Clinical trial NCT02791191
Conditions: Alzheimer's Disease
Keywords: BACE inhibitor
Sponsor: Eli Lilly and Company
Start date: 2016-06-16; Completion date: 2018-07-02
Enrollment: 316 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the safety and the effect on brain tau of the study drug LY3202626 in participants with mild Alzheimer's disease (AD) dementia.

Detailed description:

Arms: arm 1: 3 mg LY3202626 given orally once daily for 52 weeks. arm 2: 12 mg LY3202626 given orally once daily for 52 weeks. arm 3: Placebo given orally once daily for 52 weeks.
Interventions: intervention 1: LY3202626 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol I7X-MC-LLCF(c) 
 
Effect of LY3202626 on Alzheimer’s Disease Progression as Measured by Cerebral 18F-AV-
1451 Tau-PET in Mild Alzheimer’s Disease Dementia 
 
 
NCT02791191 
 
 
Approval Date: 31-Jan-2018 


I 7 X-M C -L L C F ( c) Cli ni c al Pr ot o c ol
P a g e 1
L Y 3 2 0 2 6 2 6
Pr ot o c ol I 7 X -M C -L L C F ( c)
Eff e ct of L Y 3 2 0 2 6 2 6 o n A l z h ei m er’ s Di s e a s e Pr o gr e s si o n a s 
M e a s ur e d b y  C er e br al 1 8 F- A V -1 4 5 1 T a u -P E T i n Mil d 
Al z h ei m er’ s Di s e a s e D e m e nti a
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
L Y 3 2 0 2 6 2 6, u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s :  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
L Y 3 2 0 2 6 2 6
M ulti c e nt er, r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o -c o ntr oll e d, P h a s e 2 st u d y c o m p ari n g 3 m g 
a n d 1 2 m g of L Y 3 2 0 2 6 2 6 wit h pl a c e b o o v er 5 2 w e e k s i n a p pr o xi m at el y 3 8 0 p ati e nt s wit h 
mil d Al z h ei m er’ s di s e a s e d e m e nti a.
A p pr o v al D at e: 3 1- J a n- 2 0 1 8 G M T
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 1 8 F e br u ar y 2 0 1 6
A m e n d m e nt ( a ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n 1 0 J u n e 2 0 1 6
A m e n d m e nt ( b) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n: 0 6 J ul y 2 0 1 7
A m e n d m e nt ( c ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y
o n a p pr o v al d at e pr o vi d e d b el o w.


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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................21
5.1.
Overall Design .............................................................................................................21
5.2.
Number of Participants.................................................................................................21
5.3.
End of Study Definition ...............................................................................................21
5.4.
Scientific Rationale for Study Design...........................................................................21
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle Restrictions....................................................................................................27
6.4.
Screen Failures.............................................................................................................27
6.5.
Study Partners..............................................................................................................27
7.
Treatments........................................................................................................................29
7.1.
Treatments Administered .............................................................................................29
7.1.1.
Packaging and Labelling ......................................................................................29
7.1.2.
18F-AV-1451 Dosage and Administration.............................................................29
7.1.3.
Florbetapir F 18 Dosage and Administration ........................................................30
7.1.4.
Radiation Doses Associated with PET Imaging....................................................30
7.2.
Method of Treatment Assignment ................................................................................33
7.2.1.
Selection and Timing of Doses.............................................................................33
7.3.
Blinding .......................................................................................................................33
7.4.
Dosage Modification....................................................................................................34
7.5.
Preparation/Handling/Storage/Accountability...............................................................34
7.6.
Treatment Compliance .................................................................................................34
7.7.
Concomitant Therapy...................................................................................................34
7.8.
Treatment after the End of the Study............................................................................35
7.8.1.
Continued Access.................................................................................................35


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8.
Discontinuation Criteria ....................................................................................................36
8.1.
Discontinuation from Study Treatment.........................................................................36
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................36
8.1.2.
Temporary Discontinuation from Study Treatment...............................................37
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................37
8.2.
Discontinuation from the Study....................................................................................37
8.3.
Lost to Follow-Up........................................................................................................38
9.
Study Assessments and Procedures ...................................................................................39
9.1.
Efficacy Assessments...................................................................................................39
9.1.1.
Primary Outcome Assessments ............................................................................39
9.1.2.
Secondary Efficacy Assessments..........................................................................39
9.1.3.
Screening and Exploratory Efficacy Assessments.................................................40
9.1.4.
Exploratory Biomarker Assessments....................................................................41
9.1.5.
Appropriateness of Assessments ..........................................................................42
9.1.6.
Scheduling of Cognitive and Functional Assessments ..........................................42
9.1.7.
Rater Qualifications .............................................................................................43
9.2.
Adverse Events ............................................................................................................43
9.2.1.
Serious Adverse Events........................................................................................44
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................44
9.2.2.
Complaint Handling.............................................................................................45
9.3.
Treatment of Overdose.................................................................................................45
9.4.
Safety...........................................................................................................................45
9.4.1.
Electrocardiograms ..............................................................................................45
9.4.2.
Vital Signs ...........................................................................................................45
9.4.3.
Laboratory Tests ..................................................................................................46
9.4.4.
Physical Examinations and Neurologic Examination............................................46
9.4.5.
Other Tests...........................................................................................................46
9.4.5.1.
C-SSRS..........................................................................................................46
9.4.5.2.
Eye Examination ............................................................................................47
9.4.5.3.
Skin Examination ...........................................................................................48
9.4.5.4.
Magnetic Resonance Imaging.........................................................................48
9.4.6.
Safety Monitoring ................................................................................................49
9.5.
Pharmacokinetics .........................................................................................................50
9.6.
Pharmacodynamics ......................................................................................................50
9.7.
Genetics .......................................................................................................................50
9.7.1.
Apolipoprotein E Genotyping...............................................................................50
9.7.2.
Whole Blood Sample for Pharmacogenetic Research ...........................................50
9.8.
Biomarkers Research & Development..........................................................................51


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9.9.
Medical Resource Utilization and Health Economics ...................................................52
10.
Statistical Considerations ..................................................................................................53
10.1. Sample Size .................................................................................................................53
10.1.1.
Sample size calculation ........................................................................................53
10.2. Populations for Analyses..............................................................................................54
10.3. Statistical Analyses ......................................................................................................54
10.3.1.
General Statistical Considerations ........................................................................54
10.3.2.
Treatment Group Comparability...........................................................................55
10.3.2.1.
Patient Disposition..........................................................................................55
10.3.2.2.
Patient Characteristics ....................................................................................55
10.3.2.3.
Concomitant Therapy .....................................................................................55
10.3.2.4.
Treatment Compliance....................................................................................55
10.3.3.
Efficacy Analyses ................................................................................................56
10.3.3.1.
Primary Analyses ...........................................................................................56
10.3.3.2.
Secondary Analyses........................................................................................56
10.3.3.3.
Exploratory Analyses .....................................................................................56
10.3.4.
Safety Analyses....................................................................................................56
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................57
10.3.6.
Other Analyses.....................................................................................................57
10.3.6.1.
Subgroup Analyses.........................................................................................57
10.3.7.
Interim Analyses..................................................................................................58
11.
References ........................................................................................................................59
12.
Appendices .......................................................................................................................63


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List of Tables
Table
Page
Table LLCF.1.
Objectives and Endpoints...............................................................................19
Table LLCF.2.
Radiation Doses Associated with PET Imaging..............................................32
Table LLCF.3.
Analysis Populations .....................................................................................54


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List of Figures
Figure
Page
Figure LLCF.1.
Illustration of study design for Clinical Protocol I7X-MC-LLCF. ..................21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................64
Appendix 2.
Clinical Laboratory Tests...............................................................................68
Appendix 3.
Study Governance Considerations..................................................................69
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................73
Appendix 5.
Sampling Summary .......................................................................................74
Appendix 6.
Protocol Amendment I7X-MC-LLCF(c) Summary Effect of 
LY3202626 on Alzheimer’s Disease Progression as Measured by 
Cerebral 18F-AV-1451 Tau-PET in Mild Alzheimer’s Disease Dementia.......75


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1.
Synopsis
Title of Study:
Effect of LY3202626 on Alzheimer’s Disease Progression as Measured by Cerebral 18F-AV-1451 Tau-PET in Mild 
Alzheimer’s Disease Dementia.
Rationale: 
Eli Lilly and Company (Lilly) is developing LY3202626, a synthetic small molecule which is a potent inhibitor of 
β-site amyloid precursor protein (APP)-cleaving enzyme [BACE]1, for the treatment of Alzheimer’s disease (AD).  
It is hypothesized that inhibition of BACE1 may slow or inhibit the progression of AD.  
Study I7X-MC-LLCF (LLCF), a Phase 2 study, will assess if inhibiting the production of Aβ in the brain through 
BACE1 inhibition with LY3202626 can slow the progression of disease as assessed by biomarkers of 
neurodegeneration over 52 weeks of treatment.  The 18F-AV-1451 positron emission tomography (PET) scan is the 
primary outcome measure as a marker of disease progression for this study, to assess cerebral tau neurofibrillary 
tangle load and whether there are any changes with Aβ targeted BACE inhibitor treatment.  The study will also
assess LY3202626 pharmacokinetics (PK) and pharmacodynamics (PD; plasma A), biomarkers of amyloid 
pathology (florbetapir PET) and neurodegeneration (volumetric magnetic resonance imaging [vMRI] and cerebral 
perfusion).  In addition, LY3202626, Aβ, and tau in cerebrospinal fluid (CSF) will be collected in a substudy to 
assess the PK of LY3202626, PD (CSF A), and neurodegeneration (CSF tau) within the central nervous system 
(CNS).  Clinical outcomes including cognition, functional consequences of cognition, and safety will also be 
evaluated.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To assess the change from baseline in 18F-AV-1451 
positron emission tomography (PET) after treatment 
with LY3202626 3 mg or 12 mg per day compared 
with placebo for 52 weeks among patients with mild 
Alzheimer’s disease (AD) dementia and evidence of 
brain amyloid.
The change in standardized uptake value ratio (SUVr) of 
18F-AV-1451 PET from baseline to 52 weeks. The change 
will be compared between the LY3202626 doses (3mg and 
12mg) and placebo.
Secondary

To evaluate the safety and tolerability of 
LY3202626 (3 mg and 12 mg per day) 
compared with placebo.

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 and neurological examinations

magnetic resonance imaging (MRI; amyloid-
related imaging abnormality [ARIA] and emergent 
radiological findings)

Skin examination 

Eye examination

Columbia-Suicide Severity Rating Scale (C-SSRS)


I7X-MC-LLCF(c) Clinical Protocol
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LY3202626
Objectives
Endpoints

To assess peripheral pharmacokinetics (PK)
and pharmacodynamics (PD) of LY3202626 (3
mg and 12 mg per day) over 52 weeks.

Plasma PK of LY3202626 

Plasma Pharmacodynamics A1-40, A1-42, A1-x

To assess change from baseline in cognition 
after 52 weeks of treatment among patients 
treated with LY3202626 (3 mg and 12 mg per 
day) compared with placebo.

13-item Alzheimer’s Disease Assessment Scale –
Cognitive subscale (ADAS-Cog13)

To assess change from baseline in function 
after 52 weeks among patients treated with 
LY3202626 (3 mg and 12 mg per day) 
compared with placebo.

Alzheimer’s Disease Cooperative Study-
instrumental Activities of Daily Living inventory
(ADCS-iADL)

To assess change from baseline in a composite 
measure of cognition and function after 52 
weeks among patients treated with LY3202626 
(3 mg and 12 mg per day) compared with 
placebo.

integrated Alzheimer’s Disease Rating Scale
(iADRS)
Summary of Study Design:  
Study I7X-MC-LLCF is a multicenter, multi-region, randomized, double-blind, placebo-controlled study in patients 
with mild AD dementia and demonstration of amyloid pathology by florbetapir PET tracer. The study will test the 
effect of two oral doses of LY3202626, a potent BACE1 inhibitor, on 18F-AV-1451 PET and evaluate the cognition, 
function, safety profile, PK and PD of LY3202626 in this population.
Treatment Arms and Duration:  
Patients will initially be randomized into 1 of 3 treatment groups: 2 fixed dose levels of LY3202626 (3 mg and 12 
mg per day) and placebo (1:1:1) until approximately 45 participants are enrolled in each arm; then randomization 
will change to 1:1 with subjects entering either the 12 mg or placebo arm.  Treatment duration for all subjects will 
be 52 weeks.
Number of Patients:
Approximately 380 patients will be enrolled for approximately 320 completed evaluable patients, assuming 
approximately 15% drop out.
Statistical Analysis:
Patient Characteristics:
Standard baseline characteristics of gender, age, and race will be summarized for all patients. Treatment group 
comparisons will be made using Fisher’s exact test for categorical data and an analysis of variance (ANOVA), with 
an independent factor for treatment for continuous data. Diagnosis, illness characteristics, and baseline efficacy and 
safety measures will be analyzed in a similar manner.
Efficacy:
The primary objective of this study is to assess the effect on neuropathological progression of 2 different 
LY3202626 doses in patients with mild AD dementia compared with placebo, measured by change in 18F-AV-1451 
PET standardized uptake value ratio (SUVr) at baseline and week 52. The primary measurement is change from 


I7X-MC-LLCF(c) Clinical Protocol
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LY3202626
baseline 18F-AV-1451 PET SUVr at Week 52. An analysis of covariance (ANCOVA) will be used to statistically 
evaluate change in 18F-AV-1451 PET from baseline at 52 weeks post-dose. 
Statistical analyses of mean change in efficacy and health outcome measures will be conducted.  Generally, 
statistical assessment of the efficacy and health outcome measures will be a mixed model repeated measure 
(MMRM) or an ANCOVA.  The primary comparison will be between LY3202626 12 mg versus placebo at 
endpoint.  
Safety:
Safety will be assessed by summarizing and analyzing adverse events (AEs), laboratory analytes, vital signs, 
electrocardiograms (ECGs), skin examinations, and eye examinations during the treatment period. For continuous 
safety measurements, a change from baseline will be analyzed using MMRM or ANCOVA model.  Safety analyses 
for the treatment period will include comparisons between LY3202626 dose groups and placebo.  All hypotheses 
will be tested at a 2-sided 0.05 significance level.  No adjustments for multiple comparisons will be made.
For analysis comparing proportion of treatment-emergent abnormalities between treatment groups for laboratory 
analytes, vital signs, weight, ECGs, skin examinations, and eye examinations, only patients who have both a 
baseline observation and a postbaseline observation will be included in the analysis for each analyte or parameter, 
respectively. The proportion of patients with abnormalities will be summarized and compared between treatment 
groups using Fisher’s exact test.
Pharmacokinetics/Pharmacodynamics:
Plasma LY3202626 concentration data will be analyzed using a population approach.  For each dose level and visit, 
plasma Aβ1-40, Aβ1-42 and Aβ1-x concentrations will be summarized and mean change from baseline will be 
calculated. If appropriate, a modeling approach may be used to describe the change in plasma Aβ.  Additional 
exploratory analyses of the data will be conducted as suggested by the data. If appropriate, the data from this study 
may be combined with that from other studies in a meta-analysis.
Interim Analysis:
An interim analysis is planned for when data from approximately 105 qualified patients at 12 weeks (Study Visit 8) 
and 75 patients through 24 weeks (Study Visit 11) have been obtained.  The interim analysis will be conducted for 
safety, and to support initial PK model development.  An early lock of the PK/PD dataset will be conducted after all 
patients complete 24 weeks of treatment to prepare for final PK/PD model development.


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LY3202626
2. Schedule of Activities


I7X-MC-LLCF(c) Clinical Protocol
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Study Procedure
Screening 
Period
Double Blind Period
Visita
V1b
V2
V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 Follow Up EDc
Week
-60 to -1d
0
1
2
4
8
12 16
20
24
28
32
36
40
44
48
52
56
Tolerance Interval (days)
±5
±5
±7 ±7 ±7 ±7
±7
±7
±7
±7
±7
±7
±7
±7
±10
±10
Administrative
Subject Informed Consent
X
Subject number assigned
X
Study Partner Informed Consentv
X
Randomization
X
Clinical Assessments
Demographics
X
Medical/Psychiatric History
X
Inclusion/Exclusion Criteria
X
X
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Habits
X
NIA-AA criteria review
X
Efficacy and Health Outcome Measurese
MoCAf
X
X
X
X
ADAS-Cog13
X
X
X
X
ADCS-ADL
X
X
X
X
FAQ
X
X
X
X
MMSEf
X
X
X
X
ECog
X
X
X
X
NPI
X
X
X
BASQID
X
X
X
Imaging Measuresc,g
MRI 
X
X
X
Florbetapir PET (including perfusion)
X
X
X
18F-AV-1451 PET
X
Xh
Xh
Laboratory Measures
Urinalysis
X
X
X
X
X
X
X
Blood sample for APOE genotyping
X
Blood sample for pharmacogenetics
X


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Study Procedure
Screening 
Period
Double Blind Period
Visita
V1b
V2
V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 Follow Up EDc
Week
-60 to -1d
0
1
2
4
8
12 16
20
24
28
32
36
40
44
48
52
56
Tolerance Interval (days)
±5
±5
±7 ±7 ±7 ±7
±7
±7
±7
±7
±7
±7
±7
±7
±10
±10
Blood sample for epigenetics
X
X
Blood sample for RNAi
X
X
Plasma LY3202626 (PK)j
Xk
Xk
Xl Xk Xl
Xm
X
Plasma peptides: A1-40, A1-42, A1-x
(PD)n
X
X
X
X
X
X
X
X
X
Plasma samples (EDTA) for storage 
and exploratory biomarker R&D
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry, Hematology, 
Electrolyteso
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Measures
Eye Examinationp
X
X
X
X
X
Skin Examinationq
X
X
X
X
X
Physical/Neurological Examination
X
X
X
X
X
X
X
X
Vital Signsr
X
X
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
12-lead ECG(triplicate)
Xs
X
X
X
X
X
X
X
X
X
X
X
C-SSRSt/Self Harm Supplement Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Drug
Xu
X
X
X
X
X
X
X
X
X
X
X
X
Assess Drug Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  Aβ = amyloid beta peptide; ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-ADL = Alzheimer’s 
Disease Cooperative Study-Activities of Daily Living inventory; APOE = apolipoprotein E; BASQID = Bath Assessment of Subjective Quality of Life in 
Dementia; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ECog = Everyday Cognition; ED = early discontinuation; EDTA = 
ethylenediaminetetraacetic acid; FAQ = Functional Activities Questionnaire; MMSE = Mini-Mental Status Examination; MoCA = Montreal Cognitive 
Assessment; MRI = magnetic resonance imaging; NIA-AA = National Institute on Aging-Alzheimer's Association; NPI = Neuropsychiatric Inventory; PD = 
pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; R&D = research and development; RNA = ribonucleic acid; V = visit.
a
Every effort should be made for visits to occur on the designated study days.  The overall treatment period in the protocol should be maintained (that is, visits 
should be scheduled based on the baseline visit rather than the previous visit).  Study procedures designated for a specific visit should be performed within 1 
day whenever possible.  If the time spent at the site needs to be minimized, the assessments can be completed over a longer period.


I7X-MC-LLCF(c) Clinical Protocol
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LY3202626
b
Visit 1 takes place over more than 1 day.  Clinical scales should be administered before imaging procedures are conducted.
c
Only capture imaging measures (MRI, florbetapir F 18 PET, and 18F-AV-1451 PET) at the ED visit if at least 24 weeks have passed since the baseline 
measurement was obtained.  Note:  Patients should be encouraged to remain in the study after their ED Visit until Week 52 (Visit 18), 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.  The follow-up visit (Week 56) is not required for patients who discontinue study 
treatment early and continue in the study, unless the study drug was discontinued within that last 4 weeks of the study. 
d
Screening period exceeding 60 days will not be considered a protocol deviation.  If the screening period exceeds 120 days, sites should contact the Lilly-
designated medical monitor for guidance.
e
If clinical scales are administered on the same day as medical procedures that could be stressful for the patient (for example, blood draws and imaging), the 
clinical scales should be administered first.
f
The MoCA and the MMSE should not be administered in succession (that is, at least one other scale should be administered between them) and should be 
done by different raters.
g
The baseline 18F-AV-1451 scan should not be performed until a positive florbetapir F 18 PET result has been confirmed by central read and all other 
screening criteria have been confirmed.  Florbetapir F 18 and 18F-AV-1451 scans must be at least 16 hours apart.  
h
Before the Week 52 or ED 18F-AV-1451 scan, the investigator should review the patient’s medical history to verify there is no risk factor for Torsades de 
Pointes and review the most recent ECG.  If clinically meaningful abnormalities are noted on the ECG, the advisability of the 18F-AV-1451 scan should be 
considered by the investigator in consultation with the Lilly-designated medical monitor.  Patients permanently discontinued from study treatment due to 
initiation of a prohibited medication known to prolong the QT-interval should not have an ED 18F-AV-1451 scan unless the scan can be performed prior to 
initiation of the prohibited medication.
i
Collect blood sample for RNA using PAXgene tube.
j
Pharmacokinetic samples do not need to be collected for patients who discontinue study drug, but remain in the study for follow-up.
k
At Visits 5, 6, and 8, patients are to hold their morning dose prior to the visit.  After arriving at the site, a blood sample will be collected for LY3202626, and 
patients will receive their assigned dose of study drug.  Prior to departing the site, a second blood sample will be collected for PK.
l
At Visit 7 and 9, patients will take their morning dose at their usual time.  After arriving at the site, a blood sample will be collected for PK.  Prior to the 
patient departing the site, a second blood sample will be collected for PK.
m At Visit 11, patients will take their morning dose at their usual time.  A single blood sample will be collected for PK after all cognitive testing has been 
completed. 
n
One blood sample for PD is to be taken at the same times as samples for PK.  If multiple PK samples are taken at a visit, the PD sample is to be taken with the 
first PK sample.  At Visit 18 the PD sample will be taken at the same time as the other clinical laboratory samples.
o
See Appendix 2 for analytes to be collected by Visit.
p
Eye examinations should be conducted under the supervision of an optometrist or ophthalmologist.  Additional details are provided in Section 9.4.5.2.
q
Skin examinations should be conducted by a dermatologist.  Additional details are provided in Section 9.4.5.3.
r
Vital signs to be collected are blood pressure, heart rate, and temperature.
s
All ECGs are to be conducted in triplicate.


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LY3202626
t
The Baseline/Screen form of the C-SSRS will be administered at Visit 1.  All subsequent measures will use the Since Last Visit form. The Self-Harm 
Supplement form is completed after each C-SSRS administration to enter the number of discrete events of suicidal behavior identified. If, based on 
administration of the C-SSRS, it is determined that suicide-related behaviors have occurred, then the Self-Harm Follow-Up (SHFU) form will be used to 
collect additional information to allow for a more complete assessment of these behaviors.
u
Patients should be instructed to take the first dose of study drug in the morning on the day after dispensing of drug at Visit 3.  For patients participating in the 
lumbar puncture addendum, Visit 3 LP must be performed before the first dose of study drug is administered and no later than the day after randomization.
v
If the study partner changes at any time during the study, the new study partner must sign the study partner informed consent.


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3.
Introduction
3.1.
Study Rationale
Lilly is developing LY3202626, a synthetic small molecule which is an inhibitor of β-site 
amyloid precursor protein (APP)-cleaving enzyme [BACE]1, for the treatment of mild 
Alzheimer’s disease (AD) dementia. This small molecule, at the 12 mg dose, has a high level of 
BACE1 inhibition (resulting in 90% reduction in A), which may be a differentiating 
characteristic for efficacy if the effects at an enzymatic level translate clinically.  It is 
hypothesized that inhibition of BACE1 may slow the progression of AD.  
Study I7X-MC-LLCF (LLCF), a Phase 2 study, will assess if inhibiting the production of Ain 
the brain through BACE1 inhibition with LY3202626 can slow the progression of disease as 
assessed by biomarkers of neurodegeneration over 52 weeks of treatment.  The 18F-AV-1451 
positron emission tomography (PET) scan will be the primary outcome measure as a marker of 
disease progression for this study, to assess cerebral tau neurofibrillary tangle load and whether 
there are any changes with Atargeted BACE inhibitor treatment.  The study will assess 
LY3202626 pharmacokinetics (PK) and pharmacodynamics (PD; plasma A), biomarkers of 
amyloid pathology (florbetapir F 18 PET) and neurodegeneration (volumetric magnetic 
resonance imaging [vMRI] and cerebral perfusion).  In addition, LY3202626, Aβ, and tau in 
cerebrospinal fluid (CSF) will be collected in a substudy to assess the PKs of LY3202626, PD 
(CSF A), and neurodegeneration (CSF tau) within the central nervous system (CNS). Clinical 
outcomes including cognition, functional consequences of cognition, and safety will also be 
evaluated.
3.2.
Background
Alzheimer’s disease is a gradually progressive degenerative disease affecting older people that 
results in the slow decline of cognitive and behavioral functions with a characteristic early 
symptom of memory loss in patients (Takizawa et al. 2015).  Currently available therapies for 
treatment of AD are able to variably reduce the symptoms without affecting the underlying 
pathology of the disease, so patients continue to decline clinically. Recent Phase 3 study failures 
in moderate AD (EPOCH study (press release [WWW]); Doody et al, 2014) suggest that 
treatment options may be limited once the disease has advanced.  Thus, there is a significant 
need to develop a disease-modifying treatment that will slow the progression of this debilitating 
brain disorder, and a growing emphasis to move therapeutic trials for disease-modifying agents
earlier in the disease.
After autopsy, patients with AD routinely display severe brain atrophy with neurofibrillary 
tangles and amyloid plaques (Cummings 2004). Although the definitive cause of the disease is 
not yet clearly understood, much evidence supports the hypothesis that amyloid β (Aβ) peptide 
aggregates to form amyloid plaques and acts as an initial trigger of the disease (Shankar et al. 
2008). These plaques may be toxic to neurons and are believed to lead to synapse loss, 
neurofibrillary tangle formation, and neuronal cell death. Hence, inhibition of Aβ formation is a 
logical strategy towards developing a therapy for AD.


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Amyloid β is part of the amyloid precursor protein (APP), which is a transmembrane protein 
widely expressed on the cell surface, particularly in neurons. The APP has been found to be 
cleaved through 2 cleavage pathways involving 3 secretase enzymes: -secretase, γ-secretase, 
and -secretase (now called -site APP-cleaving enzyme [BACE]1). Cleavage of APP by -
secretase precludes the formation of Aas the site is located within the Asequence. In the 
second pathway, -secretase cleaves the APP molecule, generating membrane-associated C99 
and releasing a larger secreted fragment called secreted APP (sAPP). γ-Secretase then cleaves 
C99 in a heterogeneous fashion within the membrane releasing a variety of Aspecies that 
aggregate in protofibrils, then fibrils, which seem to comprise the mass of Aplaques in AD 
brain tissue (Turner et al. 2003). While both γ- and β-secretase inhibition represent effective 
means of precluding the formation of A, -secretase inhibition may provide improved safety 
and tolerability (Doody et al. 2013).
LY3202626, a synthetic small molecule, potent BACE1 inhibitor is being developed for the 
treatment of AD dementia.  LY3202626 has been shown to reduce plasma and CSF Aβ1-40 and 
Aβ1-42 in mice, dogs, and humans.  The Phase 1 clinical Study I7X-EW-LLCA (LLCA) 
investigated the safety, tolerability, PK, and PD of single- and multiple-ascending doses of 
LY3202626 given orally, in healthy subjects and patients with AD.  In this study, single doses of 
LY3202626 from 0.1 mg to 45 mg were well tolerated, and demonstrated a robust, prolonged 
reduction in plasma Aβ concentrations.  LY3202626 was also administered as single daily doses 
of 1 mg to 26 mg for 14 days.  In this multiple dose portion of the trial, LY3202626 was well 
tolerated, and a dose-dependent reduction in both plasma and CSF Aβ concentrations was 
observed.  At steady-state, 1 mg LY3202626 was associated with an approximate 50% reduction 
in CSF Aβ1-40, while at 6 mg, reductions of approximately 75% were observed. At 26 mg, CSF 
Aβ1-40 reductions exceeded 90%.  These projected CSF Aβ1-40 reductions will be verified in a 
mild AD dementia population in the lumbar puncture (LP) addendum to this study.
This Phase 2 study will assess if inhibiting the production of Ain the brain at doses projected to 
reduce CSF Aby 70% and 90%, can slow the progression of disease as assessed by biomarkers 
of neurodegeneration over 52 weeks of treatment.  Data from the 12 mg dose arm will be used to 
assess the effect of greatest BACE inhibition on tau PET changes, other biomarkers of disease 
progression, and clinical outcomes.  All outcomes will also be assessed for the 3 mg dose arm 
though the primary focus will be safety and tolerability of the 3 mg dose over 52 weeks of 
exposure in the mild AD population.  Tau is a protein that accumulates in the brains of AD 
patients and is a defining pathology of the disease. The density and neuroanatomical localization
of tau neurofibrillary tangles correlate strongly with neurologic symptoms and AD progression.  
Until recently, the only way to determine tau pathological changes in the brain was at autopsy. 
The recent development of the 18F-AV-1451 PET tracer, has allowed for the first time, the ability 
to detect and measure tau protein in the brain of patients suspected of suffering from AD (Xia et 
al. 2013). Early use of this tracer shows increasing signal from healthy controls to mild 
cognitive impairment due to AD to mild to moderate AD. The anatomical distribution 
corresponds well to the pathological staging of Braak and Braak (Chien et al. 2013). The signal 
also increases with progression of disease, both in intensity and in spread to other cortical 
regions.  The 18F-AV-1451 PET scan will be the primary outcome measure as a marker of 


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neuropathological disease progression for this study, to assess for cerebral tau neurofibrillary 
tangle load and whether there are any changes with Atargeted BACE inhibitor treatment.
The biomarker florbetapir F 18 is a PET ligand that binds to fibrillar amyloid plaque. This 
biomarker can provide a qualitative and quantitative measurement of brain plaque load in 
patients with mild AD dementia. The absence of significant florbetapir F 18 signal indicates that 
those patients clinically manifesting dementia lack evidence of amyloid pathology. As such, 
implementation of florbetapir F 18 will provide a screening tool for entry into the clinical trials 
and provide a confirmation of amyloid pathology. Florbetapir F 18 PET also provides 
quantitative assessment of amyloid in the brain and can assess whether Alowering by BACE 
inhibition can reduce amyloid deposition.
Alzheimer’s disease progression is also associated with cerebral atrophy and hypoperfusion, 
which will be assessed by vMRI and the early post-injection data from the florbetapir F 18 PET 
scans, respectively.
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of LY3202626 are to be found in the 
Investigator’s Brochure (IB).  


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4.
Objectives and Endpoints
Table LLCF.1 shows the objectives and endpoints of the study.
Table LLCF.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the change from baseline in 18F-AV-1451
PET after treatment with LY3202626 3 mg or 12 mg 
per day compared with placebo for 52 weeks among 
patients with mild AD dementia and evidence of brain 
amyloid.
The change in SUVr of 18F-AV-1451 PET from baseline 
to 52 weeks. The change will be compared between the 
LY3202626 doses (3mg and 12mg) and placebo.  
Secondary

To evaluate the safety and tolerability of 
LY3202626 (3 mg and 12 mg per day) 
compared with placebo

Standard safety assessments: 
o
spontaneously reported AEs
o
clinical laboratory tests
o
vital sign and body weight 
measurements
o
12-lead ECGs
o
physical and neurological examinations

MRI (ARIA and emergent radiological findings)

Skin examination 

Eye examination

C-SSRS

To assess peripheral PK and PD of LY3202626 
(3 mg and 12 mg per day) over 52 weeks

Plasma Pharmacokinetics of LY3202626 

Plasma Pharmacodynamics A1-40, A1-42, A1-x

To assess change from baseline in cognition 
after 52 weeks of treatment among patients 
treated with LY3202626 (3 mg and 12 mg per 
day) compared with placebo.

ADAS-Cog13

To assess change from baseline in function 
after 52 weeks among patients treated with 
LY3202626 (3 mg and 12 mg per day) 
compared with placebo

ADCS-iADL

To assess change from baseline in a composite 
measure of cognition and function after 52 
weeks among patients treated with LY3202626 
(3 mg and 12 mg per day) compared with 
placebo

iADRS


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Objectives and Endpoints
Objectives
Endpoints
Exploratory

To assess change in cognition after 52 weeks 
among patients treated with LY3202626 (3 mg 
and 12 mg per day) compared with placebo

MoCA

To assess change in function after 52 weeks 
among patients treated with LY3202626 (3 mg 
and 12 mg per day) compared with placebo

FAQ

To assess change in cognition after 52 weeks 
among patients treated with LY3202626 (3 mg 
and 12 mg per day) compared with placebo

MMSE

To assess change in everyday functioning after 
52 weeks among patients treated with 
LY3202626 (3 mg and 12 mg per day) 
compared with placebo

ECog

To assess change in neuropsychiatric symptoms 
after 52 weeks among patients treated with 
LY3202626 (3 mg and 12 mg per day) 
compared with placebo

NPI

To assess change in subjective quality of life 
after 52 weeks among patients treated with 
LY3202626 (3 mg and 12 mg per day) 
compared with placebo

BASQID

To assess change from baseline in rCBF after 
52 weeks among patients treated with 
LY3202626 (3 mg and 12 mg per day) 
compared with placebo.

SUVr cerebral perfusion from early post-
injection florbetapir PET scan

To assess change from baseline in brain 
amyloid after 52 weeks among patients treated 
with LY3202626 (3 mg and 12 mg per day) 
compared with placebo

Florbetapir F 18 PET SUVr

To assess change from baseline in brain and 
brain regional volumes after 52 weeks among 
patients treated with LY3202626 (3 mg and 
12 mg per day) compared with placebo.

Volumetric MRI
Abbreviations:  AD = Alzheimer’s disease; ADAS-Cog13 = Alzheimer’s Disease Assessment Scale - Cognitive 
subscale, 13-item version; ADCS-iADL = Alzheimer’s Disease Cooperative Study-Activities of Daily Living 
inventory, instrumental items; AE = adverse event; ARIA = amyloid-related imaging abnormality; BASQID = 
Bath Assessment of Subjective Quality of Life in Dementia; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; ECog = Everyday Cognition; FAQ = Functional Activities Questionnaire; iADRS = 
integrated Alzheimer’s Disease Rating Scale; MMSE = Mini-Mental Status Examination; MoCA = Montreal 
Cognitive Assessment; MRI = magnetic resonance imaging; NPI = Neuropsychiatric Inventory; PET = positron 
emission tomography; PD = pharmacodynamic; PK = pharmacokinetic; rCBF = regional cerebral blood flow; 
SUVr= summary uptake value ratio.


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5.
Study Design
5.1.
Overall Design
Study LLCF is a multicenter, randomized, double-blind, placebo-controlled study in patients 
with mild AD dementia.  This study (Study LLCF) will enroll patients with mild AD dementia 
using National Institute on Aging-Alzheimer's Association (NIA-AA) work group consensus 
guidelines (McKhann et al. 2011) with amyloid deposition confirmed by florbetapir F 18 PET 
imaging.  The treatment phase will be 52 weeks.
Figure LLCF.1 illustrates the study design.
Abbreviations:  AD = Alzheimer’s disease; FP = follow-up period; LY = LY3202626.
Note: This is a multicenter, randomized, parallel-group, 52-week-long double-blind, 
placebo-controlled, study of 2 fixed dose levels of LY3202626 (3 mg and 
12 mg) in patients with mild AD dementia and evidence of amyloid pathology.
Approximately 380 mild AD dementia patients will be enrolled (approximately 
167 in the placebo and 12 mg groups, and approximately 45 in the 3 mg group).
Figure LLCF.1.
Illustration of study design for Clinical Protocol I7X-MC-LLCF.
5.2.
Number of Participants
Approximately 1000 participants will be screened to achieve approximately 380 randomized and 
approximately 320 completed evaluable participants, assuming approximately 15% drop out.
5.3.
End of Study Definition
End of the trial is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Please refer to Section 3.1.
LY 12 mg
Visit 1-2
Screening
Week 52
Visit 18
Visit 3
Randomization
Placebo-Controlled Treatment Period
LY 3 mg
Placebo
Week 56
Follow Up
FP


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5.5.
Justification for Dose
The extent of Aβ reduction necessary to influence the spread of tau in the CNS is unknown.  
Thus, to maximize the likelihood of this study demonstrating an effect on tau, it was deemed 
reasonable to reduce CSF Aβ concentrations to near-minimal levels.  Accordingly, doses of 
LY3202626 chosen for this study were based on a desire to reduce concentrations of CSF Aβ 
isoforms by 70-90% from baseline. Central and peripheral PK/PD data from healthy subjects
collected in a previous single- and multiple-dose study were used to estimate the exposures 
necessary to achieve the desired levels of CSF Aβ reduction. These exposure targets were then 
used to select daily doses of 3 mg and 12 mg LY3202626 for this study. These doses are less 
than the highest doses previously evaluated in healthy subjects (45 mg as a single dose, or 26 mg 
once a day for 14 days), which were found to be well tolerated.  LY3202626 was also found to 
be well tolerated in 2 patients with AD, when administered at a dose of 6 mg once a day, for 14 
days (the only dose level tested to date in AD patients).  Together, these data suggest that doses 
of 3 mg and 12 mg LY3202626 will be well tolerated in an AD population.  To ensure patient 
wellbeing throughout the course of the trial, safety assessments and a safety interim are 
incorporated into the study design.
Protocol amendment (b) regarding stopping enrollment after 45 subjects have randomized into 
the lower 3 mg dose (70% lowering of Aβ by BACE1 inhibition) is based on the following: (1) 
We are prioritizing the opportunity, allowed by the molecular characteristics of LY3202626, to 
evaluate near maximal inhibition of Aβ production (90% reduction with the 12 mg dose); (2) The 
study will conclude approximately 6 months earlier to address the study objectives of safety, 
tolerability, clinical, and biomarker outcomes of 90% inhibition of the production of Aβ over 
52 weeks in patients with mild AD; (3) Assessment of LY3202626 safety and tolerability 
remains a central objective; therefore, monitoring 45 subjects on 3 mg in parallel with
approximately 150 subjects on 12 mg over 52 weeks exposure provides data to assess safety for 
further clinical development.


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening:
Patient Characteristics and Diagnostic Criteria
[1]
Present with mild AD dementia based on the NIA-AA disease diagnostic 
criteria as determined by a qualified clinician approved by the Sponsor or 
designee (McKhann et al. 2011).
[2]
MMSE score of 20 to 26 inclusive at screening visit.
[3]
Is ≥55 years of age and ≤85 years of age at the time of signing the informed 
consent
[4]
Has a florbetapir F 18 PET scan, evaluated by central PET reader, with the 
presence of amyloid pathology at screening consistent with florbetapir 
eligibility criteria.
Patient Demographics
[5]
Female patients: women must be of non-childbearing potential. Female 
patients are considered of non-childbearing potential if they have undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy or tubal 
ligation), have a congenital anomaly such as mullerian agenesis, or are 
postmenopausal as defined by either:
[i] Women 55 or older not on hormone therapy, who have had at least 6 months of
spontaneous amenorrhea; or
[ii] Women at least 55 years of age with a diagnosis of menopause prior to starting 
hormone replacement therapy.


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[6]
Patient must have a reliable study partner with whom he/she cohabits or has 
regular contact (combination of face-to-face visits and telephone contact is 
acceptable).  If at all possible, the same study partner should be willing to 
participate in all study visits that require them to provide meaningful input 
into the rating scales administered in this study, for which study partner input 
is required, or be available by telephone and must have sufficient patient 
interaction.  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 patient, divided 
over multiple days.  The patient’s study partner(s) must be willing to comply 
with protocol requirements, and in the investigator’s opinion must have 
adequate literacy, vision, and hearing to complete the protocol-specified 
questionnaires.
Informed Consent
[7]
Is able and willing to give signed informed consent 
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening:
Medical Conditions
[8]
Lack, in the investigator’s opinion, of adequate premorbid literacy, adequate 
vision, or adequate hearing to complete the required psychometric tests.
[9]
Significant 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, multiple 
concussions, or epilepsy or recurrent seizures (except febrile childhood 
seizures)
[10] Current serious or unstable illnesses including retinal, cardiovascular 
(including unstable ischemic cardiovascular disease), hepatic, renal, 
gastroenterologic, respiratory, endocrinologic, neurologic (other than AD), 
psychiatric, immunologic, or hematologic disease and other conditions that, in 
the investigator’s opinion, could interfere with the analyses in this study; or 
has a life expectancy of <12 months. 
[11] 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.


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LY3202626
[12] Patients with any current primary psychiatric diagnosis other than AD 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.
[13] Is clinically judged by the investigator to be at serious risk for suicide as 
assessed by medical history, examination, or the C-SSRS.
[14] Ocular pathology that significantly limits ability to reliably evaluate vision or 
the retina. 
[15] History of alcohol or drug use disorder (except tobacco use disorder) within 2 years 
before the screening visit.
[16] Congenital QT prolongation.
[17] Intermittent second- or third-degree atrioventricular (AV) heart block or AV 
dissociation or history of ventricular tachycardia.
[18] Has a cardiac pacemaker.
[19] History of vitiligo and/or current evidence of post-inflammatory hypopigmentation
[20] Severe drug allergy to 2 or more drugs classes
[21] Known positive serologic findings for human immunodeficiency virus (HIV) 
antibodies.  Local laws and regulations may apply to whether testing is required.
Magnetic Resonance Imaging, Vital Signs, Electrocardiograms, Laboratory Tests, and 
Physical Examination
[22] Screening MRI which shows evidence of significant abnormality that would suggest 
another potential etiology for progressive dementia or a clinically significant finding 
that may impact the patient’s ability to safely participate in the study.
[23] A corrected QT (QTcF) interval measurement >450 msec (men) or >470 msec 
(women) at screening (as determined at the investigational site).  The site may request 
a central read prior to making determination of this criterion.
[24] Patients with a past history (suspected or confirmed) of Hepatitis B should have 
HBsAg testing at screening and are excluded if HBsAg is positive.  
Patients with a past history (suspected or confirmed) of Hepatitis C (resolved 
>6 months prior to enrollment) should have HCV RNA PCR testing at screening and 
are excluded if the HCV RNA PCR test is positive.
[25] Any clinically important abnormality at screening, as determined by investigator, in 
physical or neurological examination, vital signs, ECG, or clinical laboratory test 
results that could be detrimental to the patient, could compromise the study, or show 
evidence of other etiologies for dementia.
[26] Calculated creatinine clearance <30 mL/min (Cockcroft-Gault formula; 
Cockcroft and Gault 1976) at screening.


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[27] Alanine transaminase (ALT) ≥2X the upper limit of normal (ULN) of the performing 
laboratory, aspartate aminotransferase (AST) ≥2X ULN, total bilirubin level (TBL) 
≥1.5X ULN, or alkaline phosphatase (ALP) ≥1.5X ULN at screening.
NOTE:  Patients with TBL ≥1.5X ULN are not excluded if they meet all of the 
following criteria for Gilbert syndrome:
1. Bilirubin is predominantly indirect (unconjugated) at screening (direct bilirubin 
within normal limits).
2. Absence of liver disease
3. ALT, AST, and ALP ≤1X ULN at screening
4. Hemoglobin is not significantly decreased at screening.
Prior/Concomitant Therapy
[28] Changes in concomitant medications that could potentially affect cognition 
and their dosing should be stable for at least 30 days before screening, and 
between screening and randomization (does not apply to medications 
discontinued due to exclusions or with limited duration of use, such as 
antibiotics).
[29] Current use of strong inducers of CYP3A. (See the Manual of Operations for 
a list of excluded drugs.)
[30] 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.
[31] Current use of drugs known to significantly prolong the QT interval. (See the 
Manual of Operations for a list of excluded drugs).
Procedural
[32] Sensitivity to florbetapir or 18F-AV-1451.
[33] Contraindication to MRI or PET or poor venous access for blood draws.
[34] Present or planned exposure to ionizing radiation that, in combination with the 
planned administration of study PET ligands, would result in a cumulative 
exposure that exceeds local recommended exposure limits.
Prior/Concurrent Clinical Trial Experience
[35] Are currently enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.


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[36] Have participated, within the last 30 days (for Japan, 4 months) in a clinical
trial involving an investigational product.  If the previous investigational 
product is scientifically or medically incompatible with this study and has a 
long half-life, 3 months or 5 half-lives (whichever is longer) should have 
passed prior to screening.
[37] Have previously completed or withdrawn from this study or any other study 
investigating LY3202626.  
Other Exclusions
[38] Are 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.
[39] Are Lilly employees or are employees of third-party organizations (TPOs) 
involved in study who require exclusion of their employees, or have study 
partners who are Lilly employees or are employees of TPOs involved in a 
study which require exclusion of their employees.
6.3.
Lifestyle Restrictions
1. Patients should refrain from donating blood or blood products from the time of their 
screening visit until 4 weeks following the last dose of study drug.
2. Patients should avoid use of tanning beds and self-tanning products.
3. Patients should wear a hat and appropriate clothing when exposed to sunlight; use a 
sunscreen with a skin protection factor (SPF) of at least 15; and protect their lips with a 
lip balm containing sunblock.
4. Patients should avoid excessive use of alcohol from the screening visit until the study 
ends.  Excessive alcohol consumption is defined for men as consuming an average of 
more than 3 drinks per day, or more than 21 drinks per week.  For women, excessive use 
of alcohol is defined as consuming an average of more than 2 drinks per day, or more 
than 14 drinks per week.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) for reasons 
deemed by the site investigator to be medically treatable (such as a serious UTI); and/or have 
issues that are correctable or reversible (for example, study partner status); or if the initial 
MMSE score is >26, but the investigator feels there has been further cognitive decline, may be 
rescreened.  Patients may be rescreened up to 2 times.  Each time rescreening is performed the 
patient must sign a new informed consent form (ICF) and will be assigned a new identification 
number.
6.5.
Study Partners
Every patient in the study must have a study partner.  An identification code will be assigned to 
each study partner and recorded for each efficacy measure for which the study partner provides 
input.  Demographic data, including relationship to the patient, will be collected for every study 


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partner.  Several of the efficacy measures require input from the study partner.  The study partner 
should be willing to participate in every study visit that requires their input.  The study partner is 
not required to attend all study procedures, including but not limited to MRI, PET, or lumbar 
procedures, skin or eye examinations.  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, sign consent, and be assigned a new identification code. 


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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of 3 mg and 12 mg oral doses of LY3202626 administered 
daily against placebo.  Study LLCF treatment regimens are:

3 mg LY3202626 orally once per day

12 mg LY3202626 orally once per day 

Placebo orally once per day.
Both LY3202626 strengths and placebo will be identical capsules.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the patient and study 
partner

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

returning all unused medication (at the end of the study) to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law.
7.1.1.
Packaging and Labelling
Study drug will be supplied as 3-mg and 12-mg capsules.  The study drug and placebo will be 
identical in appearance and will be packaged in bottles.  Clinical trial materials will be labeled 
according to the country’s regulatory requirements.
7.1.2.
18F-AV-1451 Dosage and Administration
A total of 2 18F-AV-1451 PET scans will be performed, approximately 52 weeks apart.  The 
baseline 18F-AV-1451 scan should not be performed until a positive florbetapir F 18 PET result 
has been confirmed by central read and all other screening criteria have been confirmed. The 
Visit 18 or early discontinuation florbetapir F 18 and 18F-AV-1451 scans must be at least 
16 hours apart.  At each 18F-AV-1451 PET scanning visit, patients will receive a single 
intravenous (IV) administration of approximately 370 MBq (10 mCi) of 18F-AV-1451.  A 
30-minute scan, starting approximately 75 minutes following injection, will be acquired 
according to the procedure described in the technical operations manual provided by the 
designated imaging core laboratory.
Patients with a history of risk factors for Torsades de Pointes or taking prohibited medications 
known to prolong the QT interval should not have a 18F-AV-1451 scan.  Patients permanently 
discontinued from study treatment due to initiation of a prohibited medication known to prolong 
the QT-interval should not have an early discontinuation (ED) 18F-AV-1451 scan unless the scan 
can be performed prior to initiation of the prohibited medication.
The following assessments will be performed for 18F-AV-1451 imaging sessions:


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
A physician or a licensed/credentialed medical professional (for example, a 
PET Technologist or an imaging center nurse) designated by the site Principal 
Investigator (PI), must assess or evaluate the patient to determine if the patient 
can safely undergo a 18F-AV-1451 injection.  If a designee performs this 
activity, a physician must be available to provide medical consultation or 
supervision.

The patient will be requested to void after completion of the PET scan.

A physician or a licensed/credentialed medical professional designated by the 
site PI must assess or evaluate the patient prior to discharge from the imaging 
center to evaluate the patient’s readiness for discharge. If a designee performs 
the discharge evaluation, a physician must be available to provide medical 
consultation.

Patients will be observed for signs of adverse events (AEs) or serious adverse 
events (SAEs) while at the imaging center. The injection site will be observed 
for evidence of inflammation or allergic reaction to the surrounding tissue 
where the dose was injected.  All AEs and SAEs will be followed until 
resolution or stabilization and should be reported to Lilly or its designee via 
electronic case report form (eCRF) per Section 9.2.  See Section 9.2.1 for 
details regarding SAE reporting requirements.  
Information about the known and expected benefits, risks, and reasonably anticipated AEs of 
18F-AV-1451 may be found in the 18F-AV-1451 IB.  
7.1.3.
Florbetapir F 18 Dosage and Administration
A total of 2 florbetapir F 18 scan visits will occur, approximately 52 weeks apart.  The Visit 18
or early discontinuation florbetapir and 18F-AV-1451 scans must be at least 16 hours apart.  At 
each florbetapir F 18 PET scanning visit, the patient will receive a single IV administration of 
approximately 370 MBq (10 mCi) of florbetapir F 18, and will be scanned twice.  First, a scan of 
approximately 6 minutes duration will be obtained immediately following injection of the tracer, 
which will be administered while the patient is in the scanner.  This scan will capture the blood 
flow to the brain (perfusion PET, see Section 9.1.4 for more details).  Second, starting 
approximately 50 minutes after the tracer injection, a scan lasting approximately 20 minutes will 
be acquired.  The patient need not stay in the scanner between these 2 scans.  The injection of the 
imaging agent will be followed by a saline flush according to the injection procedure described 
in the technical operations manual provided by the designated imaging core laboratory.
7.1.4.
Radiation Doses Associated with PET Imaging
The estimated exposure to ionizing radiation per patient enrolled in this study (effective dose) is 
summarized in Table LLCF.2.  This includes contributions from florbetapir F 18 and 18F-AV-
1451 scans, along with low-dose computed tomography (CT) scans required for attenuation 
correction.  
For either florbetapir or 18F-AV-1451 scans, if the image is not interpretable based on 
predetermined criteria outlined at the central PET core lab (for example, scanner failure, patient 


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motion, etc.), the patient may be asked to schedule an additional scan visit, requiring an 
additional injection of the radiotracer. Each patient will potentially only undergo up to 1
additional PET scan beyond those scheduled in this protocol. In this case, the patient would be 
exposed to up to an additional 9.1 mSv of ionizing radiation.


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Table LLCF.2.
Radiation Doses Associated with PET Imaging
Injected 
Radioactive Dose
per Scan, mCi*
Injected 
Radioactive 
Dose per Scan, 
MBq
Effective Dose (mSv) 
per Scan
Number of Scans in One
Year (52 wks)
Total Effective dose (mSv) 
18F-AV-1451 scan
10
370
9.10
2
18.20
florbetapir F 18 scan
10
370
7.83§
2
15.66
Totals
4
33.86
Abbreviations:  CT = computed tomography; PET = positron emission tomography.
* Dose shown includes radiation exposure from the radiotracer and also assumes a non-clinical CT scan is obtained (estimated at 0.4 mSv) as part of the PET 
scan attenuation correction process when the scan is done on a PET/CT scanner. A clinical CT scan is not needed during the PET scan session because it will 
add additional radiation exposure.
§ Dose includes an additional non-clinical CT scan (estimated at 0.4 mSv) for the patients undergoing the florbetapir perfusion scan.


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7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 3.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  Randomization will be stratified by 
the following two factors:  1) patient participation of LP addendum (Y/N) and 2) type of 
perfusion (dynamic /static) of PET imaging center.  The IWRS will be used to assign bottles 
containing double-blind investigational product to each patient.  Sufficient study drug will be 
dispensed to supply the patient until the next visit.  Site personnel will confirm that they have 
located the correct drug by entering a confirmation number found on the container into the 
IWRS.
7.2.1.
Selection and Timing of Doses
The doses will be administered at approximately the same time on each day, preferably in the 
morning.  For patients who desire to regularly dose at another time of day, exceptions can be 
made in consultation with the Lilly medical monitor.  The first dose should be taken the morning
after the first dispensing of drug at Visit 3.  Patients will be requested to record the actual date 
and time of the 2 dose administrations prior to each visit at which PK will be collected (for 
example, the date and time of the previous day's dose, as well as the date and time of the dose 
prior to that). If a dose is administered at the clinic, that date and time should also be recorded.  
The date and time of these dose administrations will be recorded in the patient’s eCRF.  If the 
patient fails to follow the dosing instructions for those visits where a dose is to be administered 
at the site, blood samples are still to be collected according to the Schedule of Activities (Section 
2) and as described above. On those visits where the dose is to be administered at the site, if the 
patient fails to follow this instruction and is dosed prior to sample collection, an additional dose 
will not be administered at the visit.
7.3.
Blinding
This is a double-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All calls resulting in an unblinding event will be recorded and reported by the 
IWRS.
If an investigator, site personnel performing assessments, patient, or study partner is unblinded, 
the patient must be discontinued from the study.  In cases where there are ethical reasons to have 
the patient remain in the study, the investigator must obtain specific approval from a Lilly-
designated medical monitor for the patient to continue in the study.


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In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly-designated medical 
monitor prior to unblinding a patient’s treatment assignment unless this could delay emergency 
treatment of the patient.  If a patient’s treatment assignment is unblinded, Lilly must be notified 
immediately.
7.4.
Dosage Modification
Dose adjustments are not allowed in this study.
7.5.
Preparation/Handling/Storage/Accountability
Clinical trial material will be stored in a secure, locked location maintained at the conditions 
specified on the label.  A record of inventory transactions will be maintained that will allow 
accountability of all study drug.  Handling and storage instructions for patients will be included 
on labeling of clinical trial materials.
7.6.
Treatment 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 capsule counts when the study medication 
packaging and any unused study medication are returned at study visits.  The patient should be 
instructed to bring all unused medication to the clinic at each visit so that the clinic staff can 
record the amount of medication used since the last visit.
Only patients who consume at least 80% of the prescribed daily dose (based on capsule count)
during this study will be considered compliant.  Similarly, patients will be considered 
significantly noncompliant if they are judged by the investigator to have intentionally or 
repeatedly taken more than the prescribed amount of medication.  Patients regarded as 
noncompliant may be discontinued at the investigator’s discretion, in consultation with the Lilly-
designated medical monitor.
Drug accountability will be emphasized at the start-up meeting, and drug accountability will be 
monitored throughout the study.
7.7.
Concomitant Therapy
Concomitant medications with the potential to affect cognition will be permitted, provided the 
patient has been maintained on a stable dose regimen for at least 30 days before screening, and 
between screening and randomization.  After randomization, attempts should be made to 
maintain stable doses of symptomatic AD medication, however, changes or additions will be 
permitted when clinically indicated and must be documented in eCRF.
The following concomitant therapies are prohibited:


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
Use of any investigational drug or device not specified in this study judged to be 
scientifically or medically incompatible with this study

Use of any drug of abuse, including but not limited to cannabis, illicit amphetamine, 
cocaine, illicit opiates, propoxyphene, methadone, methaqualone, phencyclidine, or illicit 
barbiturate

Use of depigmenting agents, such as, hydroquinone

Current use of strong inducers of CYP3A (See the Manual of Operations for a list of 
excluded drugs)

Current use of drugs known to significantly prolong the QT interval (See the Manual of 
Operations for a list of excluded drugs)
The list of other excluded medications and procedures is provided in the Manual of Operations.
7.8.
Treatment after the End of the Study
7.8.1.
Continued Access
Investigational Product will not be made available to patients after conclusion of the study.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1.
Permanent Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets one of the following conditions after consultation with the 
Lilly-designated medical monitor:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X upper 
limit of normal (ULN)

alanine aminotransferase or AST >5X ULN for more than 2 weeks

alanine aminotransferase or AST >3X ULN and total bilirubin level (TBL) >2X 
ULN or prothrombin time >1.5X ULN

alanine aminotransferase or AST >3X ULN with the appearance of fatigue, 
nausea, vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

alkaline phosphatase >2.5X ULN and TBL >2X ULN

alkaline phosphatase >2.5X ULN with the appearance of fatigue, nausea, 
vomiting, right quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
In addition, patients will be discontinued from the investigational product in the following 
circumstances:

Patient decision.  The patient may discontinue treatment, without prejudice to further 
treatment, at any time.

Adverse event or clinically significant laboratory value, ECG result, physical 
examination finding (including eye or skin examination), MRI finding (such as 
symptomatic vasogenic edema), C-SRSS result, or vital sign measurement of such 
severity that, in the opinion of the investigator or Lilly-designated medical monitor, 
continued treatment is not in the best interest of the patient.

Severe non-compliance to the study protocol that results in a safety concern, in the 
judgment of the investigator.

The patient, for any reason, requires a treatment with an excluded therapeutic agent and 
temporary discontinuation criteria cannot be met (see Section 8.1.2).

The patient develops a significant uncontrolled medical condition 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.


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Patients who discontinue study treatment early should receive all early discontinuation 
procedures as described in Section 2.  Patients should be encouraged to remain in the study until 
Week 52 (Visit 18), even if study treatment has been discontinued, and they should continue to 
participate in scheduled visits as described in Section 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 PK measurements and PET scans, after 
completing the early discontinuation assessments described in Section 2, as appropriate.  The 
follow-up visit (Week 56) is not required for patients who discontinue study treatment early and 
continue in the study, unless the study drug was discontinued within that last 4 weeks of the 
study.  The Lilly-designated medical monitor may be consulted regarding the details of 
managing a specific patient who discontinues treatment but remains in the study.
8.1.2.
Temporary Discontinuation from Study Treatment 
Treatment can be temporarily discontinued (examples include short-term treatment using a 
prohibited drug, uncertain AE, and/or hospitalization).  Re-starting investigational product is 
based on the PI’s judgment. If temporary discontinuation is due to an AE, it should be reported 
to the Lilly-designated medical monitor.  Temporary treatment discontinuation and re-starting 
should be documented.  The maximum permissible treatment suspension is 4 weeks over the 
duration of the study.  Exceptions may be considered to allow a subject to resume treatment 
when the temporary suspension period exceeds 4 weeks, after consultation with the Lilly medical 
monitor.
8.1.3.
Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly-designated medical monitor
and the investigator to determine if the patient may continue in the study.  If both agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly-designated medical monitor to allow the inadvertently enrolled patient to continue in the 
study with or without treatment with investigational product.
8.2.
Discontinuation from the Study
Some possible reasons that may lead to permanent discontinuation include:

enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

investigator decision
o
the investigator decides that the patient should be discontinued from the study


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o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

patient or study partner decision:  requests their withdrawal from the study

an individual patient enrolled in the study may be discontinued based on a specific AE 
profile, as recommended by the Lilly-designated medical monitor or the Assessment 
Committee, in discussion with the PI
Patients who discontinue the study early will have end-of-study procedures performed at the 
early discontinuation visit as shown in the Schedule of Activities (Section 2) and should 
participate in the follow-up visit, 4 to 6 weeks after the last dose of study treatment.
8.3.
Lost to Follow-Up
Site personnel, or an independent third party, will attempt to collect the vital status of the patient 
within legal and ethical boundaries for all patients randomized, including those who did not get 
investigational product.  Public sources may be searched for vital status information.  If vital 
status is determined, this will be documented and the patient will not be considered lost to 
follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the clinical laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1.
Primary Outcome Assessments
18F-AV-1451 PET.  18F-AV-1451 PET scans provide an in vivo measurement of the anatomical 
distribution and load of paired-helical filament (PHF)-tau pathology in the brain (Xia et al. 
2013).  Along with amyloid plaques, tau PHF tangles are one of the defining pathological 
signatures of neuropathologically confirmed AD.  Elevated 18F-AV-1451 binding is increased in 
AD relative to control subjects and presents in an anatomical distribution consistent with 
neuropathological Braak staging (Chien et al. 2013).  In contrast to amyloid, which becomes 
elevated many years before the onset of clinical symptoms, tau pathology is more closely 
associated in time with cognitive and functional decline.  The 18F-AV-1451 assessment involves 
2 PET scans, one at baseline and another after 52 weeks of treatment (or upon early 
discontinuation).  The change in 18F-AV-1451 SUVr between the two PET scans will be the 
primary outcome measure.  The change in 18F-AV-1451 SUVr will be compared across the 
treatment groups and to total exposure to LY3202626.
9.1.2.
Secondary Efficacy Assessments
Alzheimer’s Disease Assessment Scale—Cognitive subscale (ADAS-Cog; Rosen et al. 1984).  
The ADAS is a rater-administered instrument that was designed to assess the severity of the 
dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The 
cognitive subscale of the ADAS, the ADAS-Cog13, consists of 13 items assessing areas of 
cognitive function most typically impaired in AD, for example, orientation, verbal memory, 
language, praxis, delayed free recall, and digit cancellation measures (Mohs et al. 1997). The 
ADAS-Cog13 scale ranges from 0 to 85, with higher scores indicating greater disease severity.
Alzheimer’s Disease Cooperative Study—Activities of Daily Living Inventory (ADCS-ADL; 
Galasko et al. 1997, 2004). The ADCS-ADL is a 23-item inventory developed as a rater-
administered questionnaire that is to be answered by the patient’s study partner.  The ADCS-
ADL subset of items (items 7 to 23) for instrumental activities of daily living (ADCS-iADL) will 
be used as a secondary efficacy measure.  The focus in the mild AD dementia population is on 


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the instrumental activities of daily living (iADL) rather than the basic activities of daily living
(bADL), which are thought to be affected in more severe stages of the disease.  The range for the 
iADL score is 0 to 56, with lower scores indicating greater disease severity.  For each of the 
specific items, the study partner is first asked if the patient attempted the ADL during the past 
4 weeks.  If the patient did attempt the ADL, the study partner is asked to rate the patient’s 
performance level based on a set of performance descriptions.  Scores for each item and the 
overall score for the tool are calculated.  The range for the total ADCS-ADL score is 0 to 78.
Integrated Alzheimer’s Disease Rating Scale (iADRS).  The iADRS comprises scores from 
the ADAS-Cog and the ADCS-iADL, 2 well-accepted measures in AD research.  The iADRS is 
calculated as a linear combination of the total scores of the ADAS-Cog13 (score range 0 to 85 
with higher scores reflecting worse performance) and the ADCS-iADL (score range 0 to 56 with 
higher scores reflecting better performance). To account for the opposite directionality of the 
scores, the ADAS-Cog score is multiplied by (-1) in the calculation of the integrated scale. Then 
a constant (85) is added to anchor the ADAS-Cog at 0. The iADRS score is then calculated by 
summing the transformed ADAS-Cog13 and the ADCS-iADL, as shown below:
iADRS score = [-1(ADAS-Cog13)+85]+iADL
The iADRS score ranges from 0 to 141 with lower scores indicating worse performance
(Wessels et al. 2015).
9.1.3.
Screening and Exploratory Efficacy Assessments
Montreal Cognitive Assessment (MoCA).  The MoCA is a brief 30-point cognitive screening 
test developed with high sensitivity and specificity for detecting mild cognitive impairment 
(MCI) in patients who perform in the normal range on the MMSE.  Compared to the MMSE, the 
MoCA uses more numerous and demanding tasks to assess executive function, higher level 
language abilities, memory, and complex visuospatial processing (Nasreddine et al. 2005).  The 
MoCA has also demonstrated utility in diagnosis and classification of AD dementia (Roalf et al. 
2013).
Functional Activities Questionnaire (FAQ).  A growing literature supports the FAQ as a 
measure sensitive to changes in milder AD populations (Teng et al. 2010; Tabert et al. 2002).  
The FAQ (Pfeffer et al. 1982) is a rater-administered instrument directed at the study partner that 
is aimed to assess perceived ability in performing instrumental everyday activities thought to be 
especially cognitively complex (for example, financial management, shopping, playing games, 
food preparation, traveling, keeping appointments, keeping track of current events, and 
understanding media).  Each of the 10 items offers 6 response alternatives, varying in level of 
dependence and familiarity of the task, which are recorded so that each item receives a score 
ranging from 1 (complete independence) to 4 (complete dependence).  The sum of 10 items 
provides an overall assessment of perceived functional ability.
Mini-Mental State Examination (MMSE; Folstein et al. 1975).  The MMSE is a brief 
instrument used to assess cognitive function in elderly patients.  The instrument is divided into 2 
sections.  The first section measures orientation, memory, and attention.  The maximum score for 


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the first section is 21.  The second section tests the ability of the patient to name objects, follow 
verbal and written commands, write a sentence, and copy figures.  The maximum score for the 
second section is 9.  The range for the total MMSE score is 0 to 30.
Everyday Cognition (ECog).  The ECog measures functional abilities that are mediated by 
cognition in older adults through an informant-rated questionnaire.  Study partners are asked to 
compare the patient’s current level of functioning with the level of functioning 10 years earlier 
(or for as long as the study partner has known the patient) with 4 response options from 1 (better 
or no change compared with 10 years earlier) to 4 (consistently much worse) on each of 
7 factors.  The ECog comprises 1 global factor and 6 domain-specific factors, including everyday 
memory, language, semantic knowledge, visuospatial abilities, planning, organization, and 
divided attention (Farias et al. 2008).
Neuropsychiatric Inventory (NPI).  The NPI is a tool for assessing psychopathology in patients 
with dementia and other neurologic disorders.  Information is obtained from a study partner
familiar with the patient’s behavior.  A screening question assays each subarea of the NPI—
delusions, hallucinations, agitation, apathy, anxiety, depression, euphoria, irritability, 
disinhibition, and aberrant motor behavior.  Two questions inquire about neurovegetative 
changes, including alterations in appetite and nighttime behavior disturbances.  If the answer to 
the screening question is no, no further questions are pursued.  If the answer is yes, subquestions 
are asked and ratings of the frequency and severity of the behavior are made by the study partner
through the use of scales with anchor points.  The distress induced in the study partner by each 
behavior is also rated by the study partner.  Scores for each subscale, the total tool, study partner
distress associated with each behavior, and total study partner distress are computed.  The NPI 
standard version consists of 10 items with study partner distress scale and 2 neurovegetative 
questions.  Validity and reliability of the instrument have been demonstrated (Cummings et al. 
1994).  Four subscales can be defined based on a previously reported factor analysis:  Mood 
(depression, anxiety, nighttime behavior, appetite, irritability); Psychosis (delusions, 
hallucinations, agitation); Frontal (euphoria, disinhibition); and Other (apathy, aberrant motor 
behavior) (Frisoni et al. 1999).
Bath Assessment of Subjective Quality of Life in Dementia (BASQID).  The BASQID is a 
14-item, patient-reported outcome assessing a range of quality of life issues, including 
satisfaction with physical, psychological, social, and environmental aspects of living, as well as 
abilities to perform activities and feelings of autonomy, usefulness, and happiness.  Each item is 
scored from 0 to 4, with low scores indicating poor quality of life.  The BASQID is intended to 
complement objective measures to provide a more complete assessment of dementia patients, 
including quality of life from their own perspectives (Trigg et al. 2007).
9.1.4.
Exploratory Biomarker Assessments
Florbetapir F 18 (amyloid) PET.  Florbetapir F 18 amyloid PET scans provide an in vivo 
measurement of deposited amyloid plaques in the brain.  Florbetapir F 18 cortical composite 
SUVr correlates with post-mortem assessments of amyloid plaque load (Clark et al. 2012).  
Scans will be performed twice, once at screening and again after 52 weeks of treatment (or upon 


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early discontinuation).  The change in whole grey matter standardized uptake value ratio (SUVr)
between baseline and follow-up scans will be compared across treatment groups and to total 
exposure to LY3202626.
Perfusion PET.  An additional perfusion-weighted image will be acquired at each florbetapir F 
18  PET scanning visit, with no additional tracer injection, by utilizing the initial wash-in of 
florbetapir to the brain (Section 7.1.3).  These images will provide a perfusion (or blood flow) 
map of the brain at each florbetapir F 18 PET time point.  In AD, cerebral perfusion is reduced, 
especially in temporal and parietal areas, and this pattern of hypoperfusion closely mirrors the 
hypometabolism pattern observed using 18F-fluorodeoxyglucose (FDG)-PET.  As such, the 
florbetapir F 18 perfusion PET images provide a biomarker of resting brain function.  Changes in 
florbetapir F 18 perfusion PET between the baseline and follow-up scans will be compared 
across treatment groups and to total exposure to LY3202626.
Volumetric MRI.  Brain atrophy is one of the signature biological changes associated with AD, 
with shrinkage of the medial temporal lobe (including the hippocampus) and ventricular 
enlargement particularly prominent.  The volume of different brain structures and measures of 
atrophy can be accurately quantified from vMRI scans.  Magnetic Resonance Imaging changes in 
brain volume from baseline to after 52 weeks of treatment (or early discontinuation) will be 
quantified. Measurements of brain structural changes, including, but not limited to, whole brain, 
ventricles and hippocampus will be evaluated.  Brain structural changes will be compared across 
treatment groups and to total exposure to LY3202626.
9.1.5.
Appropriateness of Assessments
As described above, this Phase 2 study will assess whether inhibition of production of Aβ in the 
brain can slow the progression of disease as assessed by biomarkers of neurodegeneration over 
52 weeks of treatment. The 18F-AV-1451 PET scan will be the primary outcome measure as a 
marker of disease progression for this study, to assess for cerebral tau neurofibrillary tangle load 
and whether there are any changes with Aβ targeted BACE inhibitor treatment. More details on 
the appropriateness of 18F-AV-1451 PET as primary outcome are provided in Section 3.2.
The ADAS-Cog and the ADCS-iADL are well recognized as measures of cognitive and 
functional abilities, respectively, in this patient population.  The iADRS is a newly developed 
measure combining scores from the ADAS-Cog and ADCS-iADL.  
Additional clinical and biomarker endpoints are included as exploratory measures.
9.1.6.
Scheduling of Cognitive and Functional Assessments
Assessments should be scheduled to allow the cognitive testing to be performed at approximately 
the same time of the day (±4 hours) at all the visits to avoid the known circadian variation of 
cognitive performance (Higuchi et al. 2000).  Patients and study partners should 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 nonstressful study procedures may be conducted during these 
breaks.


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9.1.7.
Rater Qualifications
There should be at least two independent, trained, qualified raters at each site.  The raters that 
perform screening/baseline should also be the same as those who perform the longitudinal post-
screening assessments for each patient. The ADAS-Cog13 must have a different rater than the 
rater who performs the ADCS-ADL for each patient.  For all outcome measures, every effort 
should be made to have the raters remain consistent throughout the duration of the trial.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via eCRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  In addition, site personnel will 
record any change in the condition(s) and any new conditions as AEs. Investigators should 
record their assessment of the potential relatedness of each AE to protocol procedure and 
investigational product via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, PET tracers, or a study procedure taking into account the 
disease, concomitant treatment(s), or concurrent pathologies/conditions.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, PET tracers, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF clarifying if possible, the circumstances leading 
to or discontinuations of treatment.


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9.2.1.
Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason:  important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.
Although all AEs occurring after signing the ICF are recorded in the eCRF, SAE reporting 
begins after the patient has signed the ICF and has received investigational product or PET 
imaging.  However, if an SAE occurs after signing the ICF, but prior to receiving investigational 
product or PET imaging, it needs to be reported ONLY if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.


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9.2.2.
Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB for LY3202626.
9.4.
Safety
9.4.1.
Electrocardiograms
For each patient, triplicate ECGs should be collected according to the Schedule of Activities 
(Section 2).  Electrocardiograms should be recorded according to the study specific 
recommendations included in the Manual of Operations for the study.
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the
patient receives the first dose of the investigational treatment or PET tracers should be reported 
to Lilly or its designee as an AE via eCRF per Section 9.2.
Electrocardiograms will initially be interpreted by a qualified physician (the investigator or
qualified designee) at the site as soon after the time of ECG collection as possible, and ideally 
while the patient is still present, to determine whether the subject meets entry criteria at the
relevant visit(s) and for immediate patient management, should any clinically relevant findings
be identified. Patients must meet eligibility criteria with respect to cardiac inclusion/exclusion 
criteria at the time of the screening.  The triplicate ECGs then must be transmitted for central 
reading.
Note that new findings on ECG after enrollment that do not meet entry criteria do not 
automatically indicate that subject should be discontinued.  In some cases, discontinuation may 
not be necessary and will depend on clinical significance and implications.  The investigator 
should refer to the Manual of Operations for guidance should a patient’s QTcF interval exceed 
450 msec (male) or 470 msec (female) or if >30 msec change from baseline while receiving 
study drug.  Unscheduled ECGs may be obtained at the discretion of the investigator.
9.4.2.
Vital Signs
For each patient, vital sign measurements (blood pressure, heart rate, and temperature) must be 
conducted according to the Schedule of Activities (Section 2) and following the study specific 
recommendations included in the Manual of Operations for the study.  Blood pressure and heart 
rate will be measured supine and standing.


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Any clinically significant findings from vital signs measurements that result in a diagnosis and 
that occur after the patient receives the first dose of investigational treatment or PET tracers 
should be reported to Lilly or its designee as an AE via eCRF per Section 9.2.
9.4.3.
Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational treatment or PET tracers should be 
reported to Lilly or its designee as an AE via eCRF per Section 9.2.
9.4.4.
Physical Examinations and Neurologic Examination
Physical and neurological examinations will be conducted as specified in the Schedule of 
Activities (Section 2) and as clinically indicated.
Physical examinations will include assessment of general appearance, skin, head and neck, 
lymph nodes, thyroid, abdomen (bowel sounds and liver and spleen palpation), back 
(costovertebral angle tenderness), and musculoskeletal, cardiovascular, and respiratory systems.  
Neurological examinations will include assessment of cranial nerves, motor and sensory systems, 
muscle stretch reflexes, balance and coordination, and gait.  The physical and neurological 
examination will be performed by a physician, nurse practitioner, or physician’s assistant (for 
Japan, physician only).
Body weight and height will be recorded according to the Schedule of Activities (Section 2).
If a clinically meaningful change in an MRI is noted during the study, an additional full 
neurological exam will be performed as soon as possible, along with any other medical follow-
up deemed necessary by the investigator.
Any clinically significant change from baseline on follow-up physical and neurological 
examinations should be reported to Lilly or its designee as an AE via eCRF per Section 9.2.
9.4.5.
Other Tests 
9.4.5.1.
C-SSRS
Consistent with Food and Drug Administration (FDA) regulatory guidance (FDA 2012), any 
occurrence of suicide-related thoughts and behaviors will be assessed as indicated in the 
Schedule of Activities (Section 2). The Columbia Suicide Severity Rating Scale (C-SSRS) is a 
scale that captures the occurrence, severity, and frequency of suicide-related thoughts and 
behaviors during the corresponding assessment period. The scale includes suggested questions 
to elicit the type of information needed to determine if a suicide-related thought or behavior 
occurred.
The C-SSRS is available in an adult’s and a children’s version. There is no version of the C-
SSRS designed for use in a cognitively impaired population such as patients with AD; therefore, 


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the children’s version will be used. Terms captured by the use of the C-SSRS children’s version 
can be mapped to Columbia Classification Algorithm for Suicide Assessment (Posner et al. 
2007), to facilitate future pooling of data.
The first time the scale is administered in this study (at Visit 1), the C-SSRS
“Baseline/Screening” version will be used. The C-SSRS “Since Last Visit” scale will be used 
for all subsequent assessments.  If, in the opinion of the investigator or C-SSRS administrator, 
the patient’s responses to the C-SSRS may not be reliable, the C-SSRS may be administered to 
the patient with the study partner present in person or by phone.  In this instance, responses from 
both the study partner and the patient will be considered when administering the scale. If a 
suicide-related thought or behavior is identified at any time during the study, a thorough 
evaluation will be performed by a study physician, and appropriate medical care will be 
provided.
The Lilly Self-Harm Supplement should be completed every time the C-SSRS is administered.  
If, based on administration of the C-SSRS, it is determined that suicide-related behaviors have 
occurred, then the Lilly Self-Harm Follow-Up form will be used to collect additional information 
to allow for a more complete assessment of these behaviors.
Any clinically significant findings from the C-SSRS should be reported to Lilly or its designee as 
an AE via eCRF per Section 9.2.
9.4.5.2.
Eye Examination
All patients will undergo comprehensive eye examinations performed under the supervision of 
an optometrist or ophthalmologist to assess visual function and morphology.  Scheduled 
examinations will include the following: visual acuity, intraocular pressure, dilated funduscopic 
exam (dilation only performed in patients without contraindication to mydriatics), slit lamp 
exam, color photography of the retina, and optical coherence tomography (OCT) or equivalent; 
examinations may also include color vision assessment where feasible.  Assessments will be 
performed at times shown in the Schedule of Activities (Section 2), preferably supervised by the 
same optometrist or ophthalmologist for each patient’s visit.  Patients who complain of vision 
disturbance, such as change in field of vision, color, acuity or anything potentially localizable to 
the retina, during the clinical trial should be referred to the optometrist or ophthalmologist for
unscheduled evaluation.
Data from the eye examination visits will be provided from the local optometrist or 
ophthalmologist to the Investigator.  Based on the morphological and functional results, the 
investigator will include or exclude the patient in consultation with the performing eye examiner, 
if applicable.
The local optometrist or ophthalmologist will review the color photography and OCT to aid in 
the investigator’s assessment of study eligibility and for immediate patient management.  
Additionally, the color photography of retina and OCT will be analyzed by a central reader.
Unblinded results of the eye safety data will be reviewed by the Assessment Committee (AC)
with the participation of an ophthalmologist, as specified in Section 10.3.7.


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Any clinically significant findings that result in a diagnosis should be reported to Lilly or its 
designee as a pre-existing condition or AE via eCRF per Section 9.2.  The PI will make all final 
determinations of AEs in consultation with performing eye examiner, if applicable.
9.4.5.3.
Skin Examination
A complete skin examination will be performed at the times shown in the Schedule of Activities 
(Section 2), preferably by the same dermatologist for each patient’s visit.  All skin examinations
must be performed by a dermatologist who will inspect the patient’s unclothed full body using a 
ultraviolet (UV) light.  The initial examination will include Fitzpatrick skin-type classification 
scale.
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 hypopigmented area (such as redness or 
induration). A static physician’s global assessment (sPGA) will be used to determine the 
patient’s overall hypopigmentation severity at a given time point using a visual analog scale 
(VAS) ranging from 0 to 100.  In addition, patients noted to have evidence of hypopigmentation 
will be asked to record how bothersome they find the hypopigmentation 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.
Any clinically significant findings that result in a diagnosis should be reported to Lilly or its 
designee as a pre-existing condition or AE via eCRF per Section 9.2.  The principal investigator 
will make all final determinations of AEs in consultation with the dermatologist.
9.4.5.4.
Magnetic Resonance Imaging
Magnetic resonance imaging of the brain will be performed according to the Schedule of 
Activities (Section 2) to screen patients for eligibility to participate in the study and for 
secondary efficacy assessment.  Magnetic resonance imaging screening scans should be 
performed during the screening period, after the patient has met most other screening criteria, as 
outlined in the Schedule of Activities (Section 2).  The central radiologist review of the screening 
MRI scan must be available before randomization to evaluate the inclusion/exclusion criteria.  
Any clinically significant findings that result in a diagnosis should be recorded as a pre-existing 
condition or AE per Section 9.2.
Magnetic resonance imaging scanning will be conducted under the management of a central 
vendor.  The scans will be reviewed by the investigator or qualified designee for immediate 
patient management.  The MRI scans will be acquired at the imaging sites using a standardized 
protocol.  The MRI scans will be transmitted to the imaging vendor for evaluation.
If a patient develops an acute neurological change such as symptoms suggestive of vasogenic 
edema during the study, an unscheduled MRI should be obtained.  Potential symptoms of ARIA-
E could include headache, gait instability, dizziness, tremor, worsening cognitive function, 
alteration of consciousness, seizures, unsteadiness, and vomiting (Ostrowitzki et al. 2012; 
Sperling et al. 2012).  The abnormality is best detected by fluid attenuation inversion recovery 


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(FLAIR) sequences on the MRI and ARIA-H is detected with the T2* gradient-recalled echo on 
the MRI.  It is recommended to repeat the MRIs with these sequences every 2 to 4 weeks until 
resolution of ARIA-E is documented.  For asymptomatic or mild symptoms, the patient can be 
observed; for moderate symptoms, the use of oral or IV steroids can be considered.  In the case 
of severe symptoms, it is recommended to hospitalize the patient for close observation and 
consider the use of IV steroids such as high-dose dexamethasone or a similar agent.  Study 
treatment should be discontinued if clinically symptomatic vasogenic edema, clinical 
symptomatic superficial siderosis, or clinically symptomatic incident microhemorrhage is seen.
Magnetic resonance imaging findings believed to have potential clinical significance will be 
reported to the investigator and sponsor.  Any new or aggravated clinically relevant abnormal 
MRI finding as compared with the baseline MRI should be reported to Lilly or its designee as an 
AE via an eCRF per Section 9.2.  If a clinically meaningful change in MRI is noted during the 
study, an additional, full neurological exam will be performed as soon as possible, along with 
any other medical follow-up deemed necessary by the investigator (Section 9.4.4).
9.4.6.
Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.  An AC will be designated for at least one interim evaluation of unblinded safety data 
from Study LLCF (Section 10.3.7).
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, hepatic laboratory tests (Appendix 4) must be repeated within 3 to 5 days including ALT, 
AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm 
the abnormality and to determine if it is improving or worsening.  If the abnormality persists or 
worsens, clinical and laboratory monitoring must be initiated by the investigator and in 
consultation with the study medical monitor.  Monitoring of ALT, AST, TBL, and ALP must 
continue until levels normalize or return to approximate baseline levels.
Additional safety data must be collected via the case report form (CRF) if 1 or more of the 
following conditions occur: 

Elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

Elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

Patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

Hepatic event considered to be a SAE
See Appendix 4, for hepatic eCRFs that must be completed for these patients.


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9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL each will be collected to determine the plasma concentrations of 
LY3202626.
A maximum of 2 samples may be drawn at additional time points during the study if warranted 
and agreed upon between both the investigator and sponsor.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Bioanalytical samples collected to measure LY3202626 concentrations will be retained for a 
maximum of 1 year following last subject visit for the study.  During this time, samples 
remaining after the bioanalyses may be used for exploratory analyses such as metabolism and/or 
protein binding work.
9.6.
Pharmacodynamics
The peripheral dose-dependent PD activity of LY3202626 and placebo administration will be 
evaluated by analysis of plasma A1-40, A1-42, A1-x as measured using validated immunoassays.  
These plasma based biomarkers will provide an assessment of target engagement and the data 
will inform dose optimization.  Central PD will be assessed in a substudy in which CSF is 
collected from participating patients.
Biological samples collected to measure PD parameters will be identified by the patient number 
(coded) and retained for a maximum of 15 years following last patient visit for the study at a 
facility selected by Lilly or its designee.
9.7.
Genetics
9.7.1.
Apolipoprotein E Genotyping
Apolipoprotein E (APOE) genotyping is a mandatory part of this study, unless country-specific 
laws and regulations prohibit this type of testing.  Blood sampling for APOE genotyping will be 
performed as shown in the in the Schedule of Activities (Section 2).  Neither patients nor 
investigators will receive the genotype results unless there is a country-specific law or regulation 
that requires notification of the results.  Failure to collect samples for APOE will not be 
considered a protocol deviation if country-specific regulations prohibit the testing of genetic 
material or transportation of such material outside of the country.
9.7.2.
Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.


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Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to LY3202626 and to 
investigate genetic variants thought to play a role in AD.  Assessment of variable response may 
include evaluation of AEs or differences in efficacy.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ethical review boards (ERBs)/investigational 
review boards (IRBs) impose shorter time limits, at a facility selected by Lilly.  This retention 
period enables use of new technologies, response to regulatory questions, and investigation of 
variable response that may not be observed until later in the development of LY3202626 or after 
LY3202626 become(s) commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome, exome or 
directed next-generation sequencing, genome wide association studies, and candidate gene 
studies.  Regardless of technology utilized genotyping data generated will be used only for the 
specific research scope described in this section.
9.8.
Biomarkers Research & Development
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), proteins, lipids, and other cellular elements.
Plasma and whole blood samples for RNA and epigenetic analyses will be collected for non-
pharmacogenetic biomarker research at the times specified in the Schedule of Activities
(Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3202626, pathways associated with AD, mechanism of action of LY3202626, and/or research 
methods or in validating diagnostic tools or assay(s) related to AD.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.
Samples will be retained for a maximum 15 years after the last patient visit for the study, or for a 
shorter period if local regulations and ERBs impose shorter time limits, at a facility selected by 
Lilly or its designee.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3202626 or after LY3202626 becomes commercially available.


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9.9.
Medical Resource Utilization and Health Economics
Health Economics and Medical Resource Utilization parameters were not evaluated in this study.


I 7 X-M C -L L C F ( c) Cli ni c al Pr ot o c ol
P a g e 5 3
L Y 3 2 0 2 6 2 6
1 0. St ati sti c al C o n si d er ati o n s
1 0. 1. S a m pl e Si z e
A p pr o xi matel y  3 8 0 pat ient s will be e nr olle d s o t hat a p pr o xi matel y 3 2 0 pati e nts will c o mplete t he 
st u d y.
P ati e nts w h o are ra n d o mize d b ut n ot a d mi nistere d treat me nt ma y be re place d t o e ns ure t hat 
e n o u g h s u bjects c o m plete t he st u d y.
1 0. 1. 1.
S a m pl e si z e c al c ul ati o n
T he sa m ple size was deter mi ne d base d o n i nter nal, 9 -m o nt h, l o n gi t u di nal 1 8F- A V -1 4 5 1 data.  
1 8F- A V -1 4 5 1 S U Vr val ues were calc ulate d fr o m t hese i ma ges usi n g t he 
 
 as t he refere nce re gi o n (
), a n d 
t he 
.  T he ma p pr o vi di n g t he 
s 
( M U B A D A) ( A b di 2 0 1 2) a n d c orres p o n ds t o a n i nte nsity ma p t hat reflects t he cr oss -secti o nal 
differe nce i n 1 8
C CI
F- A V -1 4 5 1 si g nal bet wee n A D s u bjects a n d healt h y c o ntr ols.  T his ma p is most 
. 
 
;
 
 
.
A p pr o xi matel y  3 8 0 pat ient s will be ra n d omize d i nt o t he trial acc or di n g t o a treat me nt rati o 1: 1: 1 
f or L Y 3 2 0 2 6 2 6 3 m g, L Y 3 2 0 2 6 2 6 1 2 m g, a n d p lace b o, u ntil a p pr o xi matel y 4 5 parti ci pa nts are 
e nr o lle d i nt o e a c h ar m, t he n 1: 1 i n t he L Y 3 2 0 2 6 2 6 1 2 m g a n d place b o ar ms u ntil 3 8 0 t otal ha ve 
bee n ra n d o mize d .  
 
 
 
 
A se nsitivit y a nal ysis was perf or me d o n dr o p - o ut rates as hi g h as 3 0 %, a n d t he po wer f or t he 
pri mar y  o ut c o me was n o w orse t ha n 7 9 %.
 
.
Wit h res pect t o 
. Base d o n 
researc h b y S c h ott a n d c ollea g ues ( 2 0 1 0) ,
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


I 7 X-M C -L L C F ( c) Cli ni c al Pr ot o c ol
P a g e 5 4
L Y 3 2 0 2 6 2 6
 
.
 
 
 
 
1 0. 2. P o p ul ati o n s f or A n al y s e s
A nal ysis p o p ulati o ns f or St u d y L L C F are defi ne d bel o w (Ta ble L L C F. 3) .
T a bl e L L C F. 3 .
A n al y si s P o p ul ati o n s
P o p ul ati o n
Descri pti o n
E nr olle d 
All partici pa nts w h o ha ve bee n assi g ne d t o treat me nt (ra n d o mize d).  
Efficac y
All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose of d o u ble -bli n d st u d y  
treat me nt a n d ha ve at least 1 p ost d ose efficac y meas ure me nt.
Safet y
All ra n d o mize d partici pa nts w h o ta ke at least 1 d ose of d o u ble -bli n d st u d y  
treat me nt.  
N ote:  Partici pa nts will be i ncl u de d i n t he treat me nt gr o u p t o w hic h t he y were ra n d o mize d.
1 0. 3. St ati sti c al A n al y s e s
1 0. 3. 1.
G e n er al St ati sti c al C o n si d er ati o n s
Stati stical a nal ysis of t his st u d y will  be t he res p o nsi bilit y of El i Lill y a n d C o m pa n y .
U nless ot her wise s pecifie d, all safety a nal yses will be c o n d ucte d o n t he safety p o p ul at i on a n d all 
efficac y a nd P D a nal yses will be c o n d ucte d o n t he efficac y  p o p ul at i on as defi ne d a b o ve 
(Ta ble L L C F. 3) .
N o a dj ust me nt s will be ma de f or m ulti ple c om par is o ns.
All t otal a n d s u bscale sc ores will be deri ve d fr o m i n di vi d ual ite ms.  I f a n y i n di vi d ual ite m is 
m issi n g, t he c orres p o n di n g t otal a n d s u bscale sc ores will be c o nsi dere d missi n g, e xce pt f or t he 
A D A S -C o g 1 3
C CI
, w hic h will be i m p ute d.  T he i m p utati on al g orit h m will be s pecifie d i n t he 
statistical a nal ysis pla n ( S A P ).
All tests of treat me nt effects of bi o l ogical  efficac y or cli nical efficac y will be c o n d ucte d at a
1- side d α = . 1 0, u nless ot her wise state d.   Safet y assess me nts will be c o n d ucte d at a 2 -si de d α =. 0 5.
A re peate d meas ures a nal ysis refers t o a restricte d ma xi m u m li keli h o o d ( R E M L) -base d, mi xe d 
effects re peate d meas ures a nal ysis usi n g all t he l o n git u di nal o bser vati o ns at eac h p ost -baseli ne 
C CI


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visit.  A repeated measures analysis model will include the fixed, categorical effects of treatment 
group, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of 
baseline and the baseline-by-visit interaction, unless otherwise noted.  Unless otherwise 
specified, when an ANOVA model is used to analyze a continuous efficacy variable, the model 
will contain the main effects of treatment.  Similar logic is applied to an ANCOVA model, which 
in general, refers to the ANOVA model with baseline value added as a covariate.  Type III sum-
of-squares for the least squares (LS) LS Means will be used for statistical comparisons using an 
ANOVA or ANCOVA.  Categorical comparisons between treatment groups will be performed 
using Fisher’s exact tests, where appropriate.
Any change to the data analysis methods described in the protocol will require an amendment to 
the protocol only if it changes a principal feature of the protocol.  Any other change to the data 
analysis methods described in the protocol, and the justification for making the change, will be 
described in the clinical study report (CSR).  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
SAS® software will be used to perform most or all statistical analyses.
10.3.2.
Treatment Group Comparability
10.3.2.1. Patient Disposition
Reasons for discontinuation for all patients will be tabulated for treatment groups, and 
comparisons between treatment groups will be assessed by Fisher’s exact test. Additionally, the 
median time to all-cause discontinuation will be compared between the treatment groups. The 
null hypothesis is that the median time to discontinuation estimated using the Kaplan-Meier 
product limit method will be identical for the LY3202626 dose groups and placebo. The log-
rank test will be used to test the null hypothesis against the alternate hypothesis that the median 
time to discontinuation is not the same between the groups. A detailed description of patient 
disposition will be provided at the end of the study.
10.3.2.2. Patient Characteristics
Standard baseline characteristics of gender, age, and race will be summarized for all patients. 
Treatment group comparisons will be made using Fisher’s exact test for categorical data and an 
ANOVA, with an independent factor for treatment for continuous data. Diagnosis, illness 
characteristics, and baseline efficacy and safety measures will be analyzed in a similar manner.
10.3.2.3. Concomitant Therapy 
Stable doses of standard-of-care (SOC) AD medications will be permitted in this study as 
described in Section 6.2.  Exploratory analyses stratified by use of SOC medications at baseline 
will be conducted.
10.3.2.4. Treatment Compliance
The proportion of patients who are significantly noncompliant as noted in Section 7.6 of this 
protocol will be summarized and compared among all treatment groups using Fisher’s exact test.


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10.3.3.
Efficacy Analyses
10.3.3.1. Primary Analyses
The primary objective of this study is to assess the PD effect of 2 different LY3202626 doses 
(3 mg and 12 mg) in patients with mild AD dementia compared with placebo, measured by 
change in 18F-AV-1451 PET SUVr at baseline and Week 52. The primary measurement is 
change from baseline 18F-AV-1451 SUVr. The method for calculating the SUVr will be 
provided in the SAP.  ANCOVA will be used to statistically evaluate change in SUVr from 
baseline at 52 weeks post-dose.  The ANCOVA will include the fixed, categorical effects of 
treatment dose, and the continuous, fixed covariate of baseline 18F-AV-1451 SUVr.
10.3.3.2. Secondary Analyses
Statistical analyses of mean change in the ADAS-Cog13, ADCS-iADL, and iADRS will be 
conducted.  Generally, statistical assessment of the efficacy and health outcome measures will be 
an MMRM or an ANCOVA.  The primary comparison will be between LY3202626 12 mg 
versus placebo at endpoint.
10.3.3.3. Exploratory Analyses 
Statistical analyses of mean change in the exploratory endpoints will be conducted.  Generally, 
statistical assessment of the efficacy and health outcome measures will be an MMRM or an 
ANCOVA.  The primary comparison will be between LY3202626 12 mg versus placebo at 
endpoint.
In addition, changes from baseline in the vMRI and the florbetapir F 18 PET will be assessed.
10.3.4.
Safety Analyses
Safety will be assessed by summarizing and analyzing AEs, laboratory analytes, vital signs, 
ECGs, skin examinations, and eye examinations during the treatment period.  For continuous 
safety measurements, a change from baseline will be analyzed using an MMRM or an ANCOVA 
model.
Safety analyses for the treatment period will include comparisons between LY3202626 dose 
groups and placebo.  All hypotheses will be tested at a 2-sided α=.05 significance level.  No 
adjustments for multiple comparisons will be made.
For analysis comparing proportion of treatment-emergent abnormalities between treatment 
groups for laboratory analytes, vital signs, weight, ECGs, skin examinations, and eye 
examinations, only patients who have both a baseline observation and a postbaseline observation 
will be included in the analysis for each analyte or parameter, respectively.  The proportion of 
patients with abnormalities will be summarized and compared between treatment groups using 
Fisher’s exact test.
Suicide-related thoughts and behaviors, based on the C-SSRS, will be listed by patient and visit. 
Only patients that show suicidal ideation/behavior will be displayed (that is, if a patient’s
answers are all “no” for the C-SSRS, then that patient will not be displayed).  However, if a 


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patient reported any ideation or behavior at any time point, then all their ideation and behavior 
will be displayed, even if not positive.
Additional safety analyses may be performed if warranted.
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses
Plasma LY3202626 concentration data will be analyzed using a population approach 
implemented with the program nonlinear mixed-effect modeling (NONMEM) on a computer 
that meets or exceeds the minimum system requirements. The version of any software used for 
the analysis will be documented, and the program will meet or exceed the Lilly requirements of 
software validation. It is possible that other validated software programs may be utilized if 
appropriate, warranted, and approved by Global PK/PD management. Basic PK parameters, 
including clearance and distribution volume, will be characterized, and covariate relationships 
will be explored as appropriate.
For each dose level and visit, plasma Aβ1-40, Aβ1-42 and A1-x concentrations will be summarized 
and mean change from baseline will be calculated.  If appropriate, a modeling approach may be 
used to describe the change in plasma Aβ.  Additional exploratory analyses of the data will be 
conducted as suggested by the data. If appropriate, the data from this study may be combined 
with that from other studies in a meta-analysis.
It is planned that two interim locks of the PK dataset will be conducted during the course of this 
study. The first lock will occur after 75 patients complete 24 weeks of treatment (Study Visit 11) 
and will be used to support initial PK model development and will be conducted by the AC.  The 
second lock will be conducted after all patients complete 24 weeks of treatment, and will be used 
by pre-specified individuals from Lilly to prepare for final model development.
10.3.6.
Other Analyses
10.3.6.1. Subgroup Analyses 
All subgroup analyses will be exploratory (post hoc) in nature.  The details of these analyses will 
be described in the SAP.


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10.3.7.
Interim Analyses
Only the AC and Internal Review Committee (IRC) are authorized to evaluate unblinded interim 
safety and efficacy analyses, respectively.  Study sites will receive information about interim 
results ONLY if results are clinically relevant for the safety of their patients.  Membership of the 
AC and IRC will be documented in the AC charter and IRC plan. Unblinding details are 
specified in the unblinding plan section of the SAP or a separate document.
Details of the timing and decision criteria of the interim analyses by the AC and IRC are 
documented in a separate interim analysis plan and/or AC charter in order to maintain study 
blind, for the primary study team. If an LY3202626 dose is recommended to be dropped at the 
interim analysis because of safety, then randomization will be modified accordingly; in this 
instance, the percentage of patients receiving placebo will not be reduced.
An initial safety interim analysis will be conducted by the AC when data from approximately 
130 qualified patients at 12 weeks and 40 patients through 24 weeks have been obtained.  The 
AC may be asked to conduct additional safety interim analyses if safety concerns are observed 
during blinded safety monitoring. In the event that blinded safety monitoring uncovers an issue 
that needs to be addressed by unblinding at the group level, only members of the AC can conduct 
additional analyses of the safety data.
Efficacy reviews of data by an IRC may occur during the course of the study and will be 
documented in the IRC plan. At the times specified in Section 10.3.5, a limited number of pre-
identified individuals may gain access to the unblinded PK/PD data, as specified in the 
unblinding plan, prior to the interim or final database lock.  Information that may unblind the 
study during the analyses will not be reported to study sites or blinded study team until the study 
has been unblinded.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
Aβ
amyloid beta peptide
AC
Assessment Committee  
AD
Alzheimer’s disease
ADAS-Cog13
13-item Alzheimer’s Disease Assessment Scale-Cognition
ADCS-ADL
ADCS-iADL
Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory
Alzheimer’s Disease Cooperative Study – Instrumental Activities of Daily Living 
Inventory (instrumental ADL items sub-score)
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
APOE
apolipoprotein E
APP
amyloid precursor protein
ARIA-E
amyloid-related imaging abnormality–edema/effusions (also known as vasogenic 
edema)
ARIA-H
amyloid-related imaging abnormality–hemosiderin deposition (also known as 
microhemorrhage)
AST
aspartate aminotransferase
BACE
Beta-site amyloid precursor protein cleaving enzyme
BASQID
Bath Assessment of Subjective Quality of Life in Dementia
blinding
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.


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CIOMS
Council for International Organizations of Medical Sciences
Complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
CRF
Case report form (sometimes referred to as clinical report form).  A printed or electronic 
form for recording study patients’ data during a clinical study, as required by the 
protocol.
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CYP3A
cytochrome P450 3A
ECG
electrocardiogram
ECog
Everyday Cognition
eCRF
electronic case report form (see CRF)
ED
Early discontinuation
efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result under 
controlled conditions.
Enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
Enter
patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
FAQ
Functional Activities Questionnaire
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
florbetapir
[18F]-AV-45 (chemical name (E)-4-(2-(6-(2-(2-(2-[18F]fluoroethoxy)ethoxy) 
ethoxy)pyridin-3-yl)vinyl)-Nmethylbenzenamine)
GCP
good clinical practice
HCV
Hepatitis C virus
HDL
High-density lipoproteins
iADRS
integrated Alzheimer’s Disease Rating Scale


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IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference for Harmonisation
IgG/IgM
immunoglobulin G/immunoglobulin M
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IRB/ERB
Institutional Review Board/Ethical Review Board:  a board or committee (institutional, 
regional, or national) composed of medical professional and nonmedical members 
whose responsibility is to verify that the safety, welfare, and human rights of the 
patients participating in a clinical study are protected.
IRC
Internal Review Committee
IWRS
interactive web-response system
LDL
Low-density lipoproteins
legal representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
Lilly
Eli Lilly and Company
LP
lumbar puncture
MCI
Mild cognitive impairment
MMRM
mixed-model repeated-measures
MMSE
Mini-Mental State Examination
MoCA
Montreal Cognitive Assessment
MRI
Magnetic resonance imaging
NIA-AA
National Institute on Aging (NIA) and the Alzheimer’s Association (AA)
NPI
Neuropsychiatric Inventory


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PCR
polymerase chain reaction
PET
positron emission tomography
PK/PD
pharmacokinetics/pharmacodynamics
QTcF
Fridericia's corrected QT interval
RBC
Red blood cells
rCBF
regional cerebral blood flow
RNA
ribonucleic acid
ULN
Upper limit of normal
SAE
serious adverse event
SAP
statistical analysis plan
Screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SHFU
Self-Harm Follow Up Forms
SUSARs
suspected unexpected serious adverse reactions
SUVr
standard uptake value ratio
TBL
total bilirubin level
TPO
third-party organizations
VAS
visual analog scale
vMRI
volumetric magnetic resonance imaging
WBC
White blood cells


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Appendix 2.
Clinical Laboratory Tests 
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Chloride
Mean cell volume
Phosphate
Mean cell hemoglobin concentration
Potassium
Leukocytes (WBC)
Total bilirubin
Neutrophils, segmented
Direct bilirubin
Lymphocytes
Alkaline phosphatase (ALP)
Monocytes
Alanine aminotransferase (ALT)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Blood urea nitrogen (BUN)
Platelets
Creatinine
Uric acid
Urinalysis
Calcium
Specific gravity
Glucose, nonfasting
pH
Albumin
Protein
Glucose
Creatine kinase (CK)
Ketones
Screening Visit 1 only
Blood
Folic acid
Urine leukocyte esterase
Vitamin B12
Hepatitis B surface antigen (HBsAg)a
Hepatitis C virus (HCV) PCRb
Screening Visit 1 and Visit 18 or ED only
Hemoglobin A1c
Creatinine clearance
Thyroid stimulating hormone
Total T3
Free T4
Cholesterol (total, HDL, LDL) and triglycerides
Other Tests
HIV (optional, at screening onlyc)
Abbreviations:  ED = early discontinuation; HIV = human immunodeficiency virus; HDL = High-density 
lipoproteins; LDL = Low-density lipoproteins; PCR = polymerase chain reaction; RBC = red blood cells; WBC = 
white blood cells.
a
Hepatitis B surface antigen (HBsAg) should be collected at screening Visit 1 only in patients with a suspected or 
past history of hepatitis B.
b
Hepatitis C virus (HCV) PCR should be collected at screening Visit 1 only in patients with a suspected or past 
history of hepatitis C.
c
Tested at the discretion of the investigator or if mandated by local regulatory authorities.


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Appendix 3.
Study Governance Considerations


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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for ensuring:

that the patient understands the potential risks and benefits of participating in 
the study

that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed 
consent form (ICF) prior to the performance of any protocol procedures and 
prior to the administration of investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical
review board (ERB) was properly constituted and convened as required by International 
Conference on Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator Brochure (IB) and updates during the course of the 
study

informed consent form

relevant curricula vitae
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party.
Appendix 3.1.4.
Investigator Information


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Investigators in this clinical trial will include neurologists, geriatricians, psychiatrists, or other 
clinicians approved by the Sponsor or designee.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
An investigator with the most qualified patients will be selected to serve as the CSR coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the CSR coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the CRFs, and 
study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.


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The investigator will keep records of all original source data.  This might include laboratory
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data collected by a third-party will be encoded by the third-party and stored 
electronically in the third-party’s database system.  Validated data will subsequently be 
transferred to the Lilly data warehouse, using standard Lilly file transfer processes.
Data managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central vendor’s database system.  Data will subsequently be transferred 
from the central vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
PK for LY3202626
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; PK = pharmacokinetics; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Sampling Summary
This table summarizes the approximate number of samples (venipunctures and lumbar 
punctures) and volumes for all sampling (screening, standard laboratory, drug concentration, 
pharmacogenetic, biomarker, and exploratory) and tests during the study.  Fewer samples may 
actually be taken, but this will not require a protocol amendment.  Lumbar punctures are only 
collected for patients participating in the optional substudy.
Protocol I7X-MC-LLCF Sampling Summary
Purpose
Sample 
Type
Maximum Amount 
per Sample
Maximum 
Number Samples
Maximum 
Total Amount
Screening testsa
Blood
3.5 mL
5
14 mL
Standard laboratory testsa
Blood
2.5 mL
23
52 mL
Drug, Aβ isoforms, tau
CSF
20 mL
2
40 mL
Drug concentration
Blood
3 mL
12
36 mL
Pharmacogenetic samples
Blood
10 mL
3
27 mL
Other exploratory samples
Blood
10 mL
22
120 mL
Total Blood and CSF
289 mL
Hepatic Monitoringb
Blood
3 - 30 mL
-
-
Abbreviation:  CSF = cerebrospinal fluid.
a
Additional samples may be drawn if needed for safety purposes.
b
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly-designated Medical Monitor.


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Appendix 6.
Protocol Amendment I7X-MC-LLCF(c) Summary 
Effect of LY3202626 on Alzheimer’s Disease Progression as 
Measured by Cerebral 18F-AV-1451 Tau-PET in Mild 
Alzheimer’s Disease Dementia
Overview
Protocol I7X-MC-LLCF Effect of LY3202626 on Alzheimer’s Disease Progression as Measured 
by Cerebral 18F-AV-1451 Tau-PET in Mild Alzheimer’s Disease Dementia has been amended.  
The new protocol is indicated by amendment (c) and will be used to conduct the study in place of 
any preceding version of the protocol.
The protocol has been amended to include the performance of additional interim analyses and 
unplanned data reviews by the AC and IRC.
The overall changes and rationale for the specific changes made to this protocol are described in 
the following table:
Amendment Summary for Protocol I7X-MC-LLCF Amendment (c)
Section # and Name
Description of Change
Brief Rationale
Section 10.3.7 Interim Analyses
Only the AC and Internal Review 
Committee (IRC) are is authorized 
to evaluate unblinded interim 
efficacy and safety and efficacy 
analyses, respectively.  Study sites 
will receive information about 
interim results ONLY if results are 
clinically relevant for the safety of
their patients.  Membership of the 
AC and IRC will be documented in 
the AC charter and IRC plan.
Unblinding details are specified in 
the unblinding plan section of the 
SAP or a separate document.
Added Interim Review Committee 
to permit review of efficacy data
Section 10.3.7 Interim Analyses
Details of the timing and decision 
criteria of the interim Details of the 
timing and decision criteria of the 
interim analysis analyses by the AC 
and IRC are documented in a 
separate interim analysis plan and/or 
AC charter in order to maintain 
Added for clarification


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study blind, for the primary study 
team.  If an LY3202626 dose may is 
recommended to be dropped at the 
interim analysis because of safety 
and the, then randomization will be
modified accordingly; in this 
instance, the percentage of patients 
receiving placebo will not be 
reduced.   
Section 10.3.7 Interim Analyses
An initial safety interim analysis will 
be conducted by the AC when data 
from approximately 
105 130 qualified patients at 12 
weeks and 75 40 patients through 24 
weeks have been obtained.  
The data from approximately 105 
qualified patients at 12 weeks is the 
data that was intended for safety 
review by the AC. The data 
obtained for 75 patients through 
24 weeks was intended to support 
initial pharmacokinetic (PK) model 
development. As the data from 
75 patients with 24 weeks of 
treatment was not needed to perform 
the safety review to meet the 
primary objective, the decision was 
made to proceed with the data lock 
with approximately 130 patients 
with 12 weeks of treatment and 
40 patients with 24 weeks of 
treatment.
Section 10.3.7 Interim Analyses
Efficacy reviews of data by an IRC 
may occur during the course of the 
study and will be documented in the 
IRC plan. At the times specified in 
Section 10.3.5, a limited number of 
pre-identified individuals may gain 
access to the unblinded PK/PD data, 
as specified in the unblinding plan, 
prior to the interim or final database 
lock.
Added to describe efficacy analyses 
by the IRC
Appendix 1 Abbreviations and 
Definitions
ICH - International Conference on
for Harmonisation
Definition added to the 
Abbreviations and Definitions 
Appendix
Appendix 1 Abbreviations and 
Definitions
IRC – Independent Review 
Committee
Definition added to the 
Abbreviations and Definitions 
Appendix


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
10.3.7. Interim Analyses
Only the AC and Internal Review Committee (IRC) are is authorized to evaluate unblinded 
interim efficacy and safety and efficacy analyses, respectively.  Study sites will receive 
information about interim results ONLY if results are clinically relevant for the safety of their 
patients.  Membership of the AC and IRC will be documented in the AC charter and IRC plan.
Unblinding details are specified in the unblinding plan section of the SAP or a separate 
document.
Details of the timing and decision criteria of the interim analysis analyses by the AC and IRC are 
documented in a separate interim analysis plan and/or AC charter in order to maintain study 
blind, for the primary study team. If an LY3202626 dose may is recommended to be dropped at 
the interim analysis because of safety and the, then randomization will be modified accordingly; 
in this instance, the percentage of patients receiving placebo will not be reduced.
An initial safety interim analysis will be conducted by the AC when data from approximately 
105 130 qualified patients at 12 weeks and 75 40 patients through 24 weeks have been obtained.  
The AC may be asked to conduct additional safety interim analyses if safety concerns are 
observed during blinded safety monitoring. In the event that blinded safety monitoring uncovers 
an issue that needs to be addressed by unblinding at the group level, only members of the AC can 
conduct additional analyses of the safety data.
Efficacy reviews of data by an IRC may occur during the course of the study and will be 
documented in the IRC plan. At the times specified in Section 10.3.5, a limited number of pre-
identified individuals may gain access to the unblinded PK/PD data, as specified in the 
unblinding plan, prior to the interim or final database lock.  Information that may unblind the 
study during the analyses will not be reported to study sites or blinded study team until the study 
has been unblinded.

SAP_001.pdf: 
Statistical Analysis Plan v2  I7X-MC-LLCF  
 
Effect of LY3202626 on Alzheimer’s Disease Progression as Measured by Cerebral 18F-AV-
1451 Tau-PET in Mild Alzheimer’s Disease Dementia 
 
NCT02791191 
 
Approval Date: 16-Aug-2018 


I7X-MC-LLCF Statistical Analysis Plan Version 2
Page 1
LY3202626
1.
Statistical Analysis Plan for LLCF:  
(I7X-MC-LLCF):  Effect of LY3202626 on Alzheimer’s 
Disease progression as Measured by Cerebral 18F-AV-
1451 Tau PET in the Mild Alzheimer’s Disease Dementia 
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries..
LY3202626 Alzheimer’s Disease
Multicenter, randomized, double-blind, placebo-controlled, Phase 2 study comparing 3 mg
and 12 mg of LY3202626 with placebo over 52 weeks in approximately 500 patients with
mild Alzheimer’s disease dementia.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
[Protocol I7X-MC-LLCF]
[Phase 2]
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 16-Aug-2018 GMT


I7X-MC-LLCF Statistical Analysis Plan Version 2
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for LLCF:   (I7X-MC-LLCF):  Effect of 
LY3202626 on Alzheimer’s Disease progression as Measured by 
Cerebral 18F-AV-1451 Tau PET in the Mild Alzheimer’s Disease 
Dementia ............................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................7
4.3.
Exploratory Objectives...................................................................................................8
5.
A Priori Statistical Methods ................................................................................................9
5.1.
General Considerations ..................................................................................................9
5.2.
Adjustments for Covariates ............................................................................................9
5.3.
Handling of Dropouts or Missing Data.........................................................................10
5.3.1.
Handling Missing Data from Subject Dropouts ....................................................10
5.3.2.
Handling Missing Items in Calculating Totals......................................................10
5.4.
Multicenter Studies ......................................................................................................10
5.5.
Multiple Comparisons/Multiplicity...............................................................................10
5.6.
Population for Analysis ................................................................................................10
5.7.
Subject Disposition ......................................................................................................12
5.8.
Subject Characteristics .................................................................................................12
5.9.
Treatment Compliance .................................................................................................13
5.10. Concomitant Therapy...................................................................................................13
5.11. Efficacy Analyses ........................................................................................................14
5.11.1.
Primary Outcome and Methodology.....................................................................14
5.11.2.
Key Secondary and Exploratory Outcomes ..........................................................14
5.11.3.
Subgroup Analyses ..............................................................................................15
5.12. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................16
5.12.1.
Analysis of Plasma A.........................................................................................16
5.12.2.
Analysis of CSF Data...........................................................................................16
5.12.3.
Analyses of AV-45 PET Data...............................................................................16
5.12.4.
Analyses of perfusion PET Data...........................................................................16
5.12.5.
Analyses of Volumetric MRI Data .......................................................................17
5.13. Safety Analyses............................................................................................................17
5.13.1.
Extent of Exposure...............................................................................................17


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5.13.2.
Adverse Events ....................................................................................................18
5.13.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................18
5.13.4.
Clinical Laboratory Evaluation.............................................................................19
5.13.5.
Vital Signs and Other Physical Findings...............................................................20
5.13.6.
Electrocardiograms ..............................................................................................21
5.13.7.
Analyses of MRI Data..........................................................................................22
5.13.8.
Additional Safety Concerns..................................................................................22
5.13.8.1.
Columbia Suicide Severity Rating Scale.........................................................22
5.13.8.2.
Skin Examination ...........................................................................................23
5.13.8.3.
Eye Examination ............................................................................................23
5.14. Safety Follow-up Visit .................................................................................................24
5.15. Protocol Violations.......................................................................................................24
5.16. Interim Analyses and Data Monitoring.........................................................................24
5.16.1.
Interim Analysis...................................................................................................25
5.17. Clinical Trial Registry Analyses...................................................................................25
6.
Appendices .......................................................................................................................26


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Table of Contents
Table
Page
Table LLCF.SAP.1.
Analysis Populations for Study I7X-MC-LLCF...................................11
Table LLCF.SAP.2.
Efficacy and Safety Measures Summarized and/or 
Analyzed for Each Analysis Population..............................................................12
Table LLCF.SAP.3.
Adverse Events of Special Interest ......................................................19


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Table of Contents
Appendix
Page
Appendix 1.
Potentially Clinically Significant ECGs..............................................................27
Appendix 2.
Potentially Clinically Significant Laboratory Values ..........................................28
Appendix 3.
Criteria of Potential Clinical Significant Vital Signs and Weight........................30
Appendix 4.
Complete List of AV-45 (Florbetapir) Parameters..............................................31


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to unblinding.  
Statistical Analysis Plan (SAP) Version 2 was approved prior to final database lock. Due to early 
termination of the study, certain analyses were removed or simplified, while others were 
clarified. The changes in SAP version 2 are summarized below:
Clarified that change from baseline to last observation is to be used in ANCOVA analysis 
if Week 52 observation is not available (Section 5.1)
Removed the exploratory analysis on subjects with study partner change during the study 
(previously Section 5.11 in Version 1)
Clarified the analysis for changes from baseline in NPI total score and BASQID total 
score will be ANCOVA instead of MMRM because they were collected only once 
during post-baseline visits (Section 5.11.2)
Specified the cut-off for defining Tau subgroups and removed the subgroup analysis 
regarding race and country (Section 5.11.3)
Removed sensitivity analysis on Tau PET using percentage changes from baseline
(previously Section 5.12.4 in Version 1)
Simplified analysis of CSF biomarkers to listing of values by visit by treatment due to 
very limited number of subjects participated in the CSF addendum (Section 5.12.2)
Added analysis on annualized change in imaging biomarkers (vMRI, AV-45 PET, AV-
1451 PET) because majority of the subjects would not have Week 52 observation due to 
early termination of the study (Section 5.12.5)
Added an incidence summary for treatment-emergent CSSRS findings (Section 5.13.8.1)
Simplified and clarified the analysis for categorical eye exam and eye imaging data
(Section 5.13.8.3)


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4.
Study Objectives
4.1.
Primary Objective
To assess the change from baseline in 18F-AV-1451 positron emission tomography (PET) after 
treatment with LY3202626 3 mg or 12 mg per day compared with placebo for 52 weeks among
patients with mild Alzheimer’s disease (AD) dementia and evidence of brain amyloid.
The endpoint used to assess this will be the change in standardized uptake value ratio (SUVr) of 
18F-AV-1451 PET from baseline to 52 weeks.  The change will be compared between the 
LY3202626 doses (3mg and 12mg) and placebo.
4.2.
Secondary Objectives
Objectives
Endpoints
Secondary

To evaluate the safety and tolerability of 
LY3202626 (3 mg and 12 mg per day) compared 
with placebo.

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 and neurological examinations

magnetic resonance imaging (MRI; amyloid-related 
imaging abnormality [ARIA] and emergent 
radiological findings)

Skin examination 

Eye examination

Columbia-Suicide Severity Rating Scale (C-SSRS)

To assess peripheral pharmacokinetic (PK) and 
pharmacodynamic (PD) of LY3202626 (3 mg and 
12 mg per day) over 52 weeks.

Plasma PK of LY3202626 

Plasma PD A1-40, A1-42, A1-x

To assess change from baseline in cognition after 52 
weeks of treatment among patients treated with 
LY3202626 (3 mg and 12 mg per day) compared 
with placebo.

13-item Alzheimer’s Disease Assessment Scale –
Cognitive subscale (ADAS-Cog13)

To assess change from baseline in function after 52 
weeks among patients treated with LY3202626 
(3 mg and 12 mg per day) compared with placebo.

Alzheimer’s Disease Cooperative Study-Activities 
of Daily Living inventory (ADCS-iADL)

To assess change from baseline in a composite 
measure of cognition and function after 52 weeks 
among patients treated with LY3202626 (3 mg and 
12 mg per day) compared with placebo.

integrated Alzheimer’s Disease Rating Scale
(iADRS)


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4.3.
Exploratory Objectives
Objectives
Endpoints
Exploratory

To assess change in cognition after 52 weeks among patients 
treated with LY3202626 (3 mg and 12 mg per day) compared with 
placebo

Montreal Cognitive Assessment
(MoCA)

To assess change in function after 52 weeks among patients 
treated with LY3202626 (3 mg and 12 mg per day) compared with 
placebo

Functional Activities Questionnaire
(FAQ)

To assess change in cognition after 52 weeks among patients 
treated with LY3202626 (3 mg and 12 mg per day) compared with 
placebo

Mini-Mental State Examination
(MMSE)

To assess change in everyday functioning after 52 weeks among 
patients treated with LY3202626 (3 mg and 12 mg per day) 
compared with placebo

Everyday Cognition (ECog)

To assess change in neuropsychiatric symptoms after 52 weeks 
among patients treated with LY3202626 (3 mg and 12 mg per 
day) compared with placebo

Neuropsychiatric Inventory (NPI)

To assess change in subjective quality of life after 52 weeks 
among patients treated with LY3202626 (3 mg and 12 mg per 
day) compared with placebo

Bath Assessment of Subjective 
Quality of Life in Dementia
(BASQID)

To assess change from baseline in rCBF after 52 weeks among 
patients treated with LY3202626 (3 mg and 12 mg per day) 
compared with placebo.

SUVr cerebral perfusion from early 
post-injection florbetapir PET scan

To assess change from baseline in brain amyloid after 52 weeks 
among patients treated with LY3202626 (3 mg and 12 mg per 
day) compared with placebo

Florbetapir PET SUVr

To assess change from baseline in brain and brain regional 
volumes after 52 weeks among patients treated with LY3202626 
(3 mg and 12 mg per day) compared with placebo.

Volumetric MRI
Abbreviations:  MRI = magnetic resonance imaging; PET = positron emission tomography; rCBF = regional 
cerebral blood flow; SUVr= standardized uptake value ratio.


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5.
A Priori Statistical Methods
5.1.
General Considerations
All tests of treatment effects of biological efficacy or clinical efficacy will be conducted at a
1-sided α=.10, unless otherwise stated.  Safety assessments will be conducted at a 2-sided α=.05.
A repeated measures analysis refers to a restricted maximum likelihood (REML)-based, mixed
effects repeated measures analysis using all the longitudinal observations at each post-baseline
visit.
All analyses will follow the intent-to-treat (ITT) principle unless otherwise specified.  An ITT 
analysis is an analysis of data by the groups to which subjects are assigned by random allocation, 
even if the subject does not take the assigned treatment, does not receive the correct treatment, or 
otherwise does not follow the protocol.
When change from baseline is assessed, subjects will be included in the analysis only if both a 
baseline and a postbaseline measure are available.  Unless otherwise defined, Visit 3 is the 
baseline visit, and baseline value is defined as last value available before or at Visit 3.
All total and subscale scores will be derived from individual items.  If any individual item is
missing, the corresponding total and subscale scores will be considered missing, except for the
ADAS-Cog13 and ADCS-iADL, which will be imputed. 
A repeated measures analysis model will include the fixed, categorical effects of treatment, visit, 
and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline, 
baseline-by-visit interaction, and age at baseline.
When an analysis of covariance (ANCOVA) model is used to analyze a continuous efficacy 
variable, the model will contain the main effects of treatment with baseline value and age at 
baseline added as covariates. For ANCOVA analysis on change from baseline to Week 52 
endpoint,  change from baseline to last observation during treatment period will be used if 
patients do not have Week 52 observation available.
Categorical comparisons between treatment groups will be performed using Fisher’s exact tests 
or logistic regression where appropriate.
Any change to the data analysis methods described in the protocol will require an amendment to
the protocol only if it changes a principal feature of the protocol.  Any other change to the data
analysis methods described in the protocol, and the justification for making the change, will be
described in the clinical study report (CSR).  Additional exploratory analyses of the data will be
conducted as deemed appropriate.
5.2.
Adjustments for Covariates
The repeated measures models will include the fixed, categorical effects of treatment, visit 
(categorical covariate), treatment-by-visit interaction, as well as the continuous, fixed covariate 
of baseline, baseline-by-visit interaction, and age at baseline. 


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When an ANCOVA model is used to analyze a continuous efficacy or safety variable, the model 
will contain the main effects of treatment and appropriate baseline value and age at baseline 
included as covariates.
5.3.
Handling of Dropouts or Missing Data
5.3.1. Handling Missing Data from Subject Dropouts
A likelihood-based mixed effects model for repeated measures will be used to handle missing 
data.  The model parameters are simultaneously estimated using restricted likelihood estimation 
incorporating all of the observed data.  Estimates have been shown to be unbiased when the 
missing data are missing at random and when there is ignorable non-random missing data.
5.3.2. Handling Missing Items in Calculating Totals
All total and subscale scores for safety, efficacy, and health outcomes measures will be derived 
from individual items.  If any of the individual items are missing or unknown, every effort will 
be made to obtain the score for the missing item or items.
For ADAS-Cog13 and ADCS-iADL, if >30% of the items are missing, the total score at that visit 
will be considered missing.  If <30% of the items are missing, the total score will be imputed by 
prorating the nonmissing items.  The imputed number will be rounded up to the nearest integer.  
For example, if the first item of ADAS-Cog13, “Word-Recall Task,” which ranges from a score 
of 0 through 10 (maximum = 10) is missing, and the second item “Commands,” which ranges 
from a score of 0-5 (maximum = 5) is missing, then the multiplication factor = 85/(85 - [10 + 5]) 
= 85/70 = 1.21 (85 is the total score for the ADAS-Cog13).  Thus, the total score for this 
example will be the sum of the remaining 11 items multiplied by 1.21.  
For all other scales, if any item is missing, any total or sum involving that item will be 
considered missing.
5.4.
Multicenter Studies
This study will be conducted by multiple investigators at multiple sites internationally.  A listing
including country, investigator site with address, number of subjects enrolled (randomized) by 
each site and unique subject IDs will be presented.
5.5.
Multiple Comparisons/Multiplicity
No adjustments will be made for multiple comparisons.
5.6.
Population for Analysis 
The Efficacy population is defined as all randomized participants who take at least 1 dose of 
double-blind study treatment and have at least 1 postdose efficacy measurement, which is used to 
assess the effectiveness of the study drug regimen; all observed data will be included (including 
data gathered after a subject discontinues study drug).


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In order to assess the study drug treatment effect, data gathered after a subject discontinues study 
drug will not be included in the analysis of per protocol population. 
Additionally, when change from baseline is assessed, subjects will be included in the analysis 
only if both a baseline and at least 1 valid post-baseline measure are available.
All subjects who received at least 1 dose of randomized study treatment (LY3202626 or placebo) 
will be included in the safety analysis set.  If an LY3202626 dose group is dropped following an 
interim analysis, subjects switched to the remaining LY3202626 dose and remaining on 
treatment will be accounted for as a separate group.
For the Lumbar Puncture addendum, the analysis sets will include all those subjects whose
eligibility was determined by the respective biomarker, who signed consent for addendum, and 
who have a baseline and at least 1 valid post-baseline cerebrospinal fluid (CSF) assessment.
The PK analysis set is defined as all subjects in the safety population who have at least 1 post-
dose PK assessment. The population PK analyses will be performed using this analysis set.
The primary and secondary efficacy measures will be analyzed using the efficacy population 
unless otherwise specified.  In addition, the primary measure will be analyzed using per-protocol 
populations to verify the robustness of the results.  Summaries and analyses for safety measures 
will be based on the safety population.
Table LLCF.SAP.1 below defines each of the analysis populations used in this study.  
Table LLCF.SAP.2 lists the study measures that will be summarized and/or analyzed for each 
population.
Table LLCF.SAP.1.
Analysis Populations for Study I7X-MC-LLCF
Population Name
Description of Population
Enrolled
All participants who have been assigned to treatment (randomized).
Efficacy
All randomized participants who take at least 1 dose of double-blind study
treatment and have at least 1 postdose efficacy measurement.
Safety
All randomized participants who take at least 1 dose of double-blind study
treatment.
Per-Protocol
All subjects in the Full Efficacy population who also:

had an assessment of the primary endpoint at each scheduled visit 
completed

had no violations of inclusion/exclusion criteria

had no study dosing algorithm violation (such as if subjects randomized 
to treatment A were given treatment B or subjects randomized to 
treatment A never received the assigned study drug)

had no unqualified raters and no raters with substantial scoring errors 
for the primary measure

was not considered non-compliant with regard to study drug


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Table LLCF.SAP.2.
Efficacy and Safety Measures Summarized and/or Analyzed for 
Each Analysis Population
Population Name
Variables Assessed
Enrolled
Listings
Efficacy
Tables, Listings and/or Figures of the following:  subject disposition, subject
characteristics, pre-existing conditions, significant historical diagnoses ADAS-
Cog13, ADCS-iADL (and factor analyses), NPI, FAQ, ECog, BASQID, MoCA,
MMSE, plasma Aparameters, vMRI parameters, CSF parameters, AV-45 and Tau 
PET parameters and concomitant medications.
Safety Population
Tables, Listings and/or Figures of the following:  Compliance, adverse events, 
laboratory results, vital signs, weight, ECG, MRI, skin examination, eye 
examination, and C-SSRS.
Per-Protocol Population
Tables, Listings and/or Figures of 18F-AV-1451 PET SUVr.
Abbreviations:  ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; 
ADCS-iADL = Alzheimer’s Disease Cooperative Study-Activities of Daily Living inventory;
BASQID = Bath Assessment of Subjective Quality of Life in Dementia; CSF = cerebrospinal fluid, 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ECog = Everyday Cognition; 
FAQ = Functional Activities Questionnaire; MMSE = Mini-Mental State Examination; MoCA = Montreal 
Cognitive Assessment; MRI = magnetic resonance imaging; NPI = Neuropsychiatric Inventory; PET = positron 
emission tomography; SUVr = standardized uptake value ratio.
5.7.
Subject Disposition
The protocol for this study makes the distinction between subject withdrawal and subject 
discontinuation of study treatment.  Subject withdrawal occurs when a subject will no longer 
participate in the study (no longer taking study treatment and no longer being assessed).  Subject 
discontinuation of study treatment occurs when a subject agrees to continue being assessed but 
will no longer take study treatment.
Reasons for discontinuation for all patients will be tabulated for treatment groups, and
comparisons between treatment groups will be assessed by Fisher’s exact test.  Additionally, the
median time to all-cause discontinuation will be compared between the treatment groups.  The
null hypothesis is that the median time to discontinuation estimated using the Kaplan-Meier
product limit method will be identical for the LY3202626 dose groups and placebo.  The log 
rank test will be used to test the null hypothesis against the alternate hypothesis that the median
time to discontinuation is not the same between the groups.
5.8.
Subject Characteristics
Standard baseline characteristics of gender, age, and race will be summarized for all patients.  
Treatment group comparisons will be made using Fisher’s exact test for categorical data and an
ANOVA with an independent factor for treatment for continuous data.  Diagnosis, illness
characteristics, and baseline efficacy and safety measures will be analyzed in a similar manner.
Baseline characteristics will be summarized for the efficacy and per-protocol populations by 
treatment group and overall.  Summaries will include descriptive statistics for continuous and 
categorical measures.  Fisher’s exact test or Pearson’s chi-square test will be used for treatment-
group comparisons of categorical data.  For continuous data, analysis of variance (ANOVA), 


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with independent factors for treatment, will be used.  Subject characteristics to be presented 
include:  

Baseline AV-45 SUVr

Baseline Tau PET SUVr

age

age group:  55-64, 65-74, ≥75

gender

race

ethnicity

height

body weight

body mass index (weight (kg) / [height (m)]2)

region

tobacco use

alcohol use

years of education

work status

ApoE4 carrier status (carrier [ε2/ε4, ε3/ε4, ε4/ε4], noncarrier [ε3/ε3, ε2/ε2, 
ε3/ε2])

ApoE4 genotype (ε2/ε4, ε3/ε4, ε4/ε4, no ε4)

having 1 or more first degree relatives with AD

AChEI and/or memantine use at baseline

Baseline severity of impairment as measured by ADAS-Cog13, ADCS-iADL 
instrumental (ADCS-iADL) and , MMSE, MoCA, NPI, ECog, BASQID , and FAQ.
Baseline characteristics will also be listed.
5.9.
Treatment Compliance
Only subjects who consume at least 80% of the prescribed daily dose during this study will be 
considered compliant.  The percentage of compliant subjects will be compared across treatment 
groups using Fisher’s exact test.
5.10. Concomitant Therapy
Prior medications are defined as those that stop before randomization (Visit 3).  Concomitant 
medications are defined as those being taken on or after randomization (Visit 3).  A summary of 


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concomitant medications will be presented as frequencies and percentages for each treatment 
group.  Fisher’s exact test will be used to test for treatment differences between groups.  
Medications will be coded using the World Health Organization (WHO) drug dictionary.
5.11. Efficacy Analyses
5.11.1. Primary Outcome and Methodology
The primary objective of this study is to assess the PD effect of 2 different LY3202626 doses
(3 mg and 12 mg) in patients with mild AD dementia compared with placebo, measured by
change from baseline in 18F-AV-1451 PET SUVrs at Week 52. 
The primary statistical analysis is the ANCOVA, which will be used to statistically evaluate 
change in composite SUVr from baseline at 52 weeks post-dose.  The ANCOVA will include the 
fixed, categorical effects of treatment dose, and the continuous, fixed covariate of baseline Tau 
PET SUVr and age at baseline.
Change from baseline analyses will be conducted on SUVrs computed from the following 
3 composite regions with the bimodal white matter serving as the reference region: MUBADA
(primary), Delta_Z, and the frontal lobe region defined as a weighted average (weights being the 
number of voxels in the region) of SUV counts, averaged bilaterally, in the following Region of 
Interests (ROIs):

cingulum anterior

Inferior frontal gyrus, opercular part

Inferior frontal gyrus, orbital part

Inferior frontal gyrus, triangular part

Middle frontal gyrus

Middle frontal gyrus, orbital part

Superior frontal gyrus

Superior frontal gyrus, medial

Superior frontal gyrus, orbital part
5.11.2. Key Secondary and Exploratory Outcomes
The additional clinical and outcome measurements listed below will be analyzed separately using 
a mixed-effect model for repeated measures (MMRM) analysis. 
The change from baseline score at each scheduled post-baseline visit (according to the Study 
Schedule - data collected at unscheduled visits, including early discontinuation visits if not 
matching the study schedule, will not be included in this analysis) during the treatment period 
will be the dependent variable.  The model will include the fixed effects of treatment, visit 


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(categorical covariate), treatment-by-visit interaction, baseline age, baseline score (continuous 
covariate) and baseline-by-visit interaction.  Visit will be considered a categorical variable with 
values equal to the visit numbers at which the scales were assessed.  An unstructured covariance 
matrix will be used to model the within-subject variance-covariance errors.  If the unstructured 
covariance structure matrix results in a lack of convergence, the following tests will be used in 
sequence: heterogeneous Toeplitz covariance structure, heterogeneous autoregressive 
covariance structure, heterogeneous compound symmetry covariance structure, and compound 
symmetry covariance structure.  The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom.  Significance tests will be based on LSMean using a 1-sided 
Alpha of 0.10.  Analyses will be implemented using SAS PROC MIXED.  Longitudinal graphs 
of the LSMean estimates at each visit from the model will be plotted and the LSMean and 95% 
confidence intervals (CIs) results will be summarized in a summary table.
The secondary outcomes that will be analyzed are the following:

Change from baseline in ADAS-Cog13.

Change from baseline in ADCS-iADL.

Change from baseline in iADRS.
The exploratory outcomes that will be analyzed are the following:

Change from baseline in MoCA total scores.

Change from baseline in FAQ.

Change from baseline in MMSE total scores.

Change from baseline in ECog.
The following exploratory outcomes will be analyzed using the ANCOVA model described in 
Section 5.1:

Change from baseline in NPI total scores.

Change from baseline in BASQID total scores.
5.11.3. Subgroup Analyses
To assess the effects of various demographic and baseline characteristics, subgroup analyses will
be performed for the primary endpoint based on the following variables:

Tau PET subgroup (MUBADA SUVr at baseline <1.1, 1.1-1.46, and >1.46)

Age: 55-64, 65-74, ≥75 

ApoE4 carrier status (carrier [ε2/ε4, ε3/ε4, ε4/ε4], noncarrier [ε3/ε3, ε2/ε2, ε3/ε2])
The primary outcome measure will be modeled using an ANCOVA approach.  This general 
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5.12. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
5.12.1. Analysis of Plasma A
To evaluate the change in plasma Aanalytes (including assayed plasma A1-40, A1-42, A1-x
after treatment, an MMRM will be used to compare percent change from baseline to week 52.  
Log transformation will be applied to data prior to analysis and result will be back-transformed 
to get percent change from baseline.
The model for the fixed effects will include terms for the following independent effects:  log-
transformed baseline plasma A, treatment, visit, treatment-by-visit interaction.  The dependent 
variable is the change from baseline in log transformed plasma Aanalytes.  Visit will be
considered a categorical variable with values equal to the visit numbers at which plasma Ais 
assessed.  A similar MMRM analysis will be performed on untransformed percent change from 
baseline in plasma Aanalytes if the residual analysis suggests the log transformed analysis is 
inappropriate.
5.12.2. Analysis of CSF Data
Due to very limited number patients participated in the addendum for CSF sample collection,
CSF biomarkers (including CSF A1-40, CSF A1-42, CSF A1-x , CSF sAPP alpha, CSF sAPP 
beta, CSF total tau, and CSF p-tau from lumbar puncture) will be listed by treatment by visit.
5.12.3. Analyses of AV-45 PET Data
The analyses of change from baseline to the post-baseline visit of the composite summary SUVr 
of AV-45 (amyloid imaging) normalized will be conducted using an ANCOVA model with 
baseline AV-45 result and baseline age as covariates and treatment as categorical effect.
Change from baseline analysis will also be conducted for SUVr of the following regions 
(average of right and left) normalized (based on AVID guidelines):  cingulum anterior, cingulum 
posterior, frontal cortex, mesial temporal cortex, occipital cortex, orbitofrontal cortex, parietal 
cortex, and temporal cortex. 
The complete listing of AV-45 parameters obtained is provided in Appendix 4.
5.12.4. Analyses of perfusion PET Data
An additional perfusion-weighted image will be acquired at each florbetapir PET scanning visit, 
with no additional tracer injection, by utilizing the initial wash-in of florbetapir to the brain.  
These images will provide a perfusion (or blood flow) map of the brain at each time point.  In 
AD, cerebral perfusion is reduced, especially in temporal and parietal areas, and this pattern of 
hypoperfusion closely mirrors the hypometabolism pattern observed using 18F-
fluorodeoxyglucose (FDG)-PET.  As such, the perfusion PET images provide a biomarker of 
resting brain function.  Changes in florbetapir perfusion PET between the baseline and follow-up 
scans will be compared across treatment groups and to total exposure to LY3202626.


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The analysis of change from baseline to the post-baseline visit of the composite summary SUVr 
of perfusion scan will be performed using an ANCOVA model with baseline biomarker result 
and baseline age as covariates and treatment as categorical effect.  
The analyses of change from baseline will also be conducted for SUVr of each individual Region 
of Interest (ROI).
5.12.5. Analyses of Volumetric MRI Data
Brain atrophy is one of the signature biological changes associated with AD, with shrinkage of 
the medial temporal lobe (including the hippocampus) and ventricular enlargement particularly 
prominent.  The volume of different brain structures and measures of atrophy can be accurately 
quantified from vMRI scans.  Magnetic resonance imaging changes in brain volume from 
baseline to after 52 weeks of treatment (or early discontinuation) will be quantified.  
Measurements of brain structural changes, including, but not limited to, whole brain, ventricles 
and hippocampus will be evaluated.  Brain structural changes will be compared across treatment 
groups and to total exposure to LY3202626.
Analyses of the following vMRI parameters will be conducted:

Right hippocampal volume (mm3)

Left hippocampal volume (mm3)

Right hippocampal volume (mm3) + Left hippocampal volume (mm3)

Right entorhinal cortex (mm3)

Left entorhinal cortex (mm3)

Atrophy of Total whole brain volume (cm3)

Enlargement of Ventricular volume (cm3)
To evaluate the changes in vMRI data after treatment, an ANCOVA model will be used to 
compare change from baseline to 52 weeks.  The change from baseline to the endpoint visit will 
be the dependent variable.  The model for the fixed effects will include terms for the following 
independent effects:  baseline vMRI value, age at baseline, and treatment.  
In addition, annualized change in imaging biomarkers (vMRI, AV-45 and AV-1451) for each 
patient will be calculated using the change at the last post-baseline visit. The annualized change 
will be compared among the treatment groups with the same ANCOVA model described above.
5.13. Safety Analyses
5.13.1. Extent of Exposure
Summary statistics will be provided for the total number of subjects who were compliant by 
treatment group during the whole study period.  The proportion of subjects who were compliant 
will be compared using Fisher’s exact test.  Only subjects who consume at least 80% of the 
prescribed daily dose during this study will be considered compliant.


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Summary statistics will be provided for the total number of days of exposure by treatment.
5.13.2. Adverse Events
Treatment-emergent adverse events (TEAEs) will be defined as events that first occurred or 
worsened after the randomization date (visit 3 date).  Should there be insufficient data for AE
start date, stop date, and time to make this comparison, the AE will be considered treatment-
emergent.
Treatment-emergent adverse events will be coded according to established Medical Dictionary 
for Regulatory Activities (MedDRA) terms and summarized by MedDRA System Organ Class 
and Preferred Term.  
Summaries of AEs by decreasing frequency of preferred term within system organ class will be 
provided for the following:

Preexisting conditions

TEAEs

TEAEs by maximum severity

TEAEs occurring in greater than or equal to 5% of subjects by preferred term

Serious adverse events (SAEs)

AEs reported as reason for study treatment discontinuation
These summaries will include number and percentages of subjects with TEAEs.  Treatment 
comparisons will be carried out using Fisher’s exact Test.  A summary of TEAEs by visit will 
also be provided.
Preexisting conditions, TEAEs, SAEs, and discontinuations due to AEs will be listed.
5.13.3. Deaths, Other Serious Adverse Events, and Other Notable
Adverse Events
An overview of AEs, including the number and percentage of subjects who died, suffered SAEs, 
discontinued due to AEs and who suffered TEAEs, will be provided.  Comparison between 
treatments will be performed using Fisher’s exact Test.
In addition, the proportion of subjects within specific clusters of TEAEs will be summarized and 
treatment comparisons will be conducted using Fisher’s exact Test.  Clusters will be created 
from MEDRA’s High Level Group Terms (HGLT) (Table LLCF.SAP.3).  Each of the 3 groups 
with multiple HLGT’s will be combined to form one cluster.  Additionally, the 2 HLGT’s in the 
skin disorder group will be analyzed separately.


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Table LLCF.SAP.3.
Adverse Events of Special Interest
AE Groups of Interest
MedDRA Search Strategy
Nervous System Disorders Neuromuscular Disorders HLGT
Eye Disorders
Retinal disorders SMQ
Skin Disorders
Hypopigmentation disorders HLT
Pigmentation changes, NEC HLT
Epidermal and Dermal Conditions HLGT
Liver Disorders
Drug related hepatic disorders – comprehensive search SMQ
Cardiovascular-type 
events - Arrhythmic
Arrhythmia related investigations, signs and symptoms SMQ
Cardiac arrhythmia terms (incl. bradyarrhythmias and tachyarrhythmias) 
SMQ
TdP/QT prolongation SMQ
Cardiovascular-type 
events - Ischemic
Ischaemic heart disease SMQ
Cardiovascular-type 
events – Stroke
Central nervous system vascular disorders SMQ
Vascular Disorders
Decreased and Nonspecific Blood Pressure Disorders and Shock HLGT
Abbreviations:  AE = adverse event; HLGT = high-level group term; HLT = high-level term; MedDRA = 
Medical Dictionary for Regulatory Activities; NEC = not elsewhere classified; SMQ = Standardized 
MedDRA Query’ TdP = Torsades de Pointes. 
5.13.4. Clinical Laboratory Evaluation
Laboratory measurements will be analyzed using continuous data (change from baseline) and 
categorical or ordinal data (proportion of treatment-emergent abnormalities). 
If there are multiple records of laboratory measurements at baseline or postbaseline visit, the last 
record will be used.
Summaries and analyses of continuous data (change from baseline) will be performed using both 
conventional and International System of Units (SI units).
Change from baseline to each post-baseline visit at which laboratory measurements are taken and 
change from baseline to the last observation will be summarized and compared between 
treatment groups using an ANCOVA model.  For each lab analyte, the rank-transformation will 
be applied to the change from baseline for all subjects and all visits prior to analysis.  Similarly, 
an independent rank-transformation will be applied to the baseline values prior to analysis.  The 
model for the fixed effects will include terms for baseline value, treatment and age.  This 
analysis will be done separately for each laboratory analyte.  
Treatment differences in the proportion of subjects with treatment-emergent high or treatment-
emergent low or treatment-emergent abnormal laboratory values at (1) anytime and (2) each 
post-baseline visit will be assessed using Fisher’s exact test.  Treatment-emergent high or low 
laboratory abnormality will be based on SI unit.  For each laboratory analyte, only subjects who 
were low or normal at baseline and have at least one post-baseline measurement will be included 
in the denominator when computing the proportion of subject with treatment-emergent high
values.  Similarly, only subjects who were high or normal at baseline and have at least one post-


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baseline measurement will be included in the denominator when computing the proportion of 
subject with treatment-emergent low values.  In addition, treatment differences in the proportion 
of subjects who were normal at baseline and change to abnormal high or abnormal low values at 
any post-baseline visit will be summarized. 
For urinalysis parameters, baseline to post-baseline shifts will be summarized at each visit.  
Likelihood ratio chi-square tests will be used to compare increase, no change and decrease shifts 
in urinalysis parameters between treatment groups at each visit.
For all laboratory analytes, frequencies of subjects with notable changes (that is, increases or 
decreases of a prespecified amount unique to each analyte) from baseline to each postbaseline 
visit were also summarized for all subjects and stratified by low, normal, or high at baseline.
The proportion of subjects with treatment-emergent clinically significant changes from a low 
value or normal value at all baseline at any time in alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), and total bilirubin will be summarized by treatment group.  Abnormal 
criteria for treatment-emergent clinically significant changes are presented in Appendix 2.   
Significant changes of interest for hepatic laboratory values are:  ALT ≥3 x upper limit of normal 
(ULN), total bilirubin ≥2 x ULN, alkaline phosphatase (ALP) >2X ULN, ALT ≥5 x ULN, ALT 
≥10 x ULN, and total bilirubin ≥2 x ULN.  Additionally, Hy’s Law analysis will be conducted by 
comparing treatment groups with regard to the proportion of patients with (ALT ≥3 x ULN OR 
aspartate aminotransferase (AST) ≥ 3 x ULN) AND total bilirubin ≥ 2 x ULN.  Comparisons 
between treatment groups will be carried out using Fisher’s exact test.
5.13.5. Vital Signs and Other Physical Findings
Vital sign measurements and weight will be analyzed using continuous data (change from 
baseline) and categorical data (proportion of potentially clinically significant changes).
If there are multiple records of vital sign or weight measurements at baseline or postbaseline 
visit, the last record will be used.  Summary statistics will be presented for observed values at 
baseline and for change from baseline results at each scheduled postbaseline visit.  Systolic and 
diastolic blood pressure and pulse (collected in sitting position), orthostatic diastolic and 
orthostatic systolic blood pressures and orthostatic pulse (measurement after 5 minutes in the 
supine position minus that after 3 minutes in the standing position), temperature, and weight by 
treatment group for all subjects in the safety population will be summarized.
With the large number of the scheduled vital sign visits, the MMRM model is not suitable for the 
change from baseline comparison of treatments due to computational challenge.  Change from 
baseline to each post-baseline visit at which vital signs are taken will be assessed using an 
ANCOVA model with treatment and as independent factors and baseline value and age as 
covariates in the model.  This analysis will be done separately for each vital sign parameter and 
weight.  
The incidence of treatment-emergent abnormal high or low vital signs and weight will be 
presented by treatment group and visit.  Treatment-emergent vital sign evaluations are defined 
for evaluations collected after the initiation of study medication.  Abnormal criteria for 


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postbaseline vital signs and weight are presented in Appendix 3.  Any vital sign or weight 
meeting the criteria will be considered abnormal.  Treatment differences in the proportion of 
subjects with treatment-emergent abnormal high or low vital signs and weight will be assessed 
between treatment groups using Fisher’s exact test at (1) any time (2) post-baseline visit.
For each vital sign at each post-baseline visit, only subjects who had a baseline result and had a 
nonmissing result at that post-baseline visit will be included in the denominator when computing 
the proportion of subjects with treatment-emergent high, low, or abnormal values.
Summary and analyses of change from baseline in weight will be provided.  The proportion of 
subjects with a weight gain or loss of greater than or equal to 7 percent of baseline body weight 
will be compared between treatment groups using Fisher’s exact test at each visit and at any 
time.  For those subjects exhibiting a weight loss of greater than or equal to 7 percent of baseline 
body weight, body mass index (BMI) will be tabulated by treatment and compared using an 
ANOVA model with factors for treatment.  In addition, categories of BMI (underweight = <18.5, 
normal = ≥18.5 - <25, overweight = ≥25 to <30, obese = ≥30) will be compared across treatment 
groups using Pearson’s chi-square test at each visit and at any time.  
A listing of treatment-emergent abnormal vital signs and weight will also be presented by subject 
and visit.
5.13.6. Electrocardiograms
Electrocardiogram measurements will be analyzed using continuous data (change from baseline) 
and categorical data (proportion of treatment-emergent abnormalities).
Since ECG is measured in triplicates, the average of triplicates will be used at baseline and each 
visit.  If there are multiple records after averaging ECG triplicates within a visit, the last record 
of averages will be used.
The analysis will be done for the following ECG measurements:  heart rate, PR, QT, QTc, and 
RR intervals and QRS duration.  All analyses of QTc will be carried out using the Fridericia 
correction (QTcF) method.  These summaries will include data from each visit ECG measures 
are performed.  Change from baseline to each post-baseline visit at which ECG measurements 
are taken and change from baseline to last observation will be assessed using an ANCOVA 
model.  The model for the fixed effects will include terms for the following independent effects:  
baseline age, baseline ECG score, and treatment.  This analysis will be done separately for each 
ECG parameter.  
Incidence of treatment-emergent abnormal ECGs will be assessed by comparisons at (1) anytime 
and (2) each post-baseline visit between treatment groups with Fisher’s exact test.  For analyses 
of treatment-emergent abnormal ECGs, baseline will be considered as all visits before the 
initiation of drug dose.
Abnormal ECG criteria and criteria for abnormal QTcF prolongation are presented in Appendix 1.
Treatment-emergent high ECG parameters (heart rate, PR interval, QRS duration, QT and QTcF 
intervals) are the values which are low or normal at all baseline visits and fall into the high 


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abnormal categories post-baseline.  Similarly, treatment-emergent low ECG parameters (Heart 
Rate, PR interval, QRS duration) are the values which are high or normal at all baseline visits 
and fall into the low abnormal categories above. 
In additional, treatment differences in the proportion of subjects who have normal baselines with 
a change to abnormal high or abnormal low values at any post-baseline visits will be 
summarized.
5.13.7. Analyses of MRI Data
Magnetic resonance imaging findings believed to have potential clinical significance will be
reported to the investigator and sponsor. Any new or aggravated clinically relevant abnormal
MRI finding as compared with the baseline MRI should be reported to Lilly or its designee as an
AE. If a clinically meaningful change in MRI is noted during the study, an additional, full 
neurological exam will be performed as soon as possible, along with any other medical follow-
up deemed necessary by the investigator.
To evaluate any changes in MRI data following treatment, Pearson’s chi-square tests will be 
used to compare frequencies of responses in the MRI parameters.
Frequencies and percentages of the following amyloid-related imaging abnormality – edema 
(ARIA-E, also known as vasogenic edema) and ARIA – hemorrhage (ARIA-H, also known as 
microhemorrhage) parameters will be summarized:

ARIA-E:
o
Severity (mild, moderate, severe, or no presence)
o
Status compared to the previous MRI(s) (increased, unchanged, partial resolution,
or complete resolution)

ARIA-H:
o
Number of ARIA-H (1, 2 to 5, 6 to 10, >10, or no presence), 
o
Baseline to endpoint changes (increase in size of pre-existing ARIA-H, increase 
in number of ARIA-H, no change, partial resolution, or complete resolution)  
A listing of abnormal MRI finding will also be presented by subject and visit.
5.13.8. Additional Safety Concerns
5.13.8.1. Columbia Suicide Severity Rating Scale
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent, based on 
the C-SSRS, will be listed by subject and visit.  Only subjects that show suicidal 
ideation/behavior or self-injurious behavior without suicidal intent will be displayed (i.e., if a 
subject answers are all ‘no’ for the C-SSRS, then that subject will not be displayed).  However, if 
a subject reported any suicidal ideation/ behavior or self-injurious behavior without suicidal 
intent at any time point then all their ideation and behavior will be displayed, even if not 
positive.


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In addition, the number and percent of patients who experienced at least one of various 
comparative measures during treatment will be presented and compared.  These include 
treatment-emergent suicidal ideation compared to recent history, treatment-emergent serious 
suicidal ideation compared to recent history, emergence of serious suicidal ideation compared to 
recent history, improvement in suicidal ideation at endpoint compared to baseline, and 
emergence of suicidal behavior compared to all prior history.  
5.13.8.2. Skin Examination
Skin color will be reported at baseline by using Fitzpatrick Scale Rating.  The frequencies of the 
outcomes (I, II, III, IV, V, and VI) will be displayed by treatment group.
Any hypopigmentation will be assessed by location, percentage of body surface area 
involvement (BSA), degree (partial/decreased pigmentation to complete depigmentation), and 
other findings in or around the hypopigmentation area (e.g., redness or induration).  A static 
physician’s global assessment (sPGA) will be used to determine the subject’s overall 
hypopigmentation severity at a given timepoint using a visual analog scale (VAS) ranging from 0 
to 100.  In addition, subjects noted to have evidence of hypopigmentation will be asked to record
how bothersome they find the hypopigmentation on a VAS ranging from 0 to 100. 
Frequency tables and summary statistics for the continuous parameters will be given by 
treatment group.  
In order to display any changes/deteriorations during treatment, the following will be reported:  
number of subjects for whom no hypopigmentation was observed at baseline, but for whom at 
least once after randomization hypopigmentation was observed during treatment period; 
summary statistics for the difference of maximum value during treatment minus baseline value 
for percentage BSA of hypopigmentation, overall severity (sPGA) and “how bothered is the 
subject”; shift table of baseline vs. maximum value during treatment for degree of overall lesion 
severity.
5.13.8.3. Eye Examination
Summary statistics will be produced for the following continuous parameters:  thickness and 
volume of eye retinal thickness grid for each left and right eye: left eye total visual acuity score, 
right eye total visual acuity score (scores expressed as logMAR calculated as the negative log 
(base 10) of the decimal scores), as well as left eye intraocular pressure and right eye intraocular 
pressure (both in mmHg). In addition, summary statistics for the difference of maximum value 
during treatment minus baseline value for left eye total visual acuity score, right eye total visual 
acuity score, left eye intraocular pressure (mmHg), and right eye intraocular pressure (mmHg)
will also be produced.
In order to assess any changes/deteriorations during treatment, number and proportion of 
subjects with any treatment-emergent abnormal finding (in slit lamp examination,  dilated fundus 
examination, color vision examination, fundus photography and ocular coherence tomograph) 
will be summarized by visit and at any time during treatment period, and compared among 
treatment groups using Fisher exact test. Treatment-emergent abnormal findings include any 


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“new” or “worsened” findings in slit lamp, dilated fundus, and color vision exams, and any 
severity category increase in fundus photography and ocular coherence tomograph parameters at 
any post-baseline visits. Potentially clinically significant findings in slit lamp, dilated fundus, 
and color vision exams will also be summarized separately. 
5.14. Safety Follow-up Visit
Follow-up visit (Week 56) is not required for patients who discontinue study treatment early and 
who continue in the study unless study drug was discontinued within the last 4 weeks of the 
study.
Adverse events, concomitant medications, vital signs, and ECGs will be collected at these visits.  
These data will be summarized by treatment received during placebo-controlled treatment 
period.
5.15. Protocol Violations
Listings of subjects with significant protocol violations will be provided for the Full Efficacy 
population.  The following list of significant protocol violations will be determined from the 
clinical database and from the clinical/medical group:

Did not have an assessment of either the primary endpoint at any of the visits at which 
the scales were scheduled to be assessed.

Protocol violations of inclusion/exclusion criteria.

Had a study dosing algorithm violation (such as if subjects randomized to treatment A 
were given treatment B or subjects randomized to treatment A never received the 
assigned study drug.)

Had unqualified raters or raters with substantial scoring errors for the co-primary 
measures.

Was not compliant with regard to study drug.
The analyses for the primary objective will be repeated for the per protocol subject population.
5.16. Interim Analyses and Data Monitoring
An assessment committee (AC) will have the responsibility to review accumulating study data at 
a pre-specified interim analysis and make recommendations to protect the safety of subjects.  
The approved AC charter enumerates the roles of the AC members and the structure of their 
meetings.  A statistical analysis plan (SAP) for analyses associated with the AC list out the 
specific analyses that the AC will review.
One scheduled interim analyses will be conducted during this study.  The AC charter will specify 
the final details of the interim analyses.  Only the AC is authorized to evaluate unblinded interim 
safety analyses.  Study sites will receive information about interim results only if they need to 
know for the safety of their subjects.


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5.16.1. Interim Analysis 
The objective of the interim analysis (IA) is to conduct a safety analysis.  One safety interim 
analysis conducted by the AC is planned when data from approximately 105 qualified patients at 
12 weeks and 75 patients through 24 weeks have been obtained.  The AC may be asked to 
conduct additional safety interim analyses if safety concerns are observed during blinded safety 
monitoring. In the event that blinded safety monitoring uncovers an issue that needs to be 
addressed by unblinding at the group level, only members of the AC can conduct additional 
analyses of the safety data.
A limited number of pre-identified individuals may gain access to the unblinded PK/PD data, as 
specified in the unblinding plan, prior to the interim or final database lock.  Information that may 
unblind the study during the analyses will not be reported to study sites or blinded study team 
until the study has been unblinded.
5.17. Clinical Trial Registry Analyses
Analyses provided for the Clinical Trial Registry requirements will include the following:
Summary of AEs, provided as a dataset which will be converted to an XML file.  Both SAEs
and ‘Other’ AEs are summarized:  by treatment group, by MedDRA preferred term.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each SAE and ‘Other’ AE, for each term and treatment group, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of subjects in every treatment group may not be included if a 5% threshold is 
chosen (5% is the minimum threshold).


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6.
Appendices


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Appendix 1.
Potentially Clinically Significant ECGs
Parameter
Unit
Low PCS Criteria
High PCS Criteria
QRS Interval
msec
NA
≥120
PR Interval
msec
NA
≥220
QTcF
msec
NA
> 500
QTc interval:  change from baseline
> 60 msec at any time after randomization
Abbreviations:  NA = not applicable; PCS = potentially clinically significant; QTc = corrected QT interval; 
QTcF = Fridericia’s corrected QT interval.


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Appendix 2.
Potentially Clinically Significant Laboratory 
Values
Parameter
Conventional 
Unit
Low PCS 
Criteria
High PCS 
Criteria
SI Unit
Low PCS 
Criteria
High PCS 
Criteria
Hematology (whole blood)
Hemoglobin 
(male)
g/dL
<11
>18
gL
110
180
Hemoglobin 
(female)
g/dL
<10
>17
gL
100
170
Hematocrit
%
<30
>50 (F)
>55 (M)
L/L
<0.3
>50 (F)
>55 (M)
Leukocyte 
(WBC Count)
X 103/uL
≤2.8
≥15
X 109/L
≤2.8
≥15
Neutrophils
Cells/mm3
1500
NA
Proportion of 
1.0
≤0.15
NA
Platelet Count
X 103/uL
≤75
≥700
109/L
≤75
≥700
Chemistry (serum or plasma)
ALT (SGPT)
U/L
NA
≥3 X ULN
U/L
NA
≥3 X ULN
AST (SGOT)
U/L
NA
≥3 X ULN
U/L
NA
≥3 X ULN
Total Bilirubin
mg/dL
NA
≥1.5 X ULN
umol/L
NA
≥1.5 X ULN
BUN
mg/dL
NA
≥30
mmol/L
NA
≥10.71
Creatinine 
Kinase (CK)
U/L
NA
≥3 X ULN
U/L
NA
≥3 X ULN
Sodium
mEq/L
≤125
≥155
mmol/L
≤125
≥155
Potassium
mEq/L
≤3.0
≥5.5
mmol/L
≤3.0
≥5.5
Calcium
mg/dL
Corrected 
Value ≤7.5
Corrected 
value ≥12.0
mmol/L
≤1.875
≥3
Alkaline 
Phosphatase
U/L
NA
≥3 X ULN
U/L
NA
≥3 X ULN
Albumin
g/dL
≤2.6
≥6.0
g/L
≤26
≥60


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Parameter
Conventional 
Unit
Low PCS 
Criteria
High PCS 
Criteria
SI Unit
Low PCS 
Criteria
High PCS 
Criteria
Chloride
mEq/L
≤85
≥120
mmol/L
≤85
≥120
Glucose 
(random)
mg/dL
≤45.1
≥200.0
mmol/L
≤2.48
≥11
Serum 
Creatinine
mg/dL
NA
>1.5 X ULN
umol/L
NA
>1.5 X ULN
Gamma-
Glutamyl 
Transferase 
(GGT)
U/L
NA
≥3 X ULN
U/L
NA
≥3 X ULN
TSH
uU/L
below normal 
range
above 
normal 
range
mIU/L
below normal 
range
above 
normal range
Urinalysis
Hb/RBCs/Blood
NA
≥+ 2
Protein/Albumin
NA
≥+ 2
Glucose
NA
≥+ 2
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; F = female; Hb = hemoglobin; 
M = male; NA = not applicable; PCS = potentially clinically significant; RBCs = red blood cells; SGOT = serum 
glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; SI = Système International; 
TSH = thyroid-stimulating hormone; ULN = upper limit of normal; WBC = white blood cell.


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Appendix 3.
Criteria of Potential Clinical Significant Vital 
Signs and Weight
Parameter
Unit
Observed Value
And/Or
Change Relative to 
Baseline
Change from Supine 
to Standing
Systolic Blood 
Pressure (supine or 
sitting)
mmHg
≥180
And
Increase of ≥20
-
≤90
And
Decrease of ≥20
-
Diastolic Blood 
Pressure (supine or 
sitting)
mmHg
≥105
And
Increase of ≥15
-
≤50
And
Decrease of ≥15
-
Systolic Blood 
Pressure (supine to 
standing)
mmHg
≤80
And
-
Decrease of ≥20
Pulse (supine or 
sitting)
bpm
≥120
And
Increase of ≥15
-
≤50
And
Decrease of ≥15
-
Orthostatic 
hypotension 
(Systolic)
Decrease in systolic blood pressure when going from 5 minutes supine to 3 minutes standing 
of ≥20 mm Hg or the inability to stand quickly for the measurements due to symptoms of 
orthostasis
Orthostatic 
hypotension 
(Diastolic)
Decrease in diastolic blood pressure when going from 5 minutes supine to 3 minutes 
standing of ≥10 mm Hg or the inability to stand quickly for the measurements due to 
symptoms of orthostasis
Orthostatic pulse 
(Tachycardia)
Increase in heart rate when going from 5 minutes supine to 3 minutes standing of ≥30 bpm
Weight
Not Applicable
Increase of ≥7%
Decrease of ≥7%


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Appendix 4.
Complete List of AV-45 (Florbetapir) Parameters
SUVr will be obtained for the regions listed below normalized (based on AVID guidelines) and 
to cerebellar gray matter:
composite summary 
caudate left
caudate right
cerebellar cortex left
cerebellar cortex right
cerebellar white matter
cingulum anterior left
cingulum anterior right
cingulum posterior left
cingulum posterior right
frontal cortex left
frontal cortex right
lateral temporal cortex left
lateral temporal cortex right
mean cerebellum gray matter
mean whole cerebellum
mesial temporal cortex left
mesial temporal cortex right
occipital cortex left
occipital cortex right
orbitofrontal cortex left
orbitofrontal cortex right
parietal cortex left
parietal cortex right
pons
putamen right
putamen left
rectus left
rectus right
subcortical white matter
temporal cortex left
temporal cortex right
thalamus left
thalamus right