptation to acute neuronal ischemia 
(Koike et al 2012), vascular development in the retina and protein processing in the retina in 
general (Cai et al 2012), and, finally, a number of yet-unidentified biological functions that could 
be deduced from identifying the unique BACE1-cleaved substrates (Kuhn et al 2012). There is a 
recent publication on muscle spindle changes and related locomotor effects in BACE1 knockout 
(KO) mice (Cheret et al 2013).
Although findings in BACE1 KO animals suggest a potential for target-related adverse events 
(AEs), the risk of reproducing such effects by pharmacological inhibition of BACE1 is unknown.
In studies of BACE1 or BACE2 KO mice, the aforementioned physiological systems appear to 
have only been affected in BACE1 -/-homozygotes. In papers describing heterozygote data (ie, 
50% BACE inhibition), there are no differences reported between wild-type mice and +/-
heterozygotes (Laird et al 2005, Savonenko et al 2008, Kim et al 2011).  Moreover, while there 
are currently no data available showing any detrimental effects in a conditional BACE1 KO, 
some of the observed KO effects may be attributed to developmental changes. These KO 
phenotypes were only apparent when the BACE1 gene was completely deleted from gestation 
onwards, and their clinical safety relevance for AD patients, in which only a degree of BACE1 
inhibition will be achieved in the central nervous system (CNS), is unknown.
Potential risks include, but are not limited to, hepatic effects, QT prolongation with overdose, 
skin or hair hypopigmentation, rash, retinal changes, and potential interactions with other drugs.  
The current study will include standard safety assessments, ie, reported AEs, clinical laboratory 
tests, vital sign and body weight measurements, 12-lead electrocardiograms (ECGs), and 
physical examinations.  
Additional safety assessments will include neurological examinations (as part of each physical 
examination), comprehensive eye examinations supervised by an ophthalmologist or optometrist, 
skin examinations supervised by a dermatologist, magnetic resonance imaging (MRI)
examinations, and suicidality evaluations using the Columbia-Suicide Severity Rating Scale 
(C-SSRS). The current study will use an Independent Data Monitoring Committee (IDMC) to 
monitor data on an ongoing basis to ensure the continuing safety of patients enrolled in this 
study.

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AZD3293 [LY3314814]
AZD3293 is a substrate of CYP3A4, and plasma AZD3293 concentrations may be increased up 
to 3-fold in the presence of strong CYP3A4 inhibitors like itraconazole. Co-administration with 
strong CYP3A4 inhibitors/inducers is, therefore, restricted in the current study.  AZD3293 has 
been characterized as a P-glycoprotein (Pgp) substrate. Co-medication with a Pgp inhibitor 
could increase AZD3293 exposure, thereby possibly increasing the risk for AEs.  AZD3293 has 
been shown to be a weak inhibitor of Pgp at the intestinal wall. AZD3293 is a breast cancer 
resistance protein (BCRP) substrate; coadministration of BCRP inhibitors could increase 
systemic AZD3293 exposure.  Use of strong inhibitors/inducers of Pgp or inhibitors of BCRP 
will be restricted in the current study.
In a radiolabeled human mass balance study, the only quantifiable circulating metabolite 
observed following a single oral dose of [14C]-LY3314814 was the O-desmethyl metabolite 
AZ13569724 (metabolite 1). 
In the 14-day MAD safety study (Study I8A-MC-AZEV/D5010C00002), daily doses of 50 mg 
LY3314814 resulted in steady-state plasma AUC of metabolite AZ13569724 that was 
approximately 30% the plasma AUC of parent. This metabolite’s lower circulating 
concentration and 10-fold lower affinity for BACE1 indicate that it is unlikely to contribute 
significantly to the therapeutic effect of AZD3293.  AZ13569724 is a Pgp substrate, but it did 
not demonstrate the potential to inhibit major CYPs (IC50>20 μM) or transporters 
(IC50>100 μM) in in vitro assays.  Plasma AZ13569724 concentrations will be monitored 
throughout the clinical program, along with those of AZD3293.
The current study includes placebo as a comparator, and approximately one-third of the patients 
will be randomized to this treatment. There are currently no disease-modifying treatments for 
AD.  Moreover, all patients during the study will have a designated study partner who will have 
regular face-to-face and/or telephone contact with the patient, accompany the patient to all study 
visits, and liaise with the study staff between visits if any issues arise (see Section 3.4 for 
additional information about the role of the study partner).
In conclusion, the available non-clinical and clinical data support the oral administration of 
AZD3293 to the intended study population according to the proposed clinical investigation plan 
and also provide a sufficient margin of safety for the proposed design and doses.  The potential 
benefits of AZD3293 showing disease-modifying properties in AD are considered to outweigh 
the potential risks.  Specific details of the non-clinical and clinical findings to date and the 
complete risk benefit assessment for AZD3293 can be found in the Investigator’s Brochure.

D5010C00009 (ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]
2. STUDY OBJECTIVES
2.1.
Primary objective
The primary objective of this study is to test the hypothesis that AZD3293, administered orally at 
doses of 20 and 50 mg daily for 104 weeks, will slow the decline of AD as compared with 
placebo in patients with early AD dementia as measured by ADAS-Cog13.  Early AD is defined 
as the continuum of patients with MCI due to AD (ie, prodromal AD) and patients diagnosed 
with mild dementia of the Alzheimer’s type.
2.2.
Secondary and exploratory objectives
Table 1.
Objectives and Endpoints
Double-Blind Treatment Period
Secondary Objectives
Endpoints
Clinical efficacy objectives:

To evaluate the efficacy of AZD3293 on 
functional, clinical, and cognitive outcomes in 
patients with early AD dementia at the end of 
the Double-Blind Treatment period 
(Week 104).  

Functional Outcome Measures
o
The Alzheimer’s Disease Cooperative 
Study Activities of Daily Living Inventory 
instrumental items (ADCS-iADL) score
o
Functional Activities Questionnaire 
(FAQ) score

Cognitive/Functional Outcome Measures
o
Integrated Alzheimer’s Disease Rating 
Scale (iADRS) score 
o
Clinical Dementia Rating – Sum of Boxes 
(CDR-SB) score

Clinical Outcome Measures
o
CDR-Global Score
o
Neuropsychiatric Inventory (NPI) score

Cognitive Outcome Measures
o
Mini-Mental State Examination (MMSE)

To evaluate the relationship between treatment 
effect of AZD3293 and time (at points other 
than the end of the Double-Blind Treatment 
period [Week 104], such as Week 26, Week 52 
and Week 78).  Specific time points will vary 
by instrument.  

ADAS-Cog13, ADCS-iADL, FAQ, CDR-SB, 
and iADRS

To test the hypothesis that AZD3293 will slow 
the rate of cognitive and functional decline 
associated with AD, compared with placebo 

ADAS-Cog13, ADCS-iADL, and FAQ using a 
slope analysis from a repeated-measures model 

To evaluate the efficacy of AZD3293 to 
prolong time in the current disease state 

CDR global score

To evaluate the clinical worsening and need  
for symptomatic treatments 

AD symptomatic treatments time of initiation

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AZD3293 [LY3314814]
Biomarker objectives:

To evaluate the effect of AZD3293 on 
cerebrospinal fluid (CSF) amyloid beta peptide 
(Aβ) pharmacodynamics (PD) markers  

CSF Aβ1-42 and Aβ1-40 concentrations

To evaluate the effect of AZD3293 on CSF 
markers of neurodegeneration

CSF total tau and phosphorylated tau 
concentrations

To evaluate the effect of AZD3293 on brain 
amyloid burden

Florbetapir amyloid scan

To evaluate the effect of AZD3293 on brain 
aggregated tau levels

18F-AV-1451 Tau PET [separate addendum] 

To evaluate the effect of AZD3293 on brain  
metabolism

Fluorodeoxyglucose (FDG) positron emission  
tomography (PET) [separate addendum]

To evaluate the effect AZD3293 on brain 
atrophy  

Brain volumes measured by magnetic 
resonance imaging (MRI) 
Pharmacokinetic objective:

To assess the population PK of AZD3293 and 
metabolite AZ13569724 in patients with early 
AD dementia  

Apparent Oral Clearance of AZD3293

Central Volume of Distribution of AZD3293 
Safety Objective

To evaluate the safety and tolerability of 
AZD3293 in patients with early AD dementia

Standard safety assessments: 
o
spontaneously reported adverse events 
(AEs)
o
clinical laboratory tests
o
vital sign and body weight measurements
o
12-lead electrocardiograms (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)
Exploratory Objectives*
Endpoints*

To evaluate the efficacy of AZD3293 on 
executive function 

Changes from baseline in the Letter Fluency, 
Category Fluency, and Digit Symbol-Coding 
test scores

To evaluate the efficacy of AZD3293 on 
neuropsychological status 

Change from screening in the Repeatable 
Battery for the Assessment of 
Neuropsychological Status (RBANS) score

To explore the effects of AZD3293 on resource 
utilization and health status 

Change from baseline in the Resource 
Utilization in Dementia (RUD)-Lite and 
EQ-5D-5L score

To explore the effects of AZD3293 on 
caregiver distress 

Change from baseline in the NPI-D score

To evaluate the dose-exposure effect 
relationships for selected efficacy, safety, and 
biomarker endpoints 

Changes in scales, adverse events and blood, 
CSF and imaging biomarkers in relation to 
exposure 

To explore the genetic effects of APOE4 allele 
status (carrier or non-carrier) 

Change from baseline on selected efficacy, 
safety, and biomarker endpoints

D5010C00009 (ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]

To explore the effect of AZD3293 on gene 
expression.

Change in levels of whole blood messenger 
ribonucleic acid (mRNA) and on plasma and 
CSF micro-ribonucleic acid (miRNA) levels
and the relation to selected efficacy, safety and 
biomarker endpoints

To explore the effect of AZD3293 on 
peripheral and central nervous system protein 
expression.  

Change in CSF or peripheral protein 
biomarkers, including CSF or plasma Aβ1-42
and Aβ1-40, neurodegenerative inflammatory 
markers, and proteomic assessments and the
relation to selected efficacy, safety, and other 
biomarker endpoints

To examine AZD3293 population PK/PD 

Exposure and selected measures of efficacy 
and/or tolerability

To optionally collect and store 
deoxyribonucleic acid (DNA) for future 
exploratory research into genes/genetic 
variation that may influence response (that is, 
distribution, safety, tolerability, and efficacy) to 
AZD3293.  Genes that will be tested for 
heritable genetic (DNA) or expression (mRNA, 
miRNA) effects will be limited to those for 
which a hypothesis for involvement in the 
pharmacology of AZD3293 or in the 
pathogenesis of AD can be formulated, as 
currently understood and as directed by future 
scientific progress in the field.

Association of genetic variation with selected 
endpoints (optional pharmacogenomics 
sampling)
*Note: the results of analyses that address some exploratory objectives may not form part of the Clinical Study 
Report, but may be described in supplementary reports as appropriate.

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AZD3293 [LY3314814]
3. STUDY PLAN AND PROCEDURES
This Clinical Study Protocol has been subject to a peer review according to sponsor standard 
procedures
3.1.
Overall study design and flowchart
Study D5010C00009 is a multicenter, randomized, parallel-group, 104-week, double-blind, 
placebo-controlled, international study of 2 fixed dose levels of AZD3293 (20 mg or 50 mg) in 
patients with early AD (ie, the continuum of patients with MCI due to AD and patients 
diagnosed with mild dementia of the Alzheimer’s type) and abnormal levels of amyloid.  Figure
1 illustrates the study design.
The study is expected to enroll a total of approximately 2202 patients from across the globe.  The 
total sample size may be increased, depending on the results of the second planned interim 
analysis (see Section 12.2.2).
Note: grey boxes after Visits 8, 12, 16, and 20 indicate the 4-week symptomatic treatment initiation window for 
subjects with progression of symptoms (Section 5.6.1).
Figure 1.
Study flow chart for Study D5010C00009.
Male and female patients, aged 55 to 85 years, who meet all inclusion criteria and no exclusion 
criteria, will be randomly assigned on Day 0 to 1 of 3 treatment groups in a 1:1:1 ratio:  20 mg 
AZD3293, 50 mg AZD3293, or placebo (approximately 734 patients per treatment group).  
Study treatment will be administered once daily, in the morning, beginning on Day 1.  
Every effort should be made for visits to occur on the designated study schedule.  The overall 
treatment period in the protocol should be maintained (that is, visits should be scheduled based 
on the randomization date (the day prior to the first administration of study drug) rather than the 
previous visit).  A visit may be split over multiple days as needed.

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AZD3293 [LY3314814]
For details regarding initiation of symptomatic AD treatments see Section 5.6.1.
Randomized treatment allocation will be centrally controlled and stratified by disease status at 
baseline (MCI due to AD or mild AD).  Randomization into either the MCI due to AD or mild 
AD groups may be stopped before the completion of the study to ensure an adequate distribution
of both strata.  In addition, all patients will undergo procedures and assessments at designated 
visits as per the Study Plan (Table 2).  
Each patient will have a study partner who has sufficient interaction with the patient to provide 
meaningful input regarding the patient (see Section 3.4).
Patients who meet other study entry requirements will be required to undergo either a florbetapir 
F18 amyloid PET scan or a lumbar puncture for CSF sampling (but not both) at screening to 
document the presence of abnormal levels of brain or CSF amyloid for study inclusion (Landau 
et al 2013, Weigand et al 2011). Historical amyloid PET scans may be allowed for study 
eligibility with central reader confirmation of amyloid positivity.  
3.1.1. Longitudinal Biomarker Sub-studies
The main study protocol also includes 2 mandatory longitudinal biomarker sub-studies: a
florbetapir F 18 amyloid PET sub-study and a CSF sub-study.  For clarification, patients who 
undergo a florbetapir F 18 PET scan at screening are included in the florbetapir F 18 PET 
substudy and will have a Visit 20 florbetapir F 18 PET scan.  Patients who undergo a lumbar 
puncture at screening are included in the CSF substudy and will have a Visit 12 and Visit 19
lumbar puncture.  At least 900 individuals will participate in the florbetapir F 18 amyloid PET 
sub-study and at least 175 patients will participate in the CSF sub-study.  After the required 
number of subjects is enrolled in these 2 sub-studies, subsequent enrollment is optional and it 
may be discontinued at any time at the discretion of the sponsor (Figure 2).
3.1.2. PET Imaging Addenda
Within the florbetapir F 18 PET sub-study, there are 2 imaging addenda:

At least 400 individuals will participate in the FDG PET [Addendum 1]  

At least 500 individuals will participate in the 18F-AV-1451 PET [Addendum 2]   
Note: individuals cannot participate in both the FDG PET and 18F-AV-1451 PET addenda.
After the required number of subjects is enrolled in these addenda, subsequent enrollment is 
optional and it may be discontinued at any time at the discretion of the sponsor.

D5010C00009 (ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]
Abbreviations:  CSF  cerebrospinal fluid; FDG  fluorodeoxyglucose; PET  positron 
emission tomography.
Figure 2.
Schematic of flow for patients participating in the longitudinal CSF
and amyloid PET sub-studies and PET imaging addenda.
An IDMC (see Section 12.4) will be established to monitor data on an ongoing basis to ensure 
the continuing safety of patients enrolled in this study, to ensure the integrity of the blinded 
nature of the study, and to oversee the 3 planned interim analyses (see Section 12.2.2).  The 
IDMC will include individuals external to the sponsor and will consist of a Chair plus at least 
1 medical expert in the relevant therapeutic area and at least 1 statistician.  An IDMC charter will 
be developed which will specify the roles and responsibilities of the members and decision rules.  
Formal implementation and communication of IDMC recommendations will be managed by the 
sponsor Executive Committee and unrelated to the AZD3293 project team.  A firewall will be 
established to maintain the study blind for the sponsor, the investigational site staff, and study 
patients and their study partners.
3.2.
Summary of study visits and assessments
The procedures and assessments to be performed at designated visits are listed in this section.  
Selected visits may be conducted by telephone to reduce the burden on the patient.  The timing 
of the procedures and assessments is provided in the Study Plan (Table 2).  Details regarding the 
specific assessments are provided in Section 6.
3.2.1. Screening period (Visits 1&2) and Informed Consent
It is strongly encouraged that the duration of the screening period be as short as possible.  
However, for logistical purposes, approximately 8 weeks will be allowed for the screening
period to confirm that patients meet all selection criteria for the study and to conduct all 
measurements required prior to randomization.  

D5010C00009 (ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]
The investigator (or an appropriate delegate at the investigational site) will obtain signed 
informed consent for study participation from each patient, the patient’s study partner, and, 
where appropriate, legally authorized representative.  Patients will consent to the use of their 
screening data for future research purposes in the event that they do not meet the criteria for 
enrollment in the study.  
APOE testing is required and included in the main consent.  Separate signed consent will be 
obtained for participation in the optional pharmacogenetic and pharmacogenomics sampling.  
Separate signed consent will also be obtained for patients who are required to participate in
either the FDG-PET or 18F-AV-1451 (tau) PET addenda (addenda 1 and 2, respectively).
Each patient who provides consent to participate in the study will be assigned a unique 
enrollment number.  The patient’s study partner will also be assigned an identification code.
Those patients who have an MMSE score of 20 to 30, inclusive, a score of ≤85 on the Delayed 
Memory Index of the RBANS, assessed in that order, and who meet diagnostic criteria for MCI 
due to AD or mild AD, amyloid positivity criteria, and other selection criteria detailed in 
Section 4 will undergo study-specific enrollment procedures.  
The hierarchical screening process for study entry is illustrated in Figure 3.  If the patient fails to 
meet specified inclusion criteria on any measure shown, testing procedures should be 
discontinued.

D5010C00009 (ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]
Abbreviations:  AD  Alzheimer’s disease; Aβ  A-beta amyloid; CDR  Clinical 
Dementia Rating; CSF  Cerebrospinal fluid; MCI  Mild cognitive impairment; MMSE  
Mini-Mental State Examination; PET  Positron emission tomography; RBANS  
Repeatable Battery for the Assessment of Neuropsychological Status.
Figure 3.
Schematic of patient screening process and entry criteria.
3.2.2. Screening - Imaging and Biomarkers
A site may use either or both methods of amyloid detection during the study, but the choice of 
which amyloid detection method is used for a particular patient will be at the discretion of the 
patient and the investigator.  Patients will not be allowed to be retested with the alternate method 
if the results from the first method do not meet the criteria for study enrollment.  
Patients previously screened for amyloid positivity for another reason may participate in this 
study, provided that they meet the patient selection criteria.  Historical amyloid PET scans may 
be accepted for study eligibility with central reader confirmation of amyloid positivity.  Patients 
who enter the study via historical amyloid PET and wish to participate in the longitudinal 
florbetapir F 18 amyloid PET substudy must also have a baseline florbetapir F 18 PET scan 
performed under this study protocol, and acquired before randomized treatment is administered.  
For patients who undergo florbetapir F 18 PET for amyloid screening, the MRI and florbetapir F 
18 PET can occur in any order and can be obtained on the same day.  For patients who undergo 
CSF sampling for amyloid screening, the MRI should be performed prior to the lumbar puncture
(Note: MRI central read results are not required prior to CSF sampling).  
Completed information relevant to the diagnosis of MCI and AD, CDR rating and results of 
other assessment scales, and associated documents/recordings (if applicable) will be provided to 

D5010C00009(ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]
the adjudication vendor (
, whowill review the information and provide diagnostic 
adjudicationprior to randomization.  
review and otherscreeningproceduresmay occur 
in parallelto ensure completion of all procedures in a timely fashion.
Patients who fail to meet study entry criteria at screening can be invited to return to the clinic for 
an informational meeting with clinic staff. 
The patient-screening workflow should be as shown in
CCI
 Figure 4.
CCI

D5010C00009(ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]
*If at anytime patient fails to meet an inclusion criterion or meets an exclusion 
criterion, stop and do not proceed further with screening.  
Note: Visit 1 neurocognitive testing must be performedprior to the CSF or PET 
screening. If LP and MRI are performed, the MRI must be done first. The order of the 
cognitive testing is described in Table 4in Section 6.3.4.1.  
Abbreviations:  CDR  Clinical Dementia Rating; CRF  Case report form; CSF  
Cerebrospinal fluid; FAQ  Functional Activities Questionnaire; MMSE  Mini-Mental 
State Examination; MRI  Magnetic resonance imaging; PET  Positron emission 
tomography; RBANS  Repeatable Battery for the Assessment of Neuropsychological 
Status.
Figure 4.
Patient-screening workflow.
CCI

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AZD3293 [LY3314814]
3.2.3. Re-screening of a potential study patient
Patients may rescreen a maximum of two times. Patients may be re-screened if they meet any of 
the following criteria:

Patients who were ineligible to participate in the study due to the entry criteria in
prior protocols, but became likely to qualify based on revised criteria from current 
edition may be re-screened.

Patients who fail to make the RBANS cutoff and have had progression in their 
cognitive decline may be re-screened once more for this criterion, no sooner than 
6 months from their initial date of RBANS screen.  

Patients who required treatment for an acute illness that resolved (for example, a 
urinary tract infection) or had stabilization of a chronic medical problem (for 
example, uncontrolled hypertension) may be re-screened.

Patients who have vitamin B12 levels suspected to confound cognitive testing at 
initial screening and who have subsequently taken vitamin B12 for at least 4 
weeks after the initial screening failure may be re-screened.

Patients who are not on stable medications, including acetylcholinesterase
inhibitors, (AChEI) during screening (see Section 5.6) may be re-screened once 
the stable dose criteria have been met.

Patients who require more time to identify an appropriate study partner may be re-
screened.

Patients who are unable to complete screening procedures within a reasonable 
timeframe.
Other circumstances may also warrant rescreening.  Please contact your medical monitor for
specific patient questions if they are not outlined here.  When re-screening is performed in the 
above circumstances, the individual must sign a new informed consent form (ICF) and will be 
assigned a new identification number and all inclusion and exclusion criteria must be met.
3.2.4. Study Plan
The Study Plan is described in Table 2 below.  

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AZD3293 [LY3314814]
Table 2.
Study Plan (D5010C00009)
Study procedurea
Screening Periodb
Double-blind treatment period
EDd
F/U
Visit number
V1
V2c
V3 V4 V5 V6 V7 V8 V9 V10V11V12V13V14V15V16V17V18V19
V20
V21
Study week 
1
4
7 13 19 26 32f 39
45
52 58f 65 71f 78 84f 91
97
104
108-110g
Tolerance interval for Visit 
(days)
±3 ±3 ±7 ±7 ±7 ±7 ±7 ±7
±7 ±10 ±7
±7
±7
±7
±7
±7
±7
±10
Informed consent
X
Demographics
X
Medical /psychiatric History
X
Prior/concomitant treatments
X
X
X
X
X
X X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
NIA-AA criteria review
X
X
X
X
FAQ
X
X
X
X
X
X
ADCS-ADL
X
X
X
X
X
X
CDRh
X
X
X
X
X
X
MMSE 
X
X
X
X
X
X
X
RBANS
X
X
X
X
ADAS-Cog13
X
X
X
X
X
X
X
NPI
X
X
X
X
X
X
Letter & Category Fluency, Digit 
Symbol-Coding tests
X
X
X
X
X
X
EQ-5D-5L (patient)
X
X
X
X
X
X
RUD-Lite
X
X
X
X
X
X
MRIi
X
X
X
X
Florbetapir F 18 Amyloid PET
X
X
X
Lumbar puncturej
X
X
X
X
Blood sample for plasma 
AZD3293 and AZ13569724 PKk
Xl
Xm
Xl
Xl
Xm
Xn
X
Blood sample for plasma 
biomarkerso
X
X
X
X

D5010C00009 (ed. 7.1) Clinical Protocol
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AZD3293 [LY3314814]
Study procedurea
Screening Periodb
Double-blind treatment period
EDd
F/U
Visit number
V1
V2c
V3 V4 V5 V6 V7 V8 V9 V10V11V12V13V14V15V16V17V18V19
V20
V21
Study week 
1
4
7 13 19 26 32f 39
45
52 58f 65 71f 78 84f 91
97
104
108-110g
Tolerance interval for Visit 
(days)
±3 ±3 ±7 ±7 ±7 ±7 ±7 ±7
±7 ±10 ±7
±7
±7
±7
±7
±7
±7
±10
Blood sample for APOE 
genotypingp
X
Blood sample for 
pharmacogeneticsq
X
Blood samples for 
pharmacogenomicsq
X
X
X
X
Laboratory testsr
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine drug screen
X
Physical, neurological 
examinations
X
X
Xs
X
Xs
Xs
X
Xs
Xs
Xs
X
X
Comprehensive eye examinationt
X
X
X
X
Skin examinationu
X
X
X
X
X
X
Vital signsv
X
X
X
X
X
X X X
X
X
X
X
X
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
X
X
X
12-Lead ECG
X
Xw
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS1
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
X
Assess drug compliancex
X
X
X
X X X Xx X
X
X
Xx
X
Xx
X
Xx
X
X
X
X
Adverse events
X
X
X
X
X
X X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
Addenda (site specific)
FDG PET 
or
18F-AV-1451 PET
X
X
X
X
X
X
X
US Medicare Claims2
X

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AZD3293 [LY3314814]
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 (ie, visits 
should be scheduled based on the randomization date rather than the previous visit).  
b The screening process will take place over more than 1 day.  After consent is obtained, most screening procedures will be performed at a single visit, however 
additional screening visits will be necessary for some procedures, eg, MRI, lumbar puncture, etc.  In addition, it may sometimes be necessary for patients to 
return for repeat assessments (eg, if MRI does not pass the quality control process).  Therefore, the duration of the screening period may be increased with the 
permission of the  
medical monitor and is not necessarily considered a screen failure.  See Section 3.2.2for order of MRI and LP testing and 
Section 6.3.4.1for order of cognitive testing.
c First dose to be administered the day after Visit 2 (randomization), preferably in the morning. 
d All patients who discontinue study treatment before Week 104 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.  MRI, and for longitudinalsub-study participants, 
florbetapir F 18 amyloid PET and lumbar puncture, should only be performed if it has been at least 24 weeks since the previous assessment.  
Note:  Patients should be encouraged to remain in the study after their ED Visit until Week 104 (Visit 20), even if study treatment has been discontinued.  
Patients who discontinue treatment, but remain in the study should continue to participate in all scheduled visits and assessments, as appropriate, with the 
exception of PK measurements and PET scans.
e Footnote e has been deleted
f Visits at Weeks 32, 58, 71, and 84 will be conducted by telephone and may include eitherthe patient or the study partner, or both, as appropriate.  The patient 
or study partner may be required to visit the clinic within ±1 week of Week 32 (Visit 9), Week 58 (Visit 13), Week 71 (Visit 15), or Week 84 (Visit 17) for 
drug dispensing.
g Patientswho complete study treatment at Week 104 or who discontinue study treatment and withdraw early should participate in a follow-up visit (Visit21), 
4to 6 weeks after the last dose of study treatment.  The follow-up visit (Visit 21) is required for patients who discontinue study treatment but remain in the 
study and continue to participate in scheduled visits.  Patients who have completed104 weeks of study treatment and consent to continue into the extension 
study, Study AZFD,are not required to complete the follow-up visit (Visit 21).
h 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 the same time of dayat each visit, if possible.
i The MRI should be performedduring screening and done prior to lumbar puncture in those individuals enrolled via CSF.
j Post-baseline CSF samples for patients in the longitudinal sub-study should be collected 2 to 3 hours post-dose.  Lumbar punctures should be scheduled at 
approximately the same time of day at all visits to avoid the known circadian variation in CSF amyloidlevels.  If a post-baseline lumbar puncture cannot be 
obtained because of procedural complications or patient issues, it will not be considered a protocol violation.
k Two blood samples for AZD3293 and AZ13569724 PK analysis will be collected just after arrival at and just prior to departure from the clinic at Week 4 
(Visit 4), Week45 (Visit 11), and Week 91 (Visit 18).  One blood sample for PK analysis will be collected at Week 19 (Visit 7), Week 39 (Visit 10), and 
Week 65 (Visit 14) or as soon as possible after treatment discontinuation (if it occurs before Week 91).  
l
CCI
A phone call will be made approximately 1businessday before the clinic visit to remind patients to hold the morning dose of study treatment on the day of 
the visit and to bring the dose to the clinic.

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AZD3293 [LY3314814]
m A phone call will be made approximately 2 business days before the clinic visit to remind patients to 1) hold the morning dose of study treatment on the day 
prior to the visit and then take that dose late in the afternoon (at least 14 hours prior to the clinic visit) and 2) hold the morning dose of study treatment on the 
day of the visit and bring that dose to the clinic.
n
A phone call will be made approximately 1 business day before the clinic visit to remind patients to take the morning dose of study treatment on the day of the 
visit, before arriving at the clinic.
o
Blood samples for determination of plasma biomarkers (Aβ1-40, Aβ1-42) will be collected from all patients at the Visit 2 and 2-3 hours post-dose at indicated 
visits.
p
APOE genotyping results are not required to be available before randomization. The APOE results are not disclosed.
q
Patients who participate in optional pharmacogenetic and 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 main study.
r
Hematology, clinical chemistry, electrolyte testing, and urinalysis are included in every laboratory determination.  Coagulation tests, cholesterol (total, HDL, 
LDL), triglycerides, creatinine clearance, vitamin B12, folic acid, RPR, follicle-stimulating hormone (women only, with less than 12 months but more than 
6 months of amenorrhea), serologic tests for hepatitis B and hepatitis C, and urine testing for drugs of abuse will be included in screening tests only.  Thyroid-
stimulating hormone, total thyroxine and hemoglobin A1c will be measured at screening, Week 52 (Visit 12) and Week 104 (Visit 20) or ED.  
s
Brief physical and full neurological examinations will be performed at these visits.  For additional physical exam details, see Section 6.4.6
t
Comprehensive eye examination includes corrected visual acuity, intraocular pressure, a slit lamp examination, and a dilated fundus examination.  
Examinations must be supervised by an ophthalmologist or optometrist. The eye examination can be performed at any point during the screening period.
u
Complete skin examination must be supervised by a dermatologist.  The skin examination can be performed at any point during the screening period.
v
Vital signs include resting supine and standing blood pressures and pulse rates, and temperature (see Section 6.4.8).  
w
Single safety ECGs are required at all time points (see Section 6.4.7).  
x
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.
1
The Baseline/Screen version of the C-SSRS will be administered at Visit 2 (baseline/randomization). All visits post-baseline will use the C-SSRS Since Last 
Visit version.
2
Enrollment into the US Medicare Claims addendum (4) can be done at beginning of trial, but can be done at later time points as needed
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; BL  baseline; CDR  Clinical Dementia Rating; CSF  Cerebrospinal fluid; C-SSRS  Columbia Suicide Severity Rating 
Scale; DSM-V  Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; ECG  Electrocardiogram; ED  early discontinuation; FAQ  Functional 
Activities Questionnaire; F/U  follow-up; HDL  High-density lipoproteins; LDL  Low-density lipoproteins; 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; PK  Pharmacokinetic; RBANS  Repeatable Battery for the Assessment of Neuropsychological Status; RUD-Lite  Resource Utilization in 
Dementia-Lite; RPR Rapid Plasma Reagin; W  Week.

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AZD3293 [LY3314814]
3.3.
Rationale for study design, doses and control groups
Overall rationale and study population
The overall purpose of this study is to evaluate the potential of AZD3293 to be a disease-
modifying treatment for early AD by providing evidence of the compound’s safety, tolerability, 
and impact on cognitive decline and on biomarkers relevant to AD in patients with early AD.
The study will enroll patients with early AD, defined as the continuum of patients with MCI due 
to AD and patients diagnosed with mild dementia of the Alzheimer’s type.  In terms of the 
recently updated NIA-AA criteria, the study population will include patients diagnosed with 
“MCI due to AD” and patients diagnosed with “probable AD dementia” (of mild severity based 
on cognitive testing) (Albert et al. 2011; McKhann et al. 2011).  Patients from the 2 early AD 
subgroups will be enrolled to represent the early disease continuum.  
A clearly defined transition point between the symptomatic pre-dementia stage and the mild 
dementia stage is generally difficult to define in individual patients (Albert et al 2011).  The 
range of cognitive scores used to classify MCI and AD dementia cohorts overlaps between the 
2 disease stages (eg, in the Alzheimer’s Disease Neuroimaging Initiative [ADNI] study, the 
MMSE score range for patients with MCI was 24 to 30, while the range for patients with mild 
AD dementia was 20 to 26; Shaw et al 2009).  There is a general consensus among clinical 
experts that progression from MCI due to AD to probable AD dementia does not occur as a 
discrete event and that the precision for defining such transition points is likely to be made even 
more difficult in the context of large international clinical studies (Aisen 2009; Dubois et al 
2007).  For these clinical reasons, it is logical to test these overlapping patient groups in a single 
study.  
The inclusion requirement for evidence of abnormal brain amyloid levels, either by CSF Aβ1-42
measurement or by amyloid PET, will increase diagnostic accuracy by ensuring that the patients 
with less severe symptoms still have underlying amyloidosis that is required for a diagnosis of 
AD pathology.
Study design
This study will be randomized, double blind, and placebo controlled.  Randomization and 
blinding of the patient, the patient’s study partner, the investigator, and the Sponsor to the 
patient’s treatment assignment are intended to minimize the potential for bias in the analysis of 
AZD3293 treatment effects.  The placebo comparator will provide a reference for the changes in 
cognition and biomarkers due to disease progression as well as inform the safety profile of 
AZD3293 in patients with early AD.
Dosing and study duration
The AZD3293 doses selected for this study (20 mg and 50 mg, administered once daily) 
represent the projected therapeutic dose range based on their levels of inhibition of BACE1 in 
the CNS as calculated from the multiple-ascending-dose study CSF Aβ data.  It is anticipated 
that 20-mg and 50-mg AZD3293 doses should achieve clinically relevant CSF Aβ reductions, 

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AZD3293 [LY3314814]
and the projected mean exposures at those doses should be well within the range of exposures 
shown to be safe and well tolerated in the Phase 1 studies.  The 20-mg dose provided >50% 
mean reduction in CSF Aβ1-42 concentrations over the dosing interval, and the 50-mg dose 
provided approximately 75% reduction in CSF Aβ1-42 concentrations over the dosing interval.  
Thus, these 2 doses are deemed sufficient to demonstrate the efficacy of AZD3293 in this study.  
The 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 safe and well tolerated.
The 104-week study duration is deemed adequate to detect the effects of AZD3293 on cognition, 
function, and biomarkers relevant to AD in the selected patient population.  The potential for 
debilitating disease progression in the placebo-treated patients will be mitigated by the fact that 
all study patients will be maintained on standard of care.  
Primary endpoint
The primary endpoint in this study is the change from baseline to Week 104 in the ADAS-Cog13.  
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 (Orgogozo et al. 2004; Salloway et al. 2004; Aronson et al. 2009).
Safety monitoring
The current study has been designed as a seamless Phase 2/3 study to take account of the need 
for Phase 2 evaluation of AZD3293.  The advantages of this approach include earlier acquisition 
of long-term safety data while collecting comparable safety data to a conventional Phase 2 study; 
a reduction in the duration of clinical development program, thereby fulfilling an unmet clinical 
need sooner; and greater efficiency from the use of patients from both Phase 2 and 3 stages, thus 
requiring fewer patients.  The initial Phase 2 stage of the study spans the time from study 
initiation to the first interim analysis (IA1), when 70 patients per group will have had the
opportunity to complete 13 weeks of treatment.  In addition to IA1, an IDMC will review safety 
data on a quarterly basis, both before and after IA1.  This schedule of safety reviews should 
provide the same degree of oversight and risk mitigation as a conventional Phase 2 study.
The study will include standard safety assessments, ie, spontaneously reported AEs, clinical 
laboratory tests, vital sign and body weight measurements, 12-lead ECGs, and physical 
examinations.  Additional safety assessments will include neurological examinations,
comprehensive eye examinations performed by an ophthalmologist, skin examinations 
performed by a dermatologist, serial MRI examinations, and suicidality evaluations using the 
C-SSRS.
3.4.
Role of the patient’s study partner
Every patient in the study must have a study partner, who must sign an ICF. As several of the 
outcome measures require input from the study partner, the study partner should be willing to
actively participate in the study and must have sufficient patient interaction to be able to provide 

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AZD3293 [LY3314814]
meaningful input. The study partner should be willing to participate in every study visit that 
requires their input for efficacy measures as outlined in Table 2. The study partner is not 
required to attend all study procedures; examples include but are not limited to MRI, PET or 
lumbar procedures, skin or eye examinations.  As outlined in inclusion criterion 21 (Section 4.1), 
the study partner must either co-habit with or have regular contact with the enrolled patient.  As 
guidance, the study partner’s ability 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 
patient, divided over multiple days. While every effort should be made to maintain the same 
study partner for a given patient throughout the study, 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. An identification code will be assigned to each 
study partner and recorded at each in-clinic study visit.  Demographic data, including date of 
birth, sex, and relationship to the patient, will be collected for every study partner.
3.5.
Discontinuation of the study
The study will be discontinued if the sponsor judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and Good Clinical Practice (GCP).
The IDMC (see Section 12.4) will monitor the general safety of the patients in this study and 
provide ongoing review to confirm that the risks subjects face are not unreasonable in 
comparison to the potential benefits.  The IDMC will do this by reviewing all safety events 
quarterly and at the formal interim analyses to determine evidence of any potential safety signals 
and their relative significance in terms of the overall benefit-risk profile of the drug. After each 
safety data review meeting, the IDMC will provide recommendations to the sponsor Executive 
Committee.  The sponsor Executive Committee will be responsible for receiving and promptly 
acting on the IDMC recommendations.  A potential outcome based upon the review of the IDMC 
recommendations includes stopping the study for safety reasons.

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4. SUBJECT SELECTION CRITERIA
Study patients will be recruited by specialist clinics with extensive referral networks.
Investigators must keep a record of patients who were considered for enrollment (those that 
signed informed consent) but were never randomized.  This information is necessary to establish 
that the patient population was selected without bias.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  In general, there can be no exceptions to this rule.  However, provision is made for 
rescreening of patients who did not meet entry criteria (see Section 3.2).
4.1.
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
General
[1]
Provision of signed, written, and dated informed consent from patient and from study 
partner prior to any study specific procedures
[2]
Male or female, aged 55 to 85 years inclusive at signing of informed consent form 
(ICF)
[3]
For inclusion in optional genetic research, provision of specific signed, written, and 
dated informed consent
Diagnostic
[4]
Gradual and progressive change in the patient’s memory function over more than 
6 months, reported by patient and study partner 
[5]
MMSE score of 20 to 30 inclusive at screening visit
[6]
Score of ≤85 on the Delayed Memory Index of the Repeatable Battery for the 
Assessment of Neuropsychological Status at screening visit
[7]
Inclusion criterion [7] has been deleted.
[8]
Inclusion criterion [8] has been deleted.
[9]
For a diagnosis of mild AD, patient (1) meets the National Institute on Aging (NIA) 
and the Alzheimer’s Association (AA) (NIA-AA) criteria for probable AD and (2) has 
a CDR global score of 0.5 or 1, with the memory box score ≥0.5 at the screening visit
[10]
For a diagnosis of MCI due to AD, patient (1) meets NIA-AA criteria for MCI due to 
AD and (2) has a CDR global score of 0.5, with the memory box score ≥0.5 at the 
screening visit
[11]
Inclusion criterion [11] has been deleted.

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AZD3293 [LY3314814]
[12]
Laboratory tests show no evidence of other etiologies for MCI or dementia, including 
but not limited to vitamin B12 level.  Patients may be enrolled if the investigator 
considers that the abnormal values are not the cause of cognitive symptoms.
[13]
PET visual reading or CSF A1-42 concentration positive for presence of amyloid.  
Please see the laboratory manual for further details.
Note:  For inclusion, amyloid positivity criteria must be met by either amyloid PET imaging or by CSF 
Aβ1-42 concentration (both are not required).  If a patient does not meet amyloid positivity criteria 
according to the first test applied (either amyloid PET or CSF Aβ1-42 concentration), the other amyloid 
test cannot be performed.  
Contraception and concomitant medication
[14]
Women must be postmenopausal or surgically sterile or infertile due to congenital 
anomaly.  A postmenopausal woman is defined as having an intact uterus, who has not 
taken hormones or oral contraceptives within 1 year, and who has had either cessation 
of menses for at least 1 year, or 6 months of spontaneous amenorrhea with follicle-
stimulating hormone (FSH) value that indicates the woman is postmenopausal.  
Surgically sterile women are defined as those who have had a hysterectomy, bilateral 
ovariectomy (oophorectomy), or bilateral tubal ligation.  
[15]
Men must abstain or be willing to use barrier contraception (ie, condoms), from the 
first day of dosing until 3 months after the last dose of study treatment.  They must 
also be willing to abstain for 24 hours after PET scans.  For this protocol, sexual 
abstinence is defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatment.  True abstinence is only acceptable 
when it is in line with the patient’s usual and preferred lifestyle.  Given the length of 
the study, the reliability of patients to adhere to this provision should be considered by 
the investigator.
[16]
All medication dosing should be stable for at least 30 days before screening, and 
between screening and randomization (does not apply to medications discontinued 
during screening, medications taken as needed, and/or medications not expected to 
substantially influence safety or efficacy assessments, in the opinion of the 
investigator, at baseline).
[17]
Treatment with memantine must be discontinued at least 3 weeks before 
randomization.
Procedural
[18]
Patient agrees to undergo APOE genotyping
[19]
For patients undergoing florbetapir F 18 amyloid PET for entry or as part of the PET 
sub-study:  able and willing to travel to a PET imaging center and complete the 
planned scanning sessions, and with past and planned exposure to ionizing radiation 
not exceeding safe and permissible levels

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AZD3293 [LY3314814]
[20]
Must have completed 6 years of formal education and/or have a history of academic 
achievement and/or employment sufficient to exclude intellectual disability
[21]
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 should be willing to participate throughout the 
study and must have sufficient patient interaction 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.
[22]
Patient and 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).
[23]
Study partner must be cognitively able to fulfill the requirements of the study.
[24]
In the opinion of the investigator, the patient and study partner will be compliant with, 
and have a high probability of completing, the study
4.2.
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
General
[1]
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 at screening or for the duration of their participation in the 
current study.
[2]
Investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted.  Employees or study partner of AstraZeneca, Lilly, or 
any third-party organizations involved in the study.
Medical
[3]
Significant and/or current neurological disease affecting the CNS, other than AD, that 
may affect cognition or ability to complete the study, including but not limited to, 
other dementias, serious infection of the brain, Parkinson’s disease, or epilepsy or 
recurrent seizures (except febrile childhood seizures)
[4]
History of clinically evident stroke, or multiple strokes based on history or imaging 
results.  

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AZD3293 [LY3314814]
[5]
History of clinically important carotid or vertebrobasilar stenosis or plaque.  Patients 
with evidence of a carotid bruit at screening should undergo an ultrasound prior to 
randomization.
[6]
History of multiple concussions or a concussion with sustained cognitive complaints 
or objective change in neuropsychological function in the last 5 years
[7]
Patients with a current Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-V) diagnosis of Major Depressive Disorder (MDD) or any current 
primary psychiatric diagnosis other than AD (as per DSM-V) if, in the judgment of the 
investigator, the psychiatric disorder or symptom is likely to confound interpretation of 
drug effect, affect cognitive assessment, or affect the patient’s ability to complete the 
study.  Patients with history of schizophrenia or other chronic psychosis are excluded.
[8]
History of alcohol, drug abuse or dependence (except nicotine dependence) (as per 
DSM-V) within 2 years before the screening visit
[9]
Within 1 year before the screening visit or between screening and baseline, any of the 
following:  myocardial infarction; moderate or severe congestive heart failure, NYHA 
class III or IV; hospitalization for, or symptoms of, unstable angina; syncope due to 
orthostatic hypotension or unexplained syncope; known significant structural heart 
disease (eg, significant valvular disease, hypertrophic cardiomyopathy); or 
hospitalization for arrhythmia
[10]
Congenital QT prolongation
[11]
Intermittent second- or third-degree atrioventricular (AV) heart block or AV 
dissociation or history of ventricular tachycardia
[12]
Exclusion criterion [12] has been deleted.
[13]
History of cancer within the last 5 years, with the exception of non-metastatic basal 
and/or squamous cell carcinoma of the skin, in situ cervical cancer, non-progressive 
prostate cancer or other cancers with low-risk of recurrence or spread.
[14]
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
[15]
History of vitiligo and/or current evidence of post-inflammatory hypopigmentation or 
exposure to depigmenting agents, eg, hydroquinone, in the 6 months prior to screening
[16]
History of 2 or more clinically important drug allergies, eg, severe drug-induced rash 
or anaphylaxis

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MRI, vital signs, electrocardiogram, and laboratory tests, physical examination
[17]
Screening MRI shows evidence of significant abnormality that would suggest another 
potential etiology for MCI or dementia, such as >5 microhemorrhages; prior 
macrohemorrhage (>1 cm3); ≥4 lacunar infarcts, or single infarct >1 cm3; evidence of 
cerebral contusion, encephalomalacia, aneurysms, vascular malformation, or clinically 
significant space-occupying lesions
[18]
Uncontrolled hypertension, ie, supine systolic blood pressure >165 mmHg or diastolic 
blood pressure >95 mmHg.  If an initial blood pressure reading is higher than this, the 
lowest value from 3 additional attempts to get a rested (>5 min), supine blood pressure 
reading should be used before excluding a patient for uncontrolled hypertension.
[19]
A corrected QT (QTcF) interval measurement >470 msec (men and women) at 
screening (as determined at the investigational site). The site may request a central 
read prior making determination of this exclusion.
[20]
Known positive serologic findings for human immunodeficiency virus (HIV) 
antibodies
[21]
Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies.
Note: Patients with positive HCV antibodies may have a follow-up polymerase chain 
reaction (PCR) test ordered. If the PCR is negative, they are not excluded.
[22]
Urine drug screen positive for inappropriate drug use.  
[23]
Any clinically important abnormality at screening, as determined by 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
[24]
Calculated creatinine clearance <30 mL/min (Cockcroft-Gault formula; Cockcroft and 
Gault 1976)
[25]
ALT ≥2 × the upper limit of normal (ULN) of the performing laboratory, AST ≥2 ×
ULN, total bilirubin ≥1.5 × ULN, or ALP ≥1.5x ULN at screening
Concomitant medications
[26]
Clinician impression of use of medications (eg, sleep aids, narcotics, anxiolytics etc.) 
in a manner that would interfere with cognitive testing. 
[27]
Use of strong inhibitors of CYP3A4 within 14 days or 5 half-lives, whichever is 
longer, before randomization, or of strong inducers of CYP3A4 within 30 days before 
randomization.
[28]
Use of strong inhibitors of Pgp or BCRP within 14 days or 5 half-lives, whichever is 
longer, prior to randomization, or inducers of Pgp within 30 days before baseline.  
[29]
Exclusion criterion [29] has been deleted.

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AZD3293 [LY3314814]
[30]
For patients who will undergo lumbar puncture for CSF collection, use of medications 
known to significantly influence coagulation, such as warfarin or heparin.  
Anti-platelet inhibitors, such as aspirin, dipyridamole, or clopidogrel, are allowed, but 
they may require washout prior to lumbar puncture, at the investigator’s discretion.  
[31]
Treatment with any investigational drug or device within 60 days or 5 half-lives prior 
to screening (whichever is longer) or between screening and randomization.  
[32]
Prior treatment with an AD vaccine.  Prior treatment with a passive anti-amyloid 
immunotherapy is allowed if completed at least 5 half-lives prior to randomization.
Procedural
[33]
Presence of any of the following MRI contraindications:  pacemaker; cardiac 
defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart 
valve; coronary or carotid stents that are not compatible with MRI; ear implant; CSF 
shunt; other implanted medical device (eg, Swan Ganz catheter, insulin pump); metal 
fragments or foreign objects in the eyes, skin, or body; severe claustrophobia that 
would contraindicate a brain MRI scan; or other contraindications due to local 
requirements
Additional exclusion criteria for patients undergoing CSF sampling at inclusion or participating 
in the CSF sub-study are as follows:
[34]
Any spinal malformations or other aspects (eg, tattoos) or other clinical findings (eg, 
papilledema seen with ophthalmoscopy) that may complicate or contraindicate lumbar 
puncture, as judged by the investigator
[35]
Current blood-clotting or bleeding disorder, including clinically significant abnormal 
findings in laboratory assessments of coagulation or hematology
Additional exclusion criteria for patients using amyloid PET for inclusion or participating in the 
florbetapir F 18 amyloid PET sub-study are as follows:
[36]
Present or planned 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
[37]
Have planned or are planning to have exposure to ionizing radiation that, in 
combination with the planned administration of study amyloid PET ligand, would 
result in a cumulative exposure that exceeds local recommended exposure limits
[38]
For patients who will obtain a florbetapir F 18 scan: hypersensitivity to the active 
substance or any of the excipients of florbetapir F 18.
For procedures for withdrawal of incorrectly enrolled patients, see Section 5.3.

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5.STUDY CONDUCT
5.1. Restrictions during the study
Patients will be required to:
1.
Refrain from donating blood from the screening visit until 3 months after the follow-
up visit
2.
Follow restrictions regarding concomitant medications according to Section 5.6
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 
sunprotection factor (SPF) 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 (ie, condoms) and not 
donate spermduring thestudy participation, through3 months after study participation 
ends.  Men must also agree to abstainfor24 hours after PET scans.
6.
Avoid excessive use of alcoholduring study participation.  Excessive alcohol 
consumption is defined for men as consuming an average of more than 3drinks per 
day, or more than 21drinks per week.  For women, excessive use of alcohol is defined 
as consuming an average of more than 2drinksper day, or more than 14drinks per 
week.
5.2. Patientenrollment and randomization
5.2.1. Procedures for enrollment
Additional information for the procedures for enrollment can be found in Section 3.2.1and the 
Study Plan (Table 2)
5.2.2. Procedures for randomization
Patient eligibility will beestablished before randomized treatment assignment (see Section 4
CCI
for 
inclusion and exclusion criteria).  The randomization will be stratified for disease status at 
baseline (MCI due to AD or mild AD).  
The stratified randomization schedule will be prepared by the  
 Biostatistics 
Department on behalf of the sponsor.  Randomization codes will be allocated in blocks within 
strata to AZD3293 20 mg, AZD3293 50 mg, or placebo in a ratio of 1:1:1, stratified by MCI due 
to AD and mild AD dementia.  Enrollment rates in MCI due to AD and mild AD strata will be 
monitored.  
If a patient withdraws from the study, the patient’s study identifierand randomization code will 
not be reused, and the patient will not be allowed to re-enter the study.  

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5.3. Procedures for handling subjects incorrectly enrolledorentered
Patientswho fail to meet the inclusion/exclusion criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.
Patients who are incorrectly entered but are not yet randomized or initiated on treatment should 
not participate in any further study-related procedures and should be withdrawn from the study.
Where patients who do not meet the study inclusion and/or exclusion criteria are enrolled in error 
or incorrectly started on treatment, or where patients subsequently fail to meet the study criteria 
post initiation, the investigator should inform the 
 medical monitorimmediately.  The 
medical monitor is to ensure all such contacts are appropriately documented.The 
 medical monitor, the sponsor’s clinical research physician/scientist,and the 
investigator willdetermine whether the patient may continue in the study, with or without 
investigational product. Inadvertently enrolled patients may be maintained in the study and on 
investigational product when the 
 medical monitor and sponsor’s clinical research 
physician/scientist agree with the investigator that it is medically appropriate for that patient. 
The patient may not continue in the study with or without investigational product if the 
 medical monitor and sponsor’s clinical research physician/scientist do not agree with 
the investigator’s determination it is medically appropriate for the subject to continue. The 
investigator must obtain documented approval from the sponsor’s clinical research 
physician/scientist to allow the inadvertently enrolled patient to continuein the study with or 
without investigational product. 
Safety information may be collected for 30 days after treatment discontinuation to ensure 
adequate follow-up.
5.4. Blinding and procedures for unblinding the study 
5.4.1. Methods for ensuring blinding
CCI
The AZD3293 and placebo tablets used in the study will be identical in appearance, smell, and 
taste.  Equal numbers of tablets will be dispensed to patients in each of the 3 treatment groups.
Packaging, labeling, and preparation of study medicationwill be performed in a way that will 
ensure blinding throughout the study.
Patients and their study partners will be unaware of the patient’s randomized treatment 
assignment.  No staff of the sponsor,  
, the investigational centers, or any other 
personnel involved in the conduct of the study on behalf of the sponsor will have access to the 
randomization scheme during the conduct of the study, except the personnel analyzing the PK 
and PD samples, responsible for the IVRS system, or preparing/managing the blinded study 
treatment kitsor the Independent Statistical Center preparing the reports for the IDMC.  The 
randomization list will be kept in a secure location until the end of the studyand until all 
regulatory obligations have been met.  
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5.4.2. Methods for unblinding the study
Individual treatment codes, indicating the treatment randomization for each randomized patient, 
will be available to the investigator(s) or pharmacists from the IVRS/IWRS for use in emergency 
situations as described below. Routines for this situation will be described in detail in the 
IVRS/IWRS materials that will be provided to each center.  
If a patient receives a treatment kit other than the one randomly assigned by the IVRS/IWRS, the 
site clinical research associate should be notified and the IVRS/IWRS should be notified and the 
site inventory updated.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomization, unless otherwise 
specified in this Clinical Study Protocol. In the case of a medical emergency, the investigator 
should make all attempts to contact the sponsor-designated medical monitor or designee prior to 
unblinding.  However, if this is not possible, it is still required to document and report the action 
to the sponsor.
The sponsor, or its pharmacovigilance agent, retains the right to have the treatment allocation 
code broken for SAEs that are unexpected and are suspected to be causally related to study 
medication and that potentially require expedited reporting to regulatory authorities. Treatment 
codes will not be broken for the planned analyses of data, unless otherwise specified for the 
interim analyses of this study (see Section 12.2.2) until all decisions on the evaluability of the 
data from each individual patient have been made and documented.
If the treatment allocation is unblinded, the patient will be discontinued from study participation.  
However, the patient should continue to be followed for safety follow-up as appropriate.  
5.5.
Treatments
5.5.1. Identity of study medication
AZD3293 (investigational product) will be provided as immediate-release tablets.  Matching 
placebo will be provided (Table 3).
Table 3.
Study Medication
Study medication
Dosage form and strength
AZD3293 
(investigational product)
Tablets (20 mg, 50 mg)
Placebo
Tablets to match AZD3293
Study medication will be dispensed at Visits 2 through 19 (see Study Plan in Table 2).  Each kit 
box will have a unique kit number, and enough tablets will be dispensed for daily dosing until 
the patient returns for the next study visit.  All study medication will be provided in blister packs 
and must be stored as per storage conditions in a secured area with limited access.  

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5.5.2. Doses and treatment regimens
Study medication is to be taken once daily, in the morning (Note: it is not a protocol violation if 
patient cannot or does not take study medication in the morning).  
Study treatments (blinded) are as follows:
AZD3293 20 mg 
AZD3293 50 mg 
Placebo to match AZD3293
Patients should not take the morning dose of study treatment at home on the days of Visit 4
(Week 4), Visit 7 (Week 19), Visit 10 (Week 39), Visit 11 (Week 45), and Visit 14 (Week 65)
because a blood sample for analysis of plasma AZD3293 and AZ13569724 concentrations will 
be drawn at the clinic before dose intake.  Patients should not take the morning dose of study 
treatment until late afternoon on the day prior to Visits 7 and 14 (that is, at least 14 hours before 
the clinic visit).  Patients should bring all study medication and kit boxes/blister packs to each 
study visit.
5.5.3. Labeling
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines.  Label text will be translated into local language where required.
5.5.4. Storage
All study medication must be kept in a secure place under appropriate storage conditions.  
Appropriate storage conditions are specified on the study medication pack label.
5.6.
Concomitant treatment(s)
Prior to randomization and during the screening period, medications should be stable to avoid 
confounding safety and efficacy assessments for baseline measures.  In general, discontinuation 
of medications is permissible and switching between formulations of the same medication is 
permissible.  Switching within a class of medications and other conditions may be permissible if 
they are unlikely to impact safety and efficacy assessments and should be approved by the 
medical monitor prior to randomization.  Patients with medication changes considered significant 
prior to randomization (also see cognition medication below) may be rescreened once this 
inclusion criterion is met (see Section 3.2.3).
Concomitant medications with the potential to affect cognition are permitted, provided the 
patient has been maintained on a stable dose regimen for at least 30 days before screening, and 
between screening and randomization.  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).  If 
a patient is taking these medications intermittently (eg, as needed for insomnia, anxiety, etc.) 

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he/she should be strongly discouraged from taking them the night before or morning of a study 
visit/testing session, unless he/she also did this for the Visit 2 (eg, he/she always does so before a 
stressful engagement).  Maintaining consistency in testing conditions should be emphasized with 
respect to taking as-needed medication.
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 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 indication, daily dose, and 
start and stop dates of administration.  All patients will be questioned about concomitant 
medications at every study visit.
5.6.1. 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 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 
Visit 8, Visit 12, Visit 16, and Visit 20 (see Figure 1).  Initiation at time outside of these 
windows is discouraged, but the 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.
5.6.2. Other medication considerations post-randomization
Initiation of treatment with medications that may affect cognition are permitted if medically 
indicated. Attempts to limit use or establish reasonable routines with respect to consistency of 
cognitive testing periods are desired.  Low-dose benzodiazepine use is allowed, such as 
lorazepam if required, for treatment of anxiety associated with study procedures such as lumbar 
puncture, MRI, or PET.  
Use of hormone-replacement therapy is permitted.
Treatment with photosensitizing drugs is allowed, but patients should be advised on appropriate 
precautions.
Permitted concomitant medications should be maintained on a stable dose regimen during the 
study whenever possible.
As there is a potential for AZD3293 to influence digoxin levels due to effects of Pgp, it is 
recommended that digoxin levels be monitored when initiating and discontinuing test drug to 

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avoid possible over- or under-digitalization. Other Pgp sensitive medications with very narrow 
therapeutic margins may also require monitoring or use with caution.
The following are prohibited 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 drugs of abuse, including but not limited to, illicit amphetamine, cannabis, 
cocaine, illicit opiates, propoxyphene, methadone, methaqualone, phencyclidine, or 
barbiturates

Use of depigmenting agents, eg, hydroquinone, during double-blind treatment

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).  
5.7.
Treatment compliance
5.7.1. Assessment of compliance
The administration of all study medication should be recorded in the appropriate sections of the 
eCRF.
Compliance will be assessed at in-clinic visits via tablet counts when study medication 
packaging and any unused study medication are returned at study visits.  The patient should be 
instructed 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 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.
Only patients who consume at least 80% of the prescribed daily dose during this study will be 
considered compliant.  Patients regarded as non-compliant may be discontinued in consultation 
with the medical monitor.
5.7.2. Accountability
It is the investigator’s responsibility to establish a system for handling the study medication to 
ensure that:

Deliveries of such products are correctly received by a responsible person (eg, 
pharmacist)

Such deliveries are recorded

Study treatments are handled and stored safely and properly

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The study medication provided for this study will be used only as directed in the study 
protocol
The study personnel will account for all medication received at the site, dispensed for the patient, 
and returned to thesite.  Any discrepancies should be documented, investigated,and 
appropriately resolved.
At the end of the study, site personnel will account for all unused study medication and for 
appropriate handling with the sponsor’s approval. Certificates of delivery, return, and/or
destruction should be signed.
5.8. Discontinuation of study treatment
Patientsmustbe discontinued from study treatmentin the following situations:
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further routine clinical care.
Adverse eventor clinically significant laboratory value, ECG result, or vital sign 
measurementof such severity that, in the opinion of the investigator ormedical monitor, 
continued treatment is not in the best interest of the patient
Severe non-compliance to the study protocolthat results in a safety concern, in the 
judgment of the investigator
The patient, for any reason, requires a treatment with an excluded therapeutic agentfor 
which temporary suspension of study treatment cannot be achieved (see Section 5.9).  In 
this case, discontinuation from study drug occurs prior to introduction of the new agent.
The patient develops a significant uncontrolled medical condition, such as a 
neuropsychiatric disorder that meets one of the exclusion criteria 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 study drug.
Patients maybe discontinued from study treatment in the following situations:
An individual patient enrolled in the study may be discontinued from dosing based on a 
specific AE profile, as recommended by the IDMC, the  
 medical monitor,
and/or the sponsor Global Study Physician/Scientist, in discussions with the Principal 
Investigator.  
Incorrect enrollment (Section 5.3)
Vasogenic edema (Section 6.4.3.7)
Elevated liver enzymes (Section6.4.5.1)
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Procedures for discontinuation
A patient who decides to discontinue study treatment will always be asked about the reason(s) 
and the presence of any AEs.  Any reported AEs will be followed up (See Sections 6.4.3and 
6.4.4).  
All study medication should be returned to the investigational site.  
Patients should be encouraged to remain in the study until Week 104 (Visit 20), even if study 
treatment has been discontinued, and they should continue to participate in scheduled visits as 
described inTable 2.Patients who agree to remain in the study after discontinuing study 
treatment should continue to participate in scheduled visits and assessments, as appropriate, with 
the exception of PKmeasurementsand PET scans, after completing the early discontinuation
assessments described inTable 2,as appropriate.  The  
 medical monitor may be 
consulted regarding the details of managing a specific patient who discontinues treatment but 
remains in the study.
Only patients on study treatment through Week 104 (Visit 20)are eligible to participate in the 
extension Study AZFD.  For those whocontinue into Study AZFD, the follow-up visit in 
StudyAZES is not required.  However, Study AZES study must be completed prior to entering
Study AZFD.  
Patients in Study AZES who complete Week 104 procedures (Visit 20) will be considered study 
completers;any statements regarding early discontinuation requirements do not apply tothese 
patients.
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 21) within 4to 6 weeks of discontinuing treatment.  If a patient 
withdraws his or her consent to participate in the study, see Section 5.10.
5.9. Suspension of study treatment
Treatment suspension and re-dosing of study drug can be considered based on the Principal 
Investigator
's judgment, if clinical symptoms have resolvedor a short-course of a prohibited 
medication is required.  The maximumcumulativepermissible treatment suspension is 6 weeks.  
Please contact your sponsor-designated medical monitor or designee for assistance.
5.10.Withdrawal from study
Patientsare at any time free to withdraw from the study (study treatmentand assessments), 
without prejudice to further routine clinical care(ie, withdrawal of consent).  Such patients will 
always be asked about the reason(s) for withdrawal and the presence of any AEs.  
Any reported AEswill be followed up (See Sections 6.4.3and6.4.4),and all study medication 
should be returned by the patientand early discontinuation procedures along with Visit 21 should 
be completed as described in
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Table 2.

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If possible, patients who withdraw from the study after the start of dosing and before study 
completion will be seen and assessed by an investigator and undergo final study assessments as 
described in Section 5.8 for patients who discontinue study treatment.  
Patients who withdraw from study treatment or study will not be eligible to re-enter this trial, any 
other potential trial with this compound, or the extension study.

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6. COLLECTION OF STUDY VARIABLES
The study assessments are described in the sections that follow, and the timing of these 
assessments is detailed in the Study Plan (Table 2).
It is recommended that cognitive and functional assessments and vital sign assessments are
performed before any blood samples are collected (unless otherwise noted in PK Section 6.5.1).  
It is recommended that cognitive efficacy assessments be performed as the first activity at 
baseline and subsequent visits.  
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 wherever possible (Higuchi et al 2000).  
6.1.
Recording of data
A Web Based Data Capture (WBDC) system will be used for data collection and query handling.
The investigator will ensure that data are recorded on the eCRF as specified in this study 
protocol and in accordance with the instructions provided.
The investigator will ensure the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA).  
The investigator will sign the completed eCRF, and a copy of the completed eCRF will be 
archived at the study site.
6.2.
Screening assessments 
This section describes specific assessments that are performed at screening and are not described 
elsewhere in in Section 6.  
6.2.1. NIA-AA criteria review
NIA-AA criteria will be reviewed at screening to assess the patient’s diagnostic status for study 
inclusion and will be reviewed for diagnostic accuracy.  This assessment will also be performed 
at Weeks 45 and 97 (Visits 11 and 19) to monitor for changes in the patient’s diagnostic status 
during the course of the study.
The NIA-AA criteria for “MCI due to AD” and “probable AD dementia” are listed below.  The 
ranges for cognitive testing results overlap between these diagnoses, consistent with the 
prevailing view of the diagnostic continuum of early AD.  The ultimate distinction between these 
diagnoses is, therefore, inherently clinical and will be based heavily on the CDR rating and the 
overall clinical impression.
MCI due to AD (Albert et al 2011)
The process for diagnosing MCI is divided into 2 broad steps:
1.
Establish clinical and cognitive criteria

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
Objective evidence of impairment in 1 or more cognitive domains, typically 
including memory (ie, formal or bedside testing to measure cognitive function in 
multiple domains);

Cognitive concern reflecting a change in cognition reported by patient or informant 
or clinician (ie, historical or observed evidence of decline over time);

Preservation of independence in functional abilities; and

Not demented (see criteria for all-cause dementia below).

Examine etiology of MCI to ensure it is consistent with AD pathophysiology

Rule out vascular, traumatic, medical causes of cognitive decline (by history and/or 
by relevant laboratory tests (such as vitamin B12 levels) and imaging studies (such as 
MRI), if available;

Provide evidence of longitudinal decline in cognition; and

Report history consistent with AD genetic factors, where relevant.
Probable AD dementia (McKhann et al 2011)
Patients must first satisfy clinical criteria for all-cause dementia, which require cognitive or 
behavioral changes that:
1.
Interfere with the ability to function at work or perform usual activities – the 
significance of this functional impact differentiates dementia from MCI, which is an 
inherently clinical judgment;
2.
Represent a decline from previous levels of functioning;
3.
Cannot be explained by delirium or a major psychiatric disorder;
4.
Can be detected and diagnosed by a combination of:

History taking from both the patient and a knowledgeable informant

Objective cognitive assessment – either “bedside” mental status examination or 
neuropsychological testing, if needed; and
5.
Involve a minimum of 2 domains, ie, has impairments in:

Acquiring and remembering new information – eg, repetitive questions

Reasoning and handling of complex tasks – eg, poor finances

Visuospatial abilities – eg, inability to recognize faces

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
Language functions – eg, difficulty with common words

Personality, behavior, or comportment – eg, mood fluctuations
For a clinical diagnosis of probable AD dementia, patients must meet criteria for all-cause 
dementia PLUS have:
1. Insidious onset (ie, no sudden changes that may suggest a cerebrovascular etiology)
2. Clear-cut history of worsening of cognition by report or observation (progression)
3. Initial and most prominent cognitive deficits in either:

Amnestic presentation:
Most prominent deficits in learning and recall of recent information
Evidence of cognitive dysfunction in at least 1 other domain

Non-amnestic presentation:
Language presentation – eg, word-finding deficits
Visuospatial presentation – eg, object agnosia, facial recognition
Executive dysfunction – eg, impaired judgment, problem-solving
Evidence of cognitive dysfunction in at least 1 other domain
4. No evidence of findings that do not suggest AD

Cerebrovascular disease – eg, stroke history or MRI with multiple infarcts or severe 
white matter disease

Core features of dementia with Lewy bodies (other than dementia)

Prominent features of behavioral variant frontotemporal dementia

Prominent features of semantic variant primary progressive aphasia or non-fluent/ 
agrammatic variant primary progressive aphasia

Evidence for other neurological or medical disease or medication use that could 
affect cognition
6.2.2. APOE genotyping
A blood sample will be taken at screening for APOE genotyping. Individual results will not be 
given to study patients, except as required by law or by an Ethics Committee (EC) or 
Institutional Review Board (IRB).

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6.3.
Efficacy 
This section describes the primary and secondary efficacy variables to be collected in the study.  
The appropriateness of the efficacy measurements and variables is addressed in Section 3.3.  The 
schedule of assessments is provided in the Study Plan (Table 2).
All efficacy assessments must be performed by trained and certified raters (see Section 6.3.4.2).  
In general, there should be a minimum of 2 raters per site: 1 rater for the global scales (see 
Section 6.3.1) and 1 rater for the remaining assessments.  The CDR scale is included in the 
global scales.  The CDR rater must, as much as possible, not have access to AE information to 
avoid bias in the CDR assessments.  It is recommended that the same rater administer a 
particular scale at each visit, if possible, to minimize variability.  
Cognitive and functional assessments should be performed in the order specified in Table 4.  It is 
strongly recommended that any assessments that are administered to both the patient and study 
partner are performed separately, because the presence of the other person may potentially 
influence the results of an assessment.  
6.3.1. Primary efficacy variable
Cognitive function will be assessed using a 13-item version of ADAS-Cog.  The ADAS-Cog13
measures severity of impairment in various cognitive domains (memory, language, orientation, 
praxis and executive functioning). 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 drug studies in AD of mild-to-moderate severity 
and is recognized by regulatory authorities. Most item scores are based on the number of words 
not recalled or the number of errors: Word Recall, Commands, Constructional Praxis, Delayed 
Word Recall, Naming, Ideational Praxis, Orientation and Word Recognition.  Remembering Test 
Instructions is rated based on the number of reminders during the Word Recognition task.  
Spoken Language Ability, Comprehension of Spoken Language, and Word-finding Difficulty are 
rated on a scale of severity of dysfunction ranging from 0 to 5, where 0 = no impairment, 
1 = very mild, 2 = mild, 3 = moderate, 4 = moderately severe, and 5 = severe.  The score for the 
Number Cancellation item ranges from 0 to 5, based on ranges of numbers of target items 
correctly crossed off by the patient within the time limit; the fewer correct responses, the higher 
the score.  
The ADAS-Cog13 is composed of the original 11-item ADAS-Cog (Rosen et al. 1984) as well as 
Delayed Word Recall and Number Cancellation items.  The Number Cancellation task has been 
shown to be reliable and sensitive to a broad range of dementia severity and, therefore, is a 
useful addition to the 11-item ADAS-Cog (Mohs et al. 1997). The additional items in 
ADAS-Cog13 demonstrate good psychometric properties, even in subjects without AD. These 
items show excellent retest reliability and no ceiling effects observed on Delayed Word Recall 
and Number Cancellation items (Raghavan 2013; Wessels et al. 2015)

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The maximum score for the ADAS-Cog13 is 85 points.  A lower score indicates a better 
performance.  
The ADAS-Cog13 word lists and number cancellation will not be the same at consecutive visits, 
that is, word lists and number cancellation will be alternated and thus vary by visit.  
ADAS-Cog13 assessment results will be recorded on worksheets.  Administration of the 
ADAS-Cog13 will be audio-recorded for quality-control and training purposes where permitted 
by local law.  Item-level scores from the worksheet will be transcribed into the eCRF.  A sample 
of the ADAS-Cog13 worksheets and audio recordings will be centrally reviewed and monitored
where permitted by local law.  Follow-up with raters will occur if concerns about administration 
and/or scoring practices are observed in central monitoring.  
6.3.2. Secondary efficacy variables
Secondary efficacy variables in this study are the changes from baseline (Visit 2) to Week 104 in 
FAQ score, ADCS-ADL score, CDR-SB, iADRS, MMSE, NPI total score; and CDR global 
score.
6.3.2.1.
Functional Activities Questionnaire
The FAQ measures functional activities that may be impaired in the early stages of AD (eg, 
ability to shop, cook, and pay bills) (Pfeffer et al 1982).  The FAQ is a study partner/ informant 
rating of the performance changes in 10 complex activities of daily living.
The ratings are obtained from a brief, approximately 5-minute, clinician interview with the 
patient’s study partner to evaluate the patient’s ability to carry out the following activities of 
daily living: 1) manage finances, 2) complete forms, 3) shop, 4) perform games of skill or 
hobbies, 5) prepare hot beverages, 6) prepare a balanced meal, 7) follow current events, 8) attend 
to television programs, books or magazines, 9) remember appointments, and 10) travel out of the 
neighborhood.  Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty 
now = 1, Never did [the activity] but could do now = 0, Normal = 0, Has difficulty but does by 
self = 1, Requires assistance = 2, Dependent = 3).  
The maximum FAQ total score is 30, with higher scores indicating greater impairment.  
The FAQ assessment results will be recorded on worksheets.  Administration of the FAQ will be 
audio-recorded for quality-control and training purposes where permitted by local law.  Item-
level scores from the worksheet will be transcribed into the eCRF.  A sample of the FAQ 
worksheets and audio recordings will be centrally reviewed and monitored where permitted by 
local law.  Follow-up with raters will occur if concerns about administration and/or scoring 
practices are observed in central monitoring.  
6.3.2.2.
The Alzheimer’s Disease Cooperative Study Activities of Daily Living 
Inventory
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 (Galasko et al 1997, Galasko et al 2004).  The basic activities include self-care tasks such as 

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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 (not able to perform the activity or 
needs extensive help) to the highest score (independently performs the activity).
The maximum ADCS-ADL total score is 78, with lower scores indicating greater impairment.  
The maximum basic items score (sum of individual basic item scores) is 22, and the maximum 
instrumental items score (sum of individual instrumental item scores) is 56 (Galasko et al 2004).
The ADCS-ADL is a study partner/informant rating, and the administration of the scale takes 
approximately 15 minutes.
The ADCS-ADL assessment results will be recorded on worksheets.  Administration of the 
ADCS-ADL will be audio-recorded for quality-control and training purposes where permitted by 
local law.  Item-level scores from the worksheet will be transcribed into the eCRF.  A sample of 
the ADCS-ADL worksheets and audio recordings will be centrally reviewed and monitored
where permitted by local law.  Follow-up with raters will occur if concerns about administration 
and/or scoring practices are observed in central monitoring.  
6.3.2.3.
Clinical Dementia Rating Scale 
The 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.  Although the rater may administer selected cognitive tasks during the interview to 
further estimate the patient’s cognitive and functional abilities, the CDR ratings do not rely 
directly on psychometric test performance.  The interview takes approximately 45 minutes to 
administer and requires a trained and experienced rater.  The CDR rater should, as much as 
possible, not have access to information regarding AEs.
The CDR includes assessment of 6 independent domains: Memory, Orientation, Judgment and 
Problem Solving, Community Affairs, Home and Hobbies, and Personal Care.  Each independent 
domain is rated at each assessment time point on a scale from 0 to 3 (0 = none, 
0.5 = questionable, 1 = mild, 2 = moderate, 3 = severe).  These domain ratings are also known as 
“box” scores.  The Sum of Boxes score is derived by adding the individual box scores at a given 
time point.  The maximum Sum of Boxes score is 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).  The CDR global score and memory box score will be used to determine patient 

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eligibility for the study and categorize patients as having either MCI due to AD or mild AD, as 
described in Section 4.1, inclusion criteria.
The CDR assessment results will be recorded on worksheets.  Administration of the CDR will be 
audio-recorded for quality-control and training purposes where permitted by local law.  The box 
scores and global scores from the worksheet will be transcribed into the eCRF.  A sample of the 
CDR worksheets and audio recordings will be centrally reviewed and monitored where permitted 
by local law.  Follow-up with raters will occur if concerns about administration and/or scoring 
practices are observed in central monitoring.
Time in the current disease state will be assessed in terms of time to loss of 1 global stage on the 
CDR global score through Week 104.  
6.3.2.4.
Integrated Alzheimer’s Disease Rating Scale (iADRS) [calculated 
assessment, not a separately administered scale]
The iADRS (Wessels et al 2015) 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 0-141; with higher scores indicating greater impairment.
6.3.2.5.
Mini-Mental State Examination
The MMSE (Folstein et al 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 (naming, comprehension and 
repetition), and spatial ability (copying a figure).  The maximum total score is 30, with a higher 
score indicating better cognitive performance.  The range of permissible scores at screening for 
enrollment of patients is 20 to 30, inclusive.  
The MMSE assessment results will be recorded on worksheets.  Administration of the MMSE 
will be audio-recorded for quality-control and training purposes where permitted by local law.  
Item-level scores from the worksheet will be transcribed into the eCRF.  A sample of the MMSE 
worksheets and audio recordings will be centrally reviewed and monitored where permitted by 

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local law.  Follow-up with raters will occur if concerns about administration and/or scoring 
practices are observed in central monitoring.
6.3.2.6.
Neuropsychiatric Inventory
The 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 
scripted questions to explore 12 different symptom domains: delusions, hallucinations, 
agitation/aggression, dysphoria, 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. For any behavior that has been present in the past 4 weeks, the study 
partner is asked to rate the frequency of the behavior on a 4-point scale (Rarely – less than once 
per week, Sometimes – about once per week, Often – several times per week but less than every 
day, Very often – once or more per day or continuously present), and the severity of the behavior 
on a 3-point scale (Mild – produces little distress in the patient, Moderate – more disturbing to 
the patient but can be redirected by the caregiver, Severe – very disturbing to the patient and 
difficult to redirect). A total score for each symptom is calculated by multiplying the frequency 
rating by the severity rating.  The total NPI score is the sum of all symptom scores and 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.  For each symptom deemed to be present in the past 4 weeks, the study 
partner is asked to rate the distress the symptom has caused him or her on a 6-point scale (based 
on response to the question “How emotionally distressing do you find this behavior?”):  0 = not 
at all, 1 = minimally, 2 = mildly, 3 = moderately, 4 = severely, 5 = very severely or extremely.  
The maximum score for the Caregiver Distress Scale is 60.
The NPI assessment results will be recorded on worksheets, and item-level scores will be 
transcribed into the eCRF.  
6.3.3. Exploratory efficacy variables
Exploratory efficacy variables in this study are the changes from screening/baseline that include 
but are not limited to:  the Letter Fluency, Category Fluency, and Digit Symbol-Coding test 
scores, the NPI-D score, as well as the changes from screening in the RBANS score.
6.3.3.1. 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 

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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 
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.
6.3.3.2. Repeatable Battery for the Assessment of Neuropsychological Status
The RBANS is a collection of 12 subtests representing 5 neurocognitive domains:  Immediate 
Memory, Visuospatial/Constructional, Language, Attention, and Delayed Memory.  The RBANS 
administration generally requires 20 to 30 minutes.
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.  
A Delayed Memory Index score of ≤85 at screening (Visit 1) is required for study eligibility.
The RBANS assessment results will be recorded on worksheets.  Administration of the RBANS 
will be audio-recorded for quality-control and training purposes where permitted by local law.  
Subtest scores and Index scores from the worksheet will be transcribed into the eCRF. A sample 
of the worksheets for these assessments and audio recordings will be centrally reviewed and 
monitored where permitted by local law. Follow-up with raters will occur if concerns about 
administration and/or scoring practices are observed in central monitoring.
6.3.4. Order of efficacy assessments and rater qualifications
6.3.4.1. Order of efficacy assessments
The screening cognitive scales in Visit 1 should be administered before performing any imaging.
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. 

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Refer to Table 4 for the relative sequencing of tests for both patient and study partner. It is 
recommended that efficacy assessments be performed as the first activity at the baseline and 
subsequent visits.  Additionally, it is recommended that, during these visits, cognitive and 
functional tests are performed in the sequence shown in Table 4. 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.
Where there are multiple raters, ie, a psychometric rater and a global rater, the recommended 
sequence of tests allows for simultaneous testing.  Table 4 describes the testing flow and 
respective rater responsibilities in this situation.

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Table 4.
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.
6.3.4.2.
Rater qualifications and blinding
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 4).  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 
administers the screening tests also performs all post-screening administrations of those tests for 
a given patient.
Every effort should be made to prevent the CDR rater from becoming aware of any AEs the 
patient may experience during the study. CDR 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 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.

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6.4.
Safety
The Principal Investigator is responsible for ensuring that all staff involved in the study are
familiar with the content of this section.
6.4.1. Definition of adverse events 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether or 
not considered causally related to the product.  An undesirable medical condition can be 
symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal results 
of an investigation if symptomatic or clinically significant (Section 6.4.3.6 for abnormal results;
eg, laboratory findings, ECG).  In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study treatment 
has been administered.
The term AE is used to include both serious and non-serious AEs.
6.4.2. Definitions of serious adverse event
A serious AE is an AE occurring during any study phase (ie, screening, double-blind treatment, 
and follow-up), that fulfills 1 or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above.  
For further guidance on the definition of an SAE, see Appendix B to the Clinical Study Protocol.
Note:  Cases where a patient shows an AST or ALT ≥3xULN and total bilirubin ≥ 2xULN may 
need to be reported as SAEs.  Refer to Appendix D “Actions required in cases of combined 
increase of aminotransferase and total bilirubin – Hy’s Law,” for further instructions.
6.4.3. Recording of adverse events
6.4.3.1.
Time period for collection of adverse events
Adverse events (including SAEs) will be collected from screening (Visit 1) throughout the 
treatment period (Visits 2 through 20) and including the follow-up period (Visit 21).

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6.4.3.2.
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last study visit are followed up by the 
investigator for as long as medically indicated, but without further recording in the 
eCRF.  The sponsor or its designated safety representative retains the right to request 
additional information for any patient with ongoing AE(s)/SAE(s) at the end of the 
study, if judged necessary.
6.4.3.3.
Intensity of adverse events
The following ratings will be used by the investigator to judge AE intensity:

Mild:  awareness of sign or symptom, but easily tolerated

Moderate:  discomfort sufficient to cause interference with normal activities

Severe:  incapacitating, with inability to perform normal activities
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 6.4.2.  An AE of severe intensity need 
not necessarily be considered serious.  For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE.  On the other hand, a stroke that results in only a 
limited degree of disability may be considered a mild stroke but would be an SAE.
6.4.3.4.
Causality collection
The investigator will assess causal relationship of all AEs.
A guide to the interpretation of the causality question is found in Appendix B to the 
Clinical Study Protocol.
6.4.3.5.
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or study partner or reported in response to the 
open question from the study personnel:  “Have you had any health problems since you were last 
asked?” or revealed by observation will be collected and recorded in the 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.
6.4.3.6.
Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests, vital sign measurements, ECG results, and 
other safety assessments will be summarized in the clinical study report.  
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 (eg, anemia versus low hemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-protocol-

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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.
6.4.3.7. Vasogenic edema
If a patient develops symptomsbelieved to besuggestive of vasogenic edema, such as headache, 
confusion, gait disturbance, or visual disturbance, theseshould be recorded as AEsand an MRI 
should be obtained.  Study treatment should be discontinued if clinically significant symptomatic 
vasogenic edema, clinically significant symptomatic superficial siderosis, or clinically significant 
symptomatic incident microhemorrhage is seen(see Section 5.9for suspension of study 
treatment).  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.  
6.4.3.8. 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 foran expert opinion.
A photograph of the rash should be taken.
A blood sample should be drawn for PK analysis.
A punch biopsy may be obtained at the discretion of the dermatologist.
If treatment is discontinued due to a suspected drug-induced rash, the 
 medical 
monitor should be notified as soon as possible, even if the rash did not meet the definition of an 
SAE.
6.4.3.9. 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. 

CCI
The investigator may initiate psychiatric management, including the use of psychiatric 
medication, as clinically needed.

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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.
6.4.3.10.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 AEsduring the study.
6.4.4. Reporting of serious adverse events
All SAEsmustbe reported, whether or not considered causally related to the study medicationor 
to the study procedure(s). All SAEs will be recorded in the source documents and in the eCRF.
If any SAE occurs in the course of the study, then the investigator or other site personnel will 
inform the designated sponsororrepresentative within 1 day of when he or she becomes aware 
of it, ie, immediately, butno later than 24 hours from the time he or she becomes aware of it, 
using the SAE Report Form.  Telephone reports must be confirmed promptly by submitting the 
completed SAE Report Form by facsimile.
For fatal or life-threatening AEswhere important or relevant information is missing, active 
follow-up will beundertaken immediately.  The investigator or other site personnel will inform 
sponsor or representativesof any follow-up information on a previously reported SAE within 
1calendar day of when he or she becomes aware of it, ie, immediately, but no later than 
24hours from the time he or she becomes aware of it.
6.4.5. Laboratory safety assessment
Blood and urine samples for determination of hematologyandclinical chemistryparameters, 
electrolytes, thyroid-stimulating hormone, total thyroxine,and urinalysis will be taken at the 
times indicated in the Study Plan (seeTable 2)
CCI
.The date of collection of all laboratory tests will 
be recorded in the eCRF.
At screening, the clinical chemistry tests will include a lipid panel and creatinine clearance.  At 
this visit, all patients will be tested for HbA1c, vitamin B12 level, folic acid, rapid plasma reagin 
(RPR),hepatitis B surface antigen, antibodies to hepatitis C, prothrombin time, partial 
thromboplastin time, and international normalized ratio(INR).  Urine will be tested for drugs of 
abuse at screening.  Human immunodeficiency virus may be tested at the discretion of the 
investigatoror if mandated by local regulatory authority.  This test may require a separate 
informed consent.
A follicle-stimulating hormone test will be performed at screening for female patients who report 
6to 12 months of spontaneous amenorrhea.  The results of this test will be used to determine if 
the patient meets criteria for exclusion from the study.  

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The laboratory variables to be measured are listed in Table 5.  
Table 5.
Safety Laboratory Variables
Variables in serum/blood and urine
Hematology (blood)
Electrolytes (serum)
Hematocrit
Bicarbonate
Hemoglobin 
Chloride
Leukocyte (white blood cell count, WBC) count
Phosphate
Absolute leukocyte differential count (neutrophils, 
basophils, monocytes, eosinophils and lymphocytes)
Potassium
Sodium
Platelet count
Coagulation
Urinalysis
Prothrombin timea
Blood
Partial thromboplastin timea
Color
International normalized ratio (INR)a
Glucose
Ketones
Clinical chemistry (serum)
Leukocyte esterase
Alanine aminotransferase (ALT)
pH
Albumin
Protein
Alkaline phosphatase
Specific gravity
Aspartate aminotransferase (AST)
Bilirubin, total 
Screening testsa
Blood urea nitrogen (BUN)
Folic acid
Cholesterol (total, HDL, LDL) and triglyceridesa
Hepatitis B surface antigen
Calcium, total
Hepatitis C antibodies
C-reactive protein
RPR
Creatine kinase (CK)
Vitamin B12
Creatinine
Urine test for drugs of abuse
Creatinine clearancea
Glucose
Other
Hemoglobin A1c (HbA1c)c
Endocrinology
Follicle-stimulating hormone (FSH)a,b
Optional/Confirmatory Testing
Thyroid-stimulating hormonec
Human immunodeficiency virusa
Total thyroxinec
Hepatitis C PCRd
a
At screening only.
b
Only for female patients for whom the investigator believes menopausal status is uncertain who report between6
and 12 months of spontaneous amenorrhea
c
At screening, Week 52, and Week 104 (or final study visit) only.
d
   Patients with positive HCV antibodies may have a follow-up PCR test ordered. 
Abbreviations: HDL High-density lipoproteins; LDL Low-density lipoproteins; PCR  polymerase chain reaction; 
RPR Rapid Plasma Reagin.
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 either not be 
enrolled or, if already enrolled, will be followed until normalization or for as long as the 

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Investigator considers necessary.  Additional laboratory tests may be performed for safety 
reasons if judged appropriate by the investigator.  See Section 6.4.3 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.
For blood volume, see Section 7.1.
6.4.5.1.
Elevation in Liver Tests
If a patient experiences AST or ALT ≥3 x ULN, total bilirubin ≥2 x ULN, or ALP ≥2x ULN, the 
investigator is to consult with the designated medical monitor regarding collection of specific 
recommended clinical information and follow-up laboratory tests.  The Liver Assessment CRFs
should be completed for these patients as information becomes available.
Note: If a patient shows an AST or ALT level ≥3 × ULN or total bilirubin ≥2 × ULN, please 
also refer to Appendix D “Actions required in cases of combined increase of aminotransferase 
and Total Bilirubin – Hy’s Law,” for further instructions.  
Discontinuation of study drug for abnormal liver tests should be considered by the investigator in 
consultation with the designated medical monitor if the patient meets one of the following 
criteria:

ALT or AST ≥8x ULN

ALT or AST ≥5x ULN for more than 2 weeks

ALT or AST ≥3x ULN and either total bilirubin >2x ULN or INR >1.5

ALT or AST ≥3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP elevations, if deemed of liver origin and drug-related as follows:
o
ALP >3x ULN
o
ALP >2.5x ULN and total bilirubin >2x ULN
o
ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
In all the above situations involving elevations in liver enzymes, every attempt should be made 
to obtain the following:

Viral hepatitis serology including:

Hepatitis A antibody (total and IgM)

Hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core 
antibody

Hepatitis C RNA PCR

Cytomegalovirus IgG and IgM antibody

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Epstein-Barr viral capsid antigen IgG and IgM antibody (or if unavailable, obtain 
heterophile antibody ofmonospot testing)
Hepatitis E IgG and IgM antibody
Blood sample for plasma PK analysis.  The date and time of the PK blood sample 
collection and dates and times of the 2 previous doses of study medication must be 
recorded.
Serum creatine phosphokinase (CPK)
Fractionate bilirubin, if total bilirubin is ≥1.5 x ULN
Anti-nuclear antibody, anti-smooth muscle antibody, and Type I anti-liver kidney 
microsomal antibodies
Liver imaging (ultrasound, MR or CT) to evaluate liver disease
Complete the Liver Assessment CRFsas information becomes available
Record of the appearance or worsening of clinical symptoms of hepatitis if applicable
Record of the use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, putative hepatotoxins, or alcohol
Consultation with a gastrointestinal or hepatology specialist should be considered
6.4.6. Physical and neurological examinations
Complete physical examinationswill be performed at screening, baseline, and Weeks 13, 52, and 
104 asindicated in the Study Plan (seeTable 2).  Brief physical examinations will be performed 
at Weeks 4, 26, 39, 65, 78, and 91.  The complete physical examination will include assessment 
of the following:  general appearance;skin, head and neck;lymph nodes;thyroid;abdomen
(bowel sounds, liver and spleenpalpation);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 performedas indicated in the Study Plan (seeTable
2).  The examinationswill include a thorough assessment of gait, balance, coordination, cranial 
nerves, sensory and motor systems, and reflexes.  
See Section 6.4.3for information regarding the recording of AEs based on examinations.
6.4.7. 12-lead ECG
Digital 12-lead ECG files will be collected using continuous 12-lead digital recorders at the 
times indicated in the Study Plan (seeTable 2)
CCI
 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 

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For each ECG timepoint shown in the Study Plan, a 90-second continuous 12-lead digital ECG 
file will be collected.  A12-lead safety ECG will be printed at the site and the digital data will be 
transmitted to 
.  The safety ECG data will be reviewed for quality and 
alerts by 
, and this information will be transmitted back to the study site.  The Principal 
Investigator or physician delegate is responsible for reviewing the safety ECG to determine if a 
patient meets eligibility criteria with respect to cardiac inclusion/exclusion criteria at the time of 
the screening.  
The ECG data sent to  
 will bestored in a centralized safety ECG database.  The digital 
90-second ECGs will be converted toInternational Society for Holter and Noninvasive 
Electrocardiology(ISHNE)format and transmitted to the AstraZeneca ECG Center for ECG 
analysis and interpretation according to the Core laboratory´s standard procedures.  The PR, 
QRS, QT, and RR intervals will be measured and reported.  Heart rate and QTcF interval will be 
calculated by the study statistician.  
From the 90-second continuous ECG recording, the sitewill 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.  If the ECG is interpreted as abnormal, it 
will be decided whether or not the abnormality is clinically significant or not clinically 
significant, and the reason for the abnormality will be recorded.  The recording date and time and 
the investigator interpretation (normal, abnormal clinically significant, abnormal not clinically 
significant) will be recorded in the eCRF, 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.  
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 samplesshould 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 (eg, 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 AstraZeneca ECG Center, 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 (eg,QTcF > 470 ms). See Section6.4.3for 
information regarding the recording of AEs based on ECG results.
6.4.8. Vital signs
Vital signs, including supine and standing blood pressuresand pulse rates, and temperaturewill 
be recorded at each in-clinic study visit(see the Study Plan inTable 2)
CCI
.  
CCI
CCI

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See Section 6.4.3 for information regarding the recording of AEs based on tests and 
examinations.
6.4.8.1.
Pulse rate and blood pressure
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.
6.4.8.2.
Height, body weight, and body temperature
Height will be measured in centimeters, and 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.  Body mass index (BMI) will be calculated from the height and body 
weight.  Temperature will be recorded using an oral or tympanic (or other acceptable route)
thermometer.
Body weight will be collected on the laboratory requisition for creatinine clearance calculations.  
Any body weight data entered into the eCRF will be used for the overall data analysis.
6.4.9. Other safety assessments
6.4.9.1.
Eye and skin examinations
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 recorded 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 
Study Plan (Table 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.  
Skin examination
A complete skin examination will be performed at the times shown in the Study Plan (Table 2).  
Only the initial examination will include Fitzpatrick scale rating.  
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 (eg, redness or 
induration).  A static physician’s global assessment (sPGA) will be used to determine the 

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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 captured in case report forms which will 
be entered into the WBDC 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 6.4.3 for information regarding the recording of AEs based on examinations.
6.4.9.2.
C-SSRS
The C-SSRS will be performed to determine of the presence of suicidality.  The assessment 
schedule is indicated in the Study Plan (see Table 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 
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.
6.4.9.3.
Magnetic resonance imaging
MRI will be used to screen and monitor patients for ARIA.  All patients will be required to, and 
thus must be able to, have an MRI scan during screening and for subsequent safety monitoring at 
Week 52 and Week 104 as shown in the Study Plan (Table 2).  
MRI screening scans should be performed during the screening period as outlined in 
Section 3.2.1.  The central radiologist review of the screening MRI scan must be available before 
randomization to evaluate the inclusion/exclusion criteria. The scans will be reviewed by the 
investigator or qualified designee for immediate patient management.  
MRI 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.  

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The imaging vendor will assist with the identification and qualification of the imaging centers, 
create a detailed procedure manual to be used by the study sites to ensure proper image 
acquisition and image transfer from the study sites to the imaging vendor, and provide training 
for imaging center staff.  
The MRI scans will be transmitted to the imaging vendor for amyloid-related imaging 
abnormalities (ARIA) evaluation and for automated derivation of volumetric brain biomarker 
data (See Section 6.6.2.2).  
All scans will be subject to quality control checks by specially trained technicians/technologists.  
Sites that encounter repeated problems with image quality or protocol adherence will be 
contacted directly by the imaging vendor to discuss the problem and potential solutions.
The scans will be evaluated by 1 independent neuroradiologist.  MRI findings believed to have 
potential clinical significance (eg, ARIA or other, incidental findings) will be reported to the 
investigator and to the sponsor.  See Section 6.4.3 for information regarding the recording of 
AEs based on tests and examinations.
6.4.10. Safety areas of specific interest
Specific safety topics of interest for this study include, but are not limited to, the following:

Adverse eye effects (see Section 6.4.9.1)

Adverse skin effects including rash and hypopigmentation (see Sections 6.4.3 and 
6.4.9.1)

Peripheral nervous system, central nervous system and muscle effects (see Section 6.4.6)

Liver toxicity (see Section 6.4.5.1)

Cardiovascular (CV) -type events (including, but not limited to, orthostatic hypotension 
and QT prolongation; see Sections 6.4.7 and 6.4.8.1)
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.  SAEs 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, eg, 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 or ventricular arrhythmias/cardiac arrest related to 
QT prolongation or to other mechanisms.
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 

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be analyzed for presentation in the Clinical Study Report in accordance with the Statistical 
Analysis Plan.
6.5.
Pharmacokinetics
6.5.1. Collection of samples
Blood samples (3 mL) for determination of plasma AZD3293 and metabolite AZ13569724 
concentrations will be collected as follows:  2 samples will be collected just after arrival at, and 
just prior to departure from, the clinic at Week 4 (Visit 4), Week 45 (Visit 11), and Week 91
(Visit 18); 1 sample will be collected at Week 19 (Visit 7), Week 39 (Visit 10), and Week 65 
(Visit 14) or final study visit.
Patients (or their study partners) will receive a telephone call prior to each visit at which 
AZD3293 PK sampling will be performed, instructing them as to when the patient should take
study medication prior to the clinic visit.
CSF samples (up to 18 mL unless prohibited by local regulations) for determination of AZD3293 
and AZ13569724 concentrations will be obtained from CSF sub-study participants at Week 52 
(Visit 12) and at Week 97 (Visit 19) or final study visit.
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.
For blood volumes, see Section 7.
Every effort should be made to collect the PK samples as described in the Study Plan (Table 2).  
Failure to do so would not be considered a protocol violation. The accurate date and time of 
each sample collection must be recorded as detailed in the Laboratory Manual.
6.5.2. Determination of drug concentration
Plasma and CSF samples for determination of AZD3293 and AZ13569724 concentrations will 
be analyzed on behalf of the sponsor by Covance or its designate, using appropriate bioanalytical 
methods.  Full details of the analytical methods used will be described in a separate bioanalytical 
report.  Samples from patients who received placebo may not be assayed for AZD3293 and 
AZ13569724 concentrations.  
Additional analyses may be conducted on the biological samples to further investigate the 
presence and/or identity of drug metabolites or to investigate any potential dosing issues.  Any 
results from such analyses may be reported separately from the Clinical Study Report.
6.6.
Pharmacodynamics
Pharmacodynamic outcome variables in this study include changes from baseline to the end of 
treatment in CSF biomarkers (concentrations of Aβ1-40, Aβ1-42, total tau, phosphorylated tau 
concentrations, and other, exploratory biomarkers [eg, sAPPβ]), imaging biomarkers (amyloid 
PET and volumetric MRI), and plasma biomarkers relevant to AD.

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6.6.1. Cerebrospinal fluid biomarkers
Participants in the CSF longitudinal biomarker sub-study will have post-baseline CSF samples 
collected at Week 52 and Week 97 (or at discontinuation of study treatment if it has been at least 
24 weeks since previous collection) for analysis of concentrations of Aβ1-40, Aβ1-42, total tau, 
phosphorylated tau, and exploratory biomarkers (eg, sAPPβ, sAPPα, 5-x amyloid) (see Study 
Plan in Table 2).  If a post-baseline CSF sample cannot be obtained because of procedural 
complications, patient issues, or patient request, it will not be considered a protocol violation.
Lumbar punctures should be scheduled at approximately the same time of the day  at all visits to 
avoid the known circadian variation of CSF amyloid levels (Lucey and Bateman 2014).  It is 
recommended that CSF samples be collected by insertion of an atraumatic spinal needle between 
vertebrae L3 and L5 (Vanderstichele et al 2012).  Before performing the lumbar puncture 
procedure, the physician must take into account the overall assessment of the patient and 
bleeding risk.
CSF Aβ1-40 and Aβ1-42 are biomarkers for BACE inhibition that enable direct measure of the 
central PD of AZD3293.  
CSF tau and phosphorylated tau concentrations are elevated in patients with AD.  Elevations in 
concentrations of tau, as well as specific phosphorylated tau species, are thought to be markers 
for progressive neurodegeneration in AD.  Accordingly, reductions from baseline in 
concentrations of CSF tau in patients who receive AZD3293 compared with patients who receive 
placebo may be indicative of reduced neuronal loss in AZD3293-treated patients.
Other CSF metabolites and/or protein species, including processed forms of APP such as sAPPβ, 
inflammatory biomarkers, other recognized or as-yet unrecognized biomarkers, and, if 
appropriate, proteomics assessments may be examined.  Biochemical signatures may help to 
explain differences in efficacy, safety, or tolerability and/or PK/PD related to AZD3293 
treatment.
Detailed sample collection and handling procedures are provided in the Laboratory Manual.
CSF aliquots from patients in the CSF sub-study will be retained for future analysis for up to 
15 years from the date of the last patient’s last visit.  CSF samples from patients who undergo 
CSF sampling at screening but fail other aspects of the screening process before CSF analysis 
will also be retained for future analysis, if the patient has provided appropriate consent. In 
countries prohibiting sample storage, it will not be considered a protocol violation if CSF is not 
collected for storage and future analysis.
For CSF sample volumes, see Section 6.5.1.
6.6.2. Imaging biomarkers
6.6.2.1.
Positron emission tomography
Florbetapir F 18 amyloid PET will be used to evaluate changes in amyloid binding from 
screening to end of treatment.  A decrease in the rate of accumulation of brain amyloid load as 
measured by florbetapir F 18 PET in AD patients taking AZD3293 may be an indicator of the 

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ability of AZD3293 to affect the underlying pathology.  In addition, the regional distribution of 
cerebral amyloid may be related to differences in efficacy/safety/tolerability and/or PK/PD with 
AZD3293 treatment.
Florbetapir F 18 amyloid PET scanning will be conducted under the management of a central 
PET vendor.  The PET imaging datawill be acquired after injection ofthe18F amyloid ligand
florbetapir F 18 injection.  
The PET imaging vendorwill provide visual interpretation and quantitative analysis of all 
florbetapir F 18 PET imaging data acquired at theimaging centers for both eligibility and 
monitoring disease progression(amyloid PET substudy). 
The details of florbetapir F 18 image acquisition methodology, analysis, quality control, and 
reader training will be documented in the technical operations manual and the image review 
charter.
Qualitative amyloid PET results for patient eligibility will indicate “positive” or “negative.”  
Amyloid PET images from those patients who do not meet screening amyloid burden criteria for 
enrollment will be retained for future research, if the patient has provided appropriate consent.
The primary quantitative florbetapir F 18 PET outcome variableswill be regional estimates of 
amyloid binding (distribution volume ratio [DVR], standard uptake value ratio [SUVR]). The 
average of the binding estimates from areas typically involved in AD, ie, the frontal, lateral 
temporal, posterior cingulate and medial parietal (precuneal) cortices, will be calculated to 
estimate the global amyloid load.
The PET imaging vendorwill provide quantitative florbetapir F 18 PET data for integration with 
the  
 clinical database and, as requested, will provide the PET images to the sponsor.  
The details of data and images to be transferredare specified in the respective data transfer 
agreements.  
6.6.2.2. Magnetic resonance imaging
MRI scans will be obtained as described in Section 6.4.9.3
CCI
under the management of the central 
imaging vendorand transferred to the vendorfor volumetric analysis. The images will be used 
to assess cerebral atrophy (hippocampal, temporal, ventricular, entorhinal cortex and whole brain 
volume changes) from baseline to end of treatment.
Atrophy represents a marker of neurodegeneration that is estimated to diverge from normal about 
5.5 years and 4 years prior to AD diagnosis in the hippocampus and the whole brain, 
respectively.  Rates of change in structural measures correlate closely with the gradual cognitive 
decline in AD and can be visualized by MRI.  Atrophy rates would generally be expected to be 
lower if the underlying disease is attenuated by effective treatment.  Thus, demonstrating an 
effect of AZD3293 on cerebral atrophy may support a disease-modifyingeffect of AZD3293.
The following volumetric measures will be derived from the MRI scansusing automated 
methods:  hippocampus volume, hippocampus atrophy, whole brain volume, whole brain 

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atrophy, ventricular volume, ventricular enlargement, entorhinal cortex volume, entorhinal 
cortex atrophy, temporal lobe volumes, and temporal lobe atrophy.
6.6.3. Plasma biomarkers
Blood samples for exploratory analysis of plasma biomarkers relevant to AD (Aβ1-40, Aβ1-42, 
inflammatory markers, and other markers of interest) will be collected from all patients at 
baseline (Visit 2), Week 52, and Week 97 (or final study visit) (see Study Plan in Table 2).
These samples will support characterization of the PD effects of AZD3293 on plasma 
biomarkers, which have not previously been studied in this patient population.  The samples will 
also enable exploratory evaluation of as-yet-unrecognized plasma biomarkers relevant to the 
diagnosis and prognosis of AD.
The vendor and methodology to analyze the plasma samples will be chosen prior to database 
lock, given the rapid technological development in this field.  
Detailed sample collection and handling procedures are provided in the Laboratory Manual.
Plasma aliquots for future analysis will be retained for up to 15 years from the date of the last 
patient’s last visit or for a shorter period if local regulations and/or ethical review boards (ERBs) 
/IRBs impose shorter time limits, at a facility selected by the Sponsor or its designee.
For blood sample volumes, see Section 7.1.
6.7.
Pharmacogenetics
A blood sample will be obtained at screening for mandatory APOE genotyping.
An optional sample will be collected and stored for future exploratory genetic research from 
patients who have given specific consent.  
Samples will be collected, labeled, stored and shipped as detailed in the Laboratory Manual.  The 
samples for future exploratory genetic research from consenting patients may be retained for up 
to 15 years or for a shorter period if local regulations and/or ERBs/IRBs impose shorter time 
limits, at a facility selected by the Sponsor or its designee.  If a patient does not consent to the 
optional genetic research, the blood sample will be discarded after the mandatory APOE
genotyping is performed.
For blood sample volumes, see Section 7.1.
6.8.
Pharmacogenomics
Blood samples for future pharmacogenomics research will be collected at baseline (Visit 2), 
Week 52, and Week 97 (or final study visit) (see Study Plan in Table 2) from patients who have 
given consent for this optional sampling.  
Samples will be collected, labeled, stored and shipped as detailed in the Laboratory Manual.  The 
samples may be retained for up to 15 years from the date of the last patient’s last visit or for a 

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shorter period if local regulations and/or ERBs/IRBs impose shorter time limits, at a facility 
selected by the Sponsor or its designee.  
For blood sample volumes, see Section 7.1.
6.9.
Health economics
Health economics variables included in this study to address an exploratory objective are the 
changes from baseline (Visit 2) to Week 104 in the RUD-Lite and EQ-5D-5L scores.  The results 
of analyses of these variables may not be included in the Clinical Study Report, but may be 
described in supplementary reports as appropriate.
6.9.1. RUD-Lite
The RUD Lite is a short version of Resource Utilization in Dementia (RUD; Wimo and Winblad 
2003) interview to assess formal resource utilization of patients with dementia as well as 
informal resource use (ie, time caregivers spend assisting the patient) during a specific time 
period.  These data make it possible to estimate costs of dementia care from a societal 
perspective.  The administration of the RUD Lite interview takes approximately 10 minutes and 
captures the following dimensions with regard to the patient:  long-term living accommodation, 
temporary changes in living situation (eg, respite care), and healthcare utilization to include 
hospital care, emergency room care, practitioner visits, and other resource use (eg, home 
healthcare, day care, care-related transportation).  In addition, the interview assesses time spent 
by the study partner providing care for the patient in the form of basic activities of daily living 
(eg, eating, grooming, dressing), instrumental activities of daily living (eg, shopping, food 
preparation, managing financial matters), and safety surveillance, as well as any time missed 
from work for caregiving responsibilities if the study partner is still working. 
A baseline version of the RUD-Lite questionnaire, given at the initial assessment, inquires about 
all dimensions of resource utilization over the previous 30 days.  The follow-up version of the 
questionnaire, administered at all subsequent assessments, assesses patient resource use since the 
last visit and caregiver time over the previous 30 days.
6.9.2. EQ-5D-5L
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.

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7. BIOLOGICAL SAMPLING PROCEDURES
7.1.
Volume of blood
The approximate volume of blood that will be drawn from each patient in this study is shown in
Table 6.
Table 6.
Volume of Blood to be Drawn From Each Patient
Assessment
Panel volume 
(mL)
No. of time points
Total volume 
(mL)
Safety
Clinical chemistry/Electrolytes
2.5
12
30
Hematology
2
12
24
Coagulation
1.8
1
1.8
Endocrinology
3.5*
3
8.5
Screening tests
8.5
1
8.5
Optional/Confirmatory Testing
11
1
11
Pharmacokinetics
AZD3293 and AZ13569724
3
9**
27
Plasma biomarkers
12
3
36
Pharmacogenetics
Mandatory APOE genetic sampling
2
1
2
Optional genetic sampling
6
1
6
Pharmacogenomics
5
3
15
Total
169.8
Note: Total volume does not include unscheduled Hepatic testing, early discontinuation, or unscheduled/follow-up 
visit
*3.5 mL collected at screening (Visit 1) and 2.5 mL collected at the other 2 visits (Visit 12 and Visit 20).
**Visits 4, 11, and 18 collects 2 time points.  See Section 6.5.1.
7.2.
Handling, storage and destruction of biological samples
The samples will be used up or disposed of after analyses or retained for further use as described 
here.
The results from future analyses will not be reported in the Clinical Study Report but separately 
in a scientific report and/or scientific publication.
7.2.1. Pharmacokinetic and/or pharmacodynamic samples
Blood and CSF samples collected for PK analysis will be disposed of after the Bioanalytical 
Report is finalized or 6 months after issuance of the draft Bioanalytical Report (whichever is 
earlier), unless retained for future analyses.  
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test PK samples.  The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical Report.

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Selected PK samples may be used for additional metabolite identification and/or quantification
or to investigate any potential dosing issues.  
Key blood and CSF samples collected for biomarker analysis may be retained for future 
investigations.  These samples will be retained for a maximum of 15 years following last 
patient’s last visit or for a shorter period if local regulations and/or ERBs/IRBs impose shorter 
time limits, at a facility selected by the Sponsor or its designee.  The results from investigations 
involving retained samples will be provided in separate reports and not in the Clinical Study 
Report.
7.2.2. Pharmacogenetic samples
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain patient confidentiality.  Samples will be stored for a maximum of 15 years from the 
date of the last patient’s last visit or for a shorter period if local regulations and/or ERBs/IRBs 
impose shorter time limits, after which they will be destroyed.  DNA is a finite resource that may 
be used up during analyses.  Samples will be stored and used until no further analyses are 
possible or the maximum storage time has been reached.
For all samples, irrespective of the type of coding used, the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information on 
the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA number 
only.  The DNA number is used to identify the sample and corresponding data at the at the 
designated contract laboratory.  No personal details identifying the individual will be available to 
any person 
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrollment/randomization code and the DNA number will be maintained and stored in 
a secure environment, with restricted access.  The link will be used to identify the relevant DNA 
samples for analysis, facilitate correlation of genotypic results with clinical data, allow 
regulatory audit, and trace samples for destruction in the case of withdrawal of consent when the 
patient has requested disposal/destruction of collected samples not yet analyzed.
7.3.
Labeling and shipment of biohazard samples
The Principal Investigator ensures that samples are labeled and shipped in accordance with the 
Laboratory Manual for this study and the Biological Substance, Category B Regulations 
(materials containing or suspected to contain infectious substances that do not meet Category A 
criteria).
Any samples identified as Infectious Category A materials are not shipped, and no further 
samples will be taken from the patient unless agreed with sponsor and appropriate labeling, 
shipment and containment provisions are approved.
7.4.
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.

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The Principal Investigator at each center keeps full traceability of collected biological samples 
from the subjects while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
The sponsor keeps oversight of the entire lifecycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the system during the entire lifecycle.
7.5.
Withdrawal of informed consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples for genetic or biomarker 
research, the samples will be disposed of/destroyed, and the action documented.  If samples are 
already analyzed, the sponsor is not obliged to destroy the results of this research.
As collection of the biological samples for genetic or biomarker research is an optional part of 
the study, then the patient may continue in the main study.
The Principal Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to the sponsor

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action documented and 
the signed document returned to the study site

Ensures that the patient and the sponsor are informed about the sample disposal.
The sponsor ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.

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8. ETHICAL AND REGULATORY REQUIREMENTS
8.1.
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the International Conference on 
Harmonization/Good Clinical Practice, applicable regulatory requirements and the sponsor
policy on Bioethics and Human Biological Samples.
8.2.
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy 
legislation.
The sponsor will not provide individual genotype results to the patient or study partner, any 
insurance company, any employer, the patient’s family members or general physician, or any 
other third party, unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient.  For example, in the case of a 
medical emergency, a sponsor Physician or an investigator might know a patient’s identity and 
also have access to his or her genetic data. Also, Regulatory authorities may require access to 
the relevant files, though the patient’s medical information and the genetic files would remain 
physically separate.
8.3.
Ethics and regulatory review
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives and by caregivers/partners.
An IRB or EC should approve the final study protocol, including the final versions of the 
Informed Consent Forms and any other written information and/or materials to be provided to 
the patients.  The investigator will ensure the distribution of these documents to the applicable 
IRB/EC, and to the study site staff.
The opinion of the IRB/EC should be given in writing. The investigator should submit the 
written approval to the sponsor before enrollment of any patient into the study. 
The IRB/EC should approve all advertising used to recruit patients for the study.
The sponsor should approve any modifications to the Informed Consent Forms that are needed to 
meet local requirements.
If required by local regulations, the protocol should be re-approved by the IRB/EC annually.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.

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The sponsor will handle the distribution of any of these documents to the national regulatory 
authorities.
The sponsor will provide Regulatory Authorities, IRBs and ECs and Principal Investigators with 
safety updates/reports according to local requirements, including SUSARs (Suspected 
Unexpected Serious Adverse Reactions), where relevant.
Each Principal Investigator is responsible for providing the IRB/EC with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with the investigational 
product.  The sponsor will provide this information to the Principal Investigator so that he/she 
can meet these reporting requirements.
8.4.
Informed consent
The Principal Investigator(s) at each center will:

Ensure each patient and his or her study partner are given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study

Ensure that each patient and study partner is informed of the optional 
pharmacogenetic/pharmacogenomic sampling and will ask the patient to consider 
providing consent for the sampling

Ensure each patient and study partner are notified that the patient is free to discontinue 
from the study at any time

Ensure that each patient and his or her study partner are given the opportunity to ask 
questions and allowed time to consider the information provided

Ensure each patient and study partner (and, where appropriate, legally authorized 
representative) provide signed and dated informed consent before any study-specific 
procedure is conducted

Ensure the original, signed and dated Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the relevant signed and dated Informed Consent Form is given to the 
patient and study partner

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in 
the Informed Consent Form that is approved by an IRB/EC.
8.5.
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International 
Co-ordinating Investigator, the Principal Investigator at each site, and the sponsor.

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If there are any substantial changes to the study protocol, then these changes will be documented 
in a study protocol amendment and, where required, in a new version of the study protocol 
(Revised Clinical Study Protocol).
The amendment is to be approved by the relevant IRB/EC and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed for 
revised protocols.
The sponsor (or its representative) will distribute any subsequent amendments and new versions 
of the protocol to each Principal Investigator(s). For distribution to IRBs and ECs, see 
Section 8.3.
If a protocol amendment requires a change to a center’s Informed Consent Form, the sponsor (or 
its representative) and the center’s IRB/EC are to approve the revised Informed Consent Form 
before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved by 
each IRB/EC.
8.6.
Audits and inspections
Authorized representatives of the sponsor, a regulatory authority, or an IRB/EC may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonization (ICH), and any applicable 
regulatory requirements.  The investigator will contact the sponsor immediately if contacted by a 
regulatory agency about an inspection at the center.

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9.STUDY MANAGEMENT 
Study management activities will be performed by  
 on behalf of the sponsor.
This study will be conducted in accordance with:
consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and CouncilforInternationalOrganizationsof
MedicalSciences(CIOMS) International Ethical Guidelines
applicable ICH GCP Guidelines
applicable laws and regulations
9.1. Pre-study activities
Before the first patientis entered into the study, it is necessary for a representative of the sponsor 
to visit the investigational study site to:
Determine the adequacy of the facilities
Determine availability of appropriate patientsfor the study
Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of the sponsor 
or its representatives.  This will be documented in a CSAbetween the sponsor and the 
investigator.
Discuss where the identification of the data will be recorded, eg, medical record(s), 
eCRF, or other associated documents.  This will be documented in the CSA.
Discuss the specific requirements of all genetic research performed in this study with the 
investigator(s) (and other personnel involved with the study) 
Confirm that appropriate raters are certified for all required study assessments
9.2. Training of study site personnel
CCI
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all investigationalstaff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.  The Principal Investigator will also maintain a record of all 
individuals involved in the study (medical, nursing and other staff).  
Training and information on all study-related processes will take place at the investigator 
meetings,at local initiation and monitoring meetings, and using web-based methods for remote 
training.  The sponsor or delegates will supply more detailed instructions to centerpersonnel as 
necessary before and during the study.  
Before the site’s first patient visit, the investigational staff will be trained to use the WBDC 
system by sponsor personnel or delegates.

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In addition, before the first patient is entered into the study the investigational staff will have an 
opportunity to discuss the procedures associated with the collection of blood samples, extraction 
of DNA,and optional and mandatory genetic research with sponsor personnelor delegates.  The 
ethical considerations specific to genotyping and the importance of the informed consent process 
for participation in the optional genetic exploratory research will be made clear.  The 
requirements for the collections of the patients’ samples will also be made clear.
Investigators and other staff who will be responsible for administering cognition and other rating 
scales (eg, CDR) must be certified and have an appropriate educational backgroundand/or
experience.  Rater training and certification will be provided by a specialized vendor.
Training for staff at the MRI and PET imagingcenters will be provided by the respective central 
imaging vendors.
Investigators should be instructed on the importance of retaining patients in the study, even if 
study treatment is discontinued (see Section 5.8), and minimizing the amount of missing data.  
9.3. Monitoring of the study
During the study, a  
 monitor, on behalf of the sponsor,will have regular contacts with 
the study site, including visits to:
Provide information and support to the investigator(s)
Confirm that facilities remain acceptable
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual,and that study medication accountability checks 
are being performed
Perform source data verification (a comparison of the data in the CRFs with the patient’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating patients.This will require 
direct access to all original records for each patient (eg, clinic charts)
Ensure withdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the patient and/or study partner.
The sponsor representative will be available between visits if the investigator(s) or other staff at 
the centerneed information and advice about the studyconduct.
9.3.1. Source data
CCI
Refer to the Source Document Agreementfor the location of source data.

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9.4.
Study agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency between 
this Clinical Study Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with 
respect to the conduct of the study and the treatment of patients and in all other respects, not 
relating to study conduct or treatment of patients, the terms of the CSA shall prevail.
Agreements between the sponsor and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.4.1. Archiving of study documents
The Investigator must follow the principles of ICH-GCP and applicable regulatory requirements 
regarding the archiving of study documents.
9.5.
Study timetable and end of study
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 Q4 of 2014 and to end by Q3 of 2019.
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice, or if recruitment is slow.  The sponsor may also 
terminate the entire study prematurely if concerns for safety arise within this study or in any 
other study with AZD3293.
The Principal Investigators will be notified by the sponsor when patient recruitment is complete.

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10. DATA MANAGEMENT
10.1.General principles
Data management will be performed by
.  Data will be entered in the WBDC system 
at the investigational site.  The WBDC system will be authorized and approved by the sponsor or 
its delegate and will be set up and maintained by 
.
The data management plan will describe in detail the methods used to collect, check, validate 
and process clinical data.  It will also clarify the roles and responsibilities for the different 
functions and personnel involved in the data management process.  Furthermore,the data 
management plan will describe the data flow and timelines within the study.
Data captured electronically will be immediately saved to the applicable database.  The data 
collected through third party sources will be obtained and reconciled against study data.  Data 
queries will be raised for inconsistent, impossible or missing data.  All entries and changes to the 
study database will be available in an audit trail.
Data associated with biological samples (blood and CSF) will be transferred to laboratories 
internal or external to the sponsor.  For information on genetic data management see 
Section10.2.
MRI and PET imaging data will be managed by the respective central imaging vendors.  The 
imaging datasetswill be transferred to  
.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the latest World Health Organization (WHO)Drug Dictionary.  
All coding will be performed by 
.
The data will be validated as defined in the data management plan.  Quality control procedures 
will be applied to eachstage of data handling to ensure that all data are reliable and have been 
processed correctly.
When all data have been coded, validated, andsigned,the final database will be locked.
10.2.Genetic data
CCI
Any genotype data generated in this study will be stored in anappropriate secure system within 
the sponsor and/or third party contracted towork with the sponsor to analyze samples.  The 
results from this genetic research may be reported in the clinical study report for the main study, 
or in a separate report asappropriate.
Some or all of the clinical datasets from the main study
 may be merged with the genetic data in a 
suitable secure environment separate from the clinical database.
CCI
CCI
CCI

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11.
EVALUATION AND CALCULATION OF VARIABLES
11.1. Calculation or derivation of efficacy variable(s)
11.1.1. ADAS-Cog13
A summary score will be computed across all dimensions of the 13-item ADAS-Cog scale.  
Changes from baseline ADAS-Cog13 score at each post-baseline time point will be calculated as 
the post-baseline score minus the baseline score.
11.1.2. Clinical Dementia Rating – Sum of Boxes
The CDR-SB score will be calculated as the sum of the individual CDR domain scores.  The 
global score summarizing the 6 domains of cognition and function will be calculated using the 
Washington University CDR-assignment algorithm (Morris 1993).
Changes from screening CDR-SB and global scores at each post-baseline time point will be 
calculated as the post-baseline score minus the baseline score.
Time in the current disease state will be assessed in terms of time to loss of 1 global stage on 
CDR global score through Week 104.  
11.1.3. Functional Activities Questionnaire
The FAQ total score will be calculated as the sum of the 10 individual FAQ item scores.  
Changes from baseline FAQ total score at each post-baseline time point will be calculated as the 
post-baseline score minus the baseline score.
11.1.4. The Alzheimer’s Disease Cooperative Study Activities of Daily 
Living Inventory
The ADCS-ADL instrumental items score will be calculated as the sum of the 17 individual 
instrumental item scores (maximum total score of 56).
Additionally, for exploratory analysis, the ADCS-ADL basic items score will be calculated as 
the sum of the individual 6 basic item scores (maximum total score of 22), and the ADCS-ADL 
total score will be calculated as the sum of all 23 instrumental and basic item scores (maximum 
total score of 78).
Changes from baseline in the ADCS-ADL instrumental items score, basic items score, and total 
score at each post-baseline time point will be calculated as the post-baseline score minus the 
baseline score.
11.1.5. Neuropsychiatric Inventory
The NPI total score will be calculated as the sum of the individual NPI item (frequency x 
severity) scores (maximum total score of 144).  

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The total NPI-D score will be calculated as the sum of the individual distress scores for each 
neuropsychiatric symptom (maximum score of 60).
Changes from baseline NPI total score and the total NPI-D score at each post-baseline time point 
will be calculated as the post-baseline score minus the baseline score.
11.1.6. Mini-mental State Examination
A total score will be computed across all dimensions of the MMSE and used as an outcome 
variable in the statistical analysis.  
Changes from screening MMSE total score at each post-baseline time point will be calculated as 
the post-baseline score minus the screening score.
11.1.7. iADRS cognitive/functional composite measure
For additional details regarding the iADRS scale see Section 6.3.2.4.
Changes from baseline iADRS total score at each post-baseline time point will be calculated as 
the post-baseline score minus the baseline score.
11.1.8. Letter and Category Fluency and Digit Symbol-Coding tests
For the Letter Fluency test, a total words score will be calculated by adding the total correct 
score from the 3 trials to the total errors score.  Changes from baseline total correct score at each 
post-baseline time point will be calculated as the post-baseline score minus the baseline score.  
Changes from baseline total words score will be calculated as the post-baseline score minus the 
baseline score.
For each administration of the Category Fluency test, a total words score will be calculated by 
adding the total correct score to the total errors score.  Changes from baseline total correct score 
at each post-baseline time point will be calculated as the post-baseline score minus the baseline 
score.  Changes from baseline total words score will be calculated as the post-baseline score 
minus the baseline score.
Changes from baseline Digit Symbol-Coding test score at each post-baseline time point will be 
calculated as the post-baseline score minus the baseline score.
11.1.9. Repeatable Battery for the Assessment of Neuropsychological 
Status
There are 12 subtests within the RBANS.  Pre- to post-treatment changes for each subtest score 
will be calculated as the final visit (Week 97) score minus the pre-treatment score obtained at 
screening (Visit 1).  Similarly, pre- to post-treatment changes in the 5 domain-specific Index 
scores (Immediate Memory, Visuospatial/Constructional, Language, Attention, and Delayed 
Memory) and RBANS total score will also be calculated.  Savings scores represent the amount of 
information that has been retained after a delay in time from the initial learning of information on 
a memory test.  The classic savings score will be calculated as a percent retention score for List 
Learning, Story Memory, and Figure Recall.

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11.2. Calculation or derivation of safety variable(s)
The onset of an AE relative to treatment will be calculated as the difference between the onset 
date of the AE and the date of the first dose of study treatment.
The duration of a resolved AE will be calculated as the difference between the resolution date of 
the AE and the onset date of the AE.  If an AE is unresolved at the time of the last contact with 
the patient, the resolution date will be entered in the database as missing and duration of the AE 
will not be calculated.  
11.2.1. Other significant adverse events (OAE)
During the evaluation of the AE data, a sponsor medically qualified expert will review the list of 
AEs that were not reported as SAEs and discontinuation AEs.  Based on the expert’s judgment, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical Study 
Report.  A similar review of laboratory, vital sign, and ECG data will be performed for 
identification of OAEs.
Examples of these are marked hematological and other laboratory abnormalities and certain 
events that lead to intervention (other than those already classified as serious), dose reduction, or 
significant additional treatment.
11.2.2. Laboratory tests (hematology, chemistry and urinalysis)
Changes in laboratory test results at each post-baseline time point will be calculated as the post-
baseline value minus the baseline value (Visit 2).  Individual patient data will be assessed for 
PCS values according to predetermined criteria as described in the statistical analysis plan.  
11.2.3. Vital signs
Changes in supine blood pressure and pulse rate at each post-baseline time point will be 
calculated as the post-baseline measurement minus the baseline measurement (Visit 2).  
Orthostatic changes in blood pressure and pulse rate will be calculated as the difference in vital 
signs after 2 and 5 minutes of standing from a supine position (ie, as the t+2 minute or t+5 
minute standing measurement minus the supine measurement at time t).  
Individual patient data will be assessed for PCS values according to predetermined criteria as 
described in the statistical analysis plan.
11.2.4. ECG results
Changes in ECG parameters at each post-baseline time point will be calculated as the post-
baseline value minus the baseline value (Visit 2).  Individual patient data will be assessed for 
PCS values according to predetermined criteria as described in the statistical analysis plan.  
For digital ECG data, smoothing of the RR and QT intervals will be performed first, before the 
derivation of the heart rate and the correction of the QT interval for heart rate (QTc interval).  
The data will be smoothed on an individual basis before descriptive and/or statistical analyses are 

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performed.  These derived parameters will be calculated by the study statistician or designee.  
For each patient, and for each target time point the mean QT and RR intervals will be calculated 
based on sampling for that time point.  The QT correction will be calculated according to the 
Fridericia method as QTcF = QT × RR(sec)-1/3.  The ventricular heart rate will be calculated 
based on the smoothed RR interval as 60.000/RR(msec).
11.2.5. Body weight and body mass index
Body mass index (BMI) will be calculated as body weight (kg) /[height (meters)]2.
Changes in body weight and BMI at each post-baseline time point will be calculated as the 
post-baseline value minus the baseline value (Visit 2).  
11.2.6. Magnetic resonance imaging
Individual patient data will be assessed for treatment-emergent ARIA.  
11.3. Calculation or derivation of pharmacokinetic variables
A population PK analysis of plasma AZD3293 and AZ13569724 concentration data will be 
performed.  The population PK analysis will involve standard PK structural modelling 
techniques using nonlinear mixed effects modelling to obtain population mean and variance 
values of specific PK parameters for AZD3293 and AZ13569724.  Potential covariate effects 
will be investigated as predictors of variability in AZD3293 and AZ13569724 PK.  Plasma 
AZD3293 and AZ13569724 concentration-time data from previous AZD3293 clinical 
pharmacology studies may be combined with data from this study.  The results of the population 
PK analysis will be provided in a separate report.
11.4. Calculation or derivation of pharmacodynamic variable(s)
11.4.1. Cerebrospinal fluid biomarkers
Changes from screening in CSF biomarker concentrations of Aβ1-40, Aβ1-42, total tau, 
phosphorylated tau and other, exploratory biomarkers (eg, sAPPβ) will be calculated for each 
post-baseline time point.  
Changes in biomarker concentration will be calculated as the post-baseline value minus the 
predose value.  
11.4.2. Imaging biomarkers
Volumetric MRI and PET imaging variables will be derived by the respective central imaging 
vendors and provided in agreed database format.  
Changes from screening/baseline will be calculated as the post-baseline value minus the predose 
value.  

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11.4.3. Relationship between pharmacokinetic and pharmacodynamic 
variables 
Plasma and CSF AZD3293 concentrations in relation to PD (biomarkers and cognitive markers) 
and other measures as appropriate will be examined graphically using plots showing predicted 
exposure to AZD3293 (AUC) and PD measures/markers.
11.4.4. Population analysis of pharmacokinetic/pharmacodynamic 
variables 
A population PK/PD analysis implementing appropriate structural models will be conducted 
following completion of the study to examine the relationships between AZD3293 and/or 
AZ13569724 and selected measures of efficacy (eg, the primary efficacy endpoint) or tolerability 
(eg, AE incidence) using nonlinear mixed effects modelling.  The results of the population 
PK/PD analysis will be provided in a separate report.
11.5. Calculation or derivation of pharmacogenetic variables
Pharmacogenetic outcomes for mRNA and miRNA in selected species will be calculated as 
change from baseline quantified with reverse transcription polymerase chain reaction (RT-PCR)
or equivalent technology.  Genetic variation in baseline DNA will be measured by direct 
resequencing of selected genes, including intronic and promoter regions.  Techniques may be 
modified as scientific advances are made.
11.6. Calculation or derivation of health economic variables
Changes in RUD-Lite and EQ-5D-5L scores at each post-baseline timepoint will be calculated as 
the post-baseline value minus the baseline value (Visit 2).  

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12.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION
12.1. Description of analysis sets
12.1.1. Efficacy
The Full Analysis Set 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.  When change from baseline is assessed, patients will be 
included in the analysis only if both a baseline and at least 1 valid post-baseline measure are 
available.
For the longitudinal CSF biomarker and PET (amyloid) sub-studies, the analysis sets will include 
all those patients whose eligibility was determined by the respective biomarker, who signed 
consent for the respective sub-studies, and who have a baseline and at least 1 valid post-baseline
CSF assessment or PET scan.
12.1.2. Safety
All patients who received at least 1 dose of randomized study treatment (AZD3293 or placebo)
will be included in the safety analysis set.  In safety data presentations, erroneously treated 
patients (eg, those randomized to “Treatment A” but actually given “Treatment B”) will be 
accounted for in their actual treatment groups.  If an AZD3293 dose group is dropped following 
an interim analysis (see Section 12.2.2), patients switched to the remaining AZD3293 dose and 
remaining on treatment will be accounted for as a separate group.  
12.1.3. Pharmacokinetics
The PK analysis set is defined as all patients in the safety population who have at least 1 
post-dose PK assessment.  The population PK analyses will be performed using this analysis set.
12.2. Methods of statistical analyses
12.2.1. General principles
The aim of the primary analysis is to evaluate whether at least 1 dose of AZD3293 is superior to 
placebo in slowing disease progression in patients with early AD (ie, the continuum of patients 
with MCI due to AD and patients diagnosed with mild dementia of the Alzheimer’s type), as 
measured by change from baseline in ADAS-Cog13 total score at Week 104.
The aim of the secondary analyses are to evaluate whether AZD3293 is superior to placebo for 
other outcomes as measured by the secondary endpoints:  FAQ score, ADCS-ADL score, 
CDR-SB score, iADRS, MMSE, time in the current disease state (CDR global score), NPI total 
score, to evaluate the clinical worsening and need for symptomatic treatments, and biomarkers 
that may be indicative of disease modification.

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A comprehensive Statistical Analysis Plan (SAP; including biomarker analyses), as well as 
separate population PK and PK/PD analysis plans, will be prepared and finalized before the 
study data are unblinded.  An interim analysis SAP will be prepared and finalized before each 
interim analysis.
12.2.2. Interim analyses
Four interim analyses may be conducted during this study.  The IDMC charter will specify the 
final details of the interim analyses.  Every effort will be made to implement this study in such a 
way that only IDMC members (see Section 12.4) and a ring-fenced external Independent 
Statistical Center will have access to unblinded data emerging from the study.  Furthermore, 
every effort will be made to conceal any of the predefined design adaptations during the course 
of the study to any party involved in the conduct of the study.  Maintaining validity and integrity 
of the study is of paramount importance to ensure its acceptability to the sponsor, the scientific 
community, and health authorities.  The sponsor Executive Committee will be established to 
review the IDMC recommendations in accordance with the prespecified objectives of the interim 
analyses.  Sponsor staff with direct roles in study conduct will not have access to the results of 
the interim data analyses.
12.2.2.1. Interim analysis 1
The first interim analysis (IA1) will be performed when approximately 70 patients per group 
have 13 weeks’ worth of data.  It is expected that, at IA1, approximately 500 patients will have 
been randomized globally.  The objective of IA1 is to assess the viability of continuing with 
AZD3293 with regard to safety.  
One of the following IDMC recommendations will result from IA1:

Continue the study unmodified

Discontinue enrollment in 1 or both AZD3293 treatment groups for reasons of an 
unacceptable safety profile.  

If 1 AZD3293 treatment group is discontinued for enrollment at IA1, the 
randomization ratio for newly enrolled patients will remain 2:1 (active:placebo). 
Patients in the discontinued AZD3293 treatment group will be switched to the other 
AZD3293 treatment group; for analysis purposes, these patients will be included in 
their originally assigned AZD3293 treatment group.  

Stop the study if enrollment in both AZD3293 treatment groups is discontinued
12.2.2.2. Interim analysis 2
The second interim analysis (IA2) will be performed when approximately 80% of patients have 
been randomized.  IA2 will assess the viability of continuing AZD3293 treatment groups with 
regard to safety and will re-assess the total sample size based on the Bayesian posterior 
predictive probabilities of the ADAS-Cog13, ADCS-iADL, and/or FAQ.  Further details will be 
described in the interim analysis SAP and finalized prior to unblinding of efficacy data.

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Any necessary sample-size adjustment will be recommended to the sponsor Executive 
Committee.
One or more of the following IDMC recommendations will result from IA2:

Continue the study unmodified

If neither AZD3293 treatment group was discontinued at IA1 and, therefore, both 
AZD3293 treatment groups remain in the study at IA2:

Discontinue enrollment in 1 or both AZD3293 treatment groups for reasons of an 
unacceptable safety profile.  If 1 dose is discontinued for enrollment at IA2, the 
randomization ratio for newly enrolled patients will remain 2:1 (active:placebo).  
Patients in the discontinued AZD3293 treatment group will be switched to the other 
AZD3293 treatment group; for analysis purposes, these patients will be included in 
their originally assigned AZD3293 treatment group.

Stop the study if both AZD3293 treatment groups are discontinued

If 1 AZD3293 treatment group was discontinued at IA1 and, therefore, 1 AZD3293 
treatment group remains in the study at IA2:

Discontinue enrollment in the remaining AZD3293 treatment group for reasons of an 
unacceptable safety profile

Stop the study if the remaining AZD3293 treatment group is discontinued

Increase the sample size
12.2.2.3. Interim analysis 3
A maximum of 2 additional interim analyses may occur following IA2. A futility interim 
analysis (IA3) may be performed if the study sample size does not increase at IA2 or there is
decreased confidence in current clinical trial design based on external data.
12.2.2.4. Interim analysis 4
An additional interim analysis (IA4) may be performed to assess for futility and for early 
stopping of the study for efficacy. Data cut-off for IA4 would occur approximately 52 weeks 
after the last patient is randomized; however, it may occur later or earlier than this expected date 
if external data warrant.  
To control for the remote possibility that the study will be stopped for efficacy, a Haybittle-Peto 
adjustment (Haybittle 1971, Peto et al 1976) will be used if efficacy is tested at IA4.  A 
significance level of α=0.001, will be used for treatment comparisons at the start of the 
multiplicity graph.  The final analysis will use a significance level of α=0.05 for treatment 
comparisons between the AZD3293 treatment groups and the placebo group at the start of the 
multiplicity graph (see Section 12.2.3). Further details will be described in the interim analysis 
SAP.

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12.2.3. Multiplicity adjustments
The proposed study design contains several elements that require multiplicity adjustments to 
strongly control the family-wise error rate (FWER):

Comparison of 2 AZD3293 treatment groups with the placebo group

Changing the randomization ratio to 2:1 if a dose is dropped at the first or second interim 
analysis

Sample size re-estimation at the second interim analysis
The first element, comparisons of the 2 AZD3293 treatment groups with the placebo group, is 
addressed by the use of a multiplicity graph.  A graphical multiplicity strategy will be used for 
testing key secondary hypotheses to protect against Type I error of falsely rejecting a null 
hypothesis.  The use of a prespecified analysis plan that employs Bretz’ graphical approach will 
provide strong control of the study-wise Type I error rate for the primary and key secondary 
hypotheses at level α=0.05 (Bretz et al. 2009, 2011). The specific multiplicity graph will be 
detailed in the SAP.
In addition, to strongly control the FWER, a confirmatory adaptive design should satisfy the 
conditional invariance principle (Brannath et al 2007):  separate test statistics will be calculated 
from the 2 patient cohorts (those patients enrolled prior to the second interim analysis [IA2], and 
those enrolled after IA2) and combined in a prespecified way (using the weighted inverse normal 
p-value combination method) for the final test decisions.  Hence, any design modification that 
preserves the distributional properties of the separate test statistics under a given null hypothesis 
of interest will not lead to an inflation of the FWER.  The p-value combination test principle 
combines the 2 p-values using a prespecified combination function and by construction satisfies 
the invariance principle.  Details on the implementation of the measures to strongly control the 
FWER will be provided in the statistical analysis plan
A separate family of biomarkers will be tested at α=0.05.  The family will include the 
biochemical biomarkers (CSF Aβ1-42, total tau, and phosphorylated tau), as well as imaging 
biomarkers (amyloid PET and volumetric MRI).  
12.2.4. Efficacy
All analyses will be performed in a manner that is consistent with the intent-to-treat (ITT) 
principle.  An ITT analysis is an analysis of data by the groups to which patients are assigned by 
random allocation, even if a patient does not take the assigned treatment or does not receive the 
correct treatment, or otherwise does not follow the protocol or is not followed to the end of the 
study (ie, Week 104).  If a treatment group is dropped at an interim analysis, the data from those 
patients will be analyzed according to the treatment group to which the patients were originally 
randomized.  When change from baseline is assessed, a modified ITT (mITT) approach will be 
used; patients will be included in the analysis only if both a baseline and a post-baseline measure 
are available.

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12.2.4.1. Primary analysis
The primary efficacy endpoint, change from baseline at Week 104 in ADAS-Cog13 total score,
will be analyzed using an MMRM model that includes the fixed effects of treatment, visit 
(categorical covariate), treatment-by-visit interaction, disease status at baseline (MCI due to AD 
or mild AD), APOE4 status (carrier versus non-carrier), baseline ADAS-Cog13 total score 
(continuous covariate), concomitant AChEI use at baseline (yes/no), age at baseline, country, and 
baseline ADAS-Cog13 total score-by-visit interaction.  An unstructured variance-covariance 
matrix will be used.
For each of the 2 AZD3293 treatment groups, the null hypothesis is that the change from 
baseline in ADAS-Cog13 total score at Week 104 is equal to the change from baseline in 
ADASCog13 total score at Week 104 for the placebo treatment group.  The alternative 
hypothesis is that the change from baseline in ADAS-Cog13 total score at Week 104 for an 
AZD3293 treatment group (μAZD3293) is not equal to the change from baseline in ADAS-Cog13
total score at Week 104 for the placebo treatment group (μPlacebo). These hypotheses can be 
represented as follows:
HNull:  μAZD3293 = μPlacebo
HAlternative:  μAZD3293 ≠ μPlacebo
The primary analysis will evaluate whether there is a difference between treatment groups in the 
mean change from baseline in ADAS-Cog13 total score at Week 104 and will be based on the 
treatment difference at Week 104 using least-squares means.  This will be accomplished by using 
appropriate linear contrasts of the parameters in the model described above.
As a sensitivity analysis, a method for missing value imputation based on pattern mixture models 
will be implemented.  It is assumed that after discontinuation from the study, patients receiving 
the AZD3293 doses will exhibit the same future evolution of the disease as patients on placebo 
treatment.  This method uses sequential regression and multiple imputation methodology to 
impute missing values for visits after a patient’s discontinuation from the study.  Based on the 
available data from placebo-treated patients, the missing values from the placebo and AZD3293 
treatment groups will be imputed sequentially using a procedure for monotone missing data 
patterns until all visits are imputed.
12.2.4.2. Secondary analyses
When a comparison between an AZD3293 dose group and the placebo group is statistically 
significant on the primary efficacy endpoint, the secondary efficacy endpoints for the AZD3293 
dose group will be tested through a graphical approach. The specific graph is detailed in the end-
of-study analysis SAP prior to the end-of-study database lock.
Categorical analyses of slowing cognitive and functional decline will be conducted comparing 
proportions of patients reaching certain levels of decline between AZD3293 treatment groups 
and the placebo group. The precise definitions of cognitive and functional decline and analysis 
methods will be detailed in the SAP prior to database lock.

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The ADAS-Cog13 total score results for change from baseline at Week 104 will be assessed for 
consistency among subgroups defined by disease status at baseline (MCI due to AD or mild AD), 
APOE4 status (carrier versus non-carrier), age, race, sex, region, and acetylcholinesterase 
inhibitor use at baseline (yes or no).  
Exploratory analyses of the NPI total score will be conducted; some of these analyses will be 
limited to the domains that are most prevalent at baseline.  Exploratory analyses of the 
ADCS-ADL basic items score and total score will also be conducted.  In an additional 
exploratory analysis, the proportion of patients with MCI due to AD who progress to mild AD, 
as assessed by the NIA-AA diagnostic criteria, over 1 year and 2 years, will be examined.  The 
Statistical Analysis Plan will provide further details of these analyses.  
Exploratory efficacy variables (see Section 6.3.3) will be analyzed using the MMRM models 
described above as well as with descriptive statistical analyses.  These variables include changes 
from screening/baseline to Week 104 that include but are not limited to: the Letter Fluency, 
Category Fluency, and Digit Symbol-Coding test scores, the NPI-D score, as well as the changes 
over time from screening to Week 97 in the RBANS score.
12.2.5. Biomarkers
Changes from screening to Week 97 in CSF biomarkers (eg, Aβ1-42, total tau, and 
phosphorylated tau) will be analyzed using an MMRM analysis that includes the fixed effects of 
treatment, visit (categorical covariate), treatment-by-visit interaction, disease status at baseline 
(MCI due to AD or mild AD), APOE4 status (carrier versus noncarrier), and predose biomarker 
value (continuous covariate).  An unstructured variance-covariance matrix will be used.  The 
primary analysis is based on the treatment difference at Week 97 using least-squares means.  The 
null hypothesis is that the difference in means between the AZD3293 group and placebo equals 
zero.  
The primary analyses of estimates of global cortical load from amyloid PET and volumetric 
brain measures from MRI will be analyzed using the same methodology as described above for 
the CSF biomarker data.
In addition, amyloid PET data, including inter-individual patterns of baseline cortical load and 
intra-individual patterns of regional amyloid deposition, as well as eventual patient-level or 
regional differences in the longitudinal change of amyloid, will be explored in relation to 
AZD3293 treatment.  Multivariate regression analysis will be performed on the level of global 
cortical amyloid load, the level of regional measures of amyloid binding and, potentially, on the 
level of single volume elements (voxels) of amyloid binding (parametric) images.  Other imaging 
(ie, volumetric MRI) and non-imaging (eg, CSF biomarker, cognitive, demographic) data may 
also be explored as covariates in the analysis model.  
12.2.6. Health economics
For the RUD-Lite, the individual item responses and the total study partner time spent in 
assisting the patient, as well as changes from baseline in these variables, will be summarized by 
treatment group and time point using descriptive statistics.  

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For the EQ-5D-5L and EQ VAS responses and changes from baseline will be summarized by 
treatment group and time point using descriptive statistics.
12.2.7. Pharmacokinetics
Plasma and CSF AZD3293 and AZ13569724 concentrations will be summarized by treatment 
and time point using descriptive statistics.  
The results of the population PK analyses described in Section 11.3 will be summarized in a 
separate report.  
12.2.8. Pharmacokinetics-pharmacodynamics
It is intended that an early lock of the PK data will be conducted to allow PK modeling to begin 
before the end of the treatment period and to ensure that exposure estimates from this study are 
available for use in exposure-response models examining the influence of PK on either efficacy 
or safety endpoints at the completion of the study. It is intended that the PK data will be locked 
after all patients complete Visit 16 (78 weeks of treatment). No safety or efficacy data will be 
included in the 78-week PK lock. An Early PK Lock Plan will be developed and implemented 
prior to this lock, which will specify the safeguards to be taken to ensure the integrity of the 
study. The results of the population PK/PD analysis described in Section 11.4.4 will be 
summarized in a separate report.
12.2.9. Pharmacogenomics
The analysis of pharmacogenomics (DNA) outcomes will consist of an analysis of the 
association of baseline variation with chosen outcome parameters, including efficacy and 
biomarker outcomes.  The analysis of mRNA and miRNA outcomes will consist of descriptive 
statistics regarding change from baseline, including stratification by endpoints.  
Pharmacogenomics outcomes will be tested in a prioritized list of genes for which a scientific 
hypothesis for interaction with the pharmacology of AZD3293 and/or the pathophysiology of 
AD can be formulated, based on knowledge in the field.  The results will be summarized in a 
separate report.  Both univariate statistics and multivariate models may be applied.
12.2.10.
Safety
The incidence and severity of treatment-emergent AEs will be summarized by treatment group.  
The results of clinical laboratory tests; 12-lead ECGs; physical, eye, skin, and neurological 
examinations; safety MRIs; suicidality evaluations (C-SSRS), body weight and body mass index; 
and vital sign measurements will be summarized with descriptive statistics, by treatment group, 
for all time points at which these variables are collected.  In addition, visual displays of the time
course of AEs will be generated, and analyses that account for time on study will be conducted.
Individual patient data for vital signs, ECG results, and laboratory test results will be assessed for 
PCS values according to predetermined criteria.  Any PCS values identified will be summarized 
by treatment group.

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12.3. Determination of sample size
12.3.1. Efficacy
The sample size for this study, 734 randomized patients in each of 3 treatment groups, was 
selected to be consistent with the hypothesis described in Section 1.2. The sample-size 
calculations are based on the primary efficacy endpoint, change from baseline in ADAS-Cog13
total score at Week 104. 
Assumptions about minimally clinically significant differences as measured by the ADAS-Cog 
total score were based on 18 month solanezumab results extrapolated to 24 months. In this 
database, the least-squares treatment difference from placebo in mean change in ADAS-Cog 
total score from baseline at 80 weeks in the mild AD population of APOE4 carriers with CDR 
global score = 0.5 was 1.68 units with a standard deviation (SD) of 9.72. A linear extrapolation 
using these results coupled with results at 28 and 52 weeks resulted in 104 week estimates of 
2.24 (12.96). Using these estimates to approximate an MCI population, this expected difference
translates into an effect size of 0.17.
Compared with the MCI population, deterioration of cognition in patients with mild AD has been 
observed to be somewhat faster. The least-squares treatment difference from placebo in mean 
change in ADAS-Cog total score from baseline at 80 weeks in the solanezumab mild AD 
population (enriched by restricting to APOE4 carriers) was 2.87 (10.16) units. A linear 
extrapolation using these results coupled with results at 28 and 52 weeks resulted in 104 week 
estimates of 3.83 (13.54). This expected difference translates into an effect size of 0.28. 
Similar calculations were made for the key secondary endpoint ADCS-iADL. The least-squares
mean change in ADCS-iADL score from baseline at 80 weeks in the mild placebo-treated 
population of APOE4 carriers with CDR global score = 0.5 was 0.31 (8.39) units.  A linear 
extrapolation using these results coupled with results at 28 and 52 weeks resulted in 104 week 
estimates of 0.41 (11.19). Using these estimates to approximate an MCI population, this 
expected difference translates into an effect size of 0.04. The least-squares mean change in 
ADCS iADL score from baseline at 80 weeks in the mild AD population (enriched by restricting 
to APOE4 carriers) was 2.14 (9.81) units.  A linear extrapolation using these results coupled with 
results at 28 and 52 weeks resulted in 104 week estimates of 2.85 (13.08). This expected 
difference translates into an effect size of 0.22.
The study will enroll a total of 2202 patients (734 patients per group). Assuming =0.025 and 
the effect size among the patients who discontinue without completing the study is 50% of the 
effect size of the completers, the power for the mixture of MCI and mild AD patients for a single 
dose is 96% for ADAS-Cog (adjusted effect size is 0.21); for iADL it is 60% (adjusted effect 
size is 0.13). The power to show statistical significance for the mild AD subpopulation is 93% 
(adjusted effect size is 0.24) and 75% (adjusted effect size is 0.19) for ADAS-Cog and iADL, 
respectively. The power to show statistical significance for the MCI subpopulation is 26% 
(adjusted effect size is 0.14) and 3% (adjusted effect size is 0.03) for ADAS-Cog and iADL, 
respectively (Table 7).

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Table 7.
Effect Size and Power per Dosefor Mild AD and MCI Patient 
Populations
Population
ADAS-Cog
ES per Dose
ADAS-Cog
Power per Dose
ADCS-iADL
ES per Dose
ADCS-iADL
Power per Dose
Overall*
0.21
96%
0.13
60%
Mild AD
0.24
93%
0.19
75%
MCI
0.14
26%
0.03
3%
*The overallpopulationeffect sizes and power calculations usea distribution of 65%mild ADpatientsand 35%
MCI patients.
Abbreviations: AD  Alzheimer’s Disease; ADAS-Cog  Alzheimer’s Disease Assessment Scale-Cognition; 
ADCS-iADL  The Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory-instrumental 
items score;ES  Effect size; MCI  Mild cognitive impairment.
12.3.2.Biomarkers
This section summarizes the sample-size estimates and power calculations for biomarkers arising 
from the CSF and PET sub-studies and for volumetric MRI data.  All biomarker analyses will 
use α=0.05 (2-sided).
12.3.2.1.CSF biomarkers
It is expected that at least 175 patients will be included in the CSF sub-study.  Three CSF 
biomarkers will be assessed:  Aβ1-42, total tau, andphosphorylated tau.  Assuming a 40% missed 
post-baseline test rate, approximately 35 patients per treatment group will have a baseline value 
and a post-randomization value.  Estimated treatment differences are based on data from the 
Alzheimer’s Disease Neuroimaging Initiative Pool C (www.adni-info.org).  
 
  
The expected mean (SD) change in CSF Aβ1-42over 104 weeks is -164 (63.25) units.  The 
minimum detectable AZD3293 difference from placebo is 49.72 units (30% reduction) with 90% 
power and 43 units (26% reduction) with 80% power, α=0.05 (2-sided, t-test).  
The expected mean (SD) change in CSF total tau over 104 weeks is -103 (61) units.  The 
minimum detectable AZD3293 difference from placebo is 41.4  units (47% reduction) with 90% 
power and 43 units (40% reduction) with 80% power, α=0.05 (2-sided, t-test).
The expected mean (SD) change in CSF phosphorylated tau over 104 weeks is -36(18) units.  
The minimum detectable AZD3293 difference from placebo is 14units (39% reduction) with 
90% power and 12 units (33% reduction) with 80% power,α=0.05 (2-sided, t-test).
12.3.2.2.PET biomarkers
CCI
To explore the effect of AZD3293 on brain amyloid plaque using PET, 900patients will be 
enrolled in the florbetapir F 18 amyloid PET sub-study to yield 540patients witha baseline and 
post-randomization value (assuming a 40% missed post-baseline testrate).  Based on the ADNI 

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study results, using florbetapiras the radioligand, the expected mean ± SD change in amyloid 
load over 104 weeks is 0.0484 ± 0.0979 in SUVR-equivalent units (for patients with a baseline 
amyloid load of 1.15 to 1.38) in the placebo treatment group.  Accordingly, the minimum 
detectable AZD3293 difference from placebo is 0.036 units (a 75% reduction) in the slope of Aβ 
accumulation with 92.1% power, and .041 units (a 85% reduction) with 97.5% power; α=0.05 
(2-sided, t-test).  Estimated treatment differences are based on data from the Alzheimer’s Disease 
Neuroimaging Initiative (www.adni-info.org): University of Berkeley analysis of florbetapir
longitudinal data, only including subjects who have moderately
 positive amyloid load in brain 
(SUVR in cortex was 1.15 to 1.38 at baseline).
12.3.2.3.MRI biomarkers
Volumetric MRI data will be obtained from all 2202patients enrolled in the study.  Assuming a 
30%dropout rate, it is expected that 1541patients (approximately 514 per treatment group) will 
complete the study. Assuming a mean (SD) decrease of 7.565 (5.242) units in MRI brain 
volume by Week 104 in the placebo group, the minimum detectable AZD3293 difference from
placebo is 1.367 units (an18% reduction) with greater than 99% power and α=0.05 (2-sided, 
t-test).  Estimated treatment differences are based on data from the Alzheimer’s Disease 
Neuroimaging Initiative Pool C (www.adni-info.org). 
 
 
12.3.3.Pharmacogenetics
The number of patients whowill agree to participate in the optional genetic research is unknown.  
It is therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A separate 
Statistical Analysis Plan will be prepared where appropriate.
12.4.Data monitoring committee 
This study will use an IDMC to monitor data on an ongoing basis to ensure the continuing safety 
of patients enrolled in the study, to ensure the integrity of the blinded nature of the study, and to 
oversee the interim analyses (see Section 12.2.2).  The IDMCwill be composed ofindividuals 
external to the sponsor and will consist of a Chair, plus at least 1medical expert in the relevant 
therapeutic area and at least 1 statistician.  The IDMC recommendations may include, but will 
not be limited to, the following:
Continue the study as designed
Modify the study and continue (including discontinuation of an AZD3293 dose group)
Stop the study (for reasons of safety, conduct, or external information)
AnIDMCcharter will be developed which will specify the Committee’s responsibilities, 
authorities, and procedures along with details ofthe interim analysis planning, decision-making 
guidance, and dissemination of the results as well as the recommendations and decisions after the 
interim analyses (see Section 12.2.2)
CCI
.  Formal implementation and communication of IDMC 

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recommendations will be managed by the sponsor Executive Committee, chaired by the sponsor 
Chief Medical Officer and unrelated to the AZD3293 project team, will receive and act on the 
recommendations from the IDMC.  A firewall will be established to ensure the maintenance of 
the study blind for the sponsor, the investigational site staff, and study patients and their study 
partners.  

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13. IMPORTANT MEDICAL PROCEDURES TO BE 
FOLLOWED BY THE INVESTIGATOR
13.1.Medical emergencies and sponsor contacts
The Principal Investigator is responsible for ensuring that procedures and expertise are available 
to handle medical emergencies during the study. Amedical emergency usually constitutes an 
SAE and is to be reported as such, see Section6.4.4
In the case of a medical emergency the Investigator may contactthe  
 Study Physician.
The treatment code may not be broken except in an emergency situation when the appropriate 
management of the patient necessitates knowledge of the treatment allocation.  In such an 
emergency, the investigator will, if time and circumstances permit,contact the local sponsor 
representative prior to breaking the treatment code (see Section 5.4.2).
13.2.Overdose 
If a patient takes more than 2total daily dosesof studymedicationin a 24-hour period,itwill be 
considered an overdose.  
There are currently no data regarding overdosing of AZD3293, and there is no known antidote 
for AZD3293.  In case of overdose, monitoring of cardiac, hepatic and hematological effects is
essential, and appropriate standard support therapy should be initiated where clinically indicated.  
If an overdose on study medication occurs in the course of the study, then investigators or other 
site personnelmust inform appropriate sponsor representativesincluding the sponsor-designated 
medical monitor.  A blood sample for determination of plasma AZD3293 concentration should 
be obtained if at all possible, and as soon as possible after the overdose becomes known, if 
associated with an AE.
An overdose without associated symptoms is only recordedonthe Overdose CRF.
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant AE 
modulesin the CRF and on the Overdose CRF.
For overdoses associated with SAEs, standard reporting timelinesand proceduresapply, see 
Section6.4.4.  The Overdose CRFis also completed.
13.3.Pregnancy
All outcomes of pregnancy either in astudy patient or pregnant partner should be reported to the 
sponsor.
13.3.1.Maternal exposure
Women of childbearing potential are not allowed to be included in this study.  Should a 
pregnancy still occurduring study treatment, the patientshould be discontinuedfrom the study 
immediately (as described in Section 5.3)
CCI
and the pregnancy reported to the sponsor.  Any 
pregnancy occurring from the date of the first dose of study treatment until 90 days after the last 

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dose and any pregnancy occurring within 90 days after amyloid PET scan should be reported to 
the sponsor and followed up for its outcome as described below.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
inform appropriate sponsor representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it.  Pregnancies are to be reported to the sponsor representatives using 
the Pregnancy Notification provided.  
The same timelines apply when outcome information is available.
13.3.2. Paternal exposure
Pregnancy of a patient’s sexual partner is not considered to be an AE.  However, any conception 
occurring from the date of the first dose until 90 days after the last dose and any pregnancy 
occurring within 90 days after amyloid PET scan should be reported to the sponsor and followed 
up for its outcome (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality).

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14.
LIST OF REFERENCES
Aisen PS. Alzheimer's disease therapeutic research: the path forward. Alzheimers Res Ther.
2009;1:2.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of 
mild cognitive impairment due to Alzheimer's disease: recommendations from the National 
Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for 
Alzheimer's disease. Alzheimers Dement. 2011;7:270-279. 
Amieva H, Le Goff M, Millet X, Orgogozo JM, Pérès K, Barberger-Gateau P, et al. Prodromal 
Alzheimer's disease: successive emergence of the clinical symptoms. Ann Neurol.
2008;64:492-498.
Alzheimer’s Disease Neuroimaging Initiative Pool C available at: www.adni-info.org
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. 
Brannath W, Koenig F, Bauer P. Multiplicity and flexibility in clinical trials. Pharmaceutical 
Statistics. 2007;6:205-216.
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604.
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches for 
multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. 
Biom J. 2011;53(6):894-913.
Cai J, Qi X, Kociok N, Skosyrski S, Emilio A, Ruan Q, et al. β-secretase (BACE1) inhibition 
causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO 
Mol Med. 2012;4:980-991.
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.
Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, Tahirovic S, et al. Bace1 and 
Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J.
2013;32:2015-2028.
Chuang-Stein C, Kirby S, Hirsch I, Atkinson G. The role of the minimum clinically important 
difference and its impact on designing a trial. Pharm Stat. 2011;10:250-256.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron.
1976;16(1):31-41.
Coley N, Andrieua S, Jaros M, Weiner M, Cedarbaum J, Vellas B. Suitability of the Clinical 
Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer’s disease trials. 
Alzheimers Dement. 2011;7:602-610.
Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. 
Neurology. 1997;48(5 Suppl 6):S10-S16.

D5010C00009 (ed. 7.1) Clinical Protocol
Page 118
AZD3293 [LY3314814]
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.
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. 
Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA 
criteria. Lancet Neurol. 2007;6:734-746.
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(3):189-198.
Forman M, Palcza J, Tseng J, Leempoels J, Ramael S, Han D et al. The novel BACE inhibitor 
MK-8931 dramatically lowers cerebrospinal fluid Ab peptides in healthy subjects following 
single- and multiple-dose administration. Alzheimers Dementia. 2012;8(4):P704.
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. 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 Geriatr Soc.
2004;52(7):1070-1076.
Grill JD, Di L, Lu PH, Lee C, Ringman J, Apostolova LG, et al. Estimating sample sizes for 
predementia Alzheimer's trials based on the Alzheimer's Disease Neuroimaging Initiative. 
Neurobiol Aging. 2013;34(1):62-72.
Hachniski VC, Iliff LD, Zilhka E, Du Boulay GH, McAllister VL, Marshall J, et al. Cerebral 
blood flow in dementia. Arch Neurol. 1975;32:632-637.
Haybittle JL. Repeated assessments of results in clinical trials of cancer treatment. B J Radiol.
1971;44(526):793-797.
Higuchi S, Liu Y, Yuasa T, Maeda A, Motohashi Y. Diurnal variation in the P300 component of 
human cognitive event-related potential. Chronobiol Int. 2000;17(5):669-678.
Hitt BD, Jaramillo TC, Chetkovich DM, Vassar R. BACE1-/- mice exhibit seizure activity that 
does not correlate with sodium channel level or axonal localization. Mol Neurodegen.
2010;5:31.
Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, et al. Bace1 modulates myelination 
in the central and peripheral nervous system. Nature Neuroscience. 2006;9:1520-1525.
Hu X, He W, Diaconu C, Tang X, Kidd GJ, Macklin WB, et al. Genetic deletion of BACE1 in 
mice affects remyelination of sciatic nerves. Faseb J. 2008;22:2970-2980.
Hu X, Zhou X, He W, Yang J, Xiong W, Wong P, et al. BACE1 deficiency causes altered 
neuronal activity and neurodegeneration. J Neurosci. 2010;30:8819-8829.
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.
Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model 
of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol.
2010;9(1):119-128.

D5010C00009 (ed. 7.1) Clinical Protocol
Page 119
AZD3293 [LY3314814]
Kim DY, Gersbacher MT, Inquimbert P, Kovacs DM. Reduced sodium channel Na(v)1.1 levels 
in BACE1-null mice. J Biol Chem. 2011;286:8106-8116.
Koike MA, Lin AJ, Pham J, Nguyen E, Yeh JJ, Rahimian R, et al. APP knockout mice 
experience acute mortality as the result of ischemia. PLoS ONE. 2012;7(8): e42665.
Kuhn PH, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, et al. Secretome protein 
enrichment identifies physiological BACE1 protease substrates in neurons. The EMBO 
Journal. 2012;31:3157-3168.
Lai R, Albala B, Kaplow JM, Aluri J, Yen M, Satlin. A: First-in-human study of E2609, a novel 
BACE1 inhibitor, demonstrates prolonged reductions in plasma betaamyloid levels after single 
dosing. Alzheimers Dementia. 2012;8(4):96.
Laird FM, Cai H, Savonenko HV, Farah MH, He K, Melnikova T, et al. BACE1, a major 
determinant of selective vulnerability of the brain to amyloid-amyloidogenesis, is essential for 
cognitive, emotional, and synaptic functions. J Neurosci. 2005;25(50):11693-11709.
Landau SM, Lu M, Joshi AD, Pontecorvo M, Mintun MA, Trojankowski JQ, Shaw LM, Jagust 
WJ, Alzheimer’s Disease Neuroimaging Initiative. Comparing positron emission tomography 
imaging and cerebrospinal fluid measurements of -amyloid. Ann Neurol. 2013;74(6):826-
836.
Lucey BP, Bateman RJ. Amyloid- β diurnal pattern: possible role of sleep in Alzheimer’s disease 
pathogenesis. Neurobiol Aging. 2014; May15. Pii:S0197-4580(14)00350-9. 
Doi:10.1016/j.neurobiolaging.2014.03.035. [Epub ahead of print].
May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN et al. Robust central 
reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. 
J Neurosci. 2011;31:16507-16516.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The 
diagnosis of dementia due to Alzheimer's disease: recommendations from the National 
Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for 
Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269.
Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, et al. 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.
Morris JC. The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology.
1993;43(11):2412-2414. Available at: http://www.biostat.wustl.edu/~adrc/cdrpgm/.
Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, et al. BACE1 
deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of 
Alzheimer's disease. Neuron. 2004;41:27-33.
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.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard V, et al. Design and analysis of 
randomized clinical trials requiring prolonged observation of each patient. I. Introduction and 
design. Br J Cancer. 1976;34(6):585-612.

D5010C00009 (ed. 7.1) Clinical Protocol
Page 120
AZD3293 [LY3314814]
Pfeffer RI, Kurosaki TT, Harrah CH, Chance JM, Filos S. Measurement of functional activities 
in older adults in the community. J Gerontol. 1982;37(3):323-329.
Raghavan N, Samtani MN, Farnum M, Yang E, Novak G, Grundman M, Narayan V, 
DiBernardo A, Alzheimer's Disease Neuroimaging I. The ADAS-Cog revisited: novel 
composite scales based on ADAS-Cog to improve efficiency in MCI and early AD trials. 
Alzheimer Dement. 2013;9(1 Suppl):S21-31. 
Rajapaksha TW, Eimer WA, Bozza TC, Vassar R. The Alzheimer's β-secretase enzyme BACE1 
is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus 
formation in the olfactory bulb. Mole Neurodegen. 2011;6:88.
Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A. Pathological verification of ischemic score 
in differentiation of dementias. Ann Neurol. 1980;7:486-488.
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry.
1984;141:1356-1364.
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.
Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC. Alteration of 
BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null 
mice. PNAS. 2008;105(14):5585-5590.
Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, et al. 
Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative 
subjects. Ann Neurol. 2009;65:403-413.
Vanderstichele H, Bibl M, Engelborghs S, Le Bastard N, Lewczuk P, Molinuevo JL, et al. 
Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for 
Alzheimer's disease diagnosis: A consensus paper from the Alzheimer's Biomarkers 
Standardization Initiative. Alzheimers Dement. 2012;8(1):65-73.
Vellas B, Carrillo MC, Sampaio C, Brashear HR, Siemers E, Hampel H, et al. Designing drug 
trials for Alzheimer's disease: what we have learned from the release of the phase III antibody 
trials: a report from the EU/US/CTAD Task Force. Alzheimers Dement. 2013;9:438-444.
Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid beta 
deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a 
prospective cohort study. Lancet Neurol. 2013;12:357-367.
Wang H, Song L, Laird FM, Wong PC, Lee HK. Beta-amyloid precursor protein cleavage 
enzyme 1 (BACE1) knockouts display deficits in activity-dependent potentiation of synaptic 
transmission at mossy fiber to CA3 synapses in the hippocampus. J Neurosci.
2008;28(35):8677-8681.
Wechsler Adult Intelligence Scale. 3rd ed. San Antonio, Texas: Psychological Corporation;
1997.
Weigand SD, Vemuri P, Wiste HJ, Senjem ML, Pankratz VS, Aisen PS, et al. Transforming 
cerebrospinal fluid Aβ42 measures into calculated Pittsburgh Compound B units of brain Aβ 
amyloid. Alzheimers Dement. 2011;7(2):133-141.

D5010C00009 (ed. 7.1) Clinical Protocol
Page 121
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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, Winblad B. Resource utilisation in dementia: RUD Lite. Brain Aging. 2003:14:48-59.
Zhou L, Barão S, Laga M, Bockstael K, Borgers M, Gijsen H, et al. The neural cell adhesion 
molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. JBC. 2012;287:25927-
25940.

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Appendix A.
Signatures
Revised Clinical Study Protocol Appendix A
Drug Substance
AZD3293 [LY3314814]
Study Code
D5010C00009 [I8D-MC-AZES]
Edition Number
7.1
Date
See Cover Page
Appendix A
Signatures
Please see electronic signature appended to this document.

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Appendix B.
Additional Safety Information
Clinical Study Protocol Appendix B
Drug Substance
AZD3293 [LY3314814]
Study Code
D5010C00009 [I8D-MC-AZES]
Edition Number
7.1
Date
See Cover Page
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS ADVERSE EVENT 
(SAE)
Life threatening
“Life-threatening” means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the subject’s 
death.  “Life-threatening” does not mean that had an AE occurred in a more severe form it might 
have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Examples of such events are:
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

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Intensive treatment in an emergency room or at home for allergic bronchospasm
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization
Development of drug dependency or drug abuse.
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
The following factors should be considered when deciding if there is a “reasonable possibility” 
that an AE may have been caused by the drug.
Time course.  Exposure to suspect drug.  Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties?
Dechallenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors.
Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? The sponsor would not normally recommend or support a 
rechallenge.
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist.
In contrast, there would not be a “reasonable possibility” of causality if none of the above criteria 
apply or where there is evidence of exposure and a reasonable time course but any dechallenge 
(if performed) is negative or ambiguous or there is another more likely cause of the AE.
In difficult cases, other factors could be considered such as:
Is this a recognised feature of overdose of the drug?
Is there a known mechanism?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in cases 

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where the disease under study has deteriorated due to lack of effect should be classified as no 
reasonable possibility.

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Appendix C.
International Airline Transportation 
Association (IATA) 6.2 Guidance Document
Clinical Study Protocol Appendix C
Drug Substance
AZD3293 [LY3314814]
Study Code
D5010C00009 [I8D-MC-AZES]
Edition Number
7.1
Date
See Cover Page
Content from Appendix C is being removed from the protocol to allow for potential changes in 
guidelines and local laws.  The confirmation that study sample shipping materials are aligned 
with International Airline Transportation Association (IATA) certification is contained in the 
Study Laboratory Manual.  The confirmation that the site has at least one IATA certified 
individual is covered during the site selection process and monitoring.

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Appendix D.
Actions Required in Cases of Combined 
Increase of Aminotransferase and Total Bilirubin - Hy’s 
Law
Clinical Study Protocol Appendix D
Drug Substance
AZD3293 [LY3314814]
Study Code
D5010C00009 [I8D-MC-AZES]
Edition Number
7.1
Date
See Cover Page
1. Introduction
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets potential 
Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with the sponsor’s clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
2. Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) and Total Bilirubin (TBL) ≥ 2xULN at any point during the study irrespective of 
an increase in Alkaline Phosphatase (ALP).  The elevations do not have to occur at the same time 
or within a specified time frame.
Hy’s Law (HL)
AST or ALT ≥ 3x ULN and TBL ≥ 2xULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral 
hepatitis, another drug.  The elevations do not have to occur at the same time or within a 
specified time frame.

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3. Identification of potential Hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the sponsor representative

Determine whether the subject meets PHL criteria (see Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits
4. Follow-up
4.1. Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will:

Inform the sponsor representative that the subject has not met PHL criteria.

Perform follow-up on subsequent laboratory results in consultation with the designated 
medical monitor.

Complete the Liver Assessment CRFs as information becomes available
4.2. Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will:
Notify the sponsor representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data.  Subsequent to this 
contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated 

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician

Complete the Liver Assessment CRFs as information becomes available 

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
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
5. Review and Assessment of potential Hy’s law cases
The instructions in this Section should be followed for all cases where PHL criteria were met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether there 
is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The 
sponsor will also be involved in this review together with other subject matter experts as 
appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the Liver 
Assessment CRF.

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term “Hy’s Law”) according to standard processes.  

The “Medically Important” serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term “Potential Hy’s Law”) applying serious criteria and causality 
assessment as per above

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review

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6. Actions required for repeat episodes of potential Hy’s law
This section is applicable when a subject meets PHL criteria on study treatment and has already 
met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met chronic or 
progressing malignant disease?
If No:  follow the process described in Section 4.2 of this Appendix.
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with when 
PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change follow the process described in Section 4.2 of this 
Appendix
# A “significant” change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this may 
be in consultation with the Study Physician if there is any uncertainty.
7. References
FDA Guidance for Industry (issued July 2009) “Drug-induced liver injury: Premarketing clinical 
evaluation”:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM174090.pdf

PPD
Leo Document ID = 2dd4e3a4-3648-4412-ab8a-b6a367c39866
Approver: 
Approval Date & Time: 17-Jul-2017 19:12:14 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Jul-2017 21:56:00 GMT
Signature meaning: Approved
PPD