Conditions: Alzheimer's Disease
Keywords: anti-amyloid monoclonal antibody
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 26
Healthy volunteers: no

Brief summary:
The main purpose of this study is to investigate the safety and efficacy of the study drug solanezumab in participants with prodromal Alzheimer's disease (AD).

Detailed description:

Arms:
arm 1: Solanezumab given intravenously (IV) once every 4 weeks for up to 2 years. arm 2: Placebo given IV once every 4 weeks for up to 2 years.

Interventions: intervention 1: Solanezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV

Protocol document:
Prot_000.pdf: 
Protocol H8A-MC-LZBE 
 
A 24-Month, Phase 3, Multicenter, Placebo-Controlled Study of Efficacy and Safety of 
Solanezumab versus Placebo in Prodromal Alzheimer’s Disease 
 
NCT02760602 
 
Approval Date: 28-Mar-2016 
 
 
 


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Protocol H8A-MC-LZBE
A 24-Month, Phase 3, Multicenter, Placebo-Controlled Study 
of Efficacy and Safety of Solanezumab versus Placebo in 
Prodromal Alzheimer’s Disease
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
solanezumab (LY2062430), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Solanezumab (LY2062430)
Study H8A-MC-LZBE is a multicenter, randomized, double-blind, placebo-controlled, 
Phase 3 study comparing solanezumab with placebo for 24 months in approximately 
2450 patients with prodromal Alzheimer’s disease (AD).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 28-Mar-2016 GMT


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Table of Contents
Section
Page
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................20
4.
Objectives and Endpoints..................................................................................................22
5.
Study Design.....................................................................................................................24
5.1.
Overview of Study Design ...........................................................................................24
5.2.
End of Double-Blind Treatment Period and End of Trial..............................................24
5.3.
Scientific Rationale for Study Design...........................................................................24
5.4.
Justification for Dose ...................................................................................................25
5.5.
Benefit/Risk Assessment..............................................................................................25
6.
Study Population...............................................................................................................26
6.1.
Inclusion Criteria..........................................................................................................26
6.2.
Exclusion Criteria ........................................................................................................27
6.3.
Screen Failures.............................................................................................................29
6.4.
Lifestyle and/or Dietary Requirements .........................................................................29
7.
Treatment..........................................................................................................................30
7.1.
Treatments Administered .............................................................................................30
7.2.
Method of Treatment Assignment ................................................................................30
7.2.1.
Selection and Timing of Doses.............................................................................30
7.3.
Blinding .......................................................................................................................30
7.4.
Packaging and Labeling ...............................................................................................31
7.5.
Preparation/Handling/Storage.......................................................................................31
7.6.
Dose Modification........................................................................................................31
7.7.
Treatment Compliance .................................................................................................31
7.8.
Concomitant Therapy...................................................................................................32
7.9.
Treatment after Study Completion................................................................................32
8.
Discontinuation Criteria ....................................................................................................33
8.1.
Discontinuation of Inadvertently Enrolled Patients.......................................................33
8.2.
Discontinuation from the Study....................................................................................33
8.3.
Patients Lost to Follow-Up...........................................................................................35
9.
Study Assessments and Procedures ...................................................................................36
9.1.
Efficacy Assessments...................................................................................................36
9.1.1.
Primary Efficacy Assessments .............................................................................36
9.1.2.
Secondary Efficacy Assessments..........................................................................36


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9.1.3.
Appropriateness of Assessments ..........................................................................39
9.2.
Safety Evaluations........................................................................................................40
9.2.1.
Adverse Events ....................................................................................................40
9.2.2.
Serious Adverse Events........................................................................................41
9.2.2.1.
Suspected Unexpected Serious Adverse Reactions..........................................42
9.2.2.2.
Adverse Events of Special Interest..................................................................42
9.2.3.
Complaint Handling.............................................................................................42
9.3.
Other Safety Assessments ............................................................................................42
9.3.1.
Physical Examinations and Neurologic Examination............................................42
9.3.2.
Electrocardiograms ..............................................................................................43
9.3.3.
Vital Signs ...........................................................................................................43
9.3.4.
Body Weight and Height......................................................................................43
9.3.5.
Laboratory Tests ..................................................................................................44
9.3.6.
Magnetic Resonance Imaging...............................................................................44
9.3.7.
Columbia Suicide Severity Rating Scale (Adult Version) .....................................44
9.3.8.
Safety Monitoring ................................................................................................45
9.4.
Sample Collection and Testing.....................................................................................45
9.4.1.
Samples for Study Qualification and Health Monitoring.......................................45
9.4.2.
CSF Aβ and Tau Proteins and Solanezumab.........................................................45
9.4.2.1.
Timing of CSF Sampling................................................................................46
9.4.2.2.
CSF Collection Procedures.............................................................................46
9.4.3.
Plasma Samples for Assessment of As and Solanezumab ...................................46
9.4.3.1.
Timing of Plasma Sampling............................................................................46
9.4.3.2.
Plasma Collection Procedures.........................................................................46
9.4.4.
Serum Samples for Anti-Solanezumab Immunogenicity.......................................47
9.4.4.1.
Timing of Blood Sampling .............................................................................47
9.4.4.2.
Blood Collection Procedures ..........................................................................47
9.4.5.
Apolipoprotein E Genotyping...............................................................................48
9.4.6.
Samples for Biomarker Research..........................................................................48
9.4.6.1.
Pharmacogenetic Samples ..............................................................................48
9.4.6.2.
Biomarker Storage Samples............................................................................48
9.5.
Health Economics ........................................................................................................49
10.
Statistical Considerations and Data Analysis.....................................................................50
10.1. Determination of Sample Size ......................................................................................50
10.2. General Statistical Considerations ................................................................................50
10.2.1.
Analysis Populations............................................................................................51
10.2.2.
Handling of Missing Items for Scales...................................................................51
10.2.3.
Pooling of Investigators........................................................................................51


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10.3. Treatment Group Comparability...................................................................................52
10.3.1.
Patient Disposition...............................................................................................52
10.3.2.
Protocol Deviations..............................................................................................52
10.3.3.
Patient Characteristics..........................................................................................52
10.3.4.
Concomitant Therapy...........................................................................................53
10.3.5.
Treatment Compliance .........................................................................................53
10.4. Primary and Secondary Analyses .................................................................................53
10.4.1.
Primary Analyses.................................................................................................53
10.4.2.
Secondary Analyses .............................................................................................54
10.4.2.1.
Clinical Outcomes ..........................................................................................54
10.4.2.2.
Biomarker Outcomes......................................................................................54
10.4.2.2.1.
Analysis of Plasma A..............................................................................54
10.4.2.2.2.
Analysis of Volumetric MRI Data.............................................................54
10.4.2.2.3.
Analysis of Amyloid PET Imaging ...........................................................55
10.4.2.2.4.
Analysis of Cerebrospinal Fluid................................................................55
10.5. Safety Analyses............................................................................................................55
10.6. Pharmacokinetic/Pharmacodynamic Analyses..............................................................56
10.7. Other Analyses.............................................................................................................56
10.7.1.
Health Economics ................................................................................................56
10.7.2.
Subgroup Analyses ..............................................................................................56
10.7.3.
Gatekeeping Strategy ...........................................................................................56
10.8. Interim Analyses and Data Monitoring Committee.......................................................57
10.8.1.
Data Monitoring Committee.................................................................................57
10.8.2.
Interim Analysis...................................................................................................57
11.
Study Governance Considerations.....................................................................................59
11.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process ...........................................................................................................59
11.1.1.
Informed Consent.................................................................................................59
11.1.2.
Ethical Review.....................................................................................................59
11.1.3.
Regulatory Considerations ...................................................................................59
11.1.4.
Investigator Information.......................................................................................60
11.1.5.
Protocol Signatures ..............................................................................................60
11.1.6.
Final Report Signature .........................................................................................60
11.2. Data Quality Assurance................................................................................................60
11.2.1.
Data Capture System............................................................................................61
11.3. Study and Site Closure .................................................................................................61
11.3.1.
Discontinuation of Study Sites .............................................................................61
11.3.2.
Discontinuation of the Study................................................................................61


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12.
References ........................................................................................................................62


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List of Tables
Table
Page
Table LZBE.1.
Objectives and Endpoints...............................................................................22
Table LZBE.2.
Effective Radiation Dose (mSv) from Florbetapir PET Scans ........................71


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................65
Appendix 2.
Clinical Laboratory Tests...............................................................................69
Appendix 3.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................70
Appendix 4.
Summary of Radiation Dose ..........................................................................71


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1.
Protocol Synopsis
Title of Study:
A 24-Month, Phase 3, Multicenter, Placebo-Controlled Study of Efficacy and Safety of Solanezumab versus Placebo 
in Prodromal Alzheimer’s Disease
Rationale: 
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive decline in 
cognitive function and the ability to perform activities of daily living, ultimately resulting in dementia, typically 
with fatal complications. The amyloid hypothesis of AD postulates that the accumulation of amyloid-β peptide (Aβ) 
is an early and necessary event in the pathogenesis of AD. This hypothesis suggests that treatments that slow the 
accumulation of Aβ in the brain or increase clearance of Aβ may be able to slow the progression of the AD clinical 
syndrome. The other hallmark neuropathological lesion of AD, intraneuronal neurofibrillary tangles consisting of 
tau proteins, is thought to be a marker for disease progression. The relationship between these 2 pathologies is still 
unclear, although the presence of both is necessary for the diagnosis of definite AD.
Like many disorders, AD occurs on a continuum from asymptomatic to prodromal AD (or mild cognitive 
impairment), then to dementia in mild, moderate, and severe stages.  Recent clinical trial results in mild-to-moderate 
AD dementia, as well as evidence from transgenic animal experiments, suggest that treating AD during the earlier 
stages would have the greatest potential benefit on the disease and its progression, particularly when considering 
therapies targeted at Aβ reduction.
Study H8A-MC-LZBE (LZBE) is a Phase 3, placebo-controlled study in patients with prodromal AD.  Study LZBE 
is designed to collect data on the safety and efficacy of solanezumab, including assessment of changes in amyloid 
and tau pathology, cognitive outcomes, functional outcomes, quality of life, and resource utilization.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To assess the hypothesis that solanezumab 400 mg 
Q4W will slow the clinical progression of prodromal 
AD over 24 months compared to placebo
Alzheimer’s Disease Assessment Scale–Cognitive subscale 
(ADAS-Cog14):  change from baseline over 24 months
Secondary
To assess the effect of solanezumab vs. placebo on 
the clinical progression of prodromal AD over 
24 months
Change from baseline to 24 months on Alzheimer’s Disease 
Cooperative Study-Activities of Daily Living scale for Mild 
Cognitive Impairment (ADCS-MCI-ADL), Mini Mental 
Status Examination (MMSE), Montreal Cognitive 
Assessment (MoCA), Functional Activities Questionnaire 
(FAQ), Neuropsychiatric Inventory (NPI), Clinical Dementia 
Rating Scale Sum of Boxes (CDR-SB), Repeatable Battery 
for the Assessment of Neuropsychological Status (RBANS), 
and Free and Cued Selective Reminding Test (FCSRT)
To assess the effect of solanezumab vs. placebo on 
quality of life and health outcomes in prodromal AD
over 24 months
Change from baseline to 24 months on Resource Utilization 
in Dementia–Lite (RUD-Lite), EuroQol 5-Dimensional 
Health-Related Quality of Life Scale (EQ-5D), Quality of 
Life in Alzheimer’s Disease (scale) (QoL-AD)


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Objectives
Endpoints
To assess the effect of solanezumab vs. placebo on 
biomarkers in prodromal AD over 24 months
Florbetapir PET or CSF Aβ / tau, vMRI, plasma Aβ, plasma 
solanezumab, sample storage for biomarkers (where 
permitted); includes CSF collected via optional addendum
To assess the hypothesis that solanezumab will slow 
the accumulation of tau pathology over 12 and 24 
months compared to placebo
Change from baseline in neocortical tau deposits (collected 
in a subset of patients using 18F-AV-1451 PET as part of an 
addendum) over 12 and 24 months
To assess the hypothesis that change from baseline in 
accumulation of tau pathology over 12 and 24 
months is associated with changes from baseline in
cognition
Changes from baseline in neocortical tau deposits (collected 
in a subset of patients using 18F-AV-1451 PET as part of an 
addendum) and ADAS-Cog14, over 12 and 24 months
To assess the hypothesis that change from baseline in 
accumulation of tau pathology over 24 months is 
associated with changes from baseline in function
Changes from baseline in neocortical tau deposits (collected 
in a subset of patients using 18F-AV-1451 PET as part of an 
addendum) and ADCS-MCI-ADL over 24 months
To assess the effect of pharmacogenomic factors on 
clinical and functional progression with solanezumab 
vs. placebo in prodromal AD over 24 months
Changes from baseline in pharmacogenomics markers 
(where permitted) and clinical and functional scales
Abbreviations:  Aβ = amyloid-β peptide; AD = Alzheimer’s disease; ADAS-Cog14 = Alzheimer’s Disease 
Assessment Scale–Cognitive subscale; ADCS-MCI-ADL = Alzheimer’s Disease Cooperative Study-Activities of 
Daily Living scale for Mild Cognitive Impairment; CDR-SB = Clinical Dementia Rating Scale–Sum of Boxes; 
CSF = cerebrospinal fluid; EQ-5D = EuroQol 5-Dimensional Health-Related Quality of Life Scale (EQ-5D);
FCSRT = Free and Cued Selective Reminding Test; MMSE = Mini Mental Status Examination; 
MoCA = Montreal Cognitive Assessment; PET = positron emission tomography; Q4W = every 4 weeks; 
QoL-AD = Quality of Life in Alzheimer’s Disease (scale); RBANS = Repeatable Battery for the Assessment of 
Neuropsychological Status; vMRI = volumetric magnetic resonance imaging.
Summary of Study Design:  
Study LZBE is a multicenter, randomized, double-blind, parallel, placebo-controlled Phase 3 trial comparing 
solanezumab with placebo for 24 months in approximately 2450 patients with prodromal AD.  Patients who meet 
entry criteria will be randomized in a 1:1 ratio to solanezumab 400 mg once every 4 weeks or placebo. The primary 
hypothesis being tested in Study LZBE is that solanezumab will slow the clinical progression of AD as compared 
with placebo, in patients with prodromal AD.
In addition, participants in the 18F-AV-1451 tau imaging addendum will be included in an interim analysis designed 
to assess the relationship between 18F-AV-1451 tau PET and solanezumab treatment.
Three months after the end of the double-blind treatment period (or 4 months after the last dose in case of early 
discontinuation), patients will come to a follow-up visit for biomarker and safety assessments.
Treatment Arms and Duration:  
Solanezumab 400 mg once every 4 weeks by intravenous infusion or placebo once every 4 weeks by intravenous 
infusion up to 2 years in duration
Number of [Patients/Subjects]:
Randomized:  approximately 2450
Completed:  approximately 1838


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Statistical Analysis:
General Considerations.  All analyses will follow the intent-to-treat principle unless otherwise specified. When 
change from baseline is assessed, patients will be included in the analysis only if both a baseline and a postbaseline
measure are available.  For analyses using last observation carried forward, the last nonmissing postbaseline 
observation (scheduled or unscheduled) will be used to calculate change from baseline.  Unless otherwise noted, all 
tests of treatment effects will be conducted at a 2-sided alpha level of 0.05; 2-sided confidence intervals will be 
displayed with a 95% confidence level.  All tests of interactions between treatment and other factors will be 
conducted at an alpha level of 0.05.
Primary Analysis. The primary objective of this study is to test the hypothesis that intravenous infusion of 
solanezumab will slow cognitive decline as compared with placebo in patients with prodromal AD.  This will be 
assessed using an mixed-effect model repeated measure (MMRM) analysis of the Alzheimer’s Disease Assessment 
Scale–Cognitive subscale (ADAS-Cog14) in patients with prodromal AD at baseline (Visit 1 Montreal Cognitive 
Assessment [MoCA] score of 17 to 28), in which the specific hypothesis is that the cognitive decline from baseline 
at the end of the treatment period (104 weeks) for solanezumab will be significantly less than that for placebo.  The 
change from baseline score on the ADAS-Cog14 each scheduled postbaseline visit (according to the Study Schedule) 
during the treatment period will be the dependent variable.  The model for the fixed effects will include terms for 
7 effects:  baseline score, pooled investigator, treatment, visit, treatment-by-visit interaction, concomitant 
acetylcholinesterase inhibitor (AChEI) and/or memantine use at baseline (yes/no), and age at baseline.  Visit will be 
considered a categorical variable with values equal to the visit numbers at which the scales were assessed.  The null 
hypothesis is that the contrast between the solanezumab-treated patients versus placebo-treated patients at the last 
visit equals zero.
Interim Analysis. A single efficacy interim analysis will be assessed by the data monitoring committee after 
550 randomized 18F-AV-1451 tau addendum participants have completed a baseline and 1-year 18F-AV-1451 
positron emissions tomography (PET) scan, unless this interim is determined to be unnecessary by results of studies 
that are ongoing at the time of initial protocol development.  The purpose of this interim analysis is to demonstrate 
that solanezumab-treated patients have less tau accumulation relative to placebo-treated patients at 12 months. In 
addition to comparison of tau changes across treatments, the interim analysis would also examine the relationship 
between changes in 18F-AV-1451 PET and changes in cognition based on the ADAS-Cog14.  It is anticipated that a 
positive correlation between these 2 measures exists – that is, patients that show increases in tau accumulation will 
show corresponding increases (more cognitive decline) in the ADAS-Cog14.  The results of the 18F-AV-1451 tau 
PET interim analysis will not affect the conduct of the overall study.  As there is no possibility of terminating the 
study early for either efficacy or futility based on this analysis, no alpha-spending adjustment will be used for the 
final analysis and all results from the tau addendum patients will be included in the final efficacy analysis.
Analysis of Biomarkers: Biomarker change from baseline to double-blind period endpoint will be analyzed to 
provide biomarker-based evidence that solanezumab affects the underlying disease pathology.
Secondary Endpoints:  Change from baseline will be assessed using MMRM or analysis of covariance analyses for 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale for Mild Cognitive Impairment 
(ADCS-MCI-ADL), Mini Mental Status Examination (MMSE), MoCA, Functional Activities Questionnaire (FAQ), 
Neuropsychiatric Inventory (NPI), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Repeatable Battery for 
the Assessment of Neuropsychological Status (RBANS), and Free and Cued Selective Reminding Test (FCSRT), 


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Resource Utilization in Dementia–Lite (RUD-Lite), EuroQol 5-Dimensional Health-Related Quality of Life Scale 
(EQ-5D), and Quality of Life in Alzheimer’s Disease (scale) (QoL-AD).  A sequential gatekeeping strategy will be 
used for hypothesis testing involving a subset of efficacy endpoints to maintain the nominal type I error rate.  
Additional subgroup analyses will be performed.
Analysis of Safety Data:  Safety will be assessed by summarizing adverse events, laboratory analytes, vital signs, 
weight, electrocardiograms, magnetic resonance imaging, and Columbia Suicide Severity Rating Scale (C-SSRS)
results.  Comparisons will be made between the treatment groups.


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2.
Schedule of Activities


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Study Period
I
Screening
II
Double Blind
Suggested Interval
6 weeks
4 weeks
Interval Allowed (days)
-0 to -56
21 – 35
Visit
V1
V2a
V3
V4
V5
V6
V7
V8
V9
End of Week Relative to Study Medication Start b
-4
0
4
8
12
16
20
24
28
Entry/Administrative Procedures
     Informed consent
X
     Patient number assigned via IWRS
X
     Inclusion/exclusion review
X
X
     Modified Hachinski Ischemia Scale
X
     Physical/neurological exam
X
     Medical history
X
     Demographics, height, and habits
X
     Florbetapir PET scan or lumbar puncture for study entry c
X
     Randomization
X
     Previous/concomitant medications
X
X
X
X
X
X
X
X
X
     Preexisting conditions/adverse events
X
X
X
X
X
X
X
X
X
     Study drug administered b
X
X
X
X
X
X
X
X
Efficacy and Health Outcomes Assessments
     FCSRT
X
     MoCA
X
     FAQ
X
X
     ADAS-Cog14
X
X
X
     ADCS-MCI-ADL
X
X
X
     CDR-SB
X
     RBANS
X
     MMSE
X
X
     NPI
X
X
     RUD-Lite
X
X
     EQ-5D
X
X
     QoL-AD
X
X


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Study Period
I
Screening
II
Double Blind
Suggested Interval
6 weeks
4 weeks
Interval Allowed (days)
-0 to -56
21 – 35
Visit
V1
V2a
V3
V4
V5
V6
V7
V8
V9
End of Week Relative to Study Medication Start b
-4
0
4
8
12
16
20
24
28
Blood Sampling
     Clinical chemistry, hematology
X
X
     Serum HCG (if applicable)
X
     Plasma solanezumab d
X
X
X
X
X
     Plasma Aβ
X
X
X
X
     Serum anti-solanezumab
X
X
X
X
     Plasma and serum for biomarker storage
X
X
X
X
     Blood for assessment of APOE genotype
X
     Blood for pharmacogenomics
X
Other Safety Assessments
     Urine HCG (if applicable, on day of PET)
X
     Vital signs and weight
X
X
X
X
     ECG
X
X
X
     MRI
X
     C-SSRS/Self-Harm Supplement Form
X
X
X
X
X
X
X
X
X
Second lumbar puncture time points (if applicable) c
X
X
X
X


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Study Period
II
Double Blind
Suggested Interval
4 weeks
Interval Allowed (days)
21 – 35
Visit
V10
V11
V12
V13
V14
V15 a
V16
V17
V18
V19
End of Week Relative to Study Medication Start b
32
36
40
44
48
52
56
60
64
68
Administrative Procedures
     Study drug administered b
X
X
X
X
X
X
X
X
X
X
Efficacy and Health Outcome Measures
     FCSRT
X
     MoCA
X
     FAQ
X
     ADAS-Cog14
X
X
X
     ADCS-MCI-ADL
X
X
X
     CDR-SB
X
     RBANS
X
     MMSE
X
     NPI
X
     RUD-Lite
X
     EQ-5D
X
     QoL-AD
X


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Study Period
II
Double Blind
Suggested Interval
4 weeks
Interval Allowed (days)
21 – 35
Visit
V10
V11
V12
V13
V14
V15 a
V16
V17
V18
V19
End of Week Relative to Study Medication Start b
32
36
40
44
48
52
56
60
64
68
Blood Sampling
     Clinical chemistry, hematology
X
     Plasma solanezumab d
X
     Plasma Aβ
X
     Serum anti-solanezumab
X
     Plasma and serum for biomarker storage
X
Other Safety Assessments
     Physical/neurological exam
X
     Concomitant medications
X
X
X
X
X
X
X
X
X
X
     Adverse events
X
X
X
X
X
X
X
X
X
X
     Urine HCG (if applicable, on day of PET)
X
     Vital signs and weight
X
X
     ECG
X
     MRI
X
     C-SSRS/Self-Harm Supplement Form
X
X
X
X
X
X
X
X
X
X
Second lumbar puncture time points (if applicable) b
X


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Study Period
II
Double Blind
III
Follow-Up
Suggested Interval
4 weeks
12 weeks
Interval Allowed (days)
21 – 35
Visit
V20
V21
V22
V23
V24
V25
V26
V27
V28a
ED a
V 301 e
End of Week Relative to Study Medication Start b
72
76
80
84
88
92
96
100
104
116
Administrative Procedures
     Study drug administered b
X
X
X
X
X
X
X
X
     Disposition Event: Study Discontinuation or Completion
X
X
Efficacy and Health Outcome Measures
     FCSRT
X
X
     MoCA
X
X
     FAQ
X
X
X
     ADAS-Cog14
X
X
X
X
     ADCS-MCI-ADL
X
X
X
X
     CDR-SB
X
X
     RBANS
X
X
     MMSE
X
X
X
     NPI
X
X
X
     RUD-Lite
X
X
X
     EQ-5D
X
X
X
     QoL-AD
X
X
X


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Study Period
II
Double Blind
III
Follow-Up
Suggested Interval
4 weeks
12 weeks
Interval Allowed (days)
21 – 35
Visit
V20
V21
V22
V23
V24
V25
V26
V27
V28a
ED a
V301 e
End of Week Relative to Study Medication Start b
72
76
80
84
88
92
96
100
104
116
Blood Sampling
     Clinical chemistry, hematology
X
X
X
     Plasma solanezumab d
X
X
X
     Plasma Aβ
X
X
X
     Serum anti-solanezumab
X
X
X
     Plasma and serum for biomarker storage
X
X
X
X
Other Safety Assessments
     Physical/neurological exam
X
X
     Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
     Adverse events
X
X
X
X
X
X
X
X
X
X
X
     Urine HCG (if applicable, on day of PET)
X
X
     Vital signs and weight
X
X
X
X
X
     ECG
X
X
X
     MRI
X
X
     C-SSRS/Self-Harm Supplement Form
X
X
X
X
X
X
X
X
X
X
X
Second lumbar puncture time points (if applicable) c
X
X
X
Second florbetapir PET scan (if applicable) c
X
X


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Schedule of Activities (concluded)
Abbreviations: Aβ = amyloid-β peptides; ADAS-COG14 = 14-item Alzheimer’s Disease Assessment Scale–Cognitive subscale; ADCS-MCI-ADL = Alzheimer’s 
Disease Cooperative Study-Mild Cognitive Impairment–Activities of Daily Living Inventory; APOE = apolipoprotein E; CDR-SB = Clinical Dementia 
Rating–Sum of Boxes; CSF = cerebrospinal fluid; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; 
EQ-5D = EuroQol 5-Dimensional Health-Related Quality of Life Scale; FAQ = Functional Activities Questionnaire; FCSRT = Free and Cued Selective 
Reminding Test; HCG = human chorionic gonadotropin; hr = Hour; INR = International Normalized Ratio; IWRS = interactive web response system; 
LP = lumbar puncture; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; MRI = magnetic resonance imaging; 
NPI = Neuropsychiatric Inventory; PET = positron emission tomography; PT = prothrombin time; PTT = partial thromboplastin time; QoL-AD = Quality of 
Life in Alzheimer’s Disease (scale); RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; RUD-Lite = Resource Utilization in 
Dementia–Lite; V = visit.
a
If desired, the following visits may take place over 2 consecutive days:  Visit 2 (randomization visit), Visit 15 (Week 52), Visit 28 (Week 104), and ED.  If 
done over 2 days, it is recommended that the following procedures be performed on Day 2:  CDR-SB, RBANS, NPI, and FCSRT, as applicable.  Dosing 
should occur at the end of the second day.
b
Visits should be scheduled as close as possible to the intended week in relation to baseline.  Furthermore, visits must be scheduled such that study drug 
administration never occurs at intervals of less than 21 days.
c
All patients will have either a florbetapir PET scan or lumbar puncture at screening to determine eligibility.  If florbetapir PET scan is used, this procedure 
will be repeated at the 24-month endpoint (or early discontinuation). If LP is used, then a second LP will be administered at 1 later time point, with LP 
patients being assigned by the IWRS to have the second LP at Week 4, 8, 12, 24, 52, 76, or 104 (or ED). Opting out of the 2nd LP will not be considered a 
protocol deviation. Any CSF collected via LP as part of the main study or the optional LP addendum will be analyzed for Aβs, tau proteins, solanezumab, 
and biomarker storage. LPs are to be performed before study drug administration. It will not be considered a protocol deviation if the LP is not performed or 
if CSF is not collected for storage and future analysis in countries prohibiting sample storage. Patients undergoing LP will have PT/INR, PTT, and platelet 
count tested prior to each LP.
d
Pharmacokinetic samples should be obtained immediately before dosing at all designated visits.  In addition, postdose samples should be taken at Visits 2 
and 5.
e
Visit 301 should be scheduled to occur 4 months after last dose (that is, 3 months after Visit 28 or in case of ED, 4 months after last dose).


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3.
Introduction
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by 
progressive decline in cognitive function and the ability to perform activities of daily living, 
ultimately resulting in dementia, typically with fatal complications. The amyloid hypothesis of 
AD postulates that the accumulation of amyloid-β peptide (Aβ) is an early and necessary event in 
the pathogenesis of AD. This hypothesis suggests that treatments that slow the accumulation of 
Aβ in the brain or increase clearance of Aβ may be able to slow the progression of the AD 
clinical syndrome. The other hallmark neuropathological lesion of AD, intraneuronal 
neurofibrillary tangles consisting of tau proteins, is thought to be a marker for disease 
progression. The relationship between these 2 pathologies is still unclear, although the presence 
of both is necessary for the diagnosis of definite AD.
Converging evidence from both genetic at-risk and age at-risk cohorts suggests that the 
pathophysiological process of AD begins well more than a decade before the clinical stage now 
recognized as AD dementia, and that neurodegeneration is already apparent on magnetic 
resonance imaging (MRI) by the stage of prodromal AD.  Like many disorders, AD occurs on a 
continuum from asymptomatic to prodromal AD (or mild cognitive impairment), then to 
dementia in mild, moderate, and severe stages. Recent clinical trial results in mild-to-moderate 
AD dementia, as well as evidence from transgenic animal experiments, suggest that treating AD 
during the earlier stages would have the greatest potential benefit on the disease and its 
progression, particularly when considering therapies targeted at Aβ reduction.
Data from autopsy cohorts and cerebrospinal fluid (CSF) and positron emission tomography 
(PET) scan amyloid imaging studies demonstrate that approximately 30% of individuals over the 
age of 65 years have evidence of amyloid pathology. More recently, PET studies have 
demonstrated a close relationship between development of amyloid and subsequent development 
of cortical tau deposition. And, focal tau deposition on tau PET is more closely related to the 
focal neurodegenerative process than is amyloid. Clinically “normal” older individuals with 
evidence of amyloid pathology on imaging perform less well on cognitive tests compared to 
amyloid-negative age- and education-matched older individuals, are more likely to report 
subjective memory or other cognitive concerns, and are at increased risk for cognitive decline 
and progression to prodromal AD and AD dementia (Doraiswamy et al. 2014).
Solanezumab is a monoclonal antibody being developed as a therapy for AD. It binds selectively 
to soluble forms of Aβ monomers, and is thought to reduce levels of free Aβ in the central 
nervous system (CNS) by changing the equilibrium of Aβ between periphery and CNS, thus 
drawing Aβ from the CNS into the bloodstream. Aβ is bound by solanezumab largely in the 
periphery with approximately 0.1% crossing the blood brain barrier, creating an equilibrium shift 
out of the CNS (the “peripheral sink” hypothesis). Solanezumab has demonstrated reasonable 
safety in prior Phase 3 studies, with the most relevant treatment-emergent adverse event (TEAE) 
being amyloid-related imaging abnormalities (ARIA) in approximately 1% of 
solanezumab-treated patients, which have typically been asymptomatic and non-serious (refer to 
current Investigator Brochure [IB] for details).


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This study of the efficacy and safety of solanezumab is a Phase 3, double-blind, 
placebo-controlled study in patients with prodromal AD.  Patients appropriate for the study have 
cognitive impairment and biomarker evidence consistent with AD pathological changes, but no 
significant impairments in instrumental activities of daily living (iADLs) nor deficits meeting a 
diagnosis of AD dementia. These disease characteristics are consistent with the term prodromal 
AD as defined by the International Working Group (IWG) for New Research Criteria for the 
Diagnosis of Alzheimer’s Disease (Dubois et al. 2007, 2010, 2014) and with the term mild cognitive 
impairment (MCI) due to AD as defined by the National Institute on Aging in conjunction with the 
Alzheimer’s Association (NIA-AA; Albert et al. 2011).  Lilly has chosen to use the term prodromal 
AD for this study because it is unique to AD, whereas there are multiple causes of MCI, making 
prodromal AD the more straightforward designation.


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4.
Objectives and Endpoints
Table LZBE.1 shows the objectives and endpoints of the study.
Table LZBE.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the hypothesis that solanezumab 400 mg 
Q4W will slow the clinical progression of prodromal 
AD over 24 months compared to placebo
Alzheimer’s Disease Assessment Scale–Cognitive subscale 
(ADAS-Cog14): change from baseline over 24 months
Secondary
To assess the effect of solanezumab vs. placebo on 
the clinical progression of prodromal AD over 
24 months
Changes from baseline to 24 months on Alzheimer’s Disease 
Cooperative Study-Activities of Daily Living scale for Mild 
Cognitive Impairment (ADCS-MCI-ADL), Mini Mental 
Status Examination (MMSE), Montreal Cognitive 
Assessment (MoCA), Functional Activities Questionnaire 
(FAQ), Neuropsychiatric Inventory (NPI), Clinical Dementia 
Rating Scale Sum of Boxes (CDR-SB), Repeatable Battery 
for the Assessment of Neuropsychological Status (RBANS),
and Free and Cued Selective Reminding Test (FCSRT)
To assess the effect of solanezumab vs. placebo on 
quality of life and health outcomes in prodromal AD
over 24 months
Changes from baseline to 24 months on Resource Utilization 
in Dementia–Lite (RUD-Lite), EuroQol 5-Dimensional 
Health-Related Quality of Life Scale (EQ-5D), Quality of 
Life in Alzheimer’s Disease (scale) (QoL-AD)
To assess the effect of solanezumab vs. placebo on 
biomarkers in prodromal AD over 24 months
Changes from baseline to 24 months in florbetapir PET or 
CSF Aβ / tau, vMRI, plasma Aβ, plasma solanezumab, 
sample storage for biomarkers (where permitted); includes 
CSF collected via optional addendum
To assess the hypothesis that solanezumab will slow 
the accumulation of tau pathology over 12 and 24 
months compared to placebo
Changes from baseline in neocortical tau deposits (collected 
in a subset of patients using 18F-AV-1451 PET as part of an 
addendum) over 12 and 24 months
To assess the hypothesis that change from baseline in 
accumulation of tau pathology over 12 and 24 
months is associated with changes from baseline in
cognition
Changes from baseline in neocortical tau deposits (collected 
in a subset of patients using 18F-AV-1451 PET as part of an 
addendum) and ADAS-Cog14, over 12 and 24 months
To assess the hypothesis that change from baseline in 
accumulation of tau pathology over 24 months is 
associated with changes from baseline in function
Changes from baseline in neocortical tau deposits (collected 
in a subset of patients using 18F-AV-1451 PET as part of an 
addendum) and ADCS-MCI-ADL over 24 months
To assess the effect of pharmacogenomic factors on 
clinical and functional progression with solanezumab 
vs. placebo in prodromal AD over 24 months
Changes from baseline in pharmacogenomics markers 
(where permitted) and clinical and functional scales


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Objectives
Endpoints
Exploratory
To generate additional data for validation of the 
Preclinical Alzheimer's Cognitive Composite score
(PACC), a composite endpoint being used in another 
Lilly study
Changes from baseline in components of the MMSE, 
RBANS, and FCSRT over 24 months
To compare MMSE and MoCA scales
Changes from baseline in MMSE and MoCA over 
24 months
To assess time to significant progression
Time to progression to CDR-SB score of 1.0, and significant 
change on other cognitive, and functional measures
Abbreviations:  Aβ = amyloid-β peptide; AD = Alzheimer’s disease; ADAS-COG14 = 14-item Alzheimer’s Disease 
Assessment Scale–Cognitive subscale; ADCS-MCI-ADL = Alzheimer’s Disease Cooperative Study-Mild 
Cognitive Impairment–Activities of Daily Living Inventory; CDR-SB = Clinical Dementia Rating–Sum of 
Boxes; CSF = cerebrospinal fluid; EQ-5D = EuroQol 5-Dimensional Health-Related Quality of Life Scale; 
FAQ = Functional Activities Questionnaire; FCSRT = Free and Cued Selective Reminding Test; MMSE = Mini-
Mental State Examination; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; 
PET = positron emission tomography; Q4W = every 4 weeks; QoL-AD =Quality of Life in Alzheimer’s Disease 
(scale); RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; RUD-Lite = Resource 
Utilization in Dementia–Lite; vMRI = volumetric magnetic resonance imaging.


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5.
Study Design
5.1.
Overview of Study Design
Study H8A-MC-LZBE (LZBE) is a multicenter, randomized, double-blind, parallel, 
placebo-controlled Phase 3 trial comparing solanezumab with placebo for 24 months in 
approximately 2450 patients with prodromal AD.  Patients who meet entry criteria will be 
randomized in a 1:1 ratio to receive an infusion of solanezumab 400 mg or placebo once every 
4 weeks. Patients will be randomized by site and by use of florbetapir PET scanning or CSF for 
study eligibility (Section 6.1). The primary hypothesis being tested in Study LZBE is that 
solanezumab will slow the clinical progression of AD as compared with placebo in patients with 
prodromal AD.
In addition, participants in the 18F-AV-1451 tau imaging addendum will be included in an
interim analysis (Section 10.8) designed to assess the relationship between 18F-AV-1451 tau PET 
and solanezumab treatment.
Three months after the end of the double-blind treatment period (or 4 months after the last dose 
in case of early discontinuation), patients will come to a follow-up visit for biomarker and safety 
assessments.
5.2.
End of Double-Blind Treatment Period and End of Trial
The analysis of the primary and secondary objectives will use data collected through the end of 
the double-blind treatment period, defined as Visit 28 (Week 104) for the last patient.  The 
resulting dataset will be used to produce the initial clinical study report (CSR) for the study.
“End of the trial” refers to the date of the last visit or last scheduled procedure shown in the 
Schedule of Activities (Section 2) for the last patient (including the follow-up visit).  The end of 
the trial will therefore occur after the end of the double-blind treatment period, after the last 
patient has completed the follow-up visit.
5.3.
Scientific Rationale for Study Design
The amyloid hypothesis, as yet unproven, postulates that amyloid-laden neuritic plaques are the 
first and likely inciting pathological cause of AD-related neurodegeneration (Hardy 1996; Selkoe 
1997; Price et al. 1998; Naslund et al. 2000). Therefore, as in most progressive diseases, the 
earlier the inciting pathology can be removed, the more likely long-term pathological impact will 
be curtailed. Moving anti-amyloid treatments earlier in the stage of AD is hypothesized to 
impact cortical neurodegeneration earlier in the disease process and thereby reduce long-term 
clinical deficits. By addressing AD pathology in the prodromal AD stage, it is theoretically 
possible to prevent or delay the onset of AD dementia, the stage of AD where patients can no 
longer perform iADLs independently. The prodromal stage of AD represents a critical stage 
during which treatment has the potential to slow the progression of disease before sufficient 
damage is done to the brain to cause dementia.
It should be noted that the stage of AD under study may be referred to as prodromal AD or as 
MCI due to AD.  Prodromal AD, as defined by the IWG (Dubois et al. 2007, 2010, 2014), refers 


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to the early symptomatic, pre-dementia stage of AD in which clinical symptoms including 
episodic memory loss of the hippocampal type (characterized by a free recall deficit on testing 
not normalized with cueing) are present, but not sufficiently severe to affect iADLs and do not 
warrant a diagnosis of dementia; and in which biomarker evidence from CSF or amyloid PET 
imaging is supportive of the presence of AD pathological changes. These diagnostic criteria are 
consistent with those established by the NIA-AA (Albert et al. 2011) for MCI due to AD, which 
likewise require the presence of a clinical and cognitive syndrome involving cognitive 
impairment consistent with that associated with AD, preservation of independence in functional 
abilities, and lack of dementia; and provide guidance on the certainty of degree of diagnosis of 
MCI due to AD based on biomarker evidence of AD pathology.
5.4.
Justification for Dose
A dose of solanezumab 400 mg administered intravenously every 4 weeks was selected based on 
current preclinical and pharmacodynamic data.  This dose is expected to produce reductions in 
plasma unbound concentrations of Aβ,  which may result in a net increase in the rate of transfer 
of Aβ from the CNS compartment to the plasma compartment, as well as show a slowing of 
cognitive and functional decline in patients diagnosed with prodromal AD.
5.5.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of solanezumab are to be found in the IB.


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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]
Is aged 55-85 years
[2]
Has a diagnosis by the study investigator of a clinical syndrome of cognitive 
impairment consistent with prodromal AD per IWG diagnostic criteria or MCI 
due to AD per NIA-AA diagnostic criteria, confirmed by all of the following:
a.
Subjective cognitive complaint or informant report of cognitive impairment
for at least 6 months prior to Visit 1
b. No significant impairment of iADLs by patient and informant report and in 
the judgment of the investigator (that is, patients are maintaining their 
independence of functioning in daily life with minimal aids or assistance)
c.
Not demented, based on IWG or NIA-AA guideline criteria
[3]
Scores 17-28 on Montreal Cognitive Assessment (MoCA) at Visit 1
[4]
Scores <27 on free recall cutoff score from the Free and Cued Selective 
Reminding Test (FCSRT) (Picture version) at Visit 1
[5]
Scores ≤4 on Modified Hachinski Ischemia Scale
[6]
Scores >0 on the Functional Activities Questionnaire (FAQ)
[7]
Has a reliable study partner who is in frequent contact with the patient 
(defined as at least 10 hours per week), will accompany the patient to the 
study visits, and will be available by telephone at designated times
Note: Study partners must be able to communicate with site personnel and be 
willing to comply with protocol requirements, and in the investigator’s
opinion must have adequate literacy to complete the protocol-specified
questionnaires. Study partners must come in person to all visits with 
assessments that require their input.
[8]
Has a florbetapir PET scan or CSF result at screening consistent with the 
presence of amyloid pathology (see also Exclusion Criterion [34]).  (Note:  
Previously acquired amyloid PET scans unrelated to Study LZBE may be 
permitted for use in meeting this criterion. Refer to specific guidance in the 
manual of operations.)


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6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening:
Diagnostic Assessments
[9]
Has had MRI or computed tomography (CT) of brain within previous 2 years 
showing pathology that would be inconsistent with a diagnosis of AD
Medical Conditions
[10] If female and of childbearing potential, tests positive for pregnancy at Visit 1
on a serum pregnancy test; or does not agree to use 1 highly effective method 
of contraception or a combination of 2 effective methods of contraception for 
the entirety of the study
[11] Lacks adequate venous access for intravenous infusions and blood samples at 
monthly visits
[12] Has history of serious infectious disease affecting CNS within previous 
5 years
[13] Has history within previous 5 years of head trauma resulting in protracted loss 
of consciousness
[14] Has a current diagnosis of major depressive disorder as per the current 
Diagnostic and Statistical Manual of Mental Disorders (DSM) or any current 
primary psychiatric diagnosis other than AD (as per DSM) 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.
[15] Has history of primary or recurrent malignant disease within previous 5 years, 
with the exception of successfully treated cutaneous squamous cell carcinoma
of the skin, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate 
cancer with normal prostate-specific antigen post-treatment
[16] Has any current unstable and/or clinically significant medical condition at 
Visit 1 that in the investigator’s opinion could interfere with participation in 
the study
[17] Has known allergy to humanized monoclonal antibodies
[18] Has history of human immunodeficiency virus (HIV), clinically significant 
multiple or severe drug allergies, or severe posttreatment hypersensitivity 
reactions (including, but not limited to, erythema multiforme major, linear 
immunoglobulin A dermatosis, toxic epidermal necrolysis, or exfoliative 
dermatitis)
[19] Has history of chronic alcohol or drug abuse or dependence within the 
previous 5 years


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[20] Is clinically judged by the investigator to be at serious risk for suicide
[21] Has electrocardiogram (ECG) abnormalities obtained at Visit 1 that, in the 
opinion of the investigator, are clinically significant with regard to the 
patient’s participation in the study
[22] Has alanine aminotransaminase (ALT/SGPT) values ≥2 times the upper limit 
of normal (ULN) of the performing laboratory, aspartate aminotransaminase 
(AST/SGOT) values ≥3 times the ULN, or total bilirubin values ≥2 times the 
ULN, at Visit 1
[23] Has an ongoing clinically significant laboratory abnormality, as determined by 
the investigator
[24] Has Visit 1 MRI with results showing >4 ARIA-H microhemorrhages or 
presence of ARIA-E (Section 9.3.6)
[25] Has any contraindications for MRI studies, including claustrophobia, the 
presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not 
compatible with MRI
Prior/Concomitant Therapy
[26] Has received treatment with a stable dose of an acetylcholinesterase inhibitor 
(AChEI) or memantine for less than 2 months before randomization. (If a 
patient has recently stopped an AChEI and/or memantine, he or she must have 
discontinued treatment at least 2 months before randomization.)
[27] Has received medications that affect the CNS for less than 4 weeks; note that
doses of chronic medications that affect the CNS must be stable for at least 4 
weeks before randomization.
Prior/Concurrent Clinical Trial Experience
[28] Has previously completed or withdrawn from this study or other solanezumab 
studies, or previous participation in any other study investigating active 
immunization against Aβ. Has previously completed or withdrawn from a 
study of passive immunization against Aβ with another antibody within the 
last 120 days.
[29] Is currently enrolled in a clinical trial involving an investigational product or 
nonapproved use of a drug or device (other than the investigational product 
used in this study), or concurrently enrolled in any other type of medical 
research judged not to be scientifically or medically compatible with this 
study. Participation in observational studies may be permitted upon review of 
the observational study protocol and approval by the sponsor.
[30] Has participated within the last 30 days (for Japan, 4 months) in a clinical trial 
involving an investigational product. If the previous investigational product 
has a long half-life, 3 months or 5 half-lives (whichever is longer) should have 
passed.


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Other Exclusions
[31] Lacks, in the investigator’s opinion, adequate premorbid literacy, adequate 
vision, or adequate hearing to complete the required psychometric tests
[32] Are investigator site personnel directly affiliated with this study and/or their 
immediate families, or have study partners who are investigator site personnel 
directly affiliated with this study. Immediate family is defined as a spouse, 
parent, child, or sibling, whether biological or legally adopted
[33] Are Lilly employees or 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 study 
who require exclusion of their employees
Exclusion Criteria for Patients Using Lumbar Puncture to Meet Inclusion Criterion [8]
[34] If using lumbar puncture (LP) to meet Inclusion Criterion [8], a patient will be 
excluded from having an LP if he or she meets any of the following criteria:  
has allergy to all local anesthetics (such as lidocaine); has any medical 
condition requiring treatment with an anticoagulant such as heparin, vitamin 
K regeneration blockers, or new oral anticoagulants; or has any other 
contraindication in the opinion of the investigator (for example, suspected 
increased intracranial pressure or MRI abnormality that would contraindicate 
LP).
6.3.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) for reasons 
other than not meeting amyloid burden criteria may be re-screened.  Individuals may be 
re-screened once.  The interval between an initial screen and a re-screen should be at least
8 weeks.  When rescreening is performed the participants must sign a new informed consent 
form (ICF) and will be assigned a new identification number.  Approval from the sponsor must 
be obtained in advance for all re-screens.
6.4.
Lifestyle and/or Dietary Requirements
Study participants should be instructed not to donate blood or blood products during the study or 
for 8 weeks following the study.
Males who undergo PET scans during the study must be instructed not to donate sperm for 
24 hours after each scan, and if they have female partners of child-bearing potential, to abstain 
from sex for 24 hours after each scan.


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7.
Treatment
7.1.
Treatments Administered
This study involves a comparison of solanezumab 400 mg versus placebo administered 
intravenously every 4 weeks.  The investigator or his/her designee is responsible for the 
following:

explaining the correct use of the investigational agent to site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study returning all unused medication to 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
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 2.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  The IWRS will be used to assign a 
vial containing double-blind investigational product to each patient. Site personnel will confirm 
that they have located the correct vial by entering a confirmation number found on the vial into 
the IWRS.
To achieve between-group comparability, the randomization will be stratified by site and by use 
of florbetapir PET scanning or CSF for study eligibility.
7.2.1. Selection and Timing of Doses
Infusion should occur over the course of at least 30 minutes. Premedication for dosing is not 
planned; however, if a patient demonstrates an infusion reaction to the study drug suggestive of 
allergy or hypersensitivity, the patient may be premedicated at the discretion of the investigator
with appropriate medications (for example, diphenhydramine hydrochloride and/or 
acetaminophen), and the infusion time may be extended for the remaining infusions. An attempt 
should be made to complete the infusion within 2 hours of when first started. Patients should be 
observed for approximately 1 hour following the first infusion of study drug at Visit 2.  Any 
premedications given are to be documented as concomitant therapy. The actual time of all dose 
administrations will be recorded in the patient’s case report form (CRF).
Note that all cognitive and functional scales are to be administered before infusions.
7.3.
Blinding
This is a double-blind study.  To preserve the blinding of the study, a minimal number of Lilly 
personnel will see the randomization table and treatment assignments before the study is 
complete.


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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 actions resulting in an unblinding event are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or patient 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 clinical research 
physician (CRP) for the patient to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP prior to unblinding 
a patient’s treatment assignment.  If a patient’s treatment assignment is unblinded, Lilly must be 
notified immediately.
7.4.
Packaging and Labeling
Clinical trial materials will be labeled according to the country’s regulatory requirements.
7.5.
Preparation/Handling/Storage
The site will be provided vials containing 400 mg/20 mL of solanezumab (or 20 mL placebo). 
The vials should be stored at 2°C to 8°C (36°F to 46°F).
For each dose, the content of 1 vial will be diluted with sterile sodium chloride intravenous
infusion (0.9%) to a total volume of approximately 70 mL. Before infusion, the diluted solution 
should be inspected visually for particulate matter or discoloration. If particulate matter or 
discoloration is present, the solution should be discarded and a new solution made. After each 
intravenous bag is prepared, it will be identified as a dose of study drug without identification of 
the drug or dose. Once prepared, the infusion solution should be stored at room temperature
(~25ᵒC) for a total of no more than 6 hours.
7.6.
Dose Modification
Not applicable.
7.7.
Treatment Compliance
Because dosing occurs at study visits, patients who attend all visits and successfully receive 
infusions are automatically compliant with treatment.  Any infusions at which 75% 
(approximately 52.5 mL when mixed in a 70-mL bag of normal saline) or more of the infusate is 
given will be considered a complete infusion.
If a patient attends a visit but does not receive a complete infusion (for example, due to technical
complications), every effort should be made to complete the infusion within 24 hours if possible.
If less than 75% of the infusion solution is given, this must be recorded as an incomplete infusion
in the CRF.


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Missed infusions should be recorded on the CRF.  A patient will be considered significantly 
noncompliant if he or she misses 2 consecutive infusions, or 4 or more infusions at any time, and
may be discontinued from the study.  Patients who miss 2 consecutive infusions or 4 or more 
infusions for medical reasons (for example, MRI findings) can continue the study with approval 
of the sponsor.
7.8.
Concomitant Therapy
For patients who are taking medications that may have an acute effect on cognition (and 
therefore on cognitive testing) and who must change doses or stop or start such medications, the 
sponsor or designee must be contacted beforehand to determine whether the patient should 
continue in the study and whether the clinical outcome measures should be performed. Starting 
on antidementia treatment is allowed during the trial for patients who worsen clinically during 
the study; however, the sponsor or designee must be contacted before initiation of therapy, and 
dosing should remain stable once a target dose is achieved.  Sponsor approval must also be 
obtained for any subsequent dosing changes. A list of medications requiring sponsor 
consultation is provided in a separate manual of operations.
All concomitant medication taken during the study must be recorded on the Concomitant 
Medication CRF. Patients and their study partners will be instructed to consult the investigator 
or other appropriate study personnel at the site before initiation of any new medications or 
supplements and before changing dose of any current concomitant medications or supplements.
Patients who are receiving AChEIs and/or memantine are permitted to enter the study if stable on 
these medications prior to randomization.
Use of sedatives or hypnotics (including medications with sedating side effects such as 
antihistamines) should be avoided for 8 hours before administration of the cognitive and 
functional tests unless they are given chronically.
7.9.
Treatment after Study Completion
The availability of an extension study will be determined before the first patient completes 
Visit 28. If an extension study is available, patients who complete Study LZBE may be eligible 
to participate if enrollment criteria for the extension study are met. Patients participating in such 
a study would receive study medication for the extension study only after all assessments for 
Study LZBE are completed. Patients not participating would not receive any study medication 
after the last infusion visit for Study LZBE (Week 100).


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8.
Discontinuation Criteria
8.1.
Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product.
8.2.
Discontinuation from the Study
Patients will be discontinued from the study drug and from the study in the following 
circumstances, and will undergo early discontinuation procedures as shown in the Schedule of 
Activities (Section 2):

Prolonged acute infusion reaction suggestive of allergic/hypersensitivity reaction
(that is, not rapidly responsive to medication such as antihistamines, nonsteroidal 
anti-inflammatory drugs, and/or narcotics and/or brief interruption of infusion)
Note: Acute allergic/hypersensitivity reactions may occur with any agent that 
causes cytokine release (for example, monoclonal antibodies or other biological 
agents). Cytokine release may or may not be related to the mechanism of the 
infused biologic agent. Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of infusion. 
Signs/symptoms may include: drug fever, arthralgia, bronchospasm, cough, 
dizziness, dyspnea, fatigue, headache, hypertension, hypotension, myalgia, 
nausea, pruritus, rash, rigors/chills, sweating (diaphoresis), tachycardia, urticaria, 
and vomiting.

Requirement for a ferromagnetic implant or insertion of a cardiac pacemaker that 
is not MRI-compatible

An investigator, site personnel performing assessments, or a patient is unblinded 
to a specific patient’s treatment assignment.

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:  The investigator decides that the patient should be discontinued
from the study.  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.


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
Patient decision:  The patient or the patient’s designee requests to be withdrawn from the 
study.

Adverse event:  If the investigator decides that the patient should be withdrawn 
from the study because of an SAE or a clinically significant laboratory value, the 
investigational product is to be discontinued and appropriate measures are to be 
taken. Lilly or its designee is to be alerted immediately (Section 8.2).
In addition, patients may be discontinued from the study drug and from the study in the 
following circumstances, and if discontinued, will undergo early discontinuation procedures as 
shown in the Schedule of Activities (Section 2):

Appearance of clinically significant new cerebral ischemic or hemorrhagic events
or ARIA-E (amyloid-related imaging abnormality—edema/effusions, also known 
as cerebral vasogenic edema) by MRI (Section 9.3.6); patients with new MRI 
findings can continue to participate in the study depending on clinical significance 
as determined by the investigator.
Note: While most cases of ARIA-E are asymptomatic, when symptoms do occur
they are reported to be most commonly headache, worsening of cognitive
function, alteration of consciousness, seizures, unsteadiness, and vomiting. Even
when symptomatic ARIA-E is present, in most cases treatment is not required
beyond discontinuation of the study medication until the imaging abnormalities 
are resolved. If a patient simultaneously develops more than one of the symptoms
suggestive of ARIA-E; that is, headache, worsening of cognitive function,
alteration of consciousness, seizures, unsteadiness, or vomiting, then an
unscheduled MRI may be obtained. A single symptom suggestive of ARIA-E of
sufficient severity may also warrant an MRI. The unscheduled MRI should be
performed in the same manner as the currently scheduled MRIs in the protocol,
which includes sending the images for central review.

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:

ALT or AST >8X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
prothrombin time >1.5X ULN

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)


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
Mean Bazett-corrected QT interval (QTcB) >500 msec and an absolute change 
>60 msec (or equivalent JTcB changes if appropriate) when compared with
baseline (the most recent measurement made at either Visit 1 or Visit 2)

Missed infusions:  If a patient misses 2 consecutive infusions, or 4 or more 
infusions at any time overall during the study, the patient may be discontinued 
from the study. Patients who miss 2 consecutive infusions or 4 or more infusions 
for medical reasons (for example, MRI findings) may continue the study with 
approval of the sponsor.
8.3.
Patients Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients and/or study partners who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of lost-to-
follow-up patients 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 laboratory tests that will be performed for this 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 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; 
ADAS-Cog refers to the cognitive subscale which was originally designed with 11 items (the 
ADAS-Cog11). An expanded version that includes 3 additional items more sensitive in patients 
at earlier stages of AD, the ADAS-Cog14 (Mohs et al. 1997), will be used as a primary efficacy 
measure.  It consists of 14 items assessing areas of cognitive function most typically impaired in 
AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation, and 
maze-completion measures. The ADAS-Cog14 allows better discrimination of differences 
among milder AD patients than the ADAS-Cog11. The ADAS-Cog14 scale ranges from 0 to 90, 
with higher scores indicating greater disease severity.
Note: The administration of the ADAS-Cog will be recorded (audio only) at each administration 
for quality review purposes except where prohibited by local laws and regulations.  The 
ADAS-Cog and Alzheimer’s Disease Cooperative Study-Mild Cognitive Impairment–Activities 
of Daily Living Inventory (ADCS-MCI-ADL) must be performed by 2 different qualified raters.
9.1.2. Secondary Efficacy Assessments
Alzheimer’s Disease Cooperative Study—Activities of Daily Living Inventory for Mildly 
Cognitively Impaired (ADCS-MCI-ADL; Pedrosa et al. 2010).  The ADCS-MCI-ADL is a 
functional evaluation scale for MCI patients, based on information provided by an informant (in 
this case the study partner), that describes the performance of patients in several ADLs. It was 
adapted from the original ADCS-ADL scale, which was constructed to evaluate patients with 
dementia in the Alzheimer’s Disease Cooperative Study, as a measure of the AD patients’ 
performance in activities of daily living (ADLs) (Galasko et al. 1997).  An 18-item 
ADCS-MCI-ADL was developed alongside the original ADCS-ADL, but more recently a 
24-item version (Pedrosa et al. 2010) was developed to incorporate additional items considered 
appropriate to the MCI population, which has been shown to better distinguish between healthy 
subjects and people with MCI.  This study will use the 24-item version.  The range for this scale 


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is 0 to 69, with lower scores indicating greater disease severity.  For each of the specific items, 
the informant is first asked if the patient attempted the ADL during the past 4 weeks.  If the 
patient did attempt the ADL, the informant 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.
Note: The administration of the ADCS-MCI-ADL will be recorded (audio only) at each 
administration for quality review purposes except where prohibited by local laws and 
regulations. The ADAS-Cog14 and ADCS-MCI-ADL must be performed by 2 different 
qualified raters.
Mini-Mental State Examination (MMSE; Folstein et al. 1975).  The MMSE is a brief
instrument used to assess cognitive function. The instrument is divided into 2 sections. The first 
section measures orientation, memory, and attention. The maximum score for 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.
Montreal Cognitive Assessment (MoCA; Nasreddine et al. 2005).  The MoCA is a brief 
30-point cognitive screening test developed with high sensitivity and specificity for detecting 
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.
Note:  The administration of the MoCA will be recorded (audio only) at each administration for 
quality review purposes except where prohibited by local laws and regulations.  The MMSE and 
MoCA should not be administered in succession (that is, at least one other scale should be 
administered in between) and if possible should be done by different raters.
Neuropsychiatric Inventory (NPI; Cummings et al. 1994).  The NPI is a tool for assessing 
psychopathology in patients with dementia and other neurologic disorders. Information is 
obtained from an informant familiar with the patient’s behavior (often a caregiver; in this study, 
the study partner). 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 informant through the use
of scales with anchor points. The distress induced in the informant by each behavior is also 
rated. Scores for each subscale, the total tool, informant distress associated with each behavior, 
and total informant distress are computed. The NPI standard version consists of 10 items with 
informant distress scale and 2 neurovegetative questions. Four subscales can be defined based 
on a previously reported factor analysis: Mood (depression, anxiety, nighttime behavior,
appetite, and irritability); Psychosis (delusions, hallucinations, and agitation); Frontal (euphoria
and disinhibition); and Other (apathy and aberrant motor behavior) (Frisoni et al. 1999).


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Clinical Dementia Rating Scale (CDR-SB; Berg et al. 1992).  The CDR is a semi-structured
interview performed with the patient and informant that provides an index of global functioning. 
The informant is queried about the patient’s memory, orientation, judgment and problem solving, 
community affairs, home and hobbies, and personal care. The patient’s memory, orientation, 
judgment, and problem-solving ability are assessed. By assigning a severity score for each of the 
6 domains, a total score known as sum of boxes is obtained—hence the abbreviation, CDR-SB.
Resource Utilization in Dementia—Lite questionnaire (RUD-Lite; Wimo et al. 1998).  The 
RUD-Lite is an abbreviated version of the Resource Utilization in Dementia (RUD) scale 
designed to assess the healthcare resource utilization of patients and their caregivers (or in this 
case, study partners) and to determine the level of formal and informal care attributable to AD. 
The data are collected through a structured interview. Information on both study partners
(caregiving time and work status) and patients (accommodation and healthcare resource 
utilization) is gathered from the baseline and final assessment interviews. Study partners will be 
asked to provide data on time spent assisting patients’ basic ADLs such as using the toilet, 
eating, dressing, grooming, walking, and bathing; assisting patients’ instrumental ADLs such as 
shopping, cooking, housekeeping, laundry, transportation, taking medication, and managing 
finances; and providing supervision. The resource utilization quantified by the RUD-Lite can be 
used for calculating cost offsets and in cost-effectiveness models.
Note that as of 2016, only the full RUD is supported by its copyright owners, such that users who 
wish to administer a shorter version must pull out questions from the RUD.  Study LZBE is 
administering the short version of the RUD once formally known as the RUD-Lite and will 
continue to use the name “RUD-Lite” for consistency with other solanezumab protocols that 
have administered this scale.
EuroQoL-5D Proxy Version (EQ-5D; Kind 1996).  The EQ-5D is a standardized instrument
used to measure overall health status and is applicable to a wide range of health conditions and
treatments. It provides both a descriptive profile and a single index value for health status. The
5D in the name refers to the 5-dimensional classification system for health states used in the
instrument. Each dimension (mobility, self-care, usual activities, pain/discomfort, and
anxiety/depression) has 5 levels of severity (no, slight, moderate, severe, and extreme problems). 
Scores on individual dimensions are recorded, as is a total score that sums the individual 
dimension scores. A visual analog scale also assesses the informant’s impression of the patient’s 
overall health state. Reliability and validity of the proxy version for use with an AD population 
have been demonstrated (Jönsson et al. 2006; Naglie et al. 2006). Scores can be converted into
weighted health state preferences for quality-adjusted life year models.
Quality of Life in Alzheimer’s Disease (QoL-AD; Logsdon et al. 2002; Thorgrimsen et al. 
2003).  The QoL-AD is a disease-specific measure of quality of life for an AD population. It
includes 13 items, each rated on a 4-point scale. Summing the items provides an overall score to
index the patient’s quality of life. The QoL-AD is administered to the patient by a rater and asks
the patient to provide ratings on mood, relationships, memory, finances, and so on. The patient’s
study partner also is asked to complete the measure. Reliability and validity in samples of AD 
patients and their caregivers have been demonstrated.


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Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; Randolph et 
al. 1998). The RBANS is a collection of 12 subtests representing 5 neurocognitive domains: 
Immediate Memory, Visuospatial/Constructional, Language, Attention, and Delayed 
Memory. The raw scores from each subtest within a domain are converted to a summary score, 
or Index Score that summarizes the patient’s overall level of performance on this measure.  
Version A of the scale will be used at baseline and endpoint; Version B will be used at the 
12-month visit.
Free and Cued Selective Reminding Test (FCSRT; Grober and Buschke 1987).  The FCSRT is 
a neuropsychological test of memory under conditions that control attention and cognitive 
processing in order to obtain an assessment of memory unconfounded by normal age-related 
changes in cognition. Both a word and picture version are available; this study will use the 
picture version.  The FCSRT has previously demonstrated sensitivity in prediction of decline 
from MCI to AD dementia in other studies (Amieva et al. 2008; Dubois et al. 2010), and in 
predicting dementia in previous cohort studies from the Baltimore Longitudinal Study of Aging 
(Grober et al. 2008) and the Einstein Study of Aging (Derby et al. 2013).
Note: The administration of the FCSRT will be recorded (audio only) at each administration for 
quality review purposes except where prohibited by local laws and regulations.
Functional Activities Questionnaire (FAQ; Pfeffer et al. 1982).  The FAQ is a 
rater-administered instrument directed at the caregiver (in this case, the study partner) that 
assesses 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.  A growing literature supports the FAQ as a measure 
sensitive to changes in AD patients at the earlier end of the disease spectrum (Tabert et al. 2002; 
Teng et al. 2010).
Note: The administration of the FAQ will be recorded (audio only) at each administration for 
quality review purposes except where prohibited by local laws and regulations.
Florbetapir PET scan.  Change in amyloid burden (as assessed by florbetapir binding) will be 
compared in solanezumab- and placebo-treated patients.  See Appendix 4 for information about 
radiation dose.
18F AV-1451 PET scan.  Changes in tau (as assessed by 18F AV-1451 binding) will be collected 
as part of an addendum.
9.1.3. Appropriateness of Assessments
Efficacy.  The ADAS-Cog is a well-accepted measure of cognitive functioning in patients with 
mild to moderate AD; the 14-item version is considered more sensitive in milder AD.  The 
ADCS-MCI-ADL is also well recognized as a measure of functional abilities in patients with 


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prodromal AD/MCI.  A growing literature supports the FAQ as a measure sensitive to changes in 
milder AD populations.  Additional descriptions and references supporting use of these and other 
scales are provided in Sections 9.1.1 and 9.1.2.
Safety.  Safety measures used in this study are all well established.
9.2.
Safety Evaluations
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.
9.2.1. Adverse Events
A clinical study AE is any untoward medical event associated with the use of a drug or drug 
delivery system in humans, whether or not it is considered related to a drug or drug delivery 
system.
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, study site personnel will record via CRF 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 investigational product and/or protocol procedure via CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, PET tracers, study device, or a study procedure, taking into 
account the disease, concomitant treatment, or pathologies.


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A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, PET tracers, study device, 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 CRF, clarifying if possible, the circumstances leading 
to any dosage modifications or discontinuations of treatment.
9.2.2. 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 after signing the ICF are recorded in the CRF, SAE reporting begins after the 
patient has signed the ICF and has received investigational product.  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 patients once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient 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.


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9.2.2.1.
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.
9.2.2.2.
Adverse Events of Special Interest
Adverse events associated with specific TEAE clusters will be monitored.  The TEAE clusters of 
interest include:

Infusion-related reactions

TEAEs associated with anti-solanezumab antibodies (immunogenicity)

ARIA-H (amyloid-related imaging abnormality—hemorrhage/hemosiderin deposition, 
also known as cerebral microhemorrhage)

ARIA-E

Hemorrhagic stroke and microhemorrhage

Cardiac ischemia-related events

Cardiac arrhythmia-related events 
Data on cerebro-cardiovascular events (for example, death, myocardial infarction, stroke, etc.) 
will be adjudicated by an external Clinical Endpoint Committee (CEC).  The role of the CEC is 
to adjudicate defined clinical events, in a blinded, consistent, and unbiased manner throughout 
the course of a study.  Complete details will be available in the CEC charter.
9.2.3. 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.
Other Safety Assessments
9.3.1. 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 


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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 CRF.
9.3.2. Electrocardiograms
For each patient, 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.
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 and for 
immediate patient management, should any clinically relevant findings be identified.
All ECGs will be electronically transmitted to a designated central ECG laboratory.  A
cardiologist at the central ECG laboratory will then conduct a full overread.  A report based on 
data from this overread will be issued to the investigative site.  When there are differences in 
ECG interpretation between the local and central readings, the locally read interpretation will be 
used for study entry and immediate patient management, and the centrally read interpretation
will be used for data analysis and report writing purposes.
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 should be reported to Lilly or its 
designee as an AE via CRF.
9.3.3. Vital Signs
For each patient, vital signs measurements should 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.
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via CRF.
9.3.4. Body Weight and Height
Body weight and height will be recorded according to the Schedule of Activities (Section 2).


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9.3.5. 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 product should be reported to Lilly or its 
designee as an AE via CRF.
9.3.6. Magnetic Resonance Imaging
Magnetic resonance imaging of the brain will be performed according to the Schedule of 
Activities (Section 2) and as clinically indicated. This technology will be used to check for 
evidence of hemorrhage/hemosiderin deposition (ARIA-H, also known as cerebral 
microhemorrhage) and edema/effusions (ARIA-E, also known as cerebral vasogenic edema). 
(The volumetric MRI data will also be used to calculate brain volumes.) The MRI scans will be 
sent for analysis to a centralized MRI vendor designated by Lilly. The scans will be reviewed by 
the investigator or qualified designee for immediate patient management or assessment of 
patient’s study eligibility as appropriate. Any clinically significant findings noted at baseline 
that result in a diagnosis should be recorded as a preexisting condition or AE. Specific analyses 
of the scans, including assessments of ARIA-H and ARIA-E and calculations of brain volumes,
will subsequently be interpreted by the centralized MRI vendor for data analysis and 
report-writing purposes. Results of centrally read MRIs regarding patient care/safety will be 
reported back to sites even though there was a local read.
9.3.7. Columbia Suicide Severity Rating Scale (Adult Version)
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) using the Columbia Suicide Severity Rating Scale (C-SSRS), 
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.
Terms captured by the use of the C-SSRS 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, the C-SSRS “Baseline” version will be 
used, and the findings will constitute the baseline assessment. The C-SSRS “Since Last Visit” 
scale will be used for all subsequent assessments. 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.


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9.3.8. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. In addition, unblinded data on safety-related measures and SAEs will be periodically 
reviewed by a Data Monitoring Committee (DMC; Section 10.8) until database lock of the 
double-blind period.  Complete details will be available in the DMC charter.
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, clinical and laboratory monitoring should be initiated by the investigator.  Details for 
hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities.  To ensure patient safety and comply with regulatory guidance, the investigator is 
to consult with the Lilly CRP regarding collection of specific recommended clinical information 
and follow-up laboratory tests.  See Appendix 3.
In the event that blinded safety monitoring identifies an issue that may need to be addressed by 
unblinding at the group level, those blinded individuals may recommend to members of the 
DMC that they should conduct additional analyses of the safety data.
9.4.
Sample Collection and Testing
The Schedule of Activities (Section 2) lists the schedule for sample collections in this study.
Appendix 2 lists the clinical laboratory tests that will be performed for this study.
9.4.1. Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.
Cerebrospinal fluid will be collected in some patients to determine whether patients meet the 
inclusion criteria, and in other patients as part of the optional LP addendum.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
9.4.2. CSF Aβ and Tau Proteins and Solanezumab
Screening LPs may be performed as part of the study eligibility criteria for patients opting to use 
CSF Aβ levels to determine patient eligibility for study participation (Section 0). For these 
patients, a second LP will be administered at 1 later time point.  These  patients will be assigned
to have the second LP at Week 4, 8, 12, 24, 52, 76, or 104 (or early discontinuation).  Specific 
instructions for the LP procedure itself will be provided in the manual of operations.


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The collected CSF will be assayed for measurement of solanezumab, Aβ species, tau proteins, 
and storage of CSF for use in future research.  The results of CSF analyses will be used to 
determine whether patients meet inclusion/exclusion criteria and to compare solanezumab and 
placebo treatment effects.  A portion of the collected CSF will be used for central laboratory
testing of CSF solanezumab, Aβ species, and tau proteins.  The remainder will be aliquotted and 
stored for future research where allowed.  In countries prohibiting sample storage, it will not be 
considered a protocol deviation if CSF is not collected for storage and future analysis.
9.4.2.1.
Timing of CSF Sampling
Visits when CSF is sampled are shown in the body and footnotes of the Schedule of Activities 
(Section 2).
9.4.2.2.
CSF Collection Procedures
Cerebrospinal fluid will be collected according to the procedure described in Appendix 3.  It is 
critical that for each CSF sample, the date of sample acquisition is accurately recorded.
Sample handling and shipment to the central laboratory will occur per instructions given to the 
investigative study site.
Samples collected from placebo-treated patients during the double-blind period will not be 
assayed for solanezumab.  Bioanalytical CSF samples collected to measure investigational 
product concentration will be retained for a maximum of 2 years following last patient visit for 
the study.
Cerebrospinal fluid samples collected to assess Aβ species and tau proteins and allow for future 
research may be stored for a maximum of 15 years following last patient visit for the trial at a 
facility selected by the sponsor (Section 9.4.6.2).
Results from analysis of screening samples of CSF in regards to patient inclusion eligibility will 
be reported to investigative sites (that is, eligible or not eligible for inclusion).
Results from analyses of CSF for solanezumab, Aβ species, and tau proteins to assess treatment 
effects will not be reported to investigative sites or other blinded personnel at a subject level.
9.4.3. Plasma Samples for Assessment of As and Solanezumab
9.4.3.1.
Timing of Plasma Sampling
Visits when plasma is sampled and the time of sampling relative to study drug dosing are shown 
in the body and footnotes of the Schedule of Activities (Section 2).  Samples from 
placebo-treated patients will not be assayed for solanezumab.  Amyloid-peptide or 
solanezumab concentration results in plasma that could unblind the study will not be reported to 
investigative sites or other blinded personnel.
9.4.3.2.
Plasma Collection Procedures
Venous blood samples will be drawn into sodium ethylenediaminetetraacetic acid tubes for the 
determination of plasma concentrations of solanezumab and Apeptides at the times indicated in 


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the Schedule of Activities (Section 2).  A saline well or heparin lock may be used to facilitate 
blood collection.
On the dosing day, the blood will be collected from the arm that did not receive the infusion of 
study drug.
It is critical that for each blood sample, date and time of sample acquisition and date and time of 
administration of study drug are accurately recorded.  Only plasma samples collected from 
patients dosed with solanezumab will be assayed for solanezumab.
Sample handling and shipment to the central laboratory will occur per instructions given to the 
investigative study site.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 2 years following last patient visit for the study.
The remainder of the plasma not used for the assessment of Aspecies may be stored for a 
maximum of 15 years following last patient visit for the study at a facility selected by the 
sponsor (Section 9.4.6.2).
Results of plasma solanezumab and Aanalyses that could unblind the study will not be reported 
to investigative sites or other blinded personnel at a subject level.
9.4.4. Serum Samples for Anti-Solanezumab Immunogenicity
9.4.4.1.
Timing of Blood Sampling
Where local regulations and ethical review boards (ERBs) allow, serum for immunogenicity 
testing will be prepared from blood drawn at the designated visits and times relative to study 
drug dosing as indicated in the body and footnotes of the Schedule of Activities (Section 2).  
Immunogenicity will be assessed by a validated assay designed to detect anti-drug antibodies in 
the presence of solanezumab.  Antibodies may be further characterized and/or evaluated for their 
ability to neutralize the activity of solanezumab.  Serum immunogenicity results and any 
associated plasma Apeptide and solanezumab drug results used to interpret immunogenicity 
test results that could unblind the study will not be reported to investigative sites or other blinded 
personnel.
9.4.4.2.
Blood Collection Procedures
It is critical that for each serum sample, date and time of sample acquisition and date and time of 
administration of study drug are accurately recorded.
Sample handling and shipment to the central laboratory will occur per instructions given to the 
investigative study site.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if regulations and ERBs impose shorter time limits, at a facility selected by 
the sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
solanezumab.


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9.4.5. 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 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.
9.4.6. Samples for Biomarker Research
9.4.6.1.
Pharmacogenetic Samples
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2) where local regulations allow.
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 solanezumab 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 ERBs impose shorter time limits, at a facility 
selected by the sponsor.  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 drug development or when the drug is 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 or exome 
sequencing, genome wide association studies, candidate gene studies, and epigenetic analyses.  
Regardless of technology utilized, genotyping data generated will be used only for the specific 
research scope described in this section.
9.4.6.2.
Biomarker Storage Samples
As discussed above, serum, plasma, and CSF samples for non-pharmacogenetic biomarker 
research will be collected 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 
solanezumab, pathways associated with AD, mechanism of action of solanezumab, and/or 
research method 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.


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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 
the sponsor.  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 drug 
development or when the drug is commercially available.
9.5.
Health Economics
Refer to Section 9.1.2 for description of health economics outcomes.


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10. Statistical Considerations and Data Analysis
10.1. Determination of Sample Size
Power and sample size calculations have been based on the analysis of the primary objective 
using an effect size calculation of treatment difference at the end of the study.
To calculate power, we used an expected decline in ADAS-Cog14 at 2 years of 4.41 points for 
placebo-treated patients and 3.21 points for solanezumab-treated patients, with a common 
standard deviation of 8 (Doraiswamy et al. 2014).  This is equivalent to a difference of 1.2 points 
over 2 years, with an effect size = 0.15.  Based on these assumptions and a 25% discontinuation 
rate, 1225 randomized patients per arm (919 completers per arm) or 2450 total randomized 
patients will have approximately 89% power to detect a significant treatment difference at 
2 years using a 2-sided significance level of 0.05.
Patients who are randomized but not administered treatment may be replaced to ensure that
enough patients may complete the study.
10.2. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
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 patients are assigned by random allocation, 
even if the patient 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, patients will be 
included in the analysis only if both a baseline and a postbaseline measure are available.  Unless 
otherwise defined, a baseline measure is the last non-missing observation collected prior to the 
first infusion of study medication.  Endpoint is the last non-missing postbaseline measurement.
For mixed-effect model repeated measure (MMRM) models, observations collected at 
nonscheduled visits will not be included in the analyses.  For analyses using last observation 
carried forward, the last non-missing postbaseline observation (scheduled or unscheduled) will 
be used to calculate change from baseline.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05; 2-sided confidence intervals (CIs) will be displayed with a 95% confidence level.  All tests
of interactions between treatment and other factors will be conducted at an alpha level of 0.05.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the CSR.  Additional exploratory analyses of the data will be conducted as deemed 
appropriate.
Complete details of the statistical methods to be used in this study are contained in the statistical 
analysis plan (SAP).


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10.2.1. Analysis Populations
The primary and secondary efficacy measures will be analyzed using the ITT population.  In 
addition, each of these measures will be analyzed using the per-protocol population and the 
completer population to verify the robustness of the results.  Summaries and analyses for safety 
measures will be based on the safety population.  Tabulation of the number and percentage of 
patients included in each population will be provided.  The SAP contains detailed descriptions 
for each of these patient populations.
10.2.2. Handling of Missing Items for Scales
If any of the individual items for the ADAS-Cog or ADCS-MCI-ADL are missing or unknown, 
every effort will be made to obtain the score for the missing item or items.
For ADAS-Cog14, if <30% (4 or fewer of a total of 14) of the items are missing, the total score
(maximum = 90) will be imputed as follows:  The total from remaining items will be multiplied 
by a factor that includes the maximum score for the missing items.  For example, if the first item, 
“Word-Recall Task,” which ranges from a score of 0 through 10 (maximum = 10), is missing, 
and the second item “Commands,” which ranges from a score of 0 to 5 (maximum = 5), is 
missing, then the multiplication factor = 90/(90 - [10 + 5]) = 90/75 = 1.2.  Thus, the total score 
for this example will be the sum of the remaining 12 items multiplied by 1.2.  The imputed 
number will be rounded up to the nearest integer.  If more than 4 items are missing, the total 
score for ADAS-Cog14 at that visit will be considered missing.
For the ADCS-MCI-ADL, if <30% of the items are missing, the total score will be imputed.  The 
sum of the nonmissing items will be prorated to the sum of total items.  The imputed number will 
be rounded up to the nearest integer.  If the nearest integer is greater than the maximum possible 
score, the imputed score will be equal to the maximum score.  If >30% of the items are missing, 
the total score for ADCS-iADL at that visit will be considered missing.
The same imputation technique will be applied to the CDR-SB.  If only 1 box (of 6) of the CDR 
is missing, the sum of the boxes will be imputed by prorating the sum from the other 5 boxes.  If 
the score from more than 1 box is not available, the CDR-SB at that visit will be considered 
missing.
For all other scales, if any item is missing, any total or sum involving that item will be 
considered missing.
10.2.3. Pooling of Investigators
This study will be conducted by multiple investigators at multiple sites internationally.  In the 
event that a site has an inadequate number of patients (defined as 0 or 1 randomized patient per 
treatment group) for the planned analyses, the following strategy will be implemented.  Data 
from all such sites within a country will be pooled.  If the resulting pool within a country is still 
inadequate, no further pooling will be performed.


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10.3. Treatment Group Comparability
10.3.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study. The 
percentage of patients discontinuing from each treatment group will be compared by reason for 
discontinuation using Fisher’s exact test.
10.3.2. Protocol Deviations
Listings of patients with significant protocol deviations will be provided for the ITT population.  
The following list of significant protocol deviations will be determined from the clinical database 
and from the Lilly clinical/medical group:

Informed consent deviation

Did not have an assessment of the ADAS-Cog at any of the visits at which the 
scale was scheduled to be assessed

Did not have an assessment of the ADCS-MCI-ADL at any of the visits at 
which the scale was scheduled to be assessed

Protocol deviations of inclusion/exclusion criteria

Had a study dosing algorithm deviation (such as if patients randomized to 
Treatment A were given Treatment B or patients randomized to Treatment A 
never received the assigned study drug)

Had unqualified rater or raters with substantial scoring errors for the 
ADAS-Cog at any time

Had unqualified rater or raters with substantial scoring errors for the 
ADCS-MCI-ADL at any time

Did not have the same study partner(s) throughout the trial

Greater than or equal to 20% of infusions are incomplete

Had change in doses of AChEI medication(s) and/or memantine or have 
started/stopped AChEI medication(s) and/or memantine anytime during the 
study without consulting the sponsor

Deviated from the protocol in any other way
10.3.3. Patient Characteristics
The patient’s age, gender, race, height, body weight, body mass index (weight (kg) / [height 
(m)]2), tobacco use, alcohol use, caffeine use, years of education, work status, time since onset of 
first AD symptoms, time since diagnosis, MMSE at Visit 1, APOE4 carrier status (carrier [ε2/ε4, 
ε3/ε4, ε4/ε4], noncarrier [ε3/ε3, ε2/ε2]), APOE4 genotype (ε2/ε4, ε3/ε4, ε4/ε4, no ε4), having 
1 or more first degree relatives with AD, and AChEI and/or memantine use at baseline will be 
recorded.


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Baseline characteristics will be summarized for the ITT 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 with 
independent factors for treatment will be used.
10.3.4. Concomitant Therapy
Approved AD medications will be permitted in this study as described in Section 7.8. Patients 
who begin such treatments during the study will be analyzed as part of the ITT population. 
Analyses stratified by use of these medications at baseline will be conducted.
10.3.5. Treatment Compliance
The proportion of patients who are significantly noncompliant as noted in Section 7.7 will be 
summarized and compared among all treatment groups using Fisher’s exact test.
10.4. Primary and Secondary Analyses
10.4.1. Primary Analyses
The primary objective of this study is to test the hypothesis that intravenous infusion of 
solanezumab will slow cognitive decline as compared with placebo in patients with prodromal
AD.  This will be assessed using an MMRM analysis of the ADAS-Cog14 in patients with 
prodromal AD at baseline (Visit 1 MoCA score of 17 to 28), in which the specific hypothesis is 
that the cognitive decline from baseline at the end of the treatment period (104 weeks) for 
solanezumab will be significantly less than that for placebo.
The change from baseline score on the ADAS-Cog14 at each scheduled postbaseline visit 
(according to the Study Schedule) during the treatment period will be the dependent variable.  
The model for the fixed effects will include terms for 7 effects:  baseline score, pooled 
investigator, treatment, visit, treatment-by-visit interaction, concomitant AChEI and/or 
memantine use at baseline (yes/no), and age at baseline.  Visit will be considered a categorical 
variable with values equal to the visit numbers at which the scales were assessed.  The null 
hypothesis is that the contrast between the solanezumab-treated patients versus placebo-treated 
patients at the last visit equals zero.  An unstructured covariance matrix will be used to model the 
within-patient variance-covariance errors.  If the unstructured covariance structure matrix results 
in a lack of convergence, the following tests will be used in sequence: heterogeneous Toeplitz 
covariance structure, heterogeneous autoregressive covariance structure, heterogeneous 
compound symmetry covariance structure, and compound symmetry covariance structure.
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom.


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10.4.2. Secondary Analyses
10.4.2.1. Clinical Outcomes
Similar to the primary analysis, each of the secondary efficacy outcomes will be assessed using 
an MMRM analysis.  These secondary efficacy outcomes include ADCS-MCI-ADL, MMSE, 
MoCA, CDR-SB, NPI, RUD-Lite, EQ-5D Proxy, QoL-AD patient and proxy, RBANS, and 
FAQ.  For each secondary efficacy measure, the change from baseline score at each scheduled 
postbaseline visit (according to the Study Schedule) during the treatment period will be analyzed 
using the same MMRM model described for the primary analysis.
An additional MMRM analysis, termed a slopes analysis, will be conducted examining the 
change from baseline score on the ADAS-Cog14, ADCS-MCI-ADL, CDR-SB, FAQ, MMSE, 
and MoCA at each scheduled postbaseline visit.  In contrast to the primary analyses, which 
considered visit (time) as a categorical variable, time from randomization will be treated as a 
continuous variable.  The model for the fixed effects will include baseline score, pooled 
investigator, treatment, time, treatment-by-time interaction, concomitant AChEI and/or 
memantine use at baseline (yes/no), and age at baseline.  The treatment-by-time interaction term 
will be examined to assess whether solanezumab and placebo have differing slopes in terms of 
cognitive or functional progression.  The effect of a quadratic term for time (and its associated 
interaction with treatment) on the model will also be examined.
Categorical analyses of slowing cognitive and functional decline will be conducted comparing 
proportions of patients reaching certain levels of decline between solanezumab and placebo.  The 
precise definitions of cognitive and functional decline and analysis methods will be detailed in 
the SAP prior to database lock.
Any additional analyses of secondary efficacy outcomes will be specified in the SAP prior to 
database lock.
10.4.2.2. Biomarker Outcomes
10.4.2.2.1.Analysis of Plasma A
To evaluate the change in plasma A(assayed plasma A1-40 and A1-42) after treatment, an 
MMRM will be used to compare change from baseline to 4, 12, 12, 24, 52, 76, and 104 weeks 
after randomization.  This analysis will be done separately for each plasma Aparameter.  The 
model for the fixed effects will include terms for the following independent effects:  baseline 
plasma A, treatment, visit, treatment-by-visit interaction, and age at baseline.  Visit will be 
considered a categorical variable with values equal to the visit numbers at which plasma Ais 
assessed.  The null hypothesis is that the difference in least squares (LS) mean between the 
solanezumab group and placebo equals zero.
10.4.2.2.2.Analysis of Volumetric MRI Data
To evaluate the changes in volumetric MRI (vMRI) data after treatment, an MMRM will be used 
to compare change from baseline to 52 and 104 weeks after randomization.  The model will 
include terms for the following independent effects:  baseline vMRI value, treatment, visit, 
treatment-by-visit interaction, and age at baseline.  Visit will be considered a categorical variable 


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with values equal to the visit numbers at which vMRI is assessed. The null hypothesis is that the 
difference in LS mean between the solanezumab group and placebo equals zero.
10.4.2.2.3.Analysis of Amyloid PET Imaging
To provide further supporting evidence that solanezumab attenuates the underlying pathologic 
process in AD, the change in brain amyloid burden obtained using florbetapir PET imaging will 
be assessed.  Parameters from various brain regions of interest as well as a composite brain 
measure will be assessed.  Each patient participating in amyloid PET imaging should provide a 
baseline and postbaseline assessment.  Change in standard uptake value ratio (SUVr) normalized 
to the appropriate reference region will be examined using an analysis of covariance (ANCOVA)
model containing terms for baseline SUVr, treatment, and age at baseline.  The null hypothesis is 
that the difference in LS mean between the solanezumab group and placebo equals zero.
10.4.2.2.4.Analysis of Cerebrospinal Fluid
To provide further supporting evidence that solanezumab attenuates the underlying pathologic 
process in AD, changes in CSF parameters, including total and free A1-40 and A1-42 species 
and total tau and P-tau181 peptides, will be assessed.  For each patient who undergoes an LP at 
the beginning of the study (screening or baseline visit) and a second LP (whether as part of the 
main protocol or the LP addendum), change from baseline in measured CSF Aand tau proteins 
will be assessed.  Changes in these CSF parameters at each postbaseline collection point will be 
examined using an ANCOVA model containing terms for baseline, treatment, and age at 
baseline.  The null hypotheses are that the difference in LS means between the solanezumab 
group and placebo equals zero at each of the scheduled time points.
10.5. Safety Analyses
Safety will be assessed by summarizing and analyzing AEs, laboratory analytes, vital signs, 
weight/height measurements, MRI scans, ECGs, and immunogenicity measures during the 
treatment period.
Safety analyses for the treatment period will include comparisons between solanezumab 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, MRI scans, and ECGs, only patients who have 
both a baseline observation and a postbaseline observation will be included in the analysis for 
each analyte or parameter, respectively.
Suicide-related thoughts and behaviors, based on the C-SSRS, will be listed by patient and visit.  
Only patients that show suicidal ideation/behavior will be displayed (that is, if a patient answers 
are all “no” for the C-SSRS, then that patient will not be displayed).  However, if a patient 
reported any ideation or behavior at any time point, then all their ideation and behavior will be 
displayed, even if not positive.


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10.6. Pharmacokinetic/Pharmacodynamic Analyses
The distribution of observed plasma solanezumab concentrations will be graphically compared to 
simulated solanezumab concentrations generated by a population pharmacokinetic (PK) model 
developed with data from previous Phase 3 trials. If warranted, the population PK model 
parameters may be updated by combining data from this study with that from previous Phase 3 
studies and re-fitting the final model. The population PK model may be used to estimate 
exposure parameters (for example, plasma solanezumab area under the curve), if appropriate. As 
warranted, the relationship between exposure estimates and safety, biomarker, or efficacy 
outcomes may be investigated through graphical or other analyses.
To evaluate the potential impact of immunogenicity on solanezumab PK, plasma solanezumab 
concentrations from patients with treatment-emergent immunogenicity will be plotted as a 
function of time, along with mean plasma solanezumab concentrations in all patients. The 
anti-solanezumab titer associated with each plasma solanezumab concentration will be indicated 
on the graph (for example, by assigning a different symbol to each titer level). A region 
representing the middle 90% of observed plasma solanezumab concentrations in all patients will 
also be presented on the graph. If this graphical analysis demonstrates a trend in plasma 
solanezumab concentrations in patients with treatment-emergent immunogenicity relative to the
overall trial population, additional work may be performed to characterize this trend.
10.7. Other Analyses
10.7.1. Health Economics
Health economics analyses are addressed in Section 10.4.2.
10.7.2. Subgroup Analyses
To assess the effects of various demographic and baseline characteristics, subgroup analyses of 
the primary endpoint, ADAS-Cog14, will be performed based on the following variables: 
gender, age, race, APOE4 carrier status, country, concomitant AD therapy, and compliance with 
study drug.  The specific groupings of patients based on these variables will be outlined in the 
SAP.  All subgroup analyses will be considered secondary analyses.  Additional subgroup 
analyses may be performed as suggested by the data.
10.7.3. Gatekeeping Strategy
A gatekeeping strategy will be used in Study LZBE for testing a prespecified set of secondary 
outcomes to ensure family-wise protection against type I error of falsely rejecting any of the null 
hypotheses.  Secondary outcomes will only be tested at the completion of the double-blind 
treatment phase (not at the interim analysis) and will be based on the nominal alpha level as 
specified in the interim analysis description below.
Details of the gatekeeping strategy will be contained in the SAP.


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10.8. Interim Analyses and Data Monitoring Committee
10.8.1. Data Monitoring Committee
Periodic study monitoring will be conducted under the auspices of an independent, external 
DMC assigned to the study.  Only the DMC is authorized to evaluate unblinded interim efficacy 
and safety analyses.  Study sites will receive information about interim results ONLY if they 
need to know for the safety of their patients.  The DMC will meet periodically as outlined in the 
DMC Charter.
Information that may unblind the study during the analyses will not be reported to study sites or 
blinded study team until the completed study has been unblinded.  Unblinding details are
specified in the unblinding plan section of the SAP or a separate unblinding plan document.
10.8.2. Interim Analysis
A single efficacy interim analysis will be assessed by the DMC after 550 randomized
18F-AV-1451 tau addendum participants have completed a baseline and 1-year 18F-AV-1451
PET scan, unless this interim is determined to be unnecessary by results of studies that are 
ongoing at the time of initial protocol development.  The purpose of this interim analysis is to 
assess the relationship between 18F-AV-1451 tau PET and solanezumab treatment at 12 months.
Based on unpublished preliminary 18F-AV-1451 PET data from untreated patients with MCI at 
9 months, a mean increase in SUVr of 0.071 units and a standard deviation of 0.105 units was 
observed.  Conservatively using these same estimates at the 1-year time point and assuming a 
reduction in tau accumulation of 40% (increase of 0.043 SUVr units) in solanezumab-treated 
patients as compared to placebo-treated patients and the same standard deviation, the effect size 
is 0.267 units SUVr.  Given 275 randomized patients per arm (550 total patients included in the 
interim analysis), this analysis will have approximately 87% power to detect a significant 
treatment difference at 1 year using a 2-sided significance level of 0.05.
In addition to comparison of tau changes across treatments, the interim analysis would also 
examine the relationship between changes in 18F-AV-1451 PET and changes in cognition based 
on the ADAS-Cog14.  It is anticipated that a positive correlation between these 2 measures exists
– that is, it is anticipated that patients who show increases in tau accumulation will show 
corresponding increases (more cognitive decline) on the ADAS-Cog14.
The results of the 18F-AV-1451 tau PET interim analysis will not affect the conduct of the overall 
study.  As there is no possibility of terminating the study early for either efficacy or futility based 
on this analysis, no alpha-spending adjustment will be used for the final analysis and all results 
from the tau addendum patients will be included in the final efficacy analysis.  Furthermore, 
should there be occasion for unblinded interim analysis results to be shared beyond the DMC, 
any such sharing would be limited to personnel who are not part of the LZBE study team, in 
order to protect its integrity as a double-blind study.


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If any additional unplanned interim analysis is deemed necessary, the appropriate Lilly medical 
director, or designee, will be consulted to determine whether it is necessary to amend the 
protocol.


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11. Study Governance Considerations
11.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process
11.1.1. 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 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.
11.1.2. Ethical Review
The investigator or an appropriate local representative must give assurance that the 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 GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
11.1.3. 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.


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11.1.4. Investigator Information
Physicians with a specialty in neurology, geriatrics, or psychiatry who have documented 
experience in AD trials will participate as investigators in this clinical trial.  In addition, licensed 
clinicians who have clearly documented extensive experience in AD trials may participate as 
investigators in the clinical trial upon approval by the sponsor.
11.1.5. 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.
11.1.6. Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The investigator with the most qualified enrolled patients will 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 regulatory sponsor’s responsible medical officer and statistician will approve the final CSR
for this study, confirming that, to the best of their knowledge, the report accurately describes the 
conduct and results of the study.
11.2. 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 


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representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
11.2.1. 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 will be encoded and stored in a clinical trial database.  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 collected by a third-party (for example, imaging) will be encoded by the third-party and 
stored electronically in the third-party’s database system.  Validated data will subsequently be 
transferred to Lilly’s 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.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
11.3. Study and Site Closure
11.3.1. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, 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.
11.3.2. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 1.
Abbreviations and Definitions
Term
Definition
Aβ
amyloid-β peptide
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-Cog14
Alzheimer’s Disease Assessment Scale–Cognitive subscale
ADCS-MCI-ADL
Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale for Mild 
Cognitive Impairment
ADLs
activities of daily living
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.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APOE
apolipoprotein E
ARIA
amyloid-related imaging abnormality
ARIA-E
amyloid-related imaging abnormality—edema/effusions, also known as cerebral 
vasogenic edema
ARIA-H
amyloid-related imaging abnormality—hemorrhage/hemosiderin deposition, also 
known as cerebral microhemorrhage
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
CDR-SB
Clinical Dementia Rating Scale–Sum of Boxes


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CEC
Clinical Endpoint Committee
CIOMS
Council for International Organizations of Medical Sciences
CNS
central nervous system
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.
CRF
case report form
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CSF
cerebrospinal fluid
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
DMC
data monitoring committee
DSM
Diagnostic and Statistical Manual of Mental Disorders
ECG
electrocardiogram
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EQ-5D
EuroQol 5-Dimensional Health-Related Quality of Life Scale
ERB
ethical review board
FAQ
Functional Activities Questionnaire
FCSRT
Free and Cued Selective Reminding Test
FDA
(United States) Food and Drug Administration
GCP
good clinical practice
iADL
instrumental activities of daily living
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation


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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.
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWG
International Working Group for New Research Criteria for the Diagnosis of 
Alzheimer’s Disease
IWRS
interactive web-response system
LP
lumbar puncture
LS
least squares
MCI
mild cognitive impairment
MMRM
mixed-effect model repeated measure
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
PET
positron emissions tomography
PK
pharmacokinetics
QoL-AD
Quality of Life in Alzheimer’s Disease (scale)
QTcB
Bazett-corrected QT interval
RBANS
Repeatable Battery for the Assessment of Neuropsychological Status
RUD
Resource Utilization in Dementia
RUD-Lite
Resource Utilization in Dementia–Lite
SAE
serious adverse event


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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. 
SUSARs
suspected unexpected serious adverse reactions
SUVr
standard uptake value ratio
TBL
total bilirubin level
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to 
have a causal relationship with this treatment.
TPO
third-party organization
ULN
upper limit of normal
vMRI
volumetric magnetic resonance imaging


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests 
Hematologya
Clinical Chemistrya
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose, nonfasting
Albumin
Cholesterol
Creatine kinase (CK)
Pregnancy Test (females only)b,c
Lumbar Puncture (screening or optional)a, d
Solanezumab
Aβ proteins
Tau proteins
Abbreviations:  Aβ = amyloid-β peptide; LP = lumbar puncture; PET = positron emissions tomography; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated (central) laboratory.
b
Assayed by local or investigator-designated laboratory.
c
Female patients of childbearing potential must test negative on a serum pregnancy test at screening and must test 
negative on a urine pregnancy test on the day of any PET scan, prior to the administration of radiopharmaceutical 
agent.
d
Patients who undergo LP will have coagulation panel (prothrombin time [PT]/International Normalized Ratio 
[INR] and partial thromboplastin time [PTT]) and platelet count) obtained from a local laboratory up to 4 weeks 
before each LP.


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Appendix 3.
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
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; 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.


H8A-MC-LZBE Clinical Protocol
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Appendix 4.
Summary of Radiation Dose
Patients who undergo florbetapir PET scans to determine eligibility for the study will be exposed 
to radiation during the PET scan.  Details on the amount of exposure estimated to occur on each 
PET imaging occasion, in each year of the study, and cumulatively, are provided in 
Table LZBE.2 below.
Table LZBE.2.
Effective Radiation Dose (mSv) from Florbetapir PET Scans
Effective 
Dose (mSv) 
per Scana
Number of 
Scans in 
First Year
Effective 
Dose (mSv) 
for Scans in 
First Year
Number 
of Scans 
in Second 
Yearb
Effective Dose 
(mSv) for 
Scans in 
Second Yearb
Total 
Effective 
Dose 
(mSv)
Florbetapir F 18 
(amyloid) Scan 
(10 mCi iv)
7.43
1
7.43
1
7.43
14.86
Abbreviations:  CT = computed tomography; iv = intravenous infusion; PET = positron emission tomography.
a
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 and because it would add additional 
radiation exposure is not recommended.
b Second florbetapir scan done at end of second year or in the event of early discontinuation.
Source:  Florbetapir F18 Injection (AmyvidTM) Package Insert, 2016.


Leo Document ID = 43ed0b34-a8cf-4fbd-b58b-a82339d146d4
Approver: 
Approval Date & Time: 28-Mar-2016 20:03:21 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 28-Mar-2016 20:59:47 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan H8A-MC-LZBE 
 
A 24-Month, Phase 3, Multicenter, Placebo-Controlled Study of Efficacy and Safety of 
Solanezumab versus Placebo in Prodromal Alzheimer’s Disease 
 
NCT02760602 
 
Approval Date: 08-Mar-2017 
 
 
 


H8A-MC-LZBE Statistical Analysis Plan Version 1
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1.
Statistical Analysis Plan:  
H8A-MC-LZBE:  A 24-Month, Phase 3, Multicenter, 
Placebo-Controlled Study of Efficacy and Safety of 
Solanezumab versus Placebo in Prodromal Alzheimer’s 
Disease
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.
Solanezumab (LY2062430) Alzheimer’s Disease
Study H8A-MC-LZBE is a multicenter, randomized, double-blind, placebo-controlled, Phase 
3 study comparing solanezumab with placebo for 24 months in approximately 
2450 subjects with prodromal Alzheimer’s disease.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol H8A-MC-LZBE
Phase 3
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 08-Mar-2017 GMT


H8A-MC-LZBE Statistical Analysis Plan Version 1
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   H8A-MC-LZBE:  A 24-Month, Phase 3, 
Multicenter, Placebo-Controlled Study of Efficacy and Safety of 
Solanezumab versus Placebo in Prodromal Alzheimer’s Disease.........................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................4
4.
Study Objectives.................................................................................................................5
5.
Study Design.......................................................................................................................7
5.1.
Summary of Study Design..............................................................................................7
5.2.
Determination of Sample Size ........................................................................................7
5.3.
Method of Assignment to Treatment ..............................................................................7
6.
A Priori Statistical Methods ................................................................................................9
6.1.
General Considerations ..................................................................................................9
6.2.
Handling of Dropouts or Missing Data...........................................................................9
6.2.1.
Handling of Missing Items for Scales.....................................................................9
6.3.
Analysis Populations....................................................................................................10
6.4.
Subject Disposition ......................................................................................................11
6.5.
Subject Characteristics .................................................................................................11
6.6.
Concomitant Therapy...................................................................................................11
6.7.
Safety Analyses............................................................................................................12
6.7.1.
Extent of Exposure...............................................................................................12
6.7.2.
Adverse Events ....................................................................................................12
6.7.3.
Clinical Laboratory Evaluation.............................................................................12
6.7.4.
Vital Signs and Other Physical Findings...............................................................13
6.7.5.
Magnetic Resonance Imaging Data ......................................................................13
6.7.6.
Suicidal Ideation or Behavior ...............................................................................13
6.8.
Interim Analyses and Data Monitoring.........................................................................13
7.
References ........................................................................................................................14


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Table of Contents
Table
Page
Table LZBE.4.1. Objectives and Endpoints ................................................................................5
Table LZBE.6.1. Analysis Populations for Study H8A-MC-LZBE ...........................................10
Table LZBE.6.2. Study Measures Summarized for Each Analysis Population...........................10


H8A-MC-LZBE Statistical Analysis Plan Version 1
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3.
Revision History
SAP Version 1 will be approved prior to the first production data transfer.


H8A-MC-LZBE Statistical Analysis Plan Version 1
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4.
Study Objectives
Table LZBE.4.1 shows the objectives and endpoints of the study.
Table LZBE.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the hypothesis that solanezumab 400 mg 
Q4W will slow the clinical progression of prodromal 
AD over 24 months compared to placebo
ADAS-Cog14:  change from baseline over 24 months
Secondary
To assess the effect of solanezumab vs placebo on 
the clinical progression of prodromal AD over 
24 months
Changes from baseline to 24 months on ADCS-MCI-ADL, 
MMSE, MoCA, FAQ, NPI, CDR-SB, RBANS, and FCSRT
To assess the effect of solanezumab vs placebo on 
quality of life and health outcomes in prodromal AD
over 24 months
Changes from baseline to 24 months on RUD-Lite, EQ-5D, 
QoL-AD
To assess the effect of solanezumab vs placebo on 
biomarkers in prodromal AD over 24 months
Changes from baseline to 24 months in florbetapir PET or 
CSF Aβ/tau, vMRI, plasma Aβ, plasma solanezumab, 
sample storage for biomarkers (where permitted); includes 
CSF collected via optional addendum
To assess the hypothesis that solanezumab will slow 
the accumulation of tau pathology over 12 and 
24 months compared to placebo
Changes from baseline in neocortical tau deposits (collected 
in a subset of subjects using 18F-AV-1451 PET as part of an 
addendum) over 12 and 24 months
To assess the hypothesis that change from baseline in 
accumulation of tau pathology over 12 and 
24 months is associated with changes from baseline 
in cognition
Changes from baseline in neocortical tau deposits (collected 
in a subset of subjects using 18F-AV-1451 PET as part of an 
addendum) and ADAS-Cog14, over 12 and 24 months
To assess the hypothesis that change from baseline in 
accumulation of tau pathology over 24 months is 
associated with changes from baseline in function
Changes from baseline in neocortical tau deposits (collected 
in a subset of subjects using 18F-AV-1451 PET as part of an 
addendum) and ADCS-MCI-ADL over 24 months
To assess the effect of pharmacogenomic factors on 
clinical and functional progression with solanezumab 
vs placebo in prodromal AD over 24 months
Changes from baseline in pharmacogenomics markers 
(where permitted) and clinical and functional scales


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Objectives and Endpoints
Objectives
Endpoints
Exploratory
To generate additional data for validation of the 
PACC score, a composite endpoint being used in 
another Lilly study
Changes from baseline in components of the MMSE, 
RBANS, and FCSRT over 24 months
To compare MMSE and MoCA scales
Changes from baseline in MMSE and MoCA over 
24 months
To assess time to significant progression
Time to progression to CDR-SB score of 1.0, and significant 
change on other cognitive and functional measures
Abbreviations:  Aβ = amyloid-β peptide; AD = Alzheimer’s disease; ADAS-COG14 = 14-item Alzheimer’s Disease 
Assessment Scale-Cognitive subscale; ADCS-MCI-ADL = Alzheimer’s Disease Cooperative Study-Mild 
Cognitive Impairment-Activities of Daily Living Inventory; CDR-SB = Clinical Dementia Rating-Sum of Boxes; 
CSF = cerebrospinal fluid; EQ-5D = EuroQol 5-Dimensional Health-Related Quality of Life Scale; FAQ = 
Functional Activities Questionnaire; FCSRT = Free and Cued Selective Reminding Test; MMSE = Mini-Mental 
State Examination; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; PACC = 
Preclinical Alzheimer's Cognitive Composite; PET = positron emission tomography; Q4W = every 4 weeks; 
QoL-AD = Quality of Life in Alzheimer’s Disease (scale); RBANS = Repeatable Battery for the Assessment of 
Neuropsychological Status; RUD-Lite = Resource Utilization in Dementia-Lite; vMRI = volumetric magnetic 
resonance imaging.


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5.
Study Design
5.1.
Summary of Study Design
Study H8A-MC-LZBE (LZBE) is a multicenter, randomized, double-blind, parallel, placebo-
controlled Phase 3 trial comparing solanezumab with placebo for 24 months in approximately 
2450 subjects with prodromal Alzheimer’s disease (AD).  Subjects who meet entry criteria will 
be randomized in a 1:1 ratio to receive an infusion of solanezumab 400 mg or placebo once 
every 4 weeks. Subjects will be randomized by site and by use of florbetapir positron emission 
tomography (PET) scanning or cerebrospinal fluid (CSF) for study eligibility.  The primary 
hypothesis being tested in Study LZBE is that solanezumab will slow the clinical progression of 
AD as compared with placebo in subjects with prodromal AD.
In addition, participants in the 18F-AV-1451 tau imaging addendum will be included in an 
interim analysis designed to assess the relationship between 18F-AV-1451 tau PET and 
solanezumab treatment.
Three months after the end of the double-blind treatment period (or 4 months after the last dose 
in case of early discontinuation), subjects will come to a follow-up visit for biomarker and safety 
assessments.
5.2.
Determination of Sample Size
Power and sample size calculations have been based on the analysis of the primary objective 
using an effect size calculation of treatment difference at the end of the study.
To calculate power, an expected decline in 14-item Alzheimer’s Disease Assessment Scale-
Cognitive subscale (ADAS-Cog14) at 2 years of 4.41 points for placebo-treated subjects and 3.21 
points for solanezumab-treated subjects was used, with a common standard deviation of 8 
(Doraiswamy et al. 2014).  This is equivalent to a difference of 1.2 points over 2 years, with an 
effect size = 0.15.  Based on these assumptions and a 25% discontinuation rate, 1225 randomized 
subjects per arm (919 completers per arm) or 2450 total randomized subjects will have 
approximately 89% power to detect a significant treatment difference at 2 years using a 2-sided 
significance level of 0.05.
Subjects who are randomized but not administered treatment may be replaced to ensure that
enough subjects complete the study.
5.3.
Method of Assignment to Treatment
Subjects who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 2.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  The IWRS will be used to assign a 
vial containing double-blind investigational product to each subject. Site personnel will confirm 
the correct vial has been located by entering a confirmation number found on the vial into the 
IWRS.


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To achieve between-group comparability, the randomization will be stratified by site and by use 
of florbetapir PET scanning or CSF for study eligibility.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (hereafter 
Lilly).
On 10 January 2017, approximately 6 months after the first subject entered the LZBE study, the 
study was discontinued due to sponsor decision.  After careful review of additional data analyses 
from the solanezumab Phase 3 EXPEDITION3 (H8A-MC-LZAX) study in subjects with mild 
dementia due to AD, Lilly did not find sufficient scientific evidence that solanezumab would likely 
demonstrate a meaningful benefit to subjects with prodromal AD as defined by the LZBE study 
protocol.  The study was not stopped for safety reasons. Based on EXPEDITION3 results, there were 
no new safety signals identified.
The 26 randomized subjects in the study are to be discontinued from the double-blind treatment 
period at the early discontinuation visit and are requested to return to the follow-up visit (Visit 
301) 4 months after the last dose according to the protocol.  The study DBL will happen at the 
end of the trial after the last subject has completed the follow-up visit. A synopsis report with 
attachments will summarize the study results for the early discontinued study and this statistical 
analysis plan will pre-specify analyses for the study synopsis. 
In general, no analyses will be conducted to address any primary, secondary, or exploratory 
efficacy objectives because sufficient data will not be available for reliable efficacy evaluation in 
this early discontinued study. Safety data will be listed or summarized.  No statistical 
comparison of treatment effect will be conducted.
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 subjectdoes 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, a baseline measure is the last non-missing observation collected prior to the 
first infusion of study medication.  Endpoint is the last non-missing postbaseline measurement.
6.2.
Handling of Dropouts or Missing Data
6.2.1. Handling of Missing Items for Scales
If any of the individual items for the ADAS-Cog or Alzheimer’s Disease Cooperative Study-
Mild Cognitive Impairment-Activities of Daily Living Inventory (ADCS-MCI-ADL) are missing 
or unknown, every effort will be made to obtain the score for the missing item or items.
For ADAS-Cog14, if <30% (4 or fewer of a total of 14) of the items are missing, the total score
(maximum = 90) will be imputed as follows:  The total from remaining items will be multiplied 
by a factor that includes the maximum score for the missing items.  For example, if the first item, 
“Word-Recall Task,” which ranges from a score of 0 through 10 (maximum = 10), is missing, 


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and the second item “Commands,” which ranges from a score of 0 to 5 (maximum = 5), is 
missing, then the multiplication factor = 90/(90 - [10 + 5]) = 90/75 = 1.2.  Thus, the total score 
for this example will be the sum of the remaining 12 items multiplied by 1.2.  The imputed 
number will be rounded up to the nearest integer.  If more than 4 items are missing, the total 
score for ADAS-Cog14 at that visit will be considered missing.
For the ADCS-MCI-ADL, if <30% of the items are missing, the total score will be imputed.  The 
sum of the nonmissing items will be prorated to the sum of total items.  The imputed number will 
be rounded up to the nearest integer.  If the nearest integer is greater than the maximum possible 
score, the imputed score will be equal to the maximum score.  If >30% of the items are missing, 
the total score for ADCS-MCI-ADL at that visit will be considered missing.
The same imputation technique will be applied to the Clinical Dementia Rating-Sum of Boxes
(CDR-SB).  If only 1 box (of 6) of the CDR is missing, the sum of the boxes will be imputed by 
prorating the sum from the other 5 boxes.  If the score from more than 1 box is not available, the 
CDR-SB at that visit will be considered missing.
For all other scales, if any item is missing, any total or sum involving that item will be 
considered missing.
6.3.
Analysis Populations
Table LZBE.6.1 below defines each of the analysis populations used in this study. Table 
LZBE.6.2 lists the study measures that will be summarized and/or analyzed in each population.
Table LZBE.6.1.
Analysis Populations for Study H8A-MC-LZBE
Population Name
Description of Population
All Subjects Entered
All subjects who signed informed consent. 
ITT Population
All randomized subjects.  
Safety Population
All randomized subjects with at least 1 complete or partial infusion of study 
medication.
Abbreviation:  ITT = intent-to treat. 
Table LZBE.6.2.
Study Measures Summarized for Each Analysis Population
Population Name
Variables Assessed
ITT Population
Tables and Listings of the following:  subject disposition, subject 
characteristics, and concomitant medications
Safety Population
Tables and Listings of the following:  adverse events, laboratory results, 
vital signs, MRI safety data, and suicidal ideation or behavior
Abbreviations:  ITT = intent-to treat; MRI = magnetic resonance imaging. 


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6.4.
Subject Disposition
The reason for discontinuation will be collected at the early discontinuation visit and at the 
follow-up visit that should occur 4 months after last dose.  A listing of subject disposition will be 
generated for all randomized subjects.
6.5.
Subject Characteristics
Baseline characteristics will be summarized for the ITT population by treatment group and 
overall.  Summaries will include descriptive statistics for continuous and categorical measures.  
Subject characteristics to be presented include the following:  

age (calculated as [date of informed consent – (year of birth, July 1)]/365.25)

gender

race

ethnicity

country

height

body weight

body mass index (weight [kg] / [height (m)]2)

tobacco use

alcohol use

caffeine use

years of education

work status 

time since onset of first prodromal AD symptoms

time since diagnosis 

Montreal Cognitive Assessment, Functional Activities Questionnaire, and Free and Cued 
Selective Reminding Test at screening (Visit 1)

Baseline severity of impairment as measured by ADAS-Cog14, ADCS-MCI-ADL, Mini-
Mental State Examination, CDR-SB, CDR global score, Neuropsychiatric Inventory, 
Resource Utilization in Dementia, EuroQol 5-Dimensional Health-Related Quality of 
Life Scale Proxy, Quality of Life in Alzheimer’s Disease (scale) patient and proxy, and 
Repeatable Battery for the Assessment of Neuropsychological Status at Visit 2

Apolipoprotein E (ApoE) genotype (ε2/ε4, ε3/ε4, ε4/ε4, no ε4)

ApoE4 carrier status (carrier [ε2/ε4, ε3/ε4, ε4/ε4], noncarrier [ε3/ε3, ε2/ε2, ε3/ε2])

having 1 or more first degree relatives with AD

acetylcholinesterase inhibitors and/or memantine use at baseline
6.6.
Concomitant Therapy
Concomitant medications are defined as those being taken on or after first infusion.  A summary 
of concomitant medications will be presented as frequencies and percentages for each treatment 
group.  


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If the start or stop dates of therapies are missing or partial to the degree that determination cannot 
be made of whether the therapy is prior or concomitant, the therapy will be deemed concomitant.
Medications will be coded using the World Health Organization  drug dictionary.
6.7.
Safety Analyses
6.7.1. Extent of Exposure
The exposure to study drug will be summarized for each treatment group.  Overall duration of 
exposure will be calculated as date of last study visit during the treatment period – date of first 
infusion + 1 day.  Exposure will be provided in a listing.
6.7.2. Adverse Events
Adverse events will be coded according to established Medical Dictionary for Regulatory 
Activities (MedDRA). 
Treatment-emergent adverse events (TEAEs) will be defined as events that first occurred or 
worsened on or after first infusion date until the follow-up visit (Visit 301).  Should there be 
insufficient data for adverse event start date, stop date, and time to make this comparison, the 
adverse event will be considered treatment emergent.  Treatment-emergent adverse events will 
be determined based on MedDRA lowest level term.
An overview of adverse events, including the number and percentage of subjects who died, 
experienced serious adverse events, discontinued due to adverse events, and who experienced
TEAEs, will be provided.  In addition, a listing of the adverse events will be provided.
6.7.3. Clinical Laboratory Evaluation
Laboratory measurements for clinical chemistry and hematology panels will be summarized 
using continuous data (change from baseline) and categorical or ordinal data (proportion of 
treatment-emergent abnormalities). 
Summaries and analyses of continuous lab data (change from baseline) will be performed using 
International System of Units (SI units). If there are multiple records of laboratory 
measurements at baseline or postbaseline visit, the last record for each time period will be used.
The proportion of subjects with treatment-emergent high or treatment-emergent low, or 
treatment-emergent abnormal laboratory values at any postbaseline visit will be summarized by 
treatment and overall.  Treatment-emergent high or low laboratory abnormality will be based on 
SI unit.  Planned and unplanned measurements will be included.  A treatment-emergent high 
value is defined as a change from a low value or normal value at all baseline visits to a value 
greater than the high limit at any time after baseline.  A treatment-emergent low value is defined 
as a change from a high value or normal value at all baseline visits to a value less than the low 
limit at any time after baseline.  A treatment-emergent abnormal value (only applies to 
categorical results) is defined as a change from normal at all baseline visits to abnormal at any 
time after baseline.


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For each laboratory analyte, only subjects who were low or normal at baseline and have at least 
one postbaseline will be included in the denominator when computing the proportion of subjects
with treatment-emergent high values.  Similarly, only subjects who were high or normal at 
baseline and have at least one postbaseline will be included in the denominator when computing 
the proportion of subjects with treatment-emergent low values.
6.7.4. Vital Signs and Other Physical Findings
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), temperature, and weight by treatment group for all subjects 
in the safety population will be summarized.
6.7.5. Magnetic Resonance Imaging Data
Magnetic resonance imaging (MRI) is scheduled to be obtained at screening (Visit 1), 52 weeks 
(Visit 15), 104 weeks (Visit 28), and early discontinuation visit (ED).  Due to early 
discontinuation of the study, MRI data will only be available at screening and ED.  Frequencies 
and percentages of the following parameters of amyloid-related imaging abnormality (ARIA) 
edema (ARIA-E, also known as vasogenic edema) and hemorrhage (ARIA-H, also known as 
microhemorrhage), will be summarized.

ARIA-H
o
Number of ARIA-H (1, 2 to 4, 5 to 10, >10, no presence,  or nonevaluable) at 
screening and ED
o
Shift from screening to early discontinuation

ARIA-E
o
Severity (mild, moderate, severe, questionable, nonevaluable, or no presence) at 
screening and ED.
o
Change (unchanged in size, increased in size, decreased in size or complete 
resolution) from screening to ED.
6.7.6. Suicidal Ideation or Behavior
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent, based on 
the Columbia-Suicide Severity Rating Scale (C-SSRS), will be collected.  A listing by subject
and visit will be provided and only includes subjects who show suicidal ideation/behavior or 
self-injurious behavior without suicidal intent (ie, if a subjectanswers 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 
ideation and behavior will be displayed, even if not positive.  
6.8.
Interim Analyses and Data Monitoring 
Due to early discontinuation of the study, there will be no planned data monitoring committee 
meeting or interim analysis.


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7.
References
Doraiswamy PM, Sperling RA, Johnson K, Reiman EM, Wong TZ, Sabbagh MN, 
Sadowsky CH, Fleisher AS, Carpenter A, Joshi AD, Lu M, Grundman M, Mintun MA, 
Skovronsky DM, Pontecorvo MJ; AV45-A11 Study Group. Florbetapir F 18 amyloid PET and 
36-month cognitive decline: a prospective multicenter study. Mol Psychiatry. 2014;19:1044-
1051.


Leo Document ID = d77292ce-48ac-412e-9ed2-0f2980555ed3
Approver: 
Approval Date & Time: 08-Mar-2017 16:11:43 GMT
Signature meaning: Approved
PPD