Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4 Study)
Phase: PHASE3
Conditions: Cognition Disorders
Sponsor: Eli Lilly and Company

H8A-MC-LZAZ(f) Clinical Protocol 
 
Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4 Study) 
 
NCT02008357   
 
Approval Date: 9-Aug-2022 
 
 

CONFIDENTIAL 
H8A-MC-LZAZ(f) 
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Title Page 
Confidential Information 
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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 
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otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4 Study) 
Protocol Number: H8A-MC-LZAZ 
Amendment Number: f 
Compound: Solanezumab (LY2062430) 
Study Phase: 3 
Acronym: A4 Study 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 11631 
NCT: NCT02008357 
Approval Date: Protocol Amendment (f) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-028549 
 
 
 
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1. Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment e 
16-Oct-2018 
Amendment d 
04-Jul-2017 
Amendment c 
14-Dec-2015 
Amendment b 
02-Sep-2014 
Amendment a 
18-Oct-2013 
Original Protocol 
08-Sep-2013 
Amendment [f] 
Overall Rationale for the Amendment: 
The rationale of this amendment is to include changes in the primary efficacy analysis and 
update other sections for minor changes. 
Section # and Name 
Description of Change 
Brief Rationale 
2. Synopsis 
Updated the section to align with the 
changes in the main body of the 
protocol 
For consistency 
6.1. Primary Objective 
6.2. Secondary Objectives 
11.1. Determination of Sample Size 
11.2.8. Analysis of Primary Outcome 
(Placebo-Controlled Period) 
11.2.9.1. Clinical Outcomes 
11.2.9.2. Sensitivity Analyses 
Revised statistical analysis from 
“mixed model repeated-measures 
(MMRM)” to “constrained 
longitudinal data analysis (cLDA) 
natural cubic spline (NCS) analysis 
(referred to as NCS henceforth)” 
The NCS analysis method was 
selected to accommodate 
disruptions to the study from the 
COVID-19 pandemic. MMRM 
analyses will be conducted as 
sensitivity analyses as described 
in the SAP 
6.2. Secondary Objectives 
 
Changed “tau peptides 
phosphorylated at the threonine 181 
position (p-tau181)” to 
“phosphorylated tau peptides (P-tau)” 
For flexibility to include other 
isoforms 
Added “and plasma” with CSF 
Correction 
Removed “at the time of database 
lock for the placebo-controlled period 
using data available up to 2 years in 
the open-label period” from the first 
bullet point of secondary objectives 
of the open-label period 
Correction 
7.1.5. Open-Label Extension Period 
Added “If the open-label period is 
extended beyond Visit 117, 
participants who complete Visit 117 
before implementation of the protocol 
amendment that includes additional 
visits will be allowed to resume study 
visits once available at their site.” 
For clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.3.1. Cerebrospinal fluid (CSF) 
11.2.9.3. Biomarker Outcomes 
Removed “181” from “p-tau181” 
For flexibility to include other 
isoforms 
10.1.4. Secondary Efficacy Clinical 
Outcome Measures, Open-Label 
Period 
Added “at Visit 66 and” and removed 
“subjective cognitive decline,” 
Correction 
10.2.3. Electrocardiograms 
Added “ECG will be collected in the 
placebo-controlled period per 
schedule of events and in the open-
label period as unscheduled ECG per 
investigator discretion.” 
For clarification 
10.3. Appropriateness of 
Measurements 
Added “and plasma” with CSF in 
Paragraph 5 
Correction 
11.2.9.2. Sensitivity Analyses 
Added “as noted in the SAP” 
For clarification 
11.2.9.3. Biomarker Outcomes 
Removed “Aβ” and added “and P-
tau, GFAP, and Neurofilament light 
chain” and “and P-tau” in Paragraph 
1; added “GFAP Neurofilament light 
chain” in Paragraph 4 
Correction 
11.2.10. Open-Label Period 
Removed “This noninferiority 
interim analysis will be conducted at 
the time of the database lock of the 
placebo-controlled period.” from 
Paragraph 5 
For clarification 
11.2.13.2. Adverse Events 
Replaced “randomization” with “the 
first infusion” 
For clarification 
Attachment 1. A4 Study Schedule: 
Study Schedule, A4 Protocol, Visits 6 
through 66 (Placebo-Controlled 
Period)a 
Changed the superscript footnote 
symbol from “j” to “i” in column 
heading “Early Term” 
Correction 
Added “Clinician Diagnostic 
Impression (CDI)” row 
Correction. The CDI was 
inadvertently left off the 
schedule in protocol amendment 
(e) but was added to the study 
database, and sites were trained 
to collect the CDI. The addition 
of this row in the Placebo-
Controlled Period study 
schedule reflects conduct of the 
study at Visit 66 
Attachment 1. A4 Study Schedule: 
Study Schedule, A4 Protocol, Visits 6 
through 66 (Laboratory Specimens, 
Placebo-Controlled Period)a 
(completed) 
Changed Visit “40” to “50” in 
Footnote “a” 
Correction 
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Section # and Name 
Description of Change 
Brief Rationale 
Attachment 4. Amendment Summary 
for Protocol H8A-MC-
LZAZ(e)/ADC-040-A4: Anti-
Amyloid Treatment in Asymptomatic 
Alzheimer’s Disease (A4 Study) 
 
Revised Protocol Sections 
Removed these sections 
Updated according to internal 
Lilly guidance 
 
 
 
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2. Synopsis 
Study 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 with fatal complications.  The amyloid hypothesis of AD 
postulates that the accumulation of amyloid- peptide (A) is an early and necessary event in the 
pathogenesis of AD.  This hypothesis suggests that treatments that slow the accumulation of A 
in the brain or increase clearance of A may be able to slow the progression of the AD clinical 
syndrome. 
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 by the stage of mild 
cognitive impairment (MCI)/prodromal AD.  Recent clinical trial results in mild-to-moderate AD 
dementia, as well as evidence from transgenic animal experiments, suggest that earlier 
intervention may be most beneficial to fully impact the clinical progression of the disease, 
particularly with 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 have evidence of amyloid pathology.  Clinically “normal” older individuals with 
biomarker evidence of elevated amyloid pathology demonstrate AD-like abnormalities on 
functional and structural imaging, perform less well on cognitive tests compared to 
amyloid-negative older individuals, are more likely to report subjective memory concerns, and 
are at increased risk for cognitive decline and progression to MCI and AD.  Recent academic 
consensus workgroups focused on developing guidelines for earlier diagnosis of AD and 
research diagnostic criteria have defined a stage of “preclinical AD,” based on biomarker 
evidence of AD pathology before the stage of clinically evident symptoms of cognitive 
impairment. 
The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease “A4” study is a Phase 3, 
double-blind, placebo-controlled study in subjects with preclinical AD.  The A4 trial preclinical 
AD study population will be defined as subjects with evidence of brain amyloid pathology on 
PET amyloid imaging who are still clinically normal but at high risk for cognitive decline.  The 
A4 study is designed to test the hypothesis that solanezumab, a monoclonal antibody that binds 
A, will slow decline on a cognitive composite measure designed to be sensitive to early decline 
in the preclinical stages of AD.  This study will collect additional data on the long-term safety 
and efficacy of solanezumab, including computerized cognitive outcomes, as well as self and 
study partner reports of daily-life cognitive function outcomes, a brief resource utilization 
inventory, and biomarker and imaging measures. 
 
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Clinical Protocol Synopsis:  Study H8A-MC-LZAZ (A4 Study) 
Name of Investigational Product:  Solanezumab (LY2062430) 
Title of Study:  Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study 
Phase of Development:  3 
Study Design:  This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing 
solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in approximately 1150 subjects 
with preclinical AD, defined as having evidence of elevated brain amyloid pathology before the stage of clinically 
evident cognitive impairment, with an optional open-label extension period. 
Objectives:  The primary objective of this study is to test the hypothesis that solanezumab, administered as an 
intravenous (IV) infusion every 4 weeks for 4.5 years, will slow cognitive decline as compared with placebo in 
subjects with preclinical AD.  The primary objective will be assessed using a natural cubic spline (NCS) analysis 
of the primary outcome measure, the Preclinical Alzheimer Cognitive Composite (PACC), a composite that is 
primarily weighted on episodic memory and executive function tests, in which the specific hypothesis is that the 
cognitive decline at Week 240 will be significantly less for solanezumab than for placebo. 
The secondary objectives of the placebo-controlled period of the study are: 
 
To test the hypothesis that solanezumab will slow the decline of perceived cognitive function and 
performance of everyday activities, as compared with placebo, using an NCS analysis of the Cognitive 
Function Index (CFI). 
 
To assess whether decline in activities of daily living begins by the end of the treatment period, and if so, 
whether an effect of solanezumab, compared with placebo, can be detected using an NCS analysis of the 
ADCS-Activities of Daily Living (ADCS-ADL) Prevention Questionnaire. 
 
To assess the relationship between treatment effect and time using the PACC. 
 
To test the hypothesis that solanezumab reduces brain amyloid burden, as compared with placebo, as 
assessed using florbetapir PET imaging. 
 
To assess effects of solanezumab on CSF concentrations of total tau and phosphorylated tau. 
 
To assess effects of solanezumab on CSF concentrations of Aβ 
 
To investigate the effect of treatment with solanezumab on volumetric magnetic resonance imaging 
(MRI). 
 
To assess the safety of solanezumab versus placebo treatment including adverse events (AEs) and 
immunogenicity. 
The secondary objectives of the open-label period of the study are: 
 
To assess the persistence of effect of solanezumab treatment in participants with preclinical AD.  That is, 
to test the hypothesis that patients originally randomized to receive placebo and later switched to 
solanezumab at the start of the open-label period do not “catch up” to patients originally randomized to 
receive solanezumab in the placebo-controlled period, using a randomized/delayed-start analysis.  The 
main efficacy objective of the open-label period will be an interim randomized/delayed-start analysis of 
the PACC. 
 
To test the hypothesis that solanezumab will continue to slow the decline associated with preclinical AD 
during open-label treatment, comparing participants initially randomized to solanezumab with participants 
initially randomized to placebo in the double-blind treatment period, using randomized/delayed-start 
analysis of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating-Sum of Boxes 
(CDR-SB), Computerized Cognitive Composite (C3), CFI, and the ADCS-ADL Prevention 
Questionnaire. 
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The exploratory objectives of the study are: 
 
To assess the effect of treatment with solanezumab as demonstrated using the MMSE. 
 
To assess the utility of a novel computerized battery, the C3, in predicting and tracking clinical decline 
and response to solanezumab. 
 
To assess the effects of treatment on healthcare resource utilization. 
 
To determine the best predictors of clinical decline based on the PACC. 
 
To develop novel sensitive outcome measures to improve the efficiency of future secondary prevention 
trials, including exploratory measures of self-reported assessment of cognitive and interpersonal 
functioning 
 
To assess the effect of treatment with solanezumab as demonstrated using the CDR scale. 
 
To assess the effect of treatment with solanezumab as demonstrated using the C-Path Consortium’s 
Participant-Reported Outcome Questionnaire (C-Path PRO). 
 
To investigate the impact of solanezumab on markers of synaptic dysfunction on functional connectivity 
MRI. 
 
To assess solanezumab-associated changes in levels of plasma Aβ species and CSF Aβ species.  The 
hypothesis that solanezumab, unlike placebo, alters amyloid-plaque associated forms of Aβ will be 
assessed by 1) demonstrating presence of plaque-associated Aβ species in the plasma, and 2) confirming 
that concentrations of CSF-free (unbound to antibody) Aβ1-42 are increased or unchanged and CSF-free 
Aβ1-40 levels are decreased with solanezumab treatment. 
 
To explore whether baseline markers of neurodegeneration (volumetric MRI or CSF tau or P-tau or 
plasma P-tau) are related to cognitive decline and response to treatment with solanezumab. 
 
To explore the impact of disclosure of amyloid status on questionnaires probing perception of amyloid 
imaging and concern about developing AD. 
 
To explore biomarker assessments collected at baseline and at the end of the placebo-controlled period as 
potential predictors of treatment effect during the open-label period. 
 
To assess preclinical AD during open-label treatment by comparing participants initially randomized to 
solanezumab in the placebo-controlled period with participants initially randomized to placebo in the 
double-blind treatment period, using randomized/delayed-start analysis of the Resource Use Inventory, 
Brief version (RUI-B). 
Diagnosis and Main Criteria for Inclusion and Exclusions:  Subjects will be males and females 65 to 85 years 
old with preclinical AD, defined as having an MMSE score between 25 and 30, a Logical Memory test, part IIa 
score between 6 and 18, and a global CDR of 0; and having screening florbetapir PET scan indicating brain 
amyloid pathology.  Subjects will be excluded if they have a screening MRI with results that show >4 ARIA-H or 
any ARIA-E, have any major or unstable illness, including unstable ischemic cardiovascular disease, or require use 
of excluded medications. 
Number of Planned Subjects:  Approximately 1150 (575 solanezumab, 575 placebo). 
Dose and Mode of Administration:  The study was initiated with solanezumab 400 mg or placebo, administered 
as an IV infusion once every 4 weeks.  Partway through the study, the dose was increased to 1600 mg every 
4 weeks.  Subjects will receive 400 mg solanezumab or placebo via IV infusion every 4 weeks for at least 2 doses, 
followed by 800 mg every 4 weeks for at least 2 doses, and then 1600 mg every 4 weeks until the conclusion of the 
study. 
Planned Duration of Treatment:   
Screening period:  Up to 90 days 
Placebo-controlled treatment period:  240 weeks 
Open-label treatment period:  Up to 204 weeks 
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Criteria for Evaluation:   
Efficacy:  PACC, MMSE, ADCS-ADL Prevention Questionnaire, CDR-SB, CFI, C3 (including the C-Path PRO 
and the Memory Complaint Questionnaire), and the RUI-B. 
Disclosure of Amyloid Status:  Perception of amyloid imaging as well as impact of disclosure will be assessed 
using the Views and Perceptions of Amyloid Imaging Questionnaire, the Concerns about Alzheimer’s Disease 
Questionnaire, the Impact of Events Scale, and the Future Time Perspective Scale. 
Biomarkers and Imaging:  Plasma solanezumab and Aβ isoforms concentrations and serum anti-solanezumab 
antibodies (immunogenicity) will be measured from processed blood samples using validated immunoassay and/or 
mass spectrometry methods.  Solanezumab treatment effects will be determined by measuring CSF Aβ isoforms 
and tau proteins in those subjects who undergo lumbar puncture and by analyzing amyloid burden on PET scans, as 
well as volumetric and functional MRI metrics. 
Pharmacokinetics:  Observed concentrations will be graphically compared to model predicted concentrations.  The 
impact of immunogenicity on pharmacokinetics (PK) will be investigated graphically.  Population PK and 
association with efficacy, biomarkers, and safety parameters may be reported. 
Safety:  Safety assessments will include routine physical and neurological examinations, AEs, vital signs 
(including temperature and weight), 12-lead electrocardiogram (ECG), and laboratory evaluations, including 
immunogenicity directed towards solanezumab.  In addition, the Assessment of Psychological Well Being will be 
used to monitor for anxiety and depression.  Suicide-related thoughts and behaviors will be evaluated using the 
Columbia Suicide Severity Rating Scale (C-SSRS).  Two types of amyloid-related imaging abnormalities 
(ARIA)—hemosiderin deposition (ARIA-H, also known as microhemorrhage) and edema/effusions (ARIA-E, also 
known as vasogenic edema) will also be assessed through scheduled MRIs. 
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Statistical Methods:   
General Considerations:  All analyses will follow the intent-to-treat (ITT) principle unless otherwise specified.  
When change from baseline is assessed, subjects will be included in the analysis only if both a baseline and a 
postbaseline measure are available (referred to as a modified ITT approach).  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 endpoint of this study, PACC, will be analyzed using an NCS analysis.   
The original modified intent-to-treat (mITT) analysis (that is, all participants as randomized to treatment who have 
a baseline and at least 1 postbaseline measure) for the primary outcome will be retained and conducted at the end 
of the treatment period, although the dose will be increased during the study; in other words, the primary analysis 
will include all data for the solanezumab group as the treatment group versus placebo.  As with the original 
analysis plan, the hypothesis for this analysis will be tested against an alpha level of .05. 
The change from baseline score at each visit when the composite score is assessed will be the dependent variable.  
Visit will be considered a categorical variable with values equal to the visit numbers at which the measure was 
scheduled.  The null hypothesis is that the treatment difference between the solanezumab group versus placebo at 
Week 240 equals zero. 
Secondary and Exploratory Endpoints:  Change from baseline will be assessed using NCS analyses for the MMSE, 
CFI, ADCS-ADL Prevention Questionnaire, CDR-SB, and C3.  Analysis will also be done on the RUI-B which 
will be used to assess health care resource utilization over the course of the study.  If a gatekeeping strategy is used 
for hypothesis testing involving a subset of efficacy endpoints, this strategy will be prespecified in the statistical 
analysis plan prior to database lock.  Additional subgroup analyses will be performed.  Imaging variables including 
PET amyloid imaging and volumetric and functional MRI will be analyzed using both region of interest methods 
and whole brain analyses.  Analyses of plasma Aβ and CSF biomarkers will be performed.  Additional sensitivity 
analyses will be performed to explore the effect of increasing the dose from 400 mg to 1600 mg partway through 
the study.  These sensitivity analyses will include analyses conducted on the PACC and other clinical measures 
after censoring all observations after the study-wide dose increase, and analyses to estimate the potential 
differences in the treatment effect for the original dose and the higher dose by modeling the effects of a time-
varying dose indicator variable. 
Randomized/Delayed-Start Analysis:  The PACC, MMSE, CDR-SB, C3, CFI, and the ADCS-ADL Prevention 
Questionnaire will be analyzed to investigate the long-term effect of anti-amyloid treatment on cognitive decline in 
preclinical AD.  If the primary A4 results in the placebo-controlled period are positive, disease-modifying effects 
will be assessed using a noninferiority hypothesis in an MMRM model, in which the specific hypothesis is that the 
advantage of solanezumab treatment demonstrated in the placebo-controlled period is sufficiently maintained in the 
open-label period.  This randomized/delayed-start analysis will assess whether solanezumab has a persistent effect 
on disease course. 
Safety:  Safety will be assessed by summarizing AEs, laboratory analytes, vital signs (including temperature and 
weight), ECGs, MRIs, C-SSRS, immunogenicity, and Assessment of Psychological Well Being results.  
Comparisons will be made between the treatment groups.  Safety analyses of the open-label extension will span 
across both the placebo-controlled study period and the open-label study period in order to be able to compare 
early-start safety risks to early-start efficacy benefits. 
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3. Table of Contents 
Anti-Amyloid Treatment in Asymptomatic Alzheimer’s 
Disease (A4 Study) 
Section 
Page 
1. 
Protocol Amendment Summary of Changes Table .................................................................2 
2. 
Synopsis ...................................................................................................................................5 
3. 
Table of Contents ..................................................................................................................10 
4. 
Abbreviations and Definitions ...............................................................................................15 
5. 
Introduction ...........................................................................................................................20 
6. 
Objectives ..............................................................................................................................24 
6.1. 
Primary Objective .............................................................................................................24 
6.2. 
Secondary Objectives .......................................................................................................24 
6.3. 
Exploratory Objectives .....................................................................................................25 
7. 
Investigational Plan ...............................................................................................................27 
7.1. 
Summary of Study Design................................................................................................27 
7.1.1. 
Prescreening .............................................................................................................27 
7.1.2. 
Screening Phase (Visits 1 to 5) ................................................................................27 
7.1.2.1. 
Initial Screening Visit (Visit 1) ..........................................................................28 
7.1.2.2. 
Screening Florbetapir PET Scan (Visit 2) ..........................................................28 
7.1.2.3. 
Amyloid Status Disclosure (Visit 3) ..................................................................29 
7.1.2.4. 
Screening MRI Scan (Visit 4) ............................................................................29 
7.1.2.5. 
Optional Lumbar Puncture (Visit 5) ...................................................................30 
7.1.3. 
Placebo-Controlled Period (Visits 6 to 66) ..............................................................30 
7.1.4. 
Dose Escalation ........................................................................................................30 
7.1.5. 
Open-Label Extension Period ..................................................................................31 
7.2. 
Discussion of Design and Control ....................................................................................31 
8. 
Study Population ...................................................................................................................34 
8.1. 
Inclusion Criteria ..............................................................................................................34 
8.2. 
Exclusion Criteria .............................................................................................................35 
8.2.1. 
Rationale for Exclusion of Certain Study Candidates .............................................37 
8.3. 
Inclusion and Exclusion Criteria:  Open-Label Extension Period....................................37 
8.4. 
Discontinuations ...............................................................................................................37 
8.4.1. 
Discontinuation of Subjects .....................................................................................37 
8.4.2. 
Discontinuation of Study Sites .................................................................................40 
8.4.3. 
Discontinuation of the Study ....................................................................................40 
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8.5. 
Recruitment and Retention Strategies ..............................................................................40 
9. 
Treatment ...............................................................................................................................41 
9.1. 
Treatments Administered .................................................................................................41 
9.2. 
Materials and Supplies .....................................................................................................42 
9.3. 
Method of Assignment to Treatment ................................................................................42 
9.4. 
Rationale for Selection of Doses in the Study ..................................................................42 
9.5. 
Administration and Timing of Doses ...............................................................................44 
9.6. 
Blinding ............................................................................................................................45 
9.7. 
Concomitant Therapy .......................................................................................................45 
9.8. 
Treatment Compliance .....................................................................................................46 
10. Outcome Measurements ........................................................................................................48 
10.1. Clinical Measures .............................................................................................................48 
10.1.1. 
Primary Efficacy Outcome Measure, Placebo-Controlled 
Period:  ADCS Preclinical Alzheimer Cognitive Composite ..................................48 
10.1.2. 
Secondary Efficacy Clinical Outcome Measures, 
Placebo-Controlled Period .......................................................................................49 
10.1.2.1. 
ADCS Activities of Daily Living – Prevention 
Questionnaire .....................................................................................................49 
10.1.2.2. 
Clinical Dementia Rating Scale .........................................................................49 
10.1.2.3. 
Cognitive Function Index ...................................................................................50 
10.1.2.4. 
Computerized Cognitive Composite ..................................................................50 
10.1.2.5. 
Resource Use Inventory—Brief Version ...........................................................50 
10.1.2.6. 
Views and Perceptions about Amyloid Imaging ................................................51 
10.1.2.7. 
Concerns about Alzheimer's Disease .................................................................51 
10.1.2.8. 
Impact of Events Scale .......................................................................................51 
10.1.2.9. 
Future Time Perspective Scale ...........................................................................51 
10.1.2.10. Research Satisfaction Survey .............................................................................51 
10.1.3. 
Biomarker Outcome Measures, Placebo-Controlled Period ....................................51 
10.1.3.1. 
Cerebrospinal Fluid (CSF) .................................................................................51 
10.1.3.2. 
Plasma Solanezumab ..........................................................................................52 
10.1.3.3. 
Genomic Samples ...............................................................................................53 
10.1.3.4. 
Samples for Biomarker Long-Term Storage ......................................................53 
10.1.3.5. 
Magnetic Resonance Imaging ............................................................................54 
10.1.3.6. 
Florbetapir PET Scan .........................................................................................54 
10.1.4. 
Secondary Efficacy Clinical Outcome Measures, Open-
Label Period .............................................................................................................54 
10.2. Safety Evaluations ............................................................................................................55 
10.2.1. 
Adverse Events ........................................................................................................55 
10.2.1.1. 
General Information ...........................................................................................55 
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10.2.1.2. 
Serious Adverse Events ......................................................................................56 
10.2.1.3. 
Suspected Unexpected Serious Adverse Reactions ...........................................57 
10.2.2. 
Columbia Suicide Severity Rating Scale .................................................................57 
10.2.3. 
Electrocardiograms ..................................................................................................57 
10.2.4. 
Immunogenicity .......................................................................................................58 
10.2.5. 
Neurological Examination .......................................................................................59 
10.2.6. 
Physical Examination ...............................................................................................59 
10.2.7. 
Safety Laboratory Samples ......................................................................................59 
10.2.8. 
Vital Signs ................................................................................................................59 
10.2.9. 
Subject Medical History/Family History/Concomitant 
Medications ..............................................................................................................59 
10.2.10. Assessment of Psychological Well-Being ...............................................................59 
10.2.11. Dose Escalation Safety Cohort ................................................................................60 
10.2.11.1. On-Site Post-Infusion Monitoring ......................................................................60 
10.2.11.2. Safety MRI .........................................................................................................60 
10.2.11.3. Electrocardiogram, Hematology, Chemistry, Urinalysis, 
and Vital Signs ...................................................................................................60 
10.2.11.4. PK/PD and Anti-Drug Antibody Assessment ....................................................60 
10.2.12. Safety Monitoring ....................................................................................................61 
10.2.13. Complaint Handling .................................................................................................61 
10.3. Appropriateness of Measurements ...................................................................................62 
11. Sample Size and Statistical Methods .....................................................................................64 
11.1. Determination of Sample Size ..........................................................................................64 
11.2. Statistical and Analytical Plans ........................................................................................64 
11.2.1. 
General Considerations ............................................................................................64 
11.2.2. 
Analysis Populations ................................................................................................65 
11.2.3. 
Handling of Missing Items for Scales ......................................................................65 
11.2.4. 
Subject Disposition ..................................................................................................65 
11.2.5. 
Subject Characteristics .............................................................................................65 
11.2.6. 
Prior and Concomitant Therapy ...............................................................................65 
11.2.7. 
Protocol Violations ..................................................................................................66 
11.2.8. 
Analysis of Primary Outcome (Placebo-Controlled Period) ....................................66 
11.2.9. 
Analysis of Secondary Outcomes (Placebo-Controlled 
Period) ......................................................................................................................66 
11.2.9.1. 
Clinical Outcomes ..............................................................................................66 
11.2.9.2. 
Sensitivity Analyses ...........................................................................................67 
11.2.9.3. 
Biomarker Outcomes ..........................................................................................68 
11.2.10. Open-Label Period ...................................................................................................68 
11.2.11. Gatekeeping Strategy ...............................................................................................69 
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11.2.12. Pharmacokinetic/Pharmacodynamic Analyses ........................................................69 
11.2.13. Safety Analyses ........................................................................................................70 
11.2.13.1. Study Drug Infusion ...........................................................................................70 
11.2.13.2. Adverse Events ...................................................................................................70 
11.2.13.3. Laboratory Analyses ..........................................................................................71 
11.2.13.4. Electrocardiograms .............................................................................................71 
11.2.13.5. Vital Signs ..........................................................................................................71 
11.2.13.6. Immunogenicity .................................................................................................71 
11.2.13.7. Amyloid-Related Imaging Abnormalities:  Magnetic 
Resonance Imaging ............................................................................................71 
11.2.13.8. Columbia Suicide Severity Rating Scale ...........................................................72 
11.2.14. Subgroup Analyses ..................................................................................................72 
11.2.15. Interim Analyses ......................................................................................................72 
12. Informed Consent, Ethical Review, and Regulatory Considerations ....................................73 
12.1. Informed Consent and HIPAA Compliance .....................................................................73 
12.1.1. 
Informed Consent .....................................................................................................73 
12.2. Ethical Review..................................................................................................................73 
12.3. Confidentiality ..................................................................................................................73 
12.4. Inclusion of Women and Minorities .................................................................................74 
12.5. Regulatory Considerations ...............................................................................................74 
12.6. Site Personnel Requirements ............................................................................................74 
12.6.1. 
Roles and Responsibilities .......................................................................................74 
12.6.2. 
Investigator/Rater Requirements ..............................................................................76 
12.7. Protocol Signatures ...........................................................................................................76 
12.8. Final Report Signature ......................................................................................................76 
12.9. Data and Safety Monitoring Board ...................................................................................76 
13. References .............................................................................................................................78 
 
 
 
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List of Tables, Figures, and Attachments 
Table 
Page 
Table A4.1. 
Treatment Regimens ..........................................................................................41 
 
 
Figure 
Page 
Figure A4.1. 
The continuum of Alzheimer’s disease versus normal aging. ...........................21 
Figure A4.2. 
A4 study design. ................................................................................................27 
Figure A4.3. 
MMRM estimates of change on the ADCS Preclinical Alzheimer 
Cognitive Composite, controlling for age, for stable and progressing 
subjects from the ADCS Prevention Instrument (PI) study. .............................96 
Figure A4.4. 
MMRM estimates of change on the ADNI data, using a similar 
Composite (RAVLT for list learning, LMIIa, Digit Symbol, and 
MMSE), controlling for age, comparing for stable NL subjects versus 
NL subjects who progressed to MCI in ADNI. .................................................97 
Figure A4.5. 
MMRM estimates of change on the ADCS Preclinical Alzheimer 
Cognitive Composite, controlling for age, from ADNI, AIBL, and the 
ADCS Prevention Instrument (PI) study. ..........................................................99 
Figure A4.6. 
Longitudinal change by Aβ status for the PACC and individual 
components tests in HABS participants.  Aβ-related decline is 
significant for the PACC4-96 (A) as well as on all individual 
components (B–G).  Z-scores are shown on the y-axis for all tests. ...............100 
 
Attachment 
Page 
Attachment 1. 
A4 Study Schedule ............................................................................................84 
Attachment 2. 
A4 Protocol Clinical Laboratory Tests ..............................................................93 
Attachment 3. 
Development of the PACC Measure .................................................................95 
 
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4. Abbreviations and Definitions 
Term 
Definition 
A4 
Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (study title) 
Aβ 
amyloid- peptide 
AchEI 
acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADCS 
Alzheimer’s Disease Cooperative Study 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study—Activities of Daily Living 
ADCS-PI 
Alzheimer’s Disease Cooperative Study—Prevention Instruments trial 
ADL 
activities of daily living 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
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. 
AIBL 
Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing 
ALT 
alanine aminotransferase 
APOE 
apolipoprotein E gene 
ARIA 
amyloid-related imaging abnormalities 
ARIA-E 
amyloid-related imaging abnormalities—edema/effusions, also known as vasogenic 
edema 
ARIA-H 
amyloid-related imaging abnormalities—hemosiderin deposition, also known as 
microhemorrhage 
AST 
aspartate aminotransferase 
ATRI 
Alzheimer’s Therapeutic Research Institute 
blinding 
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.  A double-blind study is one in which neither the subject nor any of the 
investigator or sponsor staff who are involved in the treatment or clinical evaluation of 
the subjects are aware of the treatment received. 
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C3 
Computerized Cognitive Composite 
CDI 
Clinician Diagnostic Impression 
CDR 
Clinical Dementia Rating 
CDR-G 
Clinical Dementia Rating—Global score 
CDR-SB 
Clinical Dementia Rating—Sum of Boxes score 
CFI 
Cognitive Function Index 
CI 
confidence interval 
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. 
Compliance 
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
Confirmation 
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Lilly is confident that results are 
accurate.  Confirmation will either occur immediately after initial testing or will require 
that samples be held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results. 
C-Path PRO 
C-Path Consortium’s Participant-Reported Outcome Questionnaire 
CRF/eCRF 
case report form/electronic case report form:  Sometimes referred to as clinical report 
form:  A printed or electronic form for recording study participants’ data during a 
clinical study, as required by the protocol. 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
efficacy 
Efficacy is the ability of a treatment to achieve a beneficial intended result under 
controlled conditions. 
EOS 
End of trial (study):  End of study is the date of the last visit or last scheduled procedure 
shown in the Study Schedule for the last subject.  
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Enroll 
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are 
those who have been assigned to a treatment. 
Enter 
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERB/IRB 
ethical review board/institutional review board:  A board or committee (institutional, 
regional, or national) composed of medical and nonmedical members whose 
responsibility is to verify that the safety, welfare, and human rights of the subjects 
participating in a clinical study are protected. 
FCSRT 
Free and Cued Selective Reminding Test 
FDA 
United States Food and Drug Administration 
GCP 
good clinical practice 
HABS 
Harvard Aging Brain Study 
hCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IES 
Impact of Events Scale 
IgG 
immunoglobulin G-1 
IND 
Investigational New Drug application 
informed consent 
A process by which a subject voluntarily confirms his or her willingness to participate in 
a particular trial, after having been informed of all aspects of the trial that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.   
Interim analysis 
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 
investigator 
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator. 
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ITT 
intent to treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a subject (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
subjects 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. 
IWRS 
interactive web response system 
LMIIa 
Logical Memory test, part IIa 
LP 
lumbar puncture 
LS 
least squares 
MAC-Q 
Memory Complaint Questionnaire 
MCI 
mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NIA 
National Institute on Aging 
NCS 
natural cubic spline 
PACC 
Preclinical Alzheimer’s Cognitive Composite 
PET 
positron emission tomography 
PHI 
protected health information 
PK/PD 
pharmacokinetics/pharmacodynamics 
P-tau 
phosphorylated tau 
QTcB 
QT interval corrected using Bazett’s formula 
randomize 
The process of assigning subjects to an experimental group on a random basis. 
Re-screen 
To screen a subject who was previously declared a screen failure for the same study. 
RUI 
Resource Use Inventory 
RUI-B 
Resource Use Inventory, Brief version 
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.  In this study, screening 
involves diagnostic psychological tests, urine and blood sampling, MRI, PET amyloid 
imaging, ECG, and an optional lumbar puncture. 
SSR 
sample size re-estimation 
subject 
An individual who is or becomes a participant in clinical research, either as a recipient of 
the investigational product(s) or as a control.  A subject may be either a healthy human 
or a patient. 
SUSARs 
suspected unexpected serious adverse reactions 
SUVr 
standardized uptake value ratio 
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. 
ULN 
upper limit of normal 
vMRI 
volumetric magnetic resonance imaging 
WAIS-R 
Wechsler Adult Intelligence Scale-Revised 
 
 
 
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Anti-Amyloid Treatment in Asymptomatic Alzheimer’s 
Disease (A4 Study) 
5. Introduction 
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by a 
progressive decline in cognitive function and the ability to perform activities of daily living.  
Converging evidence suggests that the pathophysiological process of AD begins more than a 
decade before the clinical stage now recognized as AD dementia (Sperling et al. 2011a; Bateman 
et al. 2012; Villemagne et al. 2013).  Even by the stage of mild cognitive impairment 
(MCI)/prodromal AD, the neurodegeneration of AD is thought to be well established (Gόmez-
Isla et al. 1996; Jack et al. 2010).  Clinical trial results in mild-to-moderate AD dementia, as well 
as evidence from transgenic animal experiments, suggest that earlier intervention may be needed 
to slow the progression of the clinical course of AD, particularly with therapies designed to 
decrease amyloid- (Aβ) (Sperling et al. 2011b).  Academic consensus workgroups focused on 
developing guidelines for earlier diagnosis of AD and research diagnostic criteria have defined a 
stage of preclinical AD, based on biomarker evidence of AD pathology, before the stage of 
clinically evident cognitive impairment (Dubois et al. 2010; Sperling et al. 2011a).  Recent 
evidence suggests that older individuals with biomarker evidence of brain amyloid accumulation 
demonstrate structural and functional imaging abnormalities consistent with those seen in AD 
dementia (Hedden et al. 2009; Sperling et al. 2009; Schott et al. 2010; Chételat et al. 2012; 
Andrews et al. 2013).  Individuals with evidence of elevated brain amyloid (amyloid-positive) 
perform less well on cognitive tests compared to those without evidence of brain amyloid 
accumulation (amyloid-negative) and are at increased risk for cognitive decline and progression 
to MCI and AD (Morris et al. 2009; Rentz et al. 2010; Knopman et al. 2012; Lim et al. 2012a, 
2012b, 2013; Ellis et al. 2013; Sperling et al. 2013; Vos et al. 2013; Petersen et al. 2016; 
Donohue et al. 2017; Mormino et al. 2017). 
Alzheimer’s disease has evolved to become conceptualized as a continuum of disease 
(Figure A4.1).  The preclinical stage of AD is postulated to begin with an asymptomatic stage of 
accumulating brain pathology followed by very subtle cognitive decline, which can be detected 
with sensitive neuropsychological tests and cognitive complaint measures (Sperling et al. 2011a). 
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Abbreviation:  MCI = mild cognitive impairment. 
Figure A4.1. 
The continuum of Alzheimer’s disease versus normal aging. 
 
Individuals in the preclinical stage of AD have evidence of amyloid pathology and often early 
signs of neurodegeneration (elevated cerebrospinal fluid [CSF] tau, mild cortical thinning) but do 
not yet have widespread, irreversible neuronal loss.  This preclinical stage of AD may precede 
MCI by several years and represents an important stage for potential early intervention aimed at 
slowing the pathophysiological process and delaying the appearance of readily appreciated 
clinical manifestations of AD. 
In this context, a study in preclinical AD titled Anti-Amyloid Treatment in Asymptomatic AD 
(the “A4” study) was designed and initiated by a collaboration between the Alzheimer Disease 
Cooperative Study (ADCS) and Lilly.  This large, multicenter, placebo-controlled study with an 
approximately 4.5-year treatment duration is now enrolling older individuals with evidence of 
brain amyloid pathology who are still clinically normal but performing in the lower end of the 
clinically normal range on memory measures and are at particularly high risk for cognitive 
decline.  Partway through the study, the study management activities of the ADCS were shifted 
to the Alzheimer’s Therapeutic Research Institute (ATRI), which serves as the Coordinating 
Center.  Some aspects of the study will involve continued collaboration between the ADCS, 
ATRI, and Lilly. 
Before initiation of the A4 study, the ADCS independently evaluated several investigational anti-
Aβ antibodies as candidates for the study, and ultimately chose solanezumab based on its safety 
profile and cognitive effects in mild AD observed in the Phase 3 studies.  The A4 study is funded 
by Lilly, the National Institutes of Health, and multiple philanthropic organizations.  The A4 
study is being conducted under Lilly’s IND 11,631 for solanezumab (FDA correspondence, 
19 March 2013); thus Lilly is the regulatory sponsor.  The overall goal of the study is to test the 
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hypothesis that targeting Aβ in the preclinical stage of AD will slow the pathophysiological 
process and cognitive decline in the preclinical stages of AD, thus affecting the clinical course of 
the disease. 
Solanezumab is a humanized anti-Aβ peptide immunoglobulin G-1 (IgG) monoclonal antibody.  
The murine anti-Aβ monoclonal antibody from which solanezumab was derived is known as 
m266.2.  These antibodies recognize a mid-domain epitope of the Aβ peptide (amino acid 
residues 16-25).  Solanezumab was designed with the intent to increase central nervous system 
clearance of Aβ, slow or reverse Aβ deposition in brain parenchyma, and with chronic treatment, 
potentially slow the progression of AD. 
The clinical development program for solanezumab includes the completed Phase 3 Studies 
H8A-MC-LZAM (LZAM) and H8A-MC-LZAN (LZAN), also known as EXPEDITION and 
EXPEDITION2, respectively, which compared 400 mg of solanezumab intravenously every 
4 weeks (400 mg Q4W) and placebo treatments for 18 months in subjects with mild-to-moderate 
AD, as well as the concluded Phase 3 open-label extension Study H8A-MC-LZAO (LZAO) in 
which all subjects are treated with solanezumab.  Although primary objectives were not met in 
either Study LZAM or LZAN, prespecified secondary analyses strongly suggested cognitive 
effects in the mild AD population using pooled data from the 2 studies. 
Based on these Phase 3 results and discussions with FDA, an additional Phase 3 study of 
solanezumab 400 mg Q4W in patients with mild AD and evidence of amyloid pathology, Study 
H8A-MC-LZAX (LZAX), was conducted.  The primary endpoint was not met in the concluded 
placebo-controlled period of Study LZAX.  Subjects treated with solanezumab 400 mg Q4W did 
not experience a statistically significant slowing in cognitive decline compared with subjects 
treated with placebo (p=.095), as measured by the 14-item Alzheimer’s Disease Assessment 
Scale-Cognitive subscale (ADAS-Cog14).  The study results directionally favored solanezumab, 
but the magnitude of the treatment difference was small.  Several secondary analyses, including 
the Clinical Dementia Rating—Sum of Boxes score (CDR-SB), ADCS-iADL, and Mini-Mental 
State Examination (MMSE), showed small, nominally statistically significant benefits of 
solanezumab. 
To date, no safety issues have been identified that would create an unfavorable benefit-risk 
balance for solanezumab.  Few differences in the incidence of deaths, serious adverse events 
(SAEs), discontinuations due to adverse events (AEs), treatment-emergent adverse events 
(TEAEs), laboratory values, electrocardiograms (ECGs), treatment-emergent immunogenicity, 
treatment-emergent changes in amyloid-related imaging abnormalities (ARIA), and infusion 
reactions were observed between placebo- and solanezumab-treated subjects in the Phase 3 
studies.  In Studies LZAM and LZAN, a potential safety signal was identified for a 
heterogeneous set of cardiac-related events that included atrial fibrillation, bradycardia, and 
angina pectoris, reported in more than 1% but less than 2% of patients.  The cardiac safety signal 
was not confirmed in Study LZAX and therefore is no longer considered a potential risk with 
solanezumab treatment.  As measured by the Columbia Suicide Severity Rating Scale (C-SSRS), 
suicidal ideation and behaviors were infrequent, but a greater prevalence was observed among 
solanezumab- compared with placebo-treated mild AD dementia patients in Study LZAX.  This 
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safety signal has not been observed in other solanezumab studies.  At this time, it cannot be 
determined whether the imbalance observed in Study LZAX is causally related to solanezumab 
treatment.  This safety signal will continue to be assessed in the ongoing A4 study.  More details 
are available in the Investigator’s Brochure (IB). 
As described in the IB, 2 types of ARIA—hemosiderin deposition (ARIA-H, also known as 
cerebral microhemorrhage) and edema/effusions (ARIA-E, also known as vasogenic edema) and 
serious hypersensitivity reactions (immediate and nonimmediate) including anaphylaxis and 
infusion-related reactions—have been identified as potential risks for Aβ-based AD therapies.  
Magnetic resonance imaging (MRI) scans and AEs will be obtained in this study to assess these 
potential risks. 
Study H8A-MC-LZAZ (LZAZ), or the A4 study (“Anti-Amyloid Treatment in Asymptomatic 
AD”), will test the hypothesis that treatment with solanezumab administered as an intravenous 
(IV) infusion every 4 weeks will slow cognitive decline in preclinical AD as compared with 
placebo.  This study will include the use of biomarkers to assess the impact of treatment with 
solanezumab on biomarkers of AD pathology.  The A4 Study was initially designed with a dose 
of 400 mg solanezumab given by IV infusion every 4 weeks over a period of approximately 
3 years.  Based on the new efficacy and safety results from Study LZAX described above, as 
well as safety and biomarker results with higher doses of solanezumab in Phase 1 and 2 studies, 
the solanezumab dose in the A4 Study was escalated to 1600 mg Q4W (Section 9.4).  In 
addition, the duration of treatment was increased to approximately 4.5 years, based on new 
information regarding the rate of amyloid-related decline among clinically normal older 
individuals over time from ongoing observational studies (Section 7.2). 
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
of solanezumab may be found in the IB.  Information on AEs expected to be related to the 
investigational product may be found in Section 7 (Development Core Safety Information) of the 
IB.  Information on SAEs expected in the study population independent of drug exposure will be 
assessed in aggregate, periodically during the course of the study, may be found in Section 6 
(Effects in Humans) of the IB. 
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6. Objectives 
6.1. Primary Objective 
The primary objective of this study is to test the hypothesis that solanezumab, administered as an 
IV infusion every 4 weeks for 4.5 years, will slow cognitive decline as compared with placebo in 
subjects with preclinical AD. The primary objective will be assessed using a constrained 
longitudinal data analysis (cLDA) natural cubic spline (NCS) analysis (referred to as NCS 
henceforth) of the primary outcome measure, the Preclinical Alzheimer Cognitive Composite 
(PACC), a composite that is primarily weighted on episodic memory and executive function 
tests, in which the specific hypothesis is that the cognitive decline at Week 240 will be 
significantly less for solanezumab than for placebo. 
6.2. Secondary Objectives 
The secondary objectives of the placebo-controlled period of the study are as follows: 
 To test the hypothesis that solanezumab will slow the decline of perceived 
cognitive function and performance of everyday activities, as compared with 
placebo, using an NCS analysis of the Cognitive Function Index (CFI). 
 To assess whether decline in activities of daily living begins by the end of the 
treatment period, and if so, whether an effect of solanezumab, compared with 
placebo, can be detected using an NCS analysis of the ADCS-Activities of 
Daily Living (ADL) Prevention Questionnaire. 
 To assess the relationship between treatment effect and time using the PACC. 
 To test the hypothesis that solanezumab reduces brain amyloid burden, as 
compared with placebo, as assessed using florbetapir positron emission 
tomography (PET) imaging. 
 To assess effects of solanezumab on CSF and plasma concentrations of total 
tau peptides and phosphorylated tau peptides (P-tau). 
 To assess effects of solanezumab on CSF concentrations of Aβ. 
 To investigate the effect of treatment with solanezumab on volumetric MRI. 
 To assess the safety of solanezumab versus placebo treatment, including AEs 
and immunogenicity. 
The secondary objectives of the open-label period of the study are as follows: 
 To assess the persistence of effect of solanezumab treatment in participants 
with preclinical AD.  That is, to test the hypothesis that patients originally 
randomized to receive placebo and later switched to solanezumab at the start 
of the open-label period do not “catch up” to patients originally randomized to 
receive solanezumab in the placebo-controlled period, using a 
randomized/delayed-start analysis.  The main efficacy objective of the 
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open-label period will be an interim randomized/delayed-start analysis of the 
PACC. 
 To test the hypothesis that solanezumab will continue to slow the decline 
associated with preclinical AD during open-label treatment, comparing 
participants initially randomized to solanezumab with participants initially 
randomized to placebo in the double-blind treatment period, using 
randomized/delayed-start analysis of the MMSE, CDR-SB, C3, CFI, and the 
ADCS-ADL Prevention Questionnaire. 
6.3. Exploratory Objectives 
The exploratory objectives of the study are follows: 
 To assess the effect of treatment with solanezumab as demonstrated using the 
MMSE. 
 To assess the utility of a novel computerized battery, the Computerized 
Cognitive Composite (C3), in predicting and tracking clinical decline and 
response to solanezumab. 
 To assess the effects of treatment on healthcare resource utilization. 
 To determine the best predictors of clinical decline based on the PACC. 
 To develop novel sensitive outcome measures to improve the efficiency of 
future secondary prevention trials, including exploratory measures of 
self-reported assessment of cognitive and interpersonal functioning. 
 To assess the effect of treatment with solanezumab as demonstrated using the 
Clinical Dementia Rating (CDR) scale. 
 To assess the effect of treatment with solanezumab as demonstrated using the 
C-Path Consortium’s Participant-Reported Outcome Questionnaire (C-Path 
PRO). 
 To investigate the impact of solanezumab on markers of synaptic dysfunction 
on functional connectivity MRI. 
 To assess solanezumab-associated changes in levels of plasma Aβ species and 
CSF Aβ species.  The hypothesis that solanezumab, unlike placebo, alters 
amyloid-plaque associated forms of Aβ will be assessed by 1) demonstrating 
presence of plaque-associated Aβ species in the plasma, and 2) confirming 
that concentrations of CSF free (unbound to antibody) Aβ1-42 are increased or 
unchanged and CSF free Aβ1-40 levels are decreased with solanezumab 
treatment. 
 To explore whether baseline markers of neurodegeneration (volumetric MRI 
or CSF tau or p-tau) are related to cognitive decline and response to treatment 
with solanezumab. 
 To explore the impact of disclosure of amyloid status on questionnaires 
probing perception of amyloid imaging and concern about developing AD. 
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 To explore biomarker assessments collected at baseline and at the end of the 
placebo-controlled period as potential predictors of treatment effect during the 
open-label period. 
 To assess preclinical AD during open-label treatment by comparing 
participants initially randomized to solanezumab in the placebo-controlled 
period with participants initially randomized to placebo in the double-blind 
treatment period, using randomized/delayed-start analysis of the RUI-B. 
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7. Investigational Plan 
7.1. Summary of Study Design 
The A4 Study is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study 
comparing solanezumab with placebo for 240 weeks in approximately 1150 subjects ages 65 to 
85 years old with preclinical AD, defined as having evidence of brain amyloid pathology without 
clinically evident cognitive impairment at screening.  Subjects who meet entry criteria will be 
randomized in a 1:1 ratio (approximately 575 per treatment arm) to solanezumab or placebo once 
every 4 weeks.  Subjects will be randomized at the site by education – high (13 or more years) or 
low (12 or less years) and the presence of one or more apolipoprotein E gene (APOE) 4 alleles 
(yes, no).  The primary hypothesis being tested is that the cognitive decline at the end of the 
treatment phase will be significantly less for solanezumab than for placebo.  Subjects completing 
the placebo-controlled period of the study can opt to participate in the open-label period of the 
study that will last for up to 204 weeks or until the primary analyses of the placebo-controlled 
period of the study are completed and reviewed. 
Figure A4.2 illustrates the study design.  The Study Schedule (Attachment 1) details procedures 
and tests occurring at specific times during the study. 
 
 
Abbreviation:  V=visit. 
Figure A4.2. 
A4 study design. 
 
7.1.1. Prescreening 
During the prescreen phase, potential subjects will be identified and assessed to determine if they 
may potentially qualify for the A4 study following the site’s standard practice. 
7.1.2. Screening Phase (Visits 1 to 5) 
The entire screening period spans the time from Visit 1 to Visit 5.  Study assessments are shown 
in the Study Schedule (Attachment 1). 
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Up to 90 days are permitted to allow for completion of all screening procedures, assessments, Aβ 
status disclosure, and evaluation of results from laboratory tests, ECGs, PET imaging, MRI, and 
optional lumbar puncture (LP).  A central read of the MRI should be completed before an LP is 
performed.   
The subject can only proceed to baseline (Visit 6) once all screening procedures as described in 
the Study Schedule (Attachment 1) are completed and the investigator or qualified designee and 
clinical monitor have confirmed that the subject is eligible to be randomized. 
Current or planned use of concomitant medications, the effects of vacations or absences on 
protocol compliance, and general compliance with the protocol will be discussed during the 
screening phase.  Subjects who do not meet all inclusion criteria or who meet any exclusion 
criteria will not be allowed to participate in the study. 
7.1.2.1. Initial Screening Visit (Visit 1) 
At or before the first screening visit (Visit 1), the full A4 study will be explained to the subject 
and study partner.  Informed consent and Health Insurance Portability and Accountability Act of 
1996 (HIPAA) authorization must be obtained from the subject before any study procedures are 
conducted. 
All subjects will be educated about amyloid imaging as part of the recruitment and informed 
consent process.  The Columbia Suicide Severity Rating Scale (C-SSRS) and psychological 
well-being questionnaires will be administered.  This information will be used to help the 
clinician determine whether or not a subject is psychologically able to participate further in the 
study and to provide a pretest baseline for predisclosure comparison on these measures.  
Additionally, questionnaires to explore subjects’ views and perceptions of amyloid imaging, 
concerns about AD, and perception of time will be administered. 
During the initial screening visit (Visit 1), the MMSE, Logical Memory test part IIa (LMIIa), and 
CDR will be administered in order to determine the subject’s general eligibility for the study.  
Safety measures will be collected to further ensure the subject meets eligibility criteria:  medical 
history/concurrent medications are reviewed, and physical/neurological exam, ECGs, and vital 
signs will be collected.  A blood draw and urinalysis for screening labs, genotyping, and 
biomarker samples will be performed.  Screening labs results must be reviewed by the 
investigator or qualified designee for assessment of the subject’s eligibility. 
For a complete list of all Visit 1 procedures, please refer to the Study Schedule (Attachment 1).  
Procedures for Visit 1 may be completed over multiple days but all Visit 1 procedures must be 
completed before the subject can proceed to the screening florbetapir PET scan (Visit 2). 
7.1.2.2. Screening Florbetapir PET Scan (Visit 2) 
A florbetapir PET scan will be performed for eligibility purposes during the screening phase.  In 
order to best identify a population that is at risk of decline, a centralized PET lab will be used to 
determine eligibility for the study based on both visual and quantitative metrics for elevated 
amyloid burden. 
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Information regarding study eligibility for each subject will be conveyed to the site principal 
investigator.  All subjects will be scheduled for an in-clinic visit to disclose the florbetapir PET 
scan results (Section 7.1.2.3). 
Specific instructions for the florbetapir PET scan will be provided in the Technical Operations 
Manual. 
7.1.2.3. Amyloid Status Disclosure (Visit 3) 
The C3 and C-Path PRO will be administered at this visit prior to disclosure.  The C3 will be 
optional in Japan. 
All subjects that undergo a florbetapir PET scan will have their results disclosed during an 
in-clinic visit with a clinical investigator approved for this role by the Coordinating Center.  
Study partner attendance is not required, but may be permitted if the subject desires.  Each 
subject’s concern about developing AD and his/her views and perceptions of amyloid imaging, 
as well as perception of time, will be assessed via questionnaires after the disclosure. 
Lastly, the Impact of Events Scale (IES) will be administered over the phone within 3 business 
days following the amyloid status disclosure visit. 
For a complete list of all Visit 3 procedures, please refer to the Study Schedule (Attachment 1). 
Subjects who meet florbetapir PET entry criteria will proceed to the next visit per the study 
schedule. 
7.1.2.4. Screening MRI Scan (Visit 4) 
All subjects who have elevated amyloid as determined by the screening florbetapir PET scan and 
wish to, and are eligible to continue in the study after the amyloid eligibility disclosure visit will 
proceed to the MRI visit. 
There are core magnetic resonance sequences required for all subjects to determine eligibility for 
the study and to acquire baseline volumetric and functional data for subsequent comparison.  
There are additional magnetic resonance sequences that will be acquired depending on scanner 
type. 
Sites must submit the MRI scan without patient identifiable information to the Coordinating 
Center in a timely fashion (preferably within 24 hours) after acquisition to facilitate central read. 
A central read will be conducted to assist in determining eligibility for the study on the basis of 
MRI findings, particularly the presence of microhemorrhages.  In instances where more than 
4 microhemorrhages or any ARIA-E are identified, the scan will be flagged for review and the 
subject will be deemed ineligible for the study.  Other findings that are flagged during the central 
read will be reviewed by the Project Director and Medical Monitors or designees to determine if 
the subject is eligible to continue.  For patients with mild to moderate AD, the presence of 
ARIA-E at baseline is extremely uncommon (<0.5%, Carlson et al. 2011); thus, in subjects with 
preclinical AD, the rate of ARIA-E at baseline is likely to be even less prevalent. 
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Eligible subjects will proceed to Visit 5 if they consented to the optional LP, otherwise they will 
proceed to baseline (Visit 6). 
For a complete list of all Visit 4 procedures, please refer to the Study Schedule (Attachment 1). 
Specific instructions for the screening MRI scan will be provided in the relevant procedures 
manual. 
7.1.2.5. Optional Lumbar Puncture (Visit 5) 
The optional LP study is available only in the US, Canada, and Japan.  Subjects who consent to 
the optional LP will have an LP performed at Visit 5.  Magnetic resonance imaging, and central 
read of the MRI, should occur prior to LP. 
Failure to perform an LP or obtain CSF will not constitute a protocol violation. 
Specific instructions for the LP will be provided in the relevant procedures manual. 
7.1.3. Placebo-Controlled Period (Visits 6 to 66) 
The placebo-controlled period is a double-blind treatment phase beginning at baseline (Visit 6).  
Subjects who meet entry criteria will be enrolled and randomized to receive either solanezumab 
or placebo once every 4 weeks administered on site as an IV infusion.  Subjects should be 
observed for approximately 1 hour following the first infusion of study drug.  Infusions will be 
administered and assessments will be performed according to the Study Schedule (Attachment 
1).  Procedures for some visits may take more than 1 day.  At the following visits (known as 
“infusion-only” visits), the only scheduled procedures are administration of the infusion and 
collection of AEs and concomitant medications:  Visits 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 
23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, 41, 43, 44, 46, 47, 49, 40, 52, 53, 55, 56, 58, 59, 61, 
62, 64, and 65. 
All visits (in-clinic and infusions) after randomization (Visit 6) should be scheduled to occur as 
close as possible to the target date, relative to baseline Day 1.  A window of ±10 days will be 
permitted for all visits. 
Final assessments in the placebo-controlled period will be performed at Visit 66 (Week 240), 
4 weeks following the subject’s last dose of study medication (Week 236) in the 
placebo-controlled period. 
7.1.4. Dose Escalation 
All subjects will be escalated to a dose of 1600 mg Q4W according to amendment (d).  After at 
least 2 infusions of 400 mg Q4W, subjects will be escalated to 800 mg Q4W for at least 
2 infusions, and then 1600 mg Q4W until the conclusion of the treatment (Section 9.1). 
At a minimum, the first 200 subjects (approximately 100 each in the solanezumab and placebo 
treatment groups) who receive the increased dose will be included in a dose escalation safety 
cohort to receive additional safety assessments and monitoring (described in Section 10.2.11) 
during dose escalation to monitor the safety of the higher doses. 
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Subjects who escalate dose after entry in the dose escalation safety cohort has been closed will 
receive safety monitoring as described in the main Study Schedule. 
All subjects who are active in the study should be escalated to a dose of 1600 mg Q4W as 
described above.  Subjects may be permitted to delay dose escalation at the investigator’s 
discretion; this will not be considered a protocol deviation. 
Additional site training will be provided to ensure appropriate implementation of the protocol 
modifications. 
7.1.5. Open-Label Extension Period 
Subjects who complete the placebo-controlled period will be eligible to participate in the open-
label extension period.  Subjects participating in the open-label period will receive open-label 
solanezumab treatment for varying durations.  While all subjects will receive solanezumab 
treatment during the open-label period, subjects, site personnel, and study teams will remain 
blinded to initial treatment assignment in the placebo-controlled period until the conclusion of 
the study. 
The open-label period uses a common close design such that all subjects will complete the period 
at the same time:  when analyses of the placebo-controlled period are completed and reviewed.  
Given the common close design, the overall duration of treatment for each patient will differ.  If 
the study is positive, participants may be offered the opportunity to continue in the open-label 
period beyond the common close.  Subjects who opt to participate in the open-label period 
should begin the open-label period at Visit 66 (Week 240) after completion of all Visit 66 tests 
and procedures.  However, subjects may enter the open-label period of the study and receive 
their first open-label infusion of study drug up to 12 weeks following completion of the 
placebo-controlled period Visit 66 assessments and procedures.  In extenuating circumstances, 
subjects may enter the open-label period after 12 weeks with the approval of a Medical Monitor 
and/or Project Director.  See the Study Schedule (Attachment 1) for the timing of events and 
measures to be assessed.  Procedures for some visits may take more than 1 day. 
Subjects who choose not to participate in the open-label period will not receive any study 
medication after the last infusion visit for the placebo-controlled period (Week 236).  Sites must 
obtain approval from the Coordinating Center before engaging in open-label activities. 
If the open-label period is extended beyond Visit 117, participants who complete Visit 117 
before implementation of the protocol amendment that includes additional visits will be allowed 
to resume study visits once available at their site.  
7.2. Discussion of Design and Control 
Study Population.  As AD is thought to represent a continuum of disease, discrete stages of AD 
will of necessity need to be operationally defined.  Entry criteria were chosen to maximize 
selection of individuals who are still considered clinically normal but who may be at high risk of 
subsequent cognitive decline and the eventual onset of clinical signs and symptoms diagnostic of 
prodromal or mild AD.  Cut-points for screening memory tests will exclude individuals who are 
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performing >0.5 standard deviation (SD) above age- and education-adjusted normative means, as 
these individuals may be better able to compensate for imminent cognitive decline over the 
course of the study.  Instead, the study will enroll people who have memory performance down 
to 1.0 SD below education-adjusted normative means, which overlaps the cognitive performance 
range of early MCI without meeting the definition for MCI (since CDR must be 0).  Recent 
evidence suggests that people with evidence of amyloid pathology are more likely to perform in 
the bottom of the “normal range” on sensitive neuropsychological tests and have a higher risk of 
cognitive decline and progression to MCI and AD dementia (Doraiswamy et al. 2012; Knopman 
et al. 2012; Sperling et al. 2013; Villemagne et al. 2013).  Furthermore, subjects are required to 
be ages 65 to 85 at the time of screening, to maximize the likelihood of identifying subjects that 
will meet the preclinical AD amyloid pathology inclusion criteria, as research in the field 
suggests that incidence/prevalence of amyloid pathology is highest in this group compared to 
those under age 65.  Measures will be in place to ensure sufficient enrollment of individuals at 
the higher end of this age range and to enroll under-represented minority populations. 
Selection of Primary Outcome Measure.  The PACC composite measure, which comprises the 
Total Recall score from the Free and Cued Selective Reminding Test (FCSRT), the Delayed 
Paragraph Recall score on the Logical Memory IIa test from the Wechsler Memory Scale, the 
Digit-Symbol Substitution test from the Wechsler Adult Intelligence Scale-Revised, and the 
MMSE total score, was developed to be sensitive to change in preclinical AD, based on evidence 
that episodic memory, executive function, and orientation are domains that show change early in 
the course of disease.  Several combinations of measures for these domains derived from well-
accepted clinical outcome measures were assessed using data from longitudinal studies in 
clinically normal populations, comparing patients who declined from normal to MCI to those 
who remained normal.  The combination of measures that showed the greatest power was one 
that included episodic memory, timed executive function, and global measures (including 
orientation) and this combination became the PACC (see Attachment 3 for more details). 
Study Duration.  Based on evidence from longitudinal studies available when Study LZAZ/A4 
was initially designed, a duration of 168 weeks (approximately 3 years) was thought to be 
appropriate to evaluate the efficacy of solanezumab compared with placebo in slowing 
progression of preclinical AD.  However, new data regarding the amount of decline over time in 
the preclinical AD population became available from observational studies during the conduct of 
the A4 study, suggesting that extending the treatment duration may increase the likelihood of 
observing a treatment effect.  For example, data from ongoing observational studies, such as the 
Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Australian Imaging, Biomarker and 
Lifestyle (AIBL) study, and the Harvard Aging Brain Study (HABS) suggest that 
amyloid-related decline among clinically normal older individuals accelerates between 3 and 6 
years of observation (Lim et al. 2016; Donohue et al. 2017; Mormino et al. 2017; Papp et al. 
2017).  Differences in decline, as measured by the PACC, the primary outcome measure in the 
A4 study, between Aβ-negative and Aβ-positive clinically normal individuals increase over time, 
with the greatest increases at the 4- and 5-year time points (Section 11.1).  Therefore, the A4 
study duration was increased to 240 weeks (approximately 4.5 years). 
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Open-Label Period.  An open-label period was added to the A4 study to determine whether 
effects of solanezumab observed at the end of the placebo-controlled period, in participants 
originally assigned to solanezumab (early start), are maintained over a longer period of time, in 
comparison to the participants originally assigned to placebo who start during the open-label 
extension period (delayed start).  If such maintenance is observed, that will indicate a persistent 
effect on disease course that is not observed when starting treatment later.  Specifically, it is 
hypothesized that the early-start group will show attenuated cognitive decline compared to 
delayed start, and that the delayed-start group will not “catch-up” to the early-start group that 
was continually treated with solanezumab, consistent with disease modification.  Secondary 
analyses to determine long-term effects of solanezumab on clinically meaningful functional 
outcomes will be investigated.  In addition, the influence of pathophysiologic disease stage, as 
assessed by biomarkers, on treatment response, will be explored in the open-label period.  The 
open-label period will extend up to 204 weeks, until the primary efficacy analyses from the 
placebo-controlled period are completed. 
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8. Study Population 
The population for this study can be characterized as at-risk clinically normal individuals with 
preclinical AD based on evidence of brain amyloid pathology and cognitive performance in the 
lower range of education-adjusted norms, which in combination puts these individuals at a high 
risk for decline. 
Eligible subjects will be males and females with preclinical AD, as specified in the entry criteria 
that follow.  Individuals who fail screening due to ineligible results on the amyloid PET scan 
may not be re-screened.   One re-screen may be permitted if subject fails screening for some 
other reason.  
Subjects who meet all of the inclusion criteria and are not excluded by any of the exclusion 
criteria are considered eligible.  Subjects with subjective memory complaint are permitted to 
enter as long as they receive a global CDR score of 0. 
Study participants should be instructed not to donate bodily fluids during the study or for 
12 weeks after receiving the last dose of study medication. 
Prospective approval of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions are not permitted. 
8.1. Inclusion Criteria 
A subject is eligible to be included in the study only if he or she meets all of the following 
criteria: 
[1] Male or female ages 65 to 85 years old. 
[2] Has an MMSE score at screening of 25 to 30. 
[3] Has a global CDR score at screening of 0. 
[4] Has a Logical Memory II score at screening of 6 to 18. 
[5] Has a florbetapir PET scan that shows evidence of brain amyloid pathology at 
Visit 2. 
[6] In general, permitted medications should be stable for 6 weeks prior to 
baseline (Visit 6).  Changes to medications that, in the opinion of the 
investigator, are not likely to impact baseline visit assessments are 
permissible. 
[7] Has a study partner that is willing to participate as a source of information and 
has at least weekly contact with the subject (contact can be in-person, via 
telephone or electronic communication).  The study partner must have 
sufficient contact such that the investigator feels the study partner can provide 
meaningful information about the subject’s daily function. 
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[8] In the investigator’s opinion, is both willing and able to participate in all 
required procedures for the duration of the study (at least 240 weeks), 
including adequate literacy in English, Spanish, or Japanese, and adequate 
vision and hearing to complete the required psychometric tests. 
8.2. Exclusion Criteria 
A subject will be excluded from the study if he or she meets any of the following criteria: 
[1] Is receiving a prescription acetylcholinesterase inhibitor (AChEI) and/or 
memantine at screening (Visit 1) or baseline (Visit 6). 
[2] Lacks good venous access, such that IV drug delivery or multiple blood draws 
would be precluded. 
[3] Has current serious or unstable illness including cardiovascular, hepatic, renal, 
gastroenterologic, respiratory, endocrinologic, neurologic, psychiatric, 
immunologic, or hematologic disease or other conditions that, in the 
investigator’s opinion, could interfere with the analyses of safety and efficacy 
in this study. 
[4] Has had a history within the last 5 years of a serious infectious disease 
affecting the brain (including neurosyphilis, meningitis, or encephalitis) or 
head trauma resulting in protracted loss of consciousness. 
[5] Has had a history within the last 5 years of a primary or recurrent malignant 
disease, with the exception of any in situ cancer that was appropriately treated 
and is being appropriately monitored, such as resected cutaneous squamous 
cell carcinoma in situ or in situ prostate cancer with normal prostate-specific 
antigen post-treatment. 
[6] Has allergies to humanized monoclonal antibodies. 
[7] Has a known history of HIV, clinically significant multiple or severe drug 
allergies, or severe post-treatment hypersensitivity reactions (including, but 
not limited to, erythema multiforme major, linear immunoglobulin A 
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis). 
[8] Has a history within the past 5 years of chronic alcohol or drug 
abuse/dependence as defined by the most current version of the Diagnostic 
and Statistical Manual of Mental Disorders (DSM). 
[9] Has a history within the past 2 years of major depression or bipolar disorder as 
defined by the most current version of the DSM. 
[10] Has a history of schizophrenia as defined by the most current version of the 
DSM. 
[11] Is clinically judged by the investigator to be at serious risk for suicide. 
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[12] Has a current or recent (within 6 weeks prior to baseline [Visit 6]) laboratory 
result (if available) that indicates a clinically significant laboratory 
abnormality that may influence baseline assessments as determined by the 
investigator.  Will allow thyroid or B12 insufficiency if adequately treated for 
3 months prior to screening (Visit 1). 
[13] Has ECG obtained during screening that, in the opinion of the investigator, is 
clinically significant with regard to the subject’s participation in the study.  
Bazett’s corrected QT (QTcB) interval must be evaluated and must not exceed 
>458 msec in males or >474 msec in females. 
[14] At screen, has alanine aminotransferase (ALT/SGPT) values >2X the upper 
limit of normal (ULN) of the performing laboratory, aspartate 
aminotransferase (AST/SGOT) values >3X ULN, or total bilirubin values 
>2X ULN. 
[15] Has a screening MRI scan (Visit 4) with results showing >4 hemosiderin 
deposits (definite microhemorrhages or areas of superficial siderosis); or any 
ARIA-E. 
[16] Has any contraindications for MRI studies, including claustrophobia, the 
presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not 
compatible with MRI. 
[17] Resides in a skilled nursing facility. 
[18] Is receiving any medication that has significant central nervous system (CNS) 
effects that in the investigator’s opinion would interfere with cognitive testing 
and protocol compliance.  The procedures manual provides a list of 
medications that impair cognition that are permitted in the study but need to 
be withheld prior to cognitive testing. 
[19] Has previously completed or withdrawn from this study or other solanezumab 
studies, or previous participation in any study investigating active 
immunization against Aβ. 
[20] Has previously completed or withdrawn from a study of passive immunization 
with another antibody within the last 120 days. 
[21] Pregnant, lactating or of child bearing potential (that is, women must be 
2 years post-menopausal or surgically sterile to be considered not child 
bearing potential). 
[22] Is investigator site personnel directly affiliated with this study and/or 
immediate family, or has a study partner who is investigator site personnel 
directly affiliated with this study.  Immediate family is defined as a spouse, 
parent, child, or sibling, whether biological or legally adopted. 
[23] Is an ADCS, ATRI, or Lilly employee, or has a study partner who is an 
ADCS, ATRI, or Lilly employee. 
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[24] 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 Project Director or one 
of the Medical Monitors. 
For subjects participating in LP, all of the above, plus: 
[25] Current use of anticoagulants, such as warfarin or dabigatran. 
8.2.1. Rationale for Exclusion of Certain Study Candidates 
Inclusion Criteria [2] through [4] eliminate subjects who already have manifest dementia in favor 
of subjects likely to have preclinical AD.  Inclusion Criterion [5] ensures brain amyloid 
pathology to eliminate subjects at low risk of cognitive decline.  Inclusion Criteria [7] and [8] 
ensure that the subject and a study partner will be available and able to comply with protocol 
requirements.  Exclusion Criterion [1] eliminates subjects receiving common AD treatments 
since such subjects are likely to be at a later stage of AD.  Exclusion Criterion [2] prevents 
incomplete dosing of study drug.  Inclusion Criterion [6] and Exclusion Criteria [3] through [17], 
[21], and [24] protect subject safety or analysis of safety.  Exclusion Criteria [18] through [20] 
exclude subjects whose concomitant medication dosing could confound the results of the study 
in the analysis of the PACC.  Exclusion Criteria [22] and [23] reduce both the possibility of 
coercion and the potential for bias that may be introduced at the study site.  Exclusion Criterion 
[25] protects safety for those participating in the optional LP. 
8.3. Inclusion and Exclusion Criteria:  Open-Label Extension Period 
All participants who complete the placebo-controlled period will be allowed to continue into the 
open-label period, even if they no longer meet the initial inclusion criteria.  Specifically, 
participants who have progressed to a Clinical Dementia Rating—Global score (CDR-G) of >0, 
started anticholinergic medications or other treatment for AD, or have accumulated ≥5 
microhemorrhages will be eligible to continue into the open-label period. 
8.4. Discontinuations 
8.4.1. Discontinuation of Subjects 
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a 
subject who did not meet enrollment criteria and who was inadvertently enrolled, the Project 
Director must be notified.  If the Monitor identifies a subject who did not meet enrollment 
criteria and who was inadvertently enrolled, the investigator site will be notified.  Inadvertently 
enrolled subjects may be maintained in the study and on investigational product when the Project 
Director agrees with the investigator that it is medically appropriate for that subject.  The 
investigator must obtain documented approval from the Project Director to allow the 
inadvertently enrolled subject to continue in the study. 
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Subjects who do not meet entry criteria or who are excluded by exclusion criteria from screening 
tests and procedures should be discontinued from the study before randomization. 
Subjects who exhibit any of the following conditions during the study may be discontinued from 
the study. 
 Appearance of clinically significant new cerebral ischemic or hemorrhagic 
events or symptomatic ARIA-E or greater than 4 new microhemorrhages 
detected on the central read on follow up MRI scans will be flagged for 
review by the central review.  Subject may be able to continue to participate in 
the study depending on clinical significance as determined by the Project 
Director, Medical Monitor, and the Site 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 treatment until the 
symptoms are resolved.  If a subject simultaneously develops more than 1 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 scan may be obtained.  A single symptom 
suggestive of ARIA-E of sufficient severity may also warrant an MRI scan.  
The unscheduled MRI scan should be performed in the same manner as the 
currently scheduled MRI scans in the protocol, which includes sending the 
images for central review.  For guidance, please refer to the instructions 
described in the relevant procedures manual. 
 Prolonged acute infusion 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 infusion reactions may occur with any agent that causes cytokine 
release (for example, some 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.  
Signs/symptoms may include: allergic reaction/hypersensitivity (including 
drug fever), arthralgia, bronchospasm, cough, dizziness, dyspnea, fatigue, 
headache, hypertension, hypotension, myalgia, nausea, pruritus, rash, 
rigors/chills, sweating (diaphoresis), tachycardia, urticaria, and vomiting. 
 Discontinuation of the study drug for abnormal liver tests should be 
considered by the investigator when a subject meet 1 of the following 
conditions after consultation with the medical monitor: 
o ALT or AST >8X ULN 
o ALT or AST >5X ULN for more than 2 weeks 
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o ALT or AST >3X ULN and total bilirubin level >2X ULN or 
prothrombin time >1.5X ULN 
o ALT or AST >3X ULN with the appearance of fatigue, nausea, 
vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%) 
In addition, subjects may be discontinued from the study drug and from the study in the 
following circumstances, including but not limited to: 
 Mean QTcB >500 msec and an absolute change >60 msec when compared 
with baseline (the most recent measurement made at either screening [Visit 1 
through 5] or baseline [Visit 6]). 
 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 
 Investigator Decision 
o The investigator decides that the subject should be discontinued from 
the study. 
o If the subject, 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. 
 Subject Decision 
o The subject requests to be withdrawn from the study. 
 Sponsor Decision 
o ATRI or Lilly or its designee stops the study. 
 Adverse Event 
o If the investigator and/or the subject decides that the subject should be 
withdrawn because of an SAE or other clinically significant AE, the 
investigational product is to be discontinued and appropriate measures 
are to be taken.  ATRI or Lilly or its designee is to be alerted 
immediately.  Refer to Safety Evaluations (Section 10.2). 
Subjects who discontinue early from the investigational product and/or study early will be 
encouraged to have an early termination visit at the point of discontinuation, with procedures 
performed as shown in the Study Schedule (Attachment 1).  Refer to the relevant procedures 
manual for further detail. 
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8.4.2. Discontinuation of Study Sites 
Study site participation may be discontinued if ATRI, Lilly, the investigator, or the ethical 
review board (ERB) of the study site judges it necessary for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and GCP. 
8.4.3. Discontinuation of the Study 
The study will be discontinued if ATRI or Lilly judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
8.5. Recruitment and Retention Strategies 
Recruitment will occur through a variety of mechanisms.  ATRI will use a coordinated 
recruitment plan to ensure that enrollment occurs in a timely fashion.  The overall goals of the 
plan are to raise awareness of AD trials among targeted populations to ensure adequate 
enrollment.  Through relationships with the National Institute on Aging (NIA) and coordination 
with its Alzheimer’s Disease Education and Referral Center, existing resources are being 
leveraged.  The study recruitment and retention team will develop materials specific to the A4 
study for use by the sites, provide ongoing recruitment assistance and support, and develop 
tracking procedures to monitor effectiveness of recruitment efforts. 
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9. Treatment 
9.1. Treatments Administered 
This study was initiated as a comparison of solanezumab 400 mg compared with placebo.  The 
active drug group was given an IV infusion of solanezumab 400 mg once every 4 weeks.  The 
study protocol was amended to increase the dose; subjects will be escalated to 800 mg Q4W for 
at least 2 infusions, and then 1600 mg Q4W until the conclusion of the treatment, as described 
below (Table A4.1).  Dosing should be once every 4 weeks; a minimum of 14 days between 
infusions is required. 
Table A4.1. 
Treatment Regimens 
Regimen 
Dose from Visit 6 (Week 0) through Visit 65 (Week 236), Placebo-Controlled Period 
Solanezumab 
 400 mg IV infusion every 4 weeks for at least 2 dosesa, and then: 
 800 mg IV infusion every 4 weeks for at least 2 doses, and 
 1600 mg IV infusion every 4 weeks through Week 236 
Placebo 
sterile saline solution (0.9% sodium chloride) IV infusion every 4 weeks (infusion volumes 
to increase accordingly with dose escalation paradigm as described in the operations 
manual) 
 
Dose from Visit 66 (Week 240) through Visit 116 (Week 440), Open-Label Period 
Early-start 
solanezumabb 
1600 mg IV infusion every 4 weeks through Week 440c 
Delayed-start 
solanezumabb 
 400 mg IV infusion every 4 weeks for at least 2 dosesa, c,  
 800 mg IV infusion every 4 weeks for at least 2 dosesc, and 
 1600 mg IV infusion every 4 weeks through Week 440c 
Abbreviation:  IV = intravenous. 
a Subjects who initiated the study before the implementation of amendment (d) may have more than 2 doses of 
400 mg Q4W. 
b “Early-start solanezumab” refers to the treatment regimen received by subjects randomized to solanezumab in the 
placebo-controlled period who continue to receive solanezumab in the open-label period.  “Delayed-start 
solanezumab” refers to the treatment regimen received by subjects randomized to placebo in the 
placebo-controlled period who switch to solanezumab treatment in the open-label period. 
c Subjects who are receiving 400 mg Q4W or 800 mg Q4W when they complete the placebo-controlled period 
may be maintained at that dose in the open-label period. 
 
Changes in the escalation schedule may be made at the investigator’s discretion with the 
notification of a Medical Monitor. 
The investigator or his/her designee is responsible for the following: 
 Explaining the correct use of the investigational agent(s) to the site personnel 
 Verifying that instructions are followed properly 
 Maintaining accurate records of investigational product dispensing and collection 
 Returning all unused medication to Lilly or its designee at the end of the study 
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Subjects 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. 
9.2. Materials and Supplies 
The site will be provided vials containing 400 mg/20 mL of solanezumab (or placebo).  The vials 
should be stored at 2ºC to 8ºC (36ºF to 46ºF).  Normal sterile saline solution (0.9% sodium 
chloride) will be used for dilution.  Details regarding preparation of the infusion are provided in 
the procedures manual.   
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 should be made.  After each IV bag is prepared, it will be identified as a dose 
of study drug without identification of the drug or dose.  Once prepared, the infusate solution 
should be stored at room temperature for a total of no more than 6 hours. 
Clinical study materials will be labeled according to the country’s regulatory requirements. 
9.3. Method of Assignment to Treatment 
Subjects who meet all criteria for enrollment will be randomized in a 1:1 ratio to double-blind 
treatment at baseline (Visit 6).  For between-group comparability, subjects will be randomized 
within site by education – high (13 or more years) or low (12 or less years), and by the presence 
of one or more APOE 4 alleles (yes, no).  Assignment to treatment groups will be determined 
by a computer-generated random sequence. 
An interactive web response system (IWRS) will be used to assign which vials are to be used for 
dosing for each subject.  Site personnel will confirm that they have located the correct vial by 
entering a confirmation number found on the label into the IWRS. 
9.4. Rationale for Selection of Doses in the Study 
The A4 study was initiated with active drug of solanezumab 400 mg given intravenously every 
4 weeks (400 mg Q4W).  Selection of the 400 mg Q4W dose was based largely but not entirely 
upon the peripheral sink hypothesis, which held that maximizing peripheral target engagement 
would change Aβ equilibria, resulting in altered amyloid deposition in the central compartment, 
ultimately leading to a slowing of disease progression.  The 400 mg Q4W dose was selected to 
lower free plasma Aβ concentrations by at least 90%, a level that exceeded what had been 
associated with slowing of amyloid plaque deposition in transgenic rodent species. 
The primary endpoint was not met in the recently concluded Phase 3 Study LZAX of 
solanezumab 400 mg Q4W in subjects with mild dementia due to AD, defined by a baseline 
MMSE score of 20 to 26.  Subjects treated with solanezumab did not experience a statistically 
significant slowing in cognitive decline compared with subjects treated with placebo (p=.095), as 
measured by the 14-item Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-
Cog14).  The study results, including several secondary clinical endpoints, directionally favored 
solanezumab, but the magnitudes of treatment differences were consistently small.  In general, 
safety findings were consistent with those observed previously in Studies LZAM and LZAN.  
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Safety analyses from Studies LZAM and LZAN individually and the pooled LZAM and LZAN 
data indicated a potential safety signal for a heterogeneous set of cardiac events, but this signal 
was not confirmed based on data from Study LZAX.  As measured by the Columbia Suicide 
Severity Rating Scale (C-SSRS), suicidal ideation and behaviors were infrequent, but greater 
frequency was observed among solanezumab- compared with placebo-treated patients in 
Study LZAX.  This safety signal has not been observed in other solanezumab studies.  At this 
time, it cannot be determined whether the imbalance observed in Study LZAX is causally related 
to solanezumab treatment.  Lilly will continue to assess this safety signal in the A4 study.  The 
negative efficacy outcome of Study LZAX suggests that an approach to dose selection based on 
peripheral target engagement may not predict clinical efficacy in Phase 3 trials.  Thus, central 
target engagement based on biomarkers may provide better predictive value for Phase 3 dose 
selection. 
Phase 2 solanezumab data suggest greater central target engagement may be achieved with 
dosing greater than 400 mg Q4W.  A dose of 400 mg every week (400 mg QW), which is 
equivalent to 1600 mg over a 4-week period, was given in Phase 2 Studies LZAJ and LZAK, and 
showed an increased CSF Aβ signal and an acceptable safety profile. 
Exposure–response analyses were conducted following the completion of Studies LZAM, 
LZAN, and LZAX, but given that only a single dose level was administered in these studies, no 
compelling relationship between exposure and change in various cognitive endpoints could be 
discerned. 
Biomarker data from patients receiving LPs in Studies LZAM, LZAN, and LZAX suggest that 
the effect of solanezumab on Aβ1-40 and Aβ1-42 species in the CNS (central target engagement) 
was present but relatively modest in those studies.  Total Aβ concentrations tended to increase 
with increasing solanezumab concentrations in the CSF, without reaching an apparent plateau, 
suggesting that higher solanezumab exposures in the CNS would lead to higher levels of target 
engagement.  Indeed, total Aβ1-40 and Aβ1-42 concentrations were observed to be substantially 
higher, with a dose of 400 mg QW examined after 12 weeks of dosing in the Phase 2 Study 
LZAJ, as compared with the Q4W dosing regimen. 
To date, the pharmacokinetics (PK) of solanezumab have been explored in single doses up to 
10 mg/kg (approximately 700 mg), or multiple doses of up to 400 mg QW.  The PK of 
solanezumab have been linear with respect to dose, and stationary with respect to time.  
Accordingly, the average plasma solanezumab concentration over 4 weeks at a dosing regimen 
of 1600 mg Q4W would be anticipated to be equivalent to the exposure over 4 weeks at the 
previously tested 400 mg QW dosing regimen.  This projected exposure is less than the no-
observed-adverse-effect level (NOAEL) exposure determined in monkeys as part of a 12-month 
chronic toxicology study.  Assuming linear PK, the projected Cmax at 1600 mg Q4W is 
anticipated to provide an exposure multiple that is similar to that calculated for the projected 
average concentration. 
Solanezumab was well tolerated in monkeys, with no adverse effects observed at the maximum 
dose studied, 100 mg/kg.  Solanezumab exposures at 1600 mg Q4W were projected using 
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clinical data collected at 400 mg Q4W.  These exposure estimates provide a 5.8X multiple to the 
exposures in monkeys at the 100 mg/kg dose. 
The safety of higher doses than 400 mg Q4W has also been studied during the solanezumab 
development program.  Single ascending-dose Studies H8A-LC-LZAH (LZAH) and 
H8A-JE-LZAI (LZAI) investigated the safety and tolerability of solanezumab in AD patients at 
doses up to 10 mg/kg, which is approximately equivalent to 700 mg.  The safety findings from 
these studies (described below) suggested an acceptable safety profile for continued development 
of solanezumab.  Phase 2 Studies LZAJ (12-week treatment duration) and LZAK (8-week 
treatment duration) included doses of 400 mg QW, the equivalent of 1600 mg of solanezumab in 
each 4-week period; these studies (described below) also demonstrated an acceptable safety 
profile for solanezumab. 
In Studies LZAH and LZAI, a total of 8 patients received single doses of solanezumab 10 mg/kg.  
Three patients reported AEs that were related to solanezumab in the opinion of the investigator.  
Two of these patients experienced AEs, including feeling cold, mild tremor, chest pressure, and 
mild dizziness, that were judged by the investigator to be most likely due to infusion reactions, 
similar to the infusion-type reactions described with other intravenously administered proteins.  
For these 2 patients, the symptoms were mild and resolved without specific treatment (for 
example, antihistamines).  A third report considered related to study drug, muscle spasms, 
occurred 0.1 hour after infusion and lasted 0.5 hours. 
In Studies LZAJ and LZAK, a total of 22 patients received solanezumab 400 mg QW for 8 to 
12 weeks.  The most commonly reported AEs were back pain, confusional state, cough, 
hyperhidrosis, and nausea, reported in 2 patients each. 
Studies LZAH, LZAI, and LZAJ were completed before ARIA-H and ARIA-E were understood 
as potential risks for anti-amyloid therapies, and thus ARIA-H and ARIA-E were not specifically 
assessed on MRI.  However, subjects underwent baseline and follow-up MRI scans, and no 
changes in MRI were reported as AEs or SAEs.  Study LZAK was the first study of solanezumab 
that specifically assessed for ARIA-H and ARIA-E on MRI.  Magnetic resonance imaging scans 
were obtained at Week 4 and Week 8 (after the final infusion).  No ARIA-E, ARIA-H, or 
infusion reactions were reported in this study.  There were no changes in MRI reported as AEs or 
SAEs. 
Taken together, these data suggest that increasing the dose to 1600 mg Q4W is appropriate to 
increase the probability of observing a treatment effect in the study while maintaining subject 
safety. 
9.5. Administration and Timing of Doses 
Details about infusion preparation and timing of administration are provided in the procedures 
manual.  If a subject demonstrates an infusion reaction to the study drug, the subject may be 
premedicated with antihistamine (such as diphenhydramine hydrochloride, 50 mg orally or 
intravenously), 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.  Subjects should be 
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observed for approximately 1 hour following the first infusion of 400 mg in the 
placebo-controlled period.  Subjects on dose escalation safety cohorts will be monitored post 
infusion as mentioned in Section 10.2.11.1. 
Note:  All clinical scales and specimen collections are to be performed before infusions. 
9.6. Blinding 
The placebo-controlled period is a double-blind study phase in which subjects and site personnel 
will be blinded to therapy.  In order to preserve blinding, a minimal number of study personnel 
that support interim analyses and safety review will see the randomization table and treatment 
assignments before the study is complete.  In the open-label period, treatment will remain 
blinded for up to the first 4 infusions to allow participants to dose escalate as described in 
Section 9.1 without unblinding subjects and site personnel to the original treatment assignment in 
the placebo-controlled period.  After the 4-visit dose escalation period, all subjects will receive 
open-label solanezumab treatment and will remain blinded to the subject’s original treatment 
assignment.  In essence, all subjects are randomized at Visit 6 to early-start or delayed-start 
solanezumab treatment.  To maintain blinding, dose reductions are not allowed during the dose 
escalation visits in the open-label period.  If a dose reduction is desired, the dose at that visit 
should be withheld; when dosing is reinstated, the participant should begin unblinded dose 
escalation at 400 mg Q4W. 
Emergency unblinding for AEs may be performed through an IWRS.  This option may be used 
ONLY if the subject’s well-being requires knowledge of the subject’s treatment assignment.  
Any unblinding event performed via the IWRS will be recorded and reported by the IWRS. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted.  Subject 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 Project Director prior to 
unblinding a subject’s treatment assignment.  If a subject’s treatment assignment is unblinded, 
ATRI and Lilly must be notified immediately. 
If an investigator, site personnel performing assessments, or subject is unblinded, the subject 
must be discontinued from the study.  In cases where there is ethical reason to have the subject 
remain in the study, the investigator must obtain specific approval from the Project Director for 
the subject to continue in the study. 
9.7. Concomitant Therapy 
All concomitant medication taken during the study must be recorded.  Subjects 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. 
Prescription acetylcholinesterase inhibitors (AChEIs) and/or memantine are exclusionary during 
initial screening.  Starting prescription AChEIs and/or memantine during the course of the study 
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will not be permitted without explicit permission for an exemption for medical necessity.  Before 
a subject starts an AChEI and/or memantine or other treatments for cognitive impairment, a 
Medical Monitor must be contacted to determine whether or not the subject should continue in 
the study and whether or not clinical outcome measures should be performed.  Participants who 
begin treatment with AChEIs and/or memantine during the placebo-controlled period will be 
eligible to continue in the open-label extension period. 
Use of benzodiazepines for treatment on an as-needed basis for insomnia or daily dosing as 
anxiolytics is permitted.  If they are being given chronically, use of sedatives or hypnotics should 
be avoided for 8 hours before administration of cognitive tests.  If sedating medication is given 
for MRI at any visit or for any short-term use, then all cognitive assessments must be 
administered at least 24 hours after administration of the sedative. 
Stable use of pain medications will be permitted.  Short-term use of narcotics is allowable if not 
administered within 24 hours prior to cognitive assessments. 
Other concomitant medications that affect CNS function may be given if the dose remains 
unchanged throughout the study.  Doses of these compounds should remain constant from 
6 weeks before randomization (Visit 6). 
To avoid effects on cognitive measures: 
 subjects should not stop receiving any medications that affect CNS function 
during the study, 
 subjects should not add any medications that affect CNS function to the 
treatment regimen, and 
 subjects should not change doses of medications that affect CNS function. 
If unforeseen starting, stopping, or changing of stable doses of drugs that affect CNS function 
occurs during the study, a Medical Monitor must be contacted to determine whether or not the 
subject should continue in the study and whether or not outcome measures should be performed. 
Anticoagulants, such as warfarin (Coumadin) and dabigatran (Pradaxa) are not permitted for 
subjects who undergo a LP.  Starting anticoagulants during the course of the study, if deemed 
medically necessary, will be permitted; however, subsequent LP will not be conducted. 
9.8. Treatment Compliance 
Because dosing occurs at study visits, subjects who attend all visits and successfully receive 
infusions are automatically compliant with treatment.  Any infusions at which 75% or more of 
the infusate is given will be considered a complete infusion. 
If a subject 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 infusate is given, this must be recorded as an incomplete infusion on the 
case report form (CRF). 
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Missed infusions should be recorded on the CRF.  Subjects who miss 3 consecutive infusions or 
10 or more cumulative infusions at any time during the course of the study may be discontinued 
from the study.  Subjects who miss 3 consecutive infusions or 10 or more cumulative infusions 
for medical reasons (for example, MRI findings) or other extenuating circumstances can 
continue in the study with the approval of a Medical Monitor and/or Project Director. 
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10. Outcome Measurements 
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule (Attachment 1). 
10.1. Clinical Measures 
Cognitive testing should always be performed before medical procedures that could be stressful 
for the subjects (for example, blood draws).  Additionally, cognitive testing for each subject 
should be performed at approximately the same time on each day that testing occurs and should 
be administered by the same rater to reduce potential variability.  More details are provided in 
the relevant procedures manual.  If a clinical measure cannot be collected at the scheduled visit, 
that assessment may be collected at a subsequent visit, if that visit occurs within 8 weeks of the 
scheduled visit window. 
10.1.1. Primary Efficacy Outcome Measure, Placebo-Controlled 
Period:  ADCS Preclinical Alzheimer Cognitive Composite 
The primary outcome measure, the PACC, will be collected at the times shown in the Study 
Schedule (Attachment 1; Mormino et al. 2017).  The PACC is a cognitive composite that is 
weighted towards episodic memory but also includes timed executive function tests and a global 
test.  Its development is described in Attachment 3.  The components include: 
 Total Recall Score from the Free and Cued Selective Reminding Test 
(FCSRT).  The FCSRT (Grober et al. 1988, 2008; Ferris et al. 2006) is a 
16-item word list with visual and auditory presentation that uses semantic 
cuing to facilitate encoding and retrieval.  The test can be scored 3 ways:  a 
free recall score ranging from 0 to 48 assesses number of words recalled 
freely (without cuing), a free and cued score ranging from 0 to 48 assesses the 
number of words recalled freely as well as those recalled with cuing, and a 
third score ranging from 0 to 96 adds the previous 2 scores together. 
 Delayed Paragraph Recall score on the Logical Memory IIa test from the 
Wechsler Memory Scale.  Logical Memory Test I and II (Delayed Paragraph 
Recall) is a modification of the episodic memory measure from the Wechsler 
Memory Scale-Revised (Wechsler 1987).  In this modified version, free recall 
of 1 short story that consists of 25 bits of information will be elicited 
immediately after it is read aloud to the subject and again after approximately 
30-minute delay.  The total bits of information from the story that are recalled 
immediately (maximum score = 25) and after the delay interval (maximum 
score = 25) are recorded.  The delay score (0-25 story units) will be used in 
the composite. 
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 Digit-Symbol Substitution Test from the Wechsler Adult Intelligence Scale-
Revised (WAIS-R).  The Digit Symbol Substitution test (Wechsler 1981) is a 
subset from the WAIS-R.  The test consists of small blank squares presented 
in rows with one of 9 numbers (1-9) randomly printed directly above each 
blank square.  A “key” is printed above the rows of blank squares.  The “key” 
pairs numbers 1 through 9 with an unfamiliar symbol.  Following a short 
series of practice trials, the subject must use the key to fill in the blank squares 
in order (working from left to right across the rows) with the symbol that is 
paired with the number over the blank square.  The subject must work as fast 
as possible for 90 seconds.  The measure of interest is number of squares 
filled in correctly within the time limit (maximum raw score = 91).  This test 
engages multiple cognitive abilities including attention, psychomotor speed, 
complex scanning, visual tracking, and immediate memory. 
 MMSE Total Score.  The MMSE (Folstein et al. 1975) is a brief, frequently 
used screening instrument for Alzheimer’s disease drug studies.  The MMSE 
scale evaluates orientation, memory, attention, concentration, naming, 
repetition, comprehension, and ability to create a sentence and to copy 
2 overlapping pentagons.  The MMSE is scored as the number of correctly 
completed items with a lower score indicative of poorer performance and 
greater cognitive impairment.  The total score ranges from 0 (worse) to 
30 (perfect performance). 
Each component score is divided by the baseline SD of that component, to form standardized 
Z-scores.  These Z-scores are summed to form the composite, so that a 4-point change on the 
composite is approximately equivalent to a change of 1 baseline SD on each component. 
The administration of the PACC should be recorded (audio only) for quality review purposes 
according to locally applicable laws and regulations. 
10.1.2. Secondary Efficacy Clinical Outcome Measures, 
Placebo-Controlled Period 
Secondary clinical outcome measures will be collected at the times shown in the Study Schedule 
(Attachment 1). 
10.1.2.1. ADCS Activities of Daily Living – Prevention Questionnaire 
The ADCS-ADL Prevention Questionnaire was developed in the ADCS-Prevention Instruments 
trial (ADCS-PI) and includes 18 questions related to activities of daily living (Galasko et al. 
2006).  Study subjects and their study partners independently rate the study subject’s level of 
ability.  Partners are additionally asked to evaluate whether activities were completed less often, 
required more time to complete, and if errors were made performing the task. 
10.1.2.2. Clinical Dementia Rating Scale 
The CDR (Morris 1993) is a clinical scale that rates the severity of dementia as absent, 
questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively).  The score 
is based on interviews with the subject and study partner, using a structured interview that 
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assesses 6 domains:  memory, orientation, judgment and problem solving, community affairs, 
home and hobbies, and personal care.  The ratings of degree of impairment obtained on each of 
the 6 categories of function are synthesized into 1 global rating of dementia (ranging from 0 to 
3), with more refined measure of change available by use of the Sum of Boxes (CDR-SB).  
Reliability and validity has been established, as has high inter-rater reliability. 
10.1.2.3. Cognitive Function Index 
The CFI is a modified version of the Mail-in Cognitive Function Screening Instrument (Walsh et 
al. 2006; Amariglio et al. 2015), a subject- and study partner-reported outcome (patient-reported 
outcome) measure developed by the ADCS.  This assessment includes 15 questions that assess 
the subject’s perceived ability to perform high level functional tasks in daily-life and their sense 
of overall cognitive functional ability.  Study subjects and their study partners independently rate 
the subject’s abilities. 
10.1.2.4. Computerized Cognitive Composite 
The C3 will include tasks from the CogState battery (Darby et al. 2011; Lim et al. 2012a) aimed 
at measuring processing speed, working memory, visual navigation, and executive function.  The 
C3 will also include 2 investigator-developed sensitive episodic memory probes of hippocampal 
function (Sperling et al. 2003; Rentz et al. 2010; Stark et al. 2010).  A composite score will be 
generated and secondary measures will include reaction time and measure subscores. 
The tablet computer iPad test session also incorporates questions about the subject’s assessments 
of their cognitive function based on the Memory Complaint Questionnaire (MAC-Q), the C-Path 
PRO, and a selection of self-report questions that may be helpful in developing novel tools for 
assessing subjective change over time in this population.  The MAC-Q (Reid et al. 2012) is a 
brief measure of subjective memory complaint in people with normal cognitive function.  The C-
Path PRO Questionnaire is an exploratory instrument being developed by the Critical Path 
Institute for use in early AD trials.  It consists of 26 questions asking for the participant’s self-
assessment of current ability to perform cognitive activities and interpersonal interaction.  
Subjects report the frequency that they experience difficulty performing these activities.   
The C3 will be optional in Japan. 
10.1.2.5. Resource Use Inventory—Brief Version 
The Resource Use Inventory (RUI) is an instrument designed to assess changes associated with 
the transition from normal aging to dementia in (1) health-related resource use (medical care, 
nonmedical care, and informal care) and (2) elders’ participation in volunteer and paid work.  
Medical care includes questions on hospitalization, outpatient treatment and procedures, assistive 
devices, and medications.  Nonmedical care includes questions on home health aides, respite 
care, and adult day care.  Informal caregiving time participants received with instrumental and 
basic ADL.  Both participants and their study partners contribute to the reporting of the RUI to 
maximize information obtained.  The RUI has been used in trials of normal aging (Sano et al. 
2006), MCI (Zhu et al. 2013), and dementia (Zhu et al. 2006), and items are included that are 
relevant to the specific stage of cognitive impairment and dementia.  For this trial, a brief version 
of the inventory will be used (the RUI-B, where B stands for brief), including only those items 
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that are relevant to this stage with a focus on volunteer and paid work and items for medical and 
nonmedical resources. 
10.1.2.6. Views and Perceptions about Amyloid Imaging 
Views and Perceptions about Amyloid Imaging is an instrument that assesses perceptions about 
amyloid imaging and reasons for obtaining an amyloid scan.  It is adapted from Roberts and 
Connell 2000. 
10.1.2.7. Concerns about Alzheimer's Disease 
Concerns about Alzheimer’s Disease is a short self-report instrument about one’s concern about 
developing Alzheimer’s disease dementia.  It is adapted from Roberts and Connell 2000. 
10.1.2.8. Impact of Events Scale 
The IES (Horowitz et al. 1979) is a 15-item self-report measure that assesses two common 
responses related to a specific stressful life event: intrusion and avoidance.  It is a reliable scale 
that can be anchored to any specific life event and permits the assessment of subjects over time, 
comparison of the degree of distress among subgroups, and comparison of the impact of various 
events.  The IES has been anchored to test-related distress in previous genetic testing studies and 
has been adapted for amyloid imaging related distress. 
10.1.2.9. Future Time Perspective Scale 
The Future Time Perspective scale (Roberts 2000; Lang and Carstensen 2002) measures a 
person’s perception of his or her remaining time which in turn has been shown to explain the 
priority of specific goals. 
10.1.2.10. 
Research Satisfaction Survey 
A Research Satisfaction Survey will be administered to the subject in order to evaluate 
satisfaction with the current study.  The survey will also reveal specific aspects of the study that 
subjects may dislike, so that improvements can be made in the design of future studies.  Past 
studies in multiple fields have also shown that consumer input and feedback is an important 
element in increasing retention (for example, in psychotherapy; Miller et al. 2005; Duncan et al. 
2010). 
10.1.3. Biomarker Outcome Measures, Placebo-Controlled Period 
Biomarker measures will be assessed as specified in the Study Schedule (Attachment 1). 
10.1.3.1. Cerebrospinal Fluid (CSF) 
Subjects who consent to the optional LP will have a baseline and endpoint LP performed in order 
to collect CSF.  Analyses include but are not limited to glucose, protein, cell count, Aβ species, 
and tau proteins.  CSF samples will also be stored for future use in research. 
CSF collection, sample handling, and sample shipment will occur according to the procedures 
described in the relevant procedures manual.  All LPs should be performed under fasting 
conditions (minimum 8-hour fast), preferably during the morning.  The postbaseline LP should 
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be performed at the same time of the day as the baseline LP, and fasting status must be recorded 
for all LPs. 
Approximately 2 mL (or more per local laboratory requirements) will be sent to a local 
laboratory for testing of glucose, protein, and cell count. 
Solanezumab- and placebo-treated associated effects on CSF AD biomarkers will be assessed 
and compared.  These AD biomarkers include, but are not limited to, total and free Aβ1-40 and 
Aβ1-42, total tau, and P-tau.  CSF concentrations of biomarkers and solanezumab will be 
determined from processed CSF samples using validated immunoassay and/or mass spectrometry 
methods.  Solanezumab- and placebo-treatment effects on CSF tau concentrations will be 
assessed and compared in this study.  CSF total tau and P-tau are both reported to be increased in 
individuals with AD.  Additional analyses are intended to confirm previously observed treatment 
effects on CSF Aβ species, which suggested that solanezumab mobilizes Aβ species from AD 
plaque.  Results from analysis of CSF for solanezumab and biomarkers to assess treatment 
effects will not be reported to investigative sites or other blinded personnel at a subject level. 
Bioanalytical samples collected to measure investigational product concentration and 
metabolism and/or protein binding will be retained for a maximum of 2 years following last 
patient visit for the study. 
Each subject will be contacted by phone 24 hours after the LP to confirm the subject’s 
well-being and to query about any new AEs. 
10.1.3.2. Plasma Solanezumab 
Plasma will be collected from all subjects for determination of plasma solanezumab 
concentration.  Not all of these samples will be assayed for solanezumab concentration.  It is 
intended that plasma solanezumab concentrations will be determined for approximately the first 
200 subjects to complete the study.  In addition, plasma solanezumab concentrations will be 
determined for any subject who also has positive anti-solanezumab titers.  Plasma concentrations 
from other subjects may be determined as warranted. 
Plasma concentrations of solanezumab and Aβ species for pharmacodynamic analysis may be 
determined from processed blood samples using validated immunoassay and/or mass 
spectrometry methods.  Analysis of Aβ species is intended to confirm the solanezumab 
pharmacodynamic effect (the “peripheral sink” effect) hypothesized to enhance Aβ clearance 
from the CNS to the peripheral circulation.  Other plasma Aβ species thought to be associated 
with amyloid plaque may also be analyzed. 
Samples from placebo-treated subjects will not be assayed for solanezumab.  Results that could 
unblind the study will not be reported to investigative sites or other blinded personnel. 
Sample collection, handling, and shipment will occur according to the procedures described in 
the relevant procedures manual. 
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year after all subjects complete the study (that is, the last subject’s visit). 
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10.1.3.3. Genomic Samples 
There is growing evidence that genomic characteristics may impact a subject’s response to 
therapy.  Variable response to therapy may be due to genomic determinants that impact drug 
absorption, distribution, metabolism, and excretion, the mechanism of action of the drug, the 
disease etiology and/or the molecular subtype of the disease being treated.  Therefore, blood 
samples will be collected for several types of genomic analysis. 
Apolipoprotein E (APOE) genotyping is a mandatory part of this study.  Neither subjects nor 
investigators will receive the genotyping results unless there is a country-specific law or 
regulation that requires notification of the results. 
In the event of an unexpected AE or the observation of unusual response, the genomic samples 
may be tested and analysis may be performed to evaluate a genomic association with response.  
The genomic samples will only be used for investigations related to disease and drug or class of 
drugs under study in the context of this clinical program.  They will not be used for broad 
exploratory unspecified disease or population genetic analysis. 
The samples will be coded with the subject number and stored for up to a maximum 15 years 
after the last subject visit for the study at a facility selected by the sponsor.  The samples and any 
data generated from them can only be linked back to the subject by investigator site personnel.  
The duration allows the sponsor to respond to regulatory requests related to the investigational 
product.  Samples will be destroyed according to a process consistent with local regulation. 
10.1.3.4. Samples for Biomarker Long-Term Storage 
Collection of biomarker samples for long-term storage is also part of this study.  Plasma, serum, 
whole blood, and CSF samples will be collected.  Sample collection, handling, and shipment will 
occur according to the procedures described in the relevant procedures manual. 
Analysis may be performed on biomarker variants thought to play a role in AD pathology to 
evaluate their association with observed clinical outcomes to solanezumab.  Other samples may 
be used for research to develop methods, assays, prognostics and/or companion diagnostics 
related to AD and/or determine mechanism of action of solanezumab.  Future research could 
include the evaluation of the effects of solanezumab on A processing and trafficking, tau 
pathologies and neuronal degeneration (tau levels are known to be elevated in patients with AD 
[Trojanowski 1996; Green et al. 1999]), and possibly the effects of solanezumab on other 
analytes that have yet to be identified.  Analysis of these data could provide an important 
biomarker that would guide future decisions by clinicians and researchers. 
The stored samples will be coded with the subject number and stored for up to a maximum 
15 years after the last subject visit for the study at a facility selected by the sponsor.  The samples 
and any data generated from them can only be linked back to the subject by investigator site 
personnel.  The duration allows the sponsor to respond to regulatory requests related to the 
investigational product.  Samples will be destroyed according to a process consistent with local 
regulation.  Because of the exploratory nature of these analyses and because the results should 
not change medical management, neither subjects nor investigators will receive the test results. 
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10.1.3.5. Magnetic Resonance Imaging 
Magnetic resonance imaging of the brain will be performed according to the Study Schedule and 
as clinically indicated.  Each site must be qualified to conduct MRI for the A4 study.  The 
procedures for site qualification and subject scanning will be described in the relevant 
procedures manual. 
All subjects will be scanned using the A4 MRI scanning protocol and must complete the A4 core 
sequences as described in the relevant procedures manual, to be eligible for randomization in the 
study.  There are additional magnetic resonance sequences that will be acquired depending on 
scanner type. 
A central read will be performed on all MRI scans for subject safety and to assist in determining 
if the subject is eligible for the study.  In instances where more than 4 microhemorrhages are 
identified or any ARIA-E at screening, it will be flagged for review and the subject will be 
deemed ineligible for the study.  Other findings that are flagged during the central read will be 
reviewed by the Project Director and Medical Monitors or designees to determine if the subject 
is eligible to continue.  All follow-up MRIs will be reviewed centrally for new occurrence of 
ARIA-E and ARIA-H that will be flagged for review by the Project Director, Medical Monitors, 
and site principal investigator.  Subjects who develop new ARIA-E or increased ARIA-H but 
remain asymptomatic may be eligible to continue treatment without interruption. 
Volumetric MRI (vMRI) analytic methods will be used to assess change in brain volume over 
the treatment period. 
Functional connectivity MRI methods will be used to assess the integrity of intrinsic brain 
networks over the treatment period. 
10.1.3.6. Florbetapir PET Scan 
Florbetapir PET imaging of the brain will be performed using the A4 PET scanning protocol.  
Each site must be qualified to conduct florbetapir PET for the A4 study.  The procedures for site 
qualification and subject scanning will be described in the relevant procedures manual. 
For each scan, the subject will receive a single IV administration of approximately 370 MBq (10 
mCi) of florbetapir F 18 (fast IV push), approximately 50 minutes prior to imaging.  The 
injection of the imaging agent will be followed by a saline flush according to the injection 
procedure described in the relevant procedures manual.  The PET procedure can last between 10 
and 30 minutes as specified in the relevant procedures manual. 
Change in brain amyloid burden (as assessed by florbetapir binding and measured by mean 
cortical standardized uptake value ratio [SUVr]) will be compared in solanezumab- and placebo-
treated subjects for those subjects who undergo baseline and endpoint florbetapir scans. 
10.1.4. Secondary Efficacy Clinical Outcome Measures, Open-Label 
Period 
The PACC, ADCS-ADL Prevention Questionnaire, CDR-SB, C3, and CFI described above for 
the placebo-controlled period of the study will also be evaluated in the open-label extension 
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period.  Additionally, a Clinician Diagnostic Impression (CDI) will be collected at Visit 66 and 
during the open-label extension period.  For the CDI, investigators will be asked to classify the 
participant’s current disease stage according to the following categories:  cognitively normal, 
MCI, or mild AD dementia.  Timing for collection of these outcome measures is presented in the 
Study Schedule (Attachment 1). 
10.2. Safety Evaluations 
Investigators are responsible for monitoring the safety of subjects 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 subject. 
The investigator is responsible for the appropriate medical care of subjects during the study. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the study, or that caused the 
subject to discontinue before completing the study.  The subject should be followed until the 
event is resolved or explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator. 
Attachment 1 lists the schedule of all safety assessments in this study.  Attachment 2 lists the 
laboratory tests that will be performed for this study. 
10.2.1. Adverse Events 
10.2.1.1. General Information 
A clinical study AE is any untoward medical event or unanticipated benefit 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. 
Reporting standards for reporting AEs will be provided in the relevant procedures manual and 
must 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 drug effect. 
Any symptomatic ARIA would be considered an AE.  Other findings on study-related MRI scans 
will be at the discretion of the site investigator to determine if it qualifies as an AE. 
Any clinically significant findings from ECGs, labs, vital sign measurements, and other 
procedures must be reported. 
Planned medical procedures should not be reported as AEs unless the underlying medical 
condition has worsened during the course of the study, in which case the worsening of the 
medical condition (not the procedure) should be reported. 
Cases of pregnancy that occur during maternal or paternal exposures to investigational product 
should be reported.  Data on fetal outcome and breast-feeding are collected for regulatory 
reporting and drug safety evaluation. 
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Study site personnel will record the occurrence and nature of each subject’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.  After the A4 study informed consent form (ICF) is signed, site personnel will record 
any change in the condition(s) and the occurrence and nature of any AEs. 
Investigators will be instructed to report their assessment of the potential relatedness of each AE 
to items that include, but not limited to, protocol procedure, studied disease state (preclinical AD, 
elevated brain amyloid), investigational product, and/or drug delivery system. 
10.2.1.2. Serious Adverse Events 
Serious adverse event collection begins after the subject has signed informed consent.  Serious 
adverse events that occur after consent but before receipt of investigational product must be 
reported but data from such events will not be submitted to ERBs by the sponsor unless thought 
to have been possibly caused by a protocol procedure. 
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study. 
Study site personnel must report any serious adverse event (SAE) within 24 hours of investigator 
awareness of the event.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information. 
An SAE is any AE from this study that results in one of the following outcomes: 
 Death 
 A life-threatening experience (that is, immediate risk of dying) 
 Persistent or significant disability/incapacity 
 Initial or prolonged inpatient hospitalization 
 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 adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Serious adverse events occurring after a subject has been administered the last dose of study drug 
will be collected for 30 days after the last dose of study drug, regardless of the investigator’s 
opinion of causation.  Thereafter, SAEs are not required to be reported unless the investigator 
feels the events were related to either study drug, drug delivery system, or a protocol procedure. 
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB. 
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10.2.1.3. 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. 
10.2.2. Columbia Suicide Severity Rating Scale 
Consistent with FDA regulatory guidance (FDA 2012), any occurrence of suicide-related 
thoughts and behaviors will be assessed.  The C-SSRS is a scale that captures the occurrence, 
severity, and frequency of suicide-related thoughts and behaviors during the corresponding 
assessment period.  The scale includes suggested questions to elicit the type of information 
needed to determine if a suicide-related thought or behavior occurred. 
The standard version of the scale will be used in this study.  The first time the scale is 
administered in this study (Visit 1), the C-SSRS “Screening/Baseline” version will be used and 
the findings will be used to assist the clinician in determining eligibility.  The C-SSRS will be 
administered at baseline (Visit 6) and at subsequent visits as outlined in the study schedule.  The 
C-SSRS “Since Last Visit” scale will be used for baseline and all subsequent assessments. 
If a suicide-related thought to 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. 
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. 
10.2.3. Electrocardiograms 
For each subject, a 12-lead digital ECG will be collected as replicates (triplicates).  Subjects 
must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but 
awake during ECG collection. 
Consecutive replicate ECGs will be obtained at approximately 1-minute intervals. 
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs (more replicates) than expected at a particular time point is allowed 
when needed to ensure high-quality records. 
ECG will be collected in the placebo-controlled period per schedule of events and in the open-
label period as unscheduled ECG per investigator discretion. 
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 subject is still present, to determine whether the subject meets entry criteria at the 
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screening and for immediate subject management, should any clinically relevant findings be 
identified at screening or during subsequent ECG visits as outlined in the Study Schedule. 
After enrollment, if a clinically significant increase in the QT/corrected QT interval from 
baseline or other clinically significant quantitative or qualitative change from baseline is 
identified, the subject will be assessed by the investigator for symptoms (for example, 
palpitations, near syncope, syncope) and to determine whether the subject can continue in the 
study.  The investigator or qualified designee is responsible for determining if any change in 
subject management is needed and must document his/her review of the ECG printed at the time 
of evaluation from at least 1 of the replicate ECGs from each time point. 
All digital ECGs will be electronically transmitted to a designated central ECG laboratory.  A 
cardiologist at the central ECG laboratory will then conduct a full overread on 1 of the replicates 
(including all intervals).  A report based on data from this overread will be issued to the 
investigative site.  For each set of replicates, the cardiologist will determine the RR and QT 
intervals, QRS duration, and heart rate on the ECGs that were not fully overread.  These data are 
not routinely reported back to the investigative site.  However, any clinically significant finding 
that was not present on the fully overread ECG will be reported to the investigator, Lilly, and 
ATRI.  All data from the overreads will be placed in the Lilly database as well as transferred to 
ATRI for analytical and study report purposes. 
When there are differences in the ECG interpretation between the investigator (or qualified 
designee) and the cardiologist at the central ECG laboratory, the investigator’s (or qualified 
designee’s) interpretation will be used for study entry and immediate subject management.  
Interpretations from the cardiologist at the central ECG laboratory will be used for data analysis 
and report-writing purposes. 
The investigator (or qualified designee) must document his/her review of 1 of the replicate ECGs 
printed at the time of collection, the final overread ECG report issued by the central ECG 
laboratory, and any alert reports. 
10.2.4. Immunogenicity 
Serum for immunogenicity testing will be prepared from blood drawn at designated visits.  
Serum immunogenicity results and any associated plasma Aβ 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. 
Sample handling and shipment of the central laboratory will occur per instructions given to the 
investigative study site.  Samples may be stored for a maximum of 15 years following last 
subject visit for the A4 study at a facility selected by Lilly to enable further analysis of immune 
responses to solanezumab.  The duration allows Lilly to respond to regulatory requests related to 
solanezumab. 
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10.2.5. Neurological Examination 
A medically qualified professional will perform a neurological examination that includes an 
assessment of cranial nerves, strength, coordination, reflexes, sensation, tremor, and gait.  
Neurological examinations will be performed as clinically indicated, and as indicated in the 
Study Schedule.  If necessary, given the training of the principal investigator, a neurologist will 
be consulted in the event of significant new findings. 
10.2.6. Physical Examination 
A medically qualified professional will perform a brief physical examination that consists of a 
review of the major body systems (that is, skin, head/ears/eyes/nose/throat, cardiovascular, 
pulmonary, abdomen, musculoskeletal, neurological, and gastrointestinal).  Physical examination 
will be performed at clinically indicated, and as indicated in the Study Schedule. 
10.2.7. Safety Laboratory Samples 
Blood and urine samples (Attachment 2) will be collected according to the Study Schedule and 
to determine whether subjects meet inclusion/exclusion criteria and to monitor subject health.  
Redraws will be permitted if a sample is not viable when received by the central laboratory or if 
sample collection is not possible during the visit. 
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. 
10.2.8. Vital Signs 
Vital signs, including temperature and weight, should be measured at all clinic visits and 
recorded in the eCRF according to the Study Schedule.  Blood pressure, respiration, and pulse 
will be measured in the sitting position.  Height will be measured at Screening Visit 1. 
10.2.9. Subject Medical History/Family History/Concomitant 
Medications 
Information regarding demographics, medical history, and family history will be gathered from 
the subject and study partner at Screening Visit 1.  Concomitant medications will be assessed at 
every visit. 
10.2.10. Assessment of Psychological Well-Being 
The Assessment of Psychological Well Being is composed of questions from a validated 
shortened version (Marteau and Bekker 1992) of the “state anxiety” portion of the State-Trait 
Anxiety Inventory (Spielberger et al. 1983) and from the Geriatric Depression Scale (Sheikh and 
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Yesavage 1986).  It is a self-report assessment designed to identify symptoms of anxiety and 
depression in the elderly.  The anxiety portion of the assessment consists of 6 questions that the 
subject indicates on a scale from 1 (not at all) to 4 (very much) on how much of a given anxiety 
symptom they are currently experiencing to assess anxiety level.  The depression portion of the 
assessment has 15 questions that the subject is asked to answer yes or no based on how they felt 
over the past week in an effort to assess depression symptoms.  The more benign items are asked 
first.  Answers to 5 of the items are negatively oriented for depression (for example, Do you feel 
full of energy?) and 10 positively oriented (for example, Do you often feel helpless?). 
10.2.11. Dose Escalation Safety Cohort 
Subjects in the dose escalation safety cohort in the placebo-controlled period (Section 7.1.4) will 
receive additional safety assessments and monitoring during dose escalation to monitor the safety 
of higher doses.  The additional study procedures and their timing are provided in the dose 
escalation safety cohort section of the Study Schedule (at the end of Attachment 1) and outlined 
below. 
10.2.11.1. 
On-Site Post-Infusion Monitoring 
Each subject will be observed for 1 hour after the first dose of 800 mg and the first dose of 
1600 mg. 
10.2.11.2. 
Safety MRI 
An additional safety MRI will be conducted at least 7 days after the second dose of 800 mg and 
at least 7 days before escalating dose to 1600 mg so results of the central read can be reviewed 
by the site before the escalation.  If a study MRI is scheduled within ±2 months of the dose 
escalation MRI, the MRI should be conducted according the dose escalation schedule as a 
substitute for the MRI specified in the main study schedule; an exception is the MRI at endpoint 
(Visit 66), which should be done according to the Study Schedule regardless of timing relative to 
dose escalation.  If a subject experiences symptoms suggestive of ARIA-E at any time, the 
investigator may obtain an unscheduled MRI. 
10.2.11.3. 
Electrocardiogram, Hematology, Chemistry, Urinalysis, and Vital 
Signs 
Additional ECGs will be obtained at the visits at which subjects receive their second dose of 
800 mg and second dose of 1600 mg. 
Additional safety blood draws (hematology, chemistry) and urinalysis will be collected at the 
visits at which subjects receive their second dose of 800 mg and second dose of 1600 mg. 
Vital signs will be monitored before all infusions. 
10.2.11.4. 
PK/PD and Anti-Drug Antibody Assessment 
Additional PK/PD and anti-drug antibody samples will be collected at each of the 2 visits at 
which subjects receive 800 mg and at the first 2 visits and the fourth visit at which subjects 
receive 1600 mg during the dose escalation period. 
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10.2.12. Safety Monitoring 
In consultation with the regulatory sponsor, Medical Monitors or designees will monitor safety 
data throughout the course of the study.  Serious adverse events will be reviewed within time 
frames mandated by procedures.  The Medical Monitors or designees will periodically review: 
 Trends in safety data 
 Laboratory analytes including blood hematology, chemistry, and urinalysis 
 AEs including monitoring of infusion reactions, ARIA-H, ARIA-E, 
hemorrhagic stroke, microhemorrhage (cerebral microhemorrhage, cerebellar 
microhemorrhage, brain stem microhemorrhage) as identified by investigator, 
cardiac ischemia, cardiac arrhythmias, AEs potentially related to 
immunogenicity and suicide-related thoughts and behaviors 
If a study patient/subject experiences elevated ALT or AST >3X ULN or elevated total bilirubin 
>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/subject safety and comply with regulatory guidance, the investigator is to 
consult with the medical monitor regarding collection of specific recommended clinical 
information, follow-up laboratory tests, and follow-up MRIs.  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 treatment until the imaging abnormalities have resolved.  If a 
subject simultaneously develops more than one of the symptoms suggestive of ARIA-E, then an 
unscheduled MRI should be performed.  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. 
Please refer to Section 12.9 for information on what occurs in the event that an issue may need to 
be addressed by unblinding at the group level. 
10.2.13. 
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. 
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or delegate will be reported. 
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study: 
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 recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose 
 faxing the completed product complaint form within 24 hours to Lilly or its designee 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product. 
10.3. Appropriateness of Measurements 
Clinical.  The PACC was developed specifically for use in this study (as described in Attachment 
3).  The measure was applied to data from several large longitudinal studies in clinically normal 
populations to determine whether it was sensitive to change among subjects who declined from 
normal to MCI.  Several datasets confirmed that the measure is able to detect cognitive decline in 
individuals who demonstrate clinical decline to the stage of MCI.  Although it is unknown how 
much progression will be observed in the present study, the PACC is believed to be an 
appropriate measure for assessing change in preclinical AD. 
The CFI and ADCS-ADL Prevention Questionnaire are instruments to track early changes in 
clinical function such as abilities to perform high-level ADL and perception of their own ability 
to perform cognitively demanding functional tasks.  These measures demonstrated significant 
decline in individuals who progressed to MCI in the ADCS-PI trial. 
Other functional outcome measures, including the CDR are well-established in MCI and AD 
studies, although it is expected that only minimal change will be observed in the CDR-SB over 
3 years in individuals who are not functionally impaired at baseline. 
Given the lack of trials in preclinical AD, many of the chosen scales do not have the same depth 
of data and literature characterizing their use and/or responsiveness to treatments in this 
population that they do for populations with more pronounced AD.  Scales were therefore 
selected with an understanding that further validation and refinement would occur as part of this 
trial. 
Biomarkers and Imaging.  There is a large body of evidence supporting CSF Aβ, CSF tau, 
amyloid imaging, and hippocampal and whole brain volume as biomarkers of AD pathology.  
Pathologic hallmarks of AD identified at autopsy include the presence of neuritic Aβ plaques, 
neurofibrillary tangles, and neuronal loss in brain regions important for cognition, such as the 
hippocampus and temporal cortex (Jack et al. 2011).  Tau and phosphorylated forms of tau 
(P-tau) as measured in CSF and plasma are known to be elevated in patients with AD 
(Trojanowski 1996; Green et al. 1999; Morris et al. 2005; Thal et al. 2006).  Cerebrospinal fluid 
Aβ1-42 concentrations are known to be reduced in patients with AD (Motter et al. 1995; Galasko 
et al. 1998, Jack et al. 2010).  Data will be collected in the A4 study to assess the impact of 
treatment with solanezumab on these well-established biomarkers of AD pathology.  In addition, 
there is growing evidence that those who are ‘cognitively normal’ but with brain amyloid 
accumulation exhibit changes consistent with abnormalities seen in AD dementia, including 
cortical thinning (Dickerson et al. 2009; Schott et al. 2010; Chételat et al. 2012) and disruption of 
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functional connectivity (Hedden et al. 2009; Sheline et al. 2010; Mormino et al. 2011); these 
markers will also be assessed in the A4 study. 
Safety.  Safety measures used in this study are all well established. 
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11. Sample Size and Statistical Methods 
11.1. Determination of Sample Size 
In order to develop an appropriate measure of cognitive decline in a preclinical population, we 
tested several combinations of measures using data from longitudinal studies in clinically normal 
populations, including the ADNI; the AIBL; the ADCS-PI trial; and the HABS (Attachment 3).   
Sample size and power at 4.5 years (240 weeks) for the PACC were estimated using data from 
ADNI and HABS.  Estimates were obtained by applying appropriate assumptions regarding 
treatment difference, SD, and attrition for a 4.5-year study in a preclinical AD population.  In 
ADNI, the difference in the composite change between subjects with and without elevated brain 
amyloid at 240 weeks was 2.13 (SD=2.85).  Similarly, in HABS, the difference in the composite 
change between subjects with and without elevated brain amyloid at 240 weeks was 
2.66 (SD=3.08).  Given the ADNI-derived estimate of SD at 240 weeks of SD=2.85 and 30% 
attrition, the total N=1150 provides 80% power (5% 2-sided alpha) to detect a treatment 
difference of 0.532 points or 0.532/2.13 = 24.9% of the amyloid group difference.  Similarly, 
based on the HABS estimate of SD at 240 weeks of SD=3.08, the study has 80% power to detect 
a treatment difference of 0.570 points or 0.570/2.66 = 21.4% of the amyloid group difference. 
For the open-label period, the estimated mean PACC difference between cognitively normal 
subjects with and without elevated brain amyloid at 336 weeks is 2.95 (SD=3.77) based on 
ADNI and 4.74 (SD=3.99) based on HABS.  Accounting for the administrative censoring that 
will be induced by the common close design of the open-label period, and assuming an overall 
attrition rate of 30%, about 266 PACCs are expected to be available at 336 weeks.  The visit-to-
visit correlation is estimated to be about 0.5.  Under these pilot estimates, 266 PACCs at 
336 weeks would provide 80% power to detect a randomized group (early-start vs delayed-start 
treatment with solanezumab) difference of about 0.9 PACC points.  This change of 0.9 PACC 
points reflects 30% of the difference between amyloid-positive and -negative participants based 
on ADNI, and 20% of that difference based on HABS. 
Sample size for the study was determined prior to the interruption caused by the COVID-19 
pandemic. Applying the NCS approach in simulated trials with a COVID-19 pandemic 
interruption suggests the study has 94% power to detect an effect size of 0.75 PACC points at 
240 weeks. 
11.2. Statistical and Analytical Plans 
11.2.1. General Considerations 
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. 
All analyses will follow the modified intent-to-treat (mITT) principle unless otherwise specified.  
An ITT analysis is an analysis of data by groups to which the subjects are assigned by random 
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allocation, even if the subject does not take the assigned treatment, does not receive the correct 
treatment, or otherwise does not follow the protocol.  A mITT analysis is an ITT analysis for all 
subjects who have a baseline and at least 1 postbaseline measure. 
Any change to the statistical 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 
statistical analysis methods described in the protocol, and the justification for making the change, 
will be described in the clinical study report.  Additional exploratory analyses of the data will be 
conducted as deemed appropriate. 
Complete details of the statistical methods to be used this study are contained in the statistical 
analysis plan (SAP). 
11.2.2. Analysis Populations 
The primary and secondary efficacy measures will be analyzed using the mITT population unless 
otherwise specified.   
11.2.3. Handling of Missing Items for Scales 
If any of the individual items for the clinical outcomes are missing, every effort will be made to 
obtain the score for the missing item or items.  The methodology for imputation will be provided 
in the SAP. 
11.2.4. Subject Disposition 
The reasons for discontinuation will be collected when the subject’s participation in the study 
ends and will be summarized by treatment group.  The percentage of subjects discontinuing will 
be compared between groups.  The median time to discontinuation will also be compared 
between treatment groups.  The comparisons will be done for the overall percentage of subjects 
who discontinue and also for specific reasons for discontinuation. 
11.2.5. Subject Characteristics 
Baseline and demographic characteristics will be summarized by treatment group and overall.  
Summaries will be provided for continuous and categorical measures. 
11.2.6. Prior and Concomitant Therapy 
Prior medications are defined as those that stop before randomization.  Concomitant medications 
are defined as those being taken on or after randomization.  A summary of concomitant 
medications will be presented as frequencies and percentages for each treatment group.  Fisher’s 
exact test will be used to test for treatment differences between groups. 
If the start or stop dates of therapies are missing or partial to the degree that determination cannot 
be made of whether the therapy is prior or concomitant, the therapy will be deemed concomitant. 
Prior and concomitant medications will also be listed. 
Medications will be coded using the World Health Organization drug dictionary. 
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11.2.7. Protocol Violations 
Protocol violations will be analyzed as frequency tables between solanezumab and placebo.  
Listings of subjects with significant protocol violations will also be provided. 
11.2.8. Analysis of Primary Outcome (Placebo-Controlled Period) 
The primary objective of this study is to test the hypothesis that IV infusion of solanezumab will 
slow cognitive decline in preclinical AD as compared with placebo. 
The original mITT analysis (that is, all participants as randomized to treatment who have a 
baseline and at least 1 postbaseline measure) for the primary outcome will be retained and 
conducted at the end of the treatment period, although the dose will be increased during the 
study; in other words, the primary analysis will include all data for the solanezumab group as the 
treatment group versus placebo.  As with the original analysis plan, the hypothesis for this 
analysis will be tested against an alpha level of .05. 
The details of this analysis including the analytic method and model are presented below. 
An NCS analysis will be used to assess the difference between treatment groups in change from 
baseline for the PACC score at 4.5 years.  The composite score at baseline and each post-
baseline visit will be the dependent variable.  Time will be treated as a continuous variable with 
values equal to years between baseline and follow-up exam dates.  We will assume an 
unstructured covariance structure.  The fixed effects will include the following terms: (i) NCS 
basis expansion terms (two terms), (ii) NCS basis expansion terms-by-treatment interaction (two 
terms), (iii) PACC test version administered, (iv) age, (v) education, (vi) APOE 4 carrier 
(yes/no), and (vii) baseline florbetapir cortical SUVr.  The model is constrained to not allow a 
difference between treatment group means at baseline. 
The null hypothesis is that the treatment difference between solanezumab and placebo for the 
PACC score at 240 weeks is equal to zero.  The primary analysis will be carried out in the mITT 
population that is randomized and has a baseline score and at least 1 postbaseline assessment.  If 
the unstructured covariance structure matrix results in a lack of convergence, the following 
structures will be used in sequence:   
 heterogeneous Toeplitz covariance structure 
 heterogeneous autoregressive order 1 covariance structure 
 heterogeneous compound symmetry covariance structure, and 
 compound symmetry covariance structure. 
The sensitivity analyses of the effect of dose change on clinical outcomes are included in 
Section 11.2.9.2. 
11.2.9. Analysis of Secondary Outcomes (Placebo-Controlled Period) 
11.2.9.1. Clinical Outcomes 
Similar to the primary analysis, each of the secondary efficacy outcomes will be assessed using 
an NCS analysis.  These secondary efficacy outcomes include MMSE, ADCS-ADL Prevention 
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Questionnaire, CDR-SB, CFI, and C3.  For each secondary efficacy measure, the baseline score 
and scores at each post-baseline visit during the treatment period will be analyzed using NCS. 
Also similar to the primary analysis, all data from all patients regardless of dose increase will be 
included for the solanezumab and placebo groups. 
Each of the secondary efficacy outcomes will be assessed using an MMRM analysis.  These 
secondary efficacy outcomes include MMSE, ADCS-ADL Prevention Questionnaire, CDR-SB, 
CFI, and C3.  For each secondary efficacy measure, scores at each post-baseline visit during the 
treatment period will be analyzed using MMRM. 
An additional MMRM analysis, termed a slopes analysis, will be conducted examining the 
change from baseline score on the PACC at each scheduled postbaseline visit.  The slope 
analysis will treat time from randomization as a continuous variable. 
11.2.9.2. Sensitivity Analyses  
Sensitivity analyses of the effect of dose change on clinical outcomes will be conducted as noted 
in the SAP. 
1. An MMRM analysis will be performed separately on the PACC and other clinical 
measures after censoring all observations after the dose increase.  In other words, change 
from baseline for the clinical measure will be obtained only through the last available 
value prior to first dose escalation for each subject. 
 
The null hypothesis is that the treatment difference between solanezumab and placebo for 
the PACC score is equal to zero.  Since the timing (visit) of dose escalation will vary for 
each subject, a specific endpoint for comparison between treatment groups will not be 
available.  Therefore, the hypothesis will be tested using the p-value obtained for the 
overall treatment effect. 
 
2. Additionally, we will implement a sensitivity analysis to estimate the potential 
differences in the treatment effect for the original dose and the higher dose by modeling 
the effects of a time-varying dose indicator variable (with values placebo, low, and high).  
The time-varying dose indicator variable will be fitted as a separate variable to the ITT 
model of change from baseline on the primary measure (PACC) and other secondary 
measures. 
 
The fixed effects in the model for the sensitivity analysis will be constructed as follows: 
 
Change from baseline = baseline score + dose+ visit + dose-by-visit interaction + age + 
education + baseline cortical SUVr  
 
The coefficient for this new time-varying dose indicator variable will provide estimates to 
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compare and contrast all dose groups at the relevant time points at which the different 
doses were assigned. 
 
3. Another sensitivity analysis will include the mean dose for each subject as a separate 
co-variable.  The fixed effects in the model will be the following: 
 
Change from baseline = baseline score + treatment + visit + treatment-by-visit interaction 
+ age + education + baseline cortical SUVr + mean dose. 
 
Additional sensitivity analyses will be included in the SAP. 
11.2.9.3. Biomarker Outcomes 
Analysis of Plasma Change in plasma A and P-tau, GFAP, and Neurofilament light chain after 
treatment will be compared between treatment groups.  This analysis will be done separately for 
each plasma A and P-tau parameter. 
Analysis of vMRI Data.  Change in vMRI data after treatment will be compared between 
treatment groups.  This analysis will be done separately for each vMRI parameter. 
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 compared between treatment groups. 
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-tau peptides, GFAP Neurofilament light 
chain, will be compared between treatment groups. 
11.2.10. 
Open-Label Period 
When change from baseline is assessed, subjects will be included in the summary only if both a 
baseline and a postbaseline measure are available.  For efficacy analyses (noninferiority and 
superiority analyses), the baseline will be the last non-missing observation collected prior to the 
initiation of treatment in the placebo-controlled period, generally, Visit 6. 
Treatment group comparisons used in the statistical analysis will be the treatment group to which 
the subjects were randomized in the placebo-controlled period (subjects randomized to 
solanezumab [early start] versus patients randomized to placebo [delayed start]). 
For analyses using MMRM, an unstructured covariance matrix will be used to model the 
within-patient variance–covariance errors.  If the unstructured covariance matrix results in a lack 
of convergence, the heterogeneous Toeplitz covariance structure, followed by the heterogeneous 
autoregressive covariance structure, will be used.  The Kenward–Roger approximation will be 
used to estimate the denominator degrees of freedom. 
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In the event that the primary contrast for the placebo-controlled period at 240 weeks is 
statistically significant, delayed-start analyses will proceed based on the methods described by 
Liu-Seifert and colleagues (2015).  Several efficacy measures (PACC, ADCS-ADL Prevention 
Questionnaire, CDR-SB, C3, and CFI) will be analyzed separately using a noninferiority 
hypothesis in an MMRM model, in which the specific hypothesis is that the advantage of 
solanezumab treatment demonstrated in the placebo-controlled period is sufficiently maintained 
in the open-label period.  This randomized/delayed-start analysis will assess whether 
solanezumab has a persistent effect on disease course.  That is, the hypothesis is that subjects 
originally randomized to receive placebo and later switched to solanezumab at the start of the 
open-label period do not “catch up” to subjects originally randomized to receive solanezumab in 
the placebo-controlled period.  This may be understood as a comparison of the treatment 
difference at the end of the placebo-controlled period with the treatment difference at the end of 
the open-label period. 
The noninferiority margin for this hypothesis is specified as 50% of the treatment difference 
observed at the end of the placebo-controlled period.  The hypothesis will be tested by 
constructing a 90% one-sided CI of the difference in LS means at the last visit in the open-label 
period.  If the lower limit of the CI rules out the difference that would have been obtained if 50% 
of the observed difference had been lost, the disease progression for the treatment groups will be 
considered parallel, indicating that the treatment effect is independent of symptomatic effects.  
The interim noninferiority analysis of the PACC up to Week 336 in the open-label period will be 
considered the main efficacy analysis for the open-label period.   
In addition to the noninferiority test, superiority of early-start subjects compared with 
delayed-start subjects at the 336-week analysis in the open-label period will also be assessed.  
The PACC, ADCS-ADL Prevention Questionnaire, CDR-SB, C3, and CFI will be analyzed. 
11.2.11. 
Gatekeeping Strategy 
Given continuing evolution in the field regarding assessment of clinical meaningfulness in a 
preclinical AD population, a formal gatekeeping strategy is not currently planned.  If a 
gatekeeping strategy is used, it will be specified in an SAP before database lock. 
11.2.12. 
Pharmacokinetic/Pharmacodynamic Analyses 
The distribution of observed plasma solanezumab concentrations will be graphically compared to 
simulated solanezumab concentrations generated by a population 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 subjects with treatment-emergent immunogenicity will be plotted as a 
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function of time, along with mean plasma solanezumab concentrations in all subjects.  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 subjects will 
also be presented on the graph.  If this graphical analysis demonstrates a trend in plasma 
solanezumab concentrations in subjects with treatment-emergent immunogenicity relative to the 
overall trial population, additional work may be performed to characterize this trend. 
11.2.13. 
Safety Analyses 
All analyses will depend on the analysis populations being specified.  For the analyses and 
summary statistics, the 2 analysis populations to be used are randomized subject population and 
placebo-controlled population.  The randomized subject population will include all randomized 
subjects in the A4 study and will include observations across both the placebo-controlled period 
and the open-label period.  The placebo-controlled population will include all enrolled subjects 
who have entered the placebo-controlled period of the A4 study and will be limited to 
observations collected during the placebo-controlled period of the study. 
Safety will be assessed by summarizing and analyzing AEs, laboratory analytes, vital signs, MRI 
scans, ECGs, immunogenicity measures, and the C-SSRS during the treatment period.  Safety 
analyses of the open-label extension will span across both the placebo-controlled study period 
and the open-label study period in order to be able to compare early-start safety risks to 
early-start efficacy benefits. 
For safety assessments, 3 separate sets of analyses will be conducted:  1 set of analyses for all 
data when the subjects were on 400 mg Q4W, 1 set of analyses for all data when the subjects 
were receiving doses higher than 400 mg Q4W, and 1 set of analyses for all data (regardless of 
dose). 
11.2.13.1. 
Study Drug Infusion 
Summary statistics will be provided for the total number of subjects who received complete 
infusions, duration of complete infusion, and volume of complete infusion by treatment group at 
each visit.  The proportions of subjects who received complete infusion between treatments will 
be compared between treatment groups.  Duration of complete infusion and volume of complete 
infusion will also be compared between treatment groups. 
Frequencies and percentages of reasons why infusion was incomplete or not done will also be 
presented. 
11.2.13.2. 
Adverse Events 
Adverse events will be coded according to established Medical Dictionary for Regulatory 
Activities (MedDRA) terms and summarized by MedDRA System Organ Class and Preferred 
Term. 
Treatment-emergent adverse events will be defined as events that first occurred or worsened on 
or after the first infusion. 
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An overview of AEs, including the number and percentage of subjects who died, suffered SAEs, 
discontinued due to AEs, and who suffered TEAEs, will be provided.  Comparison between 
treatments will be performed. 
Summaries of AEs by decreasing frequency of preferred term within system organ class will be 
provided for the following: 
 Preexisting conditions 
 TEAEs 
 TEAEs by maximum severity 
 TEAEs occurring in greater than 5% of subjects by Preferred Term 
 SAEs 
A summary of TEAEs by visit will also be provided. 
In addition, the proportion of subjects within specific clusters of TEAEs, such as infusion-related 
reactions, hemorrhagic stroke and cerebral microhemorrhage, cardiac ischemia-related events, 
cardiac arrhythmia-related events, and suicidal ideation or behaviors will be summarized and 
treatment comparisons will be conducted. 
Preexisting conditions, TEAEs, SAEs, and discontinuations due to AEs will be listed. 
11.2.13.3. 
Laboratory Analyses 
Laboratory measurements will be analyzed using continuous data (change from baseline) and 
categorical data (proportion of treatment-emergent abnormalities). 
11.2.13.4. 
Electrocardiograms 
The ECG measurements will be analyzed using continuous data (change from baseline) and 
categorical data (proportion of treatment-emergent abnormalities). 
11.2.13.5. 
Vital Signs 
Vital sign measurements (including temperature and weight) will be analyzed using continuous 
data (change from baseline) and categorical data (proportion of treatment-emergent 
abnormalities). 
11.2.13.6. 
Immunogenicity 
Immunogenicity data (anti-solanezumab) after treatment will be compared between the treatment 
groups. 
11.2.13.7. 
Amyloid-Related Imaging Abnormalities:  Magnetic Resonance 
Imaging 
The incidence of ARIA-E will be summarized.  Change in ARIA-E status from baseline, to each 
postbaseline MRI will be compared between treatment groups. 
The incidence of ARIA-H will be summarized.  Change in ARIA-H status from baseline to each 
postbaseline MRI will be compared between treatment groups. 
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11.2.13.8. 
Columbia Suicide Severity Rating Scale 
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent occurring 
during treatment, based on the C-SSRS, will be summarized.  In particular, for each of the 
following events, the number and percentage of patients with the event will be enumerated by 
treatment:  completed suicide, nonfatal suicide attempt, interrupted attempt, aborted attempt, 
preparatory acts or behavior, active suicidal ideation with specific plan and intent, active suicidal 
ideation with some intent to act without specific plan, active suicidal ideation with any methods 
(no plan) without intent to act, nonspecific active suicidal thoughts, wish to be dead, and self-
injurious behavior without suicidal intent. 
Results will be summarized for “at any time” (irrespective of baseline) and “treatment emergent” 
(new or worsening since baseline) events. 
In addition, the number and percentage of patients who experienced at least 1 component of 
various composite measures will be presented.  Composite endpoints are defined below. 
 Suicidal ideation:  A “yes” answer at any time during treatment to any 1 of the 5 suicidal 
ideation questions on the C-SSRS. 
 Suicidal behavior:  A “yes” answer at any time during treatment to any 1 of the 5 suicidal 
behavior questions on the C-SSRS. 
11.2.14. 
Subgroup Analyses 
To assess the effects of various demographic and baseline characteristics, subgroup analyses of 
the efficacy outcomes will be performed. 
11.2.15. 
Interim Analyses 
An interim analysis for futility may be conducted.  If an interim analysis for futility is conducted, 
the details will be described in the SAP prior to the analysis.  Only the data and safety 
monitoring board (DSMB) 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 subjects. 
Unblinding details will be specified in the unblinding plan section of the SAP or a separate 
unblinding plan document. 
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12. Informed Consent, Ethical Review, and Regulatory 
Considerations 
12.1. Informed Consent and HIPAA Compliance 
12.1.1. Informed Consent 
The investigator is responsible for ensuring that the subject and study partner(s) understand the 
potential risks and benefits of participating in the study, including answering any questions the 
subject may have throughout the study and sharing in a timely manner any new information that 
may be relevant to the subject’s willingness to continue his or her participation in the trial. 
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study, and to document that the 
subject is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study. 
The investigator is responsible for ensuring that informed consent is given by each subject before 
the performance of any protocol procedures and before the administration of investigational 
product.  The investigator is also responsible for ensuring that study partners provide informed 
consent. 
As used in this protocol, the term “informed consent” includes all consent and assent given by 
subjects and study partners. 
12.2. Ethical Review 
The ATRI must approve all ICFs before they are submitted to the ERB and used at investigative 
sites.  All ICFs must be compliant with the International Conference on Harmonisation (ICH) 
guideline on GCP.  Standard ATRI Regulatory Affairs procedures will be followed tracking, 
monitoring and assisting with ERB reviews at the sites. 
As part of study initiation, documentation of ERB approval of the protocol and the ICF must be 
provided to ATRI as part of the regulatory packages before the study may begin at the 
investigative sites.  The standard ATRI Regulatory Approval process will be followed.  The 
ERB(s) will review the protocol as required. 
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol. 
12.3. Confidentiality 
An identification code assigned by the investigator to each subject will be used in lieu of the 
subject’s name in order to protect the subject’s identity when reporting AEs and/or other 
trial-related data. 
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In addition, information about study subjects will be kept confidential and managed according to 
the requirements of HIPAA.  Those regulations require a signed subject authorization informing 
the subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (that is, that the subject is 
alive) at the end of their scheduled study period. 
12.4. Inclusion of Women and Minorities 
Special efforts will be made to encourage minority enrollment, with a requirement to screen at 
least one out of every 5 subjects from an under-represented minority, and minority recruitment 
will be monitored throughout the study.  Minority enrollment will be facilitated through minority 
outreach effort coordinated by the Recruitment and Retention group at the ATRI.  Each site will 
be encouraged to employ specific efforts (for example, media and community outreach 
activities) to attract appropriate minority subjects to the trial.  Spanish translation is available for 
a variety of instruments deployed in this trial.  The success of minority recruitment is based on 
the specific efforts of each site (for example, media and community outreach efforts) as well as 
the criteria for entry.  This trial has been designed to maximize minority participation in both 
ways.  No subject will be excluded due to their sex, race, or ethnic group. 
12.5. Regulatory Considerations 
This study will be conducted in accordance with: 
[1] 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 
[2] the ICH GCP Guideline [E6] 
[3] applicable laws and regulations 
The investigator or designee will promptly submit the protocol to applicable ERB(s). 
12.6. Site Personnel Requirements 
12.6.1. Roles and Responsibilities 
At a minimum, 3 staff members (Site Principal Investigator, Study Coordinator, 
Psychometrician) will be required to conduct the protocol at each site.  Additional functions are 
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outlined below that may be covered by one staff member at certain sites; for other sites there will 
be multiple staff assigned.  Details will be provided in the relevant procedures manual. 
 Site Principal Investigator.  This person is responsible for ensuring that the 
local ERB approves the protocol and oversees all site activity for the study; 
this person may also serve as the study physician.  See also Section 12.6.2. 
 Study Physician.  This person is responsible for conducting or supervising the 
amyloid disclosure process, and clinical evaluation of all subjects, including 
physical and neurological examinations, reviewing AEs, interpreting 
laboratory results; ensuring enrollment and protocol adherence.  The study 
physician will supervise project personnel and ensure that raters maintain a 
high level of skill and accuracy in conducting assessments. 
 Study Coordinator.  This person will be responsible for managing the day-to-
day conduct of the trial, ensuring accurate administration of all instruments, 
maintaining online data and scheduling study procedures, processing 
laboratory samples, serving as liaison with the clinical monitor, and 
coordinating clinic visits.  The study coordinator may perform several ratings, 
including the CDR. 
 Rater/Psychometrician.  This person will have at least 1 year experience 
administering cognitive assessments to older and cognitively impaired 
subjects. 
 CDR Rater:  This person must have a current rater certification through 
Washington University and should have at least 2 years of clinical experience 
in interviewing and assessing older and cognitively impaired subjects, and 
will render the CDR rating based on clinical judgment of study subject and 
study partner. 
 Regulatory:  This person will be responsible for managing all regulatory 
related documents for the duration of the trial, including submitting all 
required regulatory documents to ATRI regulatory affairs. 
 Billing Remittance and Statement:  This person will be responsible for 
reviewing and verifying payments from the ATRI are in alignment with 
procedures completed, along with accepting and processing payments from 
the ATRI. 
 MRI Contact:  This person will be responsible for conducting necessary scan 
for site qualification purposes using the appropriate scanning sequence.  As 
well as conducting subject MRI scans per protocol and ensuring the scans are 
uploaded to the A4 portal in a timely manner. 
 PET Contact:  This person will be responsible for conducting necessary scan 
for site qualification purposes and as needed to assess for drift using the 
appropriate scanning sequence.  As well as conducting subject PET scans per 
protocol and ensuring the scans are uploaded to the A4 portal in a timely 
manner. 
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12.6.2. Investigator/Rater Requirements 
Physicians with expertise in neurology, geriatrics, or psychiatry will participate as investigators 
in this clinical study.  Contact information for investigators, clinical laboratories, and other 
medical and/or technical department(s) and/or institutions involved in the clinical study are 
maintained in the study records. 
Cognitive assessments must be administered by an individual trained in the use of these 
instruments.  Investigators and site personnel who will perform ratings will be trained and 
approved by ATRI or its designee prior to participating in the study.  In most cases, evaluation 
and notification will occur at the investigator meeting.  Individuals who do not attend the rater 
evaluation and training portion of the investigator meeting and who wish to perform the ratings 
in this study must be appropriately trained prior to performing any ratings.  If possible, the 
measurements should be performed on a given subject by the same rater at each visit.  The 
primary investigator has the responsibility of selecting who will administer the instruments at the 
site, as long as all training requirements have been met by those raters. 
12.7. Protocol Signatures 
The regulatory sponsor’s responsible medical officer, the ATRI Director, and the Project 
Director will approve the protocol, confirming that, to the best of their 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 ATRI. 
12.8. Final Report Signature 
The clinical study report coordinating investigator will sign the final clinical study report 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 number of qualified, enrolled subjects will be considered when determining the coordinating 
investigator for the clinical study report.  If this investigator is unable to fulfill this function, 
another investigator will be chosen by Lilly to serve as the clinical study report coordinating 
investigator. 
The regulatory sponsor’s responsible medical officer and statistician will approve the final 
clinical study report for this study, confirming that, to the best of their knowledge, the report 
accurately describes the conduct and results of the study. 
12.9. Data and Safety Monitoring Board 
The DSMB will review the safety of all subjects on an ongoing basis.  The initial task of the 
DSMB will be to review the protocol and consent forms to identify any necessary modifications.  
If modifications are necessary, revisions will be reviewed by the DSMB prior to its 
recommendation on initiation of the project.  The DSMB, based on its review of the protocol, 
will identify the data parameters and format of the information to be regularly reported.  The 
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DSMB will be informed of the occurrence of any SAEs and immediately notified of fatal or life 
threatening events.  The DSMB may at any time request additional information.  The DSMB will 
initially be provided with data blinded to treatment status, but they may request unblinded data if 
there is a safety concern.  The DSMB and NIA representative will meet in person or by 
conference call on a quarterly basis.  Based on the review of safety data, the DSMB will make 
recommendations regarding the conduct of the study.  These may include amending safety 
monitoring procedures, modifying the protocol or consent, terminating the study or continuing 
the study as designed.  The Board will also be informed in a real-time basis of all immediately 
reportable AE (FDA-defined serious AE).  All reports are stripped of identifying information.  
Using the ATRI Safety Review Process and the DSMB, there is substantial oversight and case 
review to alert the investigators, in a timely manner, to any safety issues that may arise.  For 
further details, please refer to the DSMB charter. 
 
 
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13. References 
Amariglio Donohue MC, Marshall GA, Rentz DM, Salmon DP, Ferris SH, Karantzoulis S, Aisen 
PS, Sperling RA; Alzheimer’s Disease Cooperative Study. Tracking early decline in cognitive 
function in older individuals at risk for Alzheimer disease dementia: the Alzheimer’s Disease 
Cooperative Study Cognitive Function Instrument. JAMA Neurol. 2015;72(4):446-454.  
Erratum in: JAMA Neurol. 2015;72(5):608. 
Andrews KA, Modat M, Macdonald KE, Yeatman T, Cardoso MJ, Leung KK, Barnes J, 
Villemagne VL, Rowe CC, Fox NC, Ourselin S, Schott JM; Australian Imaging, Biomarkers 
and Lifestyle Flagship Study of Ageing. Atrophy rates in asymptomatic amyloidosis: 
implications for Alzheimer prevention trials. PLoS One. 2013;8(3):e58816. 
Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, 
Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, 
Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, 
Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited 
Alzheimer Network. Clinical and biomarker changes in dominantly inherited 
Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804. 
Carlson C, Estergard W, Oh J, Suhy J, Jack CR Jr, Siemers E, Barakos J. Prevalence of 
asymptomatic vasogenic edema in pretreatment Alzheimer’s disease study cohorts from phase 
3 trials of semagacestat and solanezumab. Alzheimers Dement. 2011;7(4):396-401. 
Chételat G, Villemagne VL, Villain N, Jones G, Ellis KA, Ames D, Martins RN, Masters CL, 
Rowe CC; AIBL Research Group. Accelerated cortical atrophy in cognitively normal elderly 
with high β-amyloid deposition. Neurology. 2012;78(7):477-484. 
Darby DG, Brodtmann A, Pietrzak RH, Fredrickson J, Woodward M, Villemagne VL, 
Fredrickson A, Maruff P, Rowe C. Episodic memory decline predicts cortical amyloid status 
in community-dwelling older adults. J Alzheimers Dis. 2011;27(3):627-637. 
Dickerson BC, Bakkour A, Salat DH, Feczko E, Pacheco J, Greve DN, Grodstein F, Wright CI, 
Blacker D, Rosas HD, Sperling RA, Atri A, Growdon JH, Hyman BT, Morris JC, Fischl B, 
Buckner RL. The cortical signature of Alzheimer’s disease: regionally specific cortical 
thinning relates to symptom severity in very mild to mild AD dementia and is detectable in 
asymptomatic amyloid-positive individuals. Cereb Cortex. 2009;19(3):497-510. 
Donohue MC, Sperling RA, Petersen R, Sun CK, Weiner MW, Aisen PS. Association between 
elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. 
JAMA. 2017;317(22):2305-2316. 
Doraiswamy PM, Sperling RA, Coleman RE, Johnson KA, Reiman EM, Davis MD, 
Grundman M, Sabbagh MN, Sadowsky CH, Fleisher AS, Carpenter A, Clark CM, Joshi AD, 
Mintun MA, Skovronsky DM, Pontecorvo MJ; AV45-A11 Study Group. Amyloid-β assessed 
by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology. 
2012;79(16):1636-1644. 
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, 
Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, 
O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, 
Approved on 09 Aug 2022 GMT

CONFIDENTIAL 
H8A-MC-LZAZ(f) 
LY2062430 
Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet 
Neurol. 2010;9(11):1118-1127. 
Duncan BL, Miller SD, Wampold BE, Hubble MA, eds. The Heart and Soul of Change: 
Delivering What Works in Therapy. 2nd ed. Washington, DC: American Psychological 
Association; 2010. 
Ellis KA, Lim YY, Harrington K, Ames D, Bush AI, Darby D, Martins RN, Masters CL, 
Rowe CC, Savage G, Szoeke C, Villemagne VL, Maruff P; AIBL Research Group. Decline in 
cognitive function over 18 months in healthy older adults with high amyloid-β. J Alzheimers 
Dis. 2013;34(4):861-871. 
[FDA] United States Food and Drug Administration. Guidance for Industry. Suicidal Ideation 
and Behavior:  Prospective Assessment of Occurrence in Clinical Trials [draft guidance], 
August 2012. Available at: http://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf. 
Accessed February 4, 2013. 
Ferris SH, Aisen PS, Cummings J, Galasko D, Salmon DP, Schneider L, Sano M, 
Whitehouse PJ, Edland S, Thal LJ; Alzheimer’s Disease Cooperative Study Group. ADCS 
Prevention Instrument Project: overview and initial results. Alzheimer Dis Assoc Disord. 
2006;20(4)(suppl 3):S109-S123. 
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(13):189-198. 
Galasko D, Bennett DA, Sano M, Marson D, Kaye J, Edland SD; Alzheimer’s Disease 
Cooperative Study. ADCS Prevention Instrument Project: assessment of instrumental activities 
of daily living for community-dwelling elderly individuals in dementia prevention clinical 
trials. Alzheimer Dis Assoc Disord. 2006;20(4)(suppl 3):S152-S169. 
Galasko D, Chang L, Motter R, Clark CM, Kaye J, Knopman D, Thomas R, Kholodenko D, 
Schenk D, Lieberburg I, Miller B, Green R, Basherad R, Kertiles L, Boss MA, Seubert P. High 
cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer 
disease and relation to apolipoprotein E genotype. Arch Neurol. 1998;55(7):937-945. 
Gόmez-Isla T, Price JL, McKeel DW, Jr, Morris JC, Growdon JH, Hyman BT. Profound loss of 
layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci. 
1996;16(14):4491-4500. 
Green AJ, Harvey RJ, Thompson EJ, Rossor MN. Increased tau in the cerebrospinal fluid of 
patients with frontotemporal dementia and Alzheimer’s disease. Neurosci Lett. 
1999;259(2):133-135. 
Grober E, Hall CB, Lipton RB, Zonderman AB, Resnick SM, Kawas C. Memory impairment, 
executive dysfunction, and intellectual decline in preclinical Alzheimer’s disease. J Int 
Neuropsych Soc. 2008;14(2):266-278. 
Grober E, Buschke H, Crystal H, Bang S, Dresner R. Screening for dementia by memory testing. 
Neurology. 1988;38(6):900-903. 
Hedden T, Van Dijk KR, Becker JA, Mehta A, Sperling RA, Johnson KA, Buckner RL. 
Disruption of functional connectivity in clinically normal older adults harboring amyloid 
burden. J Neurosci. 2009;29(40):12686-12694. 
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Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress. 
Psychosom Med. 1979;41(3):209-218. 
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, 
Phelps CH. Introduction to the recommendations from the National Institute on Aging-
Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. 
Alzheimers Dement. 2011;7(3):257-262. 
Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, 
Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological 
cascade. Lancet Neurol. 2010;9(1):119-128. 
Knopman DS, Jack C Jr, Wiste HJ, Weigand SD, Vemuri P, Lowe V, Kantarci K, Gunter JL, 
Senjem ML, Ivnik RJ, Roberts RO, Boeve BF, Petersen RC. Short-term clinical outcomes for 
stages of NIA-AA preclinical Alzheimer Disease. Neurology. 2012;78(20):1576-1582. 
Lang FR, Carstensen LL. Time counts: future time perspective, goals and social relationships. 
Psychol Aging. 2002;17(1):125-139. 
Lim YY, Ellis KA, Harrington K, Ames D, Martins RN, Masters CL, Rowe C, Savage G, 
Szoeke C, Darby D, Maruff P; The Aibl Research G. Use of the CogState Brief Battery in the 
assessment of Alzheimer’s disease related cognitive impairment in the Australian Imaging, 
Biomarkers and Lifestyle (AIBL) study. J Clin Exp Neuropsychol. 2012a;34(4):345-358. 
Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, Martins R, Masters CL, 
Rowe C, Savage G, Szoeke C, Villemagne V, Maruff P; The AIBL Research Group. Stronger 
effect of amyloid load than APOE genotype on cognitive decline in healthy older adults. 
Neurology. 2012b;79(16):1645-1652. 
Lim YY, Laws SM, Villemagne VL, Pietrzak RH, Porter T, Ames D, Fowler C, Rainey-Smith S, 
Snyder PJ, Martins RN, Salvado O, Bourgeat P, Rowe CC, Masters CL, Maruff P. 
Abeta-related memory decline in APOE epsilon4 noncarriers: Implications for Alzheimer 
disease, Neurology. 2016;86(17):1635-1642. 
Lim YY, Pietrzak RH, Ellis KA, Jaeger J, Harrington K, Ashwood T, Szoeke C, Martins RN, 
Bush AI, Masters CL, Rowe CC, Villemagne VL, Ames D, Darby D, Maruff P. Rapid decline 
in episodic memory in healthy older adults with high amyloid-β. J Alzheimers Dis. 
2013;33(3):675-679. 
Liu-Seifert H, Andersen SW, Lipkovich I, Holdridge KC, Siemers E. A novel approach to 
delayed-start analyses for demonstrating disease-modifying effects in Alzheimer’s disease. 
PLoS One. 2015;10(3):e0119632. 
Marteau TM, Bekker H. The development of a six-item short-form of the state scale of the 
Spielberger State-Trait Anxiety Inventory (STAI). Br J Clin Psychol. 1992;31(Pt 3):301-306. 
Miller SD, Duncan BL, Sorrell R, Brown GS. The partners for change outcome management 
system. J Clin Psychol. 2005;61(2):199-208. 
Mormino E, Papp KV, Rentz DM, Donohue MC, Amariglio R, Quiroz YT, Chhatwal J, Marshall 
GA, Donovan N, Jackson J, Gatchel JR, Hanseeuw BJ, Schultz AP, Aisen PS, Johnson KA, 
Sperling RA. Early and late change on the preclinical Alzheimer’s cognitive composite in 
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clinically normal older individuals with elevated betaamyloid. Alzheimers Dement. 
2017;13(9):1004-1012. 
Mormino EC, Smiljic A, Hayenga AO, Onami SH, Greicius MD, Rabinovici GD, Janabi M, 
Baker SL, Yen IV, Madison CM, Miller BL, Jagust WJ. Relationships between β-amyloid and 
functional connectivity in different components of the default mode network in aging. Cereb 
Cortex. 2011;21(10):2399-2407. 
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 
1993;43(11):2412-2414. 
Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, Fagan AM, Holtzman DM, 
Mintun MA. Pittsburgh compound B imaging and prediction of progression from cognitive 
normality to symptomatic Alzheimer disease. Arch Neurol. 2009;66(12):1469-1475. 
Morris JC, Quaid KA, Holtzman DM, Kantarci K, Kaye J, Reiman EM, Klunk WE, Siemers ER. 
Role of biomarkers in studies of presymptomatic Alzheimer’s disease. Alzheimers Dement, 
2005;1(2):145-151. 
Motter R, Vigo-Pelfrey C, Kholodenko D, Barbour R, Johnson-Wood K, Galasko D, Chang L, 
Miller B, Clark C, Green R. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of 
patients with Alzheimer’s disease. Ann Neurol. 1995;38(4):643-648. 
Papp KV, Rentz DM, Mormino EC, Schultz AP, Amariglio RE, Quiroz Y, Johnson KA, Sperling 
RA. Cued memory decline in biomarker-defined preclinical Alzheimer’s disease. Neurology. 
2017;88(15):1431-1438. 
Petersen RC, Wiste HJ, Weigand SD, Rocca WA, Roberts RO, Mielke MM, Lowe VJ, Knopman 
DS, Pankratz VS, Machulda MM, Geda YE, Jack CR Jr. Association of elevated amyloid 
levels with cognition and biomarkers in cognitively normal people from the community. JAMA 
Neurol. 2016;73(1):85-92. 
Reid M, Parkinson L, Gibson R, Schofield P, D’Este C, Attia J, Tavener M, Byles J. Memory 
complaint questionnaire performed poorly as screening tool: validation against psychometric 
tests and affective measures. J Clin Epidemiol. 2012;65(2);199-205. 
Roberts JS. Anticipating response to predictive genetic testing for Alzheimer's disease: a survey 
of first-degree relatives. Gerontologist. 2000;40(1):43-52. 
Roberts JS, Connell CM. Illness representations among first-degree relatives of people with 
Alzheimer disease. Alzheimer Dis Assoc Disord. 2000;14(3):129-136. 
Rentz DM, Locascio JJ, Becker JA, Moran EK, Eng E, Buckner RL, Sperling RA, Johnson KA. 
Cognition, reserve, and amyloid deposition in normal aging. Ann Neurol. 2010;67(3):353-364. 
Sano M, Zhu CW, Whitehouse PJ, Whitehouse PJ, Edland S, Jin S, Ernstrom K, Thomas RG, 
Thal LJ, Ferris SH; Alzheimer Disease Cooperative Study Group. ADCS Prevention 
Instrument Project: pharmacoeconomics: assessing health-related resource use among healthy 
elderly. Alzheimer Dis Assoc Disord. 2006;20(4)(suppl 3):S191-S202. 
Schott JM, Bartlett JW, Fox NC, Barnes J; Alzheimer’s Disease Neuroimaging Initiative 
Investigators. Increased brain atrophy rates in cognitively normal older adults with low 
cerebrospinal fluid Aβ1-42. Ann Neurol. 2010;68(6):825-834. 
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Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of 
a shorter version. In: Brink TL, ed. Clinical Gerontology: A Guide to Assessment and 
Intervention. New York, NY: The Haworth Press; 1986:p 165-173. 
Sheline YI, Raichle ME, Snyder AZ, Morris JC, Head D, Wang S, Mintun MA. Amyloid plaques 
disrupt resting state default mode network connectivity in cognitively normal elderly. Biol 
Psychiatr. 2010;67(6):584-587. 
Sperling R, Chua E, Cocchiarella A, Rand-Giovannetti E, Poldrack R, Schacter DL, Albert M. 
Putting names to faces: successful encoding of associative memories activates the anterior 
hippocampal formation. Neuroimage. 2003;20(2):1400-1410. 
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Jr, 
Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, 
Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the 
preclinical stages of Alzheimer’s disease: recommendations from the National Institute on 
Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer’s disease. 
Alzheimers Dement. 2011a;7(3):280-292. 
Sperling RA, Jack CR Jr, Aisen PS. Testing the right target and right drug at the right stage. 
Sci Transl Med. 2011b;3(111):111cm133. 
Sperling RA, Johnson KA, Doraiswamy PM, Reiman EM, Fleisher AS, Sabbagh MN, 
Sadowsky CH, Carpenter A, Davis MD, Lu M, Flitter M, Joshi AD, Clark CM, Grundman M, 
Mintun MA, Skovronsky DM, Pontecorvo MJ; AV45-A05 Study Group. Amyloid deposition 
detected with florbetapir F 18 ((18)F-AV-45) is related to lower episodic memory performance 
in clinically normal older individuals. Neurobiol Aging. 2013;34(3):822-831. 
Sperling RA, Laviolette PS, O’Keefe K, O’Brien J, Rentz DM, Pihlajamaki M, Marshall G, 
Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA. Amyloid deposition 
is associated with impaired default network function in older persons without dementia. 
Neuron. 2009;63(2):178-188. 
Spielberger CD, Gorsuch RL, Lushene PR, Vagg PR, Jacobs GA. Manual for the State-Trait 
Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press, Inc.; 1983. 
Stark SM, Yassa MA, Stark CE. Individual differences in spatial pattern separation performance 
associated with healthy aging in humans. Learn Mem. 2010;17(6):284-288. 
Thal LJ, Kantarci K, Reiman EM, Klunk WE, Weiner MW, Zetterberg H, Galasko D, Praticò D, 
Griffin S, Schenk D, Siemers E. The role of biomarkers in clinical trials for Alzheimer disease. 
Alzheimers Dis Assoc Disord. 2006;20(1):6-15. 
Trojanowski JQ. The cellular and molecular correlates of cognitive impairments in the 
Alzheimer’s disease brain. Neurobiol Aging 1996;17(6):941–943 with discussion 945–947 
(Comment on: Neurobiol Aging;17(6):921–933). 
Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, 
Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL; Australian Imaging 
Biomarkers and Lifestyle (AIBL) Research Group. Amyloid β deposition, neurodegeneration, 
and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet 
Neurol. 2013;12(4):357-367. 
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Vos SJ, Xiong C, Visser PJ, Jasielec MS, Hassenstab J, Grant EA, Cairns NJ, Morris JC, 
Holtzman DM, Fagan AM. Preclinical Alzheimer’s disease and its outcome: a longitudinal 
cohort study. Lancet Neurol. 2013;2(10):957-965. 
Walsh SP, Raman R, Jones KB, Aisen PS; Alzheimer’s Disease Cooperative Study Group. 
ADCS Prevention Instrument Project: the Mail-In Cognitive Function Screening Instrument 
(MCFSI). Alzheimer Dis Assoc Disord. 2006;20(4)(suppl 3):S170-S178. 
Wechsler D. Manual for the Wechsler adult intelligence scale—revised. San Antonio, TX: The 
Psychological Corporation; 1981. 
Wechsler D. Wechsler Memory Scale–Revised. New York: The Psychological Corporation; 
1987. 
Zhu CW, Scarmeas N, Torgan R, Albert M, Brandt J, Blacker D, Sano M, Stern Y. Clinical 
features associated with costs in early AD: baseline data from the Predictors Study. Neurology. 
2006;66(7):1021-1028. 
Zhu CW, Sano M, Ferris SH, Whitehouse PJ, Patterson MB, Aisen 
PS.  Health-related resource use and costs in elderly adults with and 
without mild cognitive impairment. J Am Geriatr Soc. 2013;61(3):396-402. 
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Attachment 1. A4 Study Schedule 
 
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H8A-MC-LZAZ(f) 
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Study Schedule, A4 Protocol, Visits 1 through 5 (Screening Period) 
Visit Purpose:
Category   
   Procedure 
Consent and 
general eligibility 
PET amyloid 
imaging 
Amyloid status 
disclosure 
MRI  
Fasting LP 
(optional)d 
Visit No.:
SC V1 
SC V2 
SC V3 
SC V4 
SC V5 
Tolerance Interval for Screening Period 
←  ←  ←  ←  ←  ←  ←   ≤90 days   →  →  →  →  →  →  →  
Consent and HIPAA Authorization 
X 
 
 
 
 
Safety Assessments 
 
 
 
 
 
Demographics, subject medical history/family 
history, preexisting symptoms 
X 
 
 
 
 
Concomitant medications 
X 
 
 
 
X 
Adverse events 
X 
X 
 
X 
X 
C-SSRSa 
X 
 
 
 
 
Assessment of Psychological Well Being 
X 
 
 
 
 
Physical/neurological examination 
X 
 
 
 
 
Vital signs 
X 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
Screening MRI 
 
 
 
X 
 
Amyloid Disclosure Assessments 
 
 
 
 
 
Views & Perceptions of Amyloid Imaging Scale 
X 
 
X (post disclosure) 
 
 
Concerns about Alzheimer’s Disease Scale 
X 
 
X (post disclosure) 
 
 
Future Time Perspective Scale 
X 
 
X (post disclosure) 
 
 
Impact of Events Scaleb 
 
 
X 
 
 
continued on next page 
 
 
 
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H8A-MC-LZAZ(f) 
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Study Schedule, A4 Protocol, Visits 1 through 5 (Screening Period) (completed) 
Visit Purpose:
Category   
   Procedure 
Consent and 
general eligibility 
PET amyloid 
imaging 
Amyloid status 
disclosure 
MRI  
Fasting LP 
(optional)d 
Visit No.:
SC V1 
SC V2 
SC V3 
SC V4 
SC V5 
Tolerance Interval for Screening Period 
←  ←  ←  ←  ←  ←  ←   ≤90 days   →  →  →  →  →  →  →  
Efficacy/Health Outcomes/Imaging/LP 
 
 
 
 
 
PACC (version SC)f 
X 
 
 
 
 
C3e 
X 
 
X (before disclosure) 
 
 
CDR 
X 
 
 
 
 
CFI (self and study partner) 
X 
 
 
 
 
ADCS-ADL Prevention Questionnaire (self and 
study partner) 
X 
 
 
 
 
Florbetapir PET scan 
 
X 
 
 
 
Amyloid status disclosure 
 
 
X 
 
 
Fasting LP (optional)d 
 
 
 
 
X 
Collection of Laboratory Specimens 
 
 
 
 
 
Clinical chemistry, hematology, HbA1c 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
Blood for APOE Genotyping 
X 
 
 
 
 
    Addendum 1 Blood Samplesc 
X 
 
Xc 
 
 
Abbreviations:  ADCS-ADL Prevention Questionnaire = Alzheimer’s Disease Cooperative Study – Activities of Daily Living Prevention Questionnaire; PACC = 
Preclinical Alzheimer’s Cognitive Composite; APOE = apolipoprotein E gene; C3 = Computerized Cognitive Composite; CDR = Clinical Dementia Rating; 
CFI = Cognitive Function Index; C-SSRS = Columbia Suicide Severity Rating Scale; HbA1c = hemoglobin A1c; HIPAA = Health Insurance Portability and 
Accountability Act; LP = lumbar puncture; MRI = magnetic resonance imaging; PET = florbetapir positron emission tomography; SC = screening; 
SC V = screening visit. 
a If C-SSRS indicates suicide-related behavior has occurred, the Lilly Self Harm Form is to be completed and follow-up must occur by a site clinician. 
b Administered by phone within 3 business days of SC V3. 
c See Addendum 1 for details; Addendum 1 blood samples to be taken under fasted conditions. 
d Optional LP is available in US, Canada, and Japan only. 
e The C3 will be optional in Japan. 
f Every effort should be made to administer the PACC before all other procedures on the same day. 
 
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Study Schedule, A4 Protocol, Visits 6 through 66 (Placebo-Controlled Period)a 
Category   
  Procedure 
Rand  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early 
Termi 
Visit Noa.: V6 V9 V12V15V18V21V24V27V30V33V36V39V42V45V48V51 V54V57V60V63V66 
 
Week: 0 
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 
 
Tolerance Interval for Visit (days) 
 
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 
 
  Infusionh 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Concomitant medications 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Adverse events 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Assessment of Psychological Well Being 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
  C-SSRSb 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
  Physical/neurological examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Vital signs 
X 
X X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
  Electrocardiogram 
X 
X X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  MRIc 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Amyloid Disclosure Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Future Time Perspective Scale 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Concerns about AD Scale 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Efficacy and Health Outcomes Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  PACC (version SC, A, or B, as shown)d,j 
A 
 
B 
 
SC 
 
A 
 
B 
 
A 
 
B 
 
A 
 
SC 
 
B 
 
A 
X 
  C3g,j 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
  CDRj 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
  CFI (self and study partner)j 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
  ADCS-ADL Prevention Questionnaire (self and 
study partner)j 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
  RUI-Bj 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Florbetapir PET scan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
  Fasting LP (optional)f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
  Research Satisfaction Survey  
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Clinician Diagnostic Impression (CDI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
continued on next page 
 
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H8A-MC-LZAZ(f) 
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Study Schedule, A4 Protocol, Visits 6 through 66 (Laboratory Specimens, Placebo-Controlled Period)a (completed) 
 
Procedure 
Rand 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early 
Termi 
Visit No.a: V6 V9 V12 V15 V18 V21 V24 V27 V30 V33 V36 V39 V42 V45 V48 V51 V54 V57 V60 V63 V66 
 
Week:
0 
12 
24 
36 
48 
60 
72 
84 
96 108 120 132 144 156 168 180 192 204 216 228 240 
 
Tolerance Interval for Visit (days) 
 
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 
 
Collection of Laboratory Specimense 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Clinical chemistry, hematology, HbA1c 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  High sensitivity C-reactive protein  
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Urinalysis 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Immunogenicity specimen 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Plasma for solanezumab 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Plasma for biomarker long-term storage 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Serum for biomarker long-term storage 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
  Whole blood for biomarker long-term 
storage 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Abbreviations:  AD = Alzheimer’s disease; ADCS-ADL Prevention Questionnaire = Alzheimer’s Disease Cooperative Study – Activities of Daily Living 
Prevention Questionnaire; PACC = Preclinical Alzheimer’s Cognitive Composite; AE = adverse event; CFI = Cognitive Function Index; CRF = case report 
form; C-SSRS = Columbia Suicide Severity Rating Scale; EOS = end of study; HbA1c = hemoglobin A1c; LP = lumbar puncture; MRI = magnetic resonance 
imaging; PET = positron emission tomography; Rand = randomization; RUI-B = Resource Use Inventory, Brief version; SC = screening; V = Visit. 
a At all visits not shown on the table (Visits 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, 29, 31, 32, 34, 35, 37, 38, 40, 41, 43, 44, 46, 47, 49, 50, 52, 
53, 55, 56, 58, 59, 61, 62, 64, and 65), infusion and collection of AE and concomitant medication information will occur. 
b If C-SSRS indicates suicide-related behavior has occurred, the Lilly Self Harm Form is to be completed and follow-up must occur by a site clinician. 
c If MRI is done on the same day as cognitive and other assessments, then it should be done after cognitive and other tests.  MRI may be done before other visit 
procedures, including cognitive and other tests, but in that case MRI must be done at least 1 day before other visit procedures.  The V66 MRI may be done up 
to 4 weeks before other V66 procedures, but must be done after the completion of V65. 
d Every effort should be made to administer the PACC before all other procedures on the same day.  PACC version at early term visit should be the next 
version in series (not including SC). 
e Blood samples should be collected before beginning infusion.  Record the date and times of sample collection on the Lab Requisition Form. 
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f Optional LP is available in US, Canada, and Japan only.  The postbaseline LP should be performed during the same time of the day as the baseline LP and 
fasting status must be recorded for all LPs. 
g The C3 will be optional in Japan. 
h Visit intervals are every 4 weeks ±10 days throughout the trial.  In addition, there are to be a minimum of 14 days between infusions once a subject is 
receiving solanezumab at doses of 800 or 1600 mg Q4W. 
i 
Depending on the timing of the most recent visit, not all procedures/tests may be required at early termination.  Consult medical monitor for early 
terminations.  
j 
Efficacy measures (including PACC, C3, CDR-SB, CFI, ADCS-ADL Prevention Questionnaire, and RUI-B) that are not collected at the scheduled visit may 
be collected at a subsequent visit within 8 weeks of the scheduled visit window.  If the PACC is collected at a subsequent visit, it must be the same version 
that was missed (SC, A, or B). 
 
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Study Schedule, A4 Protocol, Dose Escalation Safety Cohort 
Dose (mg) 
800 
800 
1600 
1600 
1600 
1600 
Week relative to first dose of 800 mg: 
0 
4 
8 
12 
16 
20 
Consent and HIPAA Authorizationa 
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
 
X 
 
X 
 
 
MRIb 
 
 
X 
 
 
 
Plasma for solanezumab (PK/PD) 
X 
X 
X 
X 
 
X 
Immunogenicity specimen 
X 
X 
X 
X 
 
X 
Clinical chemistry, hematology, urinalysis 
 
X 
 
X 
 
 
Infusion (800 mg)c 
X 
X 
 
 
 
 
Infusion (1600 mg)c 
 
 
Xd 
Xd 
Xd 
Xd 
1-Hour Post-Infusion Monitoring 
X 
 
X 
 
 
 
Abbreviations:  HIPAA = Health Insurance Portability and Accountability Act; MRI = magnetic resonance imaging; PD = pharmacodynamics; PK = 
pharmacokinetics. 
a 
Consent and HIPAA authorization can take place at time point 0 or any time before the first dose of 800 mg is given. 
b Additional safety MRI will be conducted at least 7 days after the second dose of 800 mg and at least 7 days before escalating dose to 1600 mg so results of the 
central read can be reviewed by the site before the escalation.  If the MRI cannot be read before the first scheduled dose of 1600 mg, the subject should 
continue to receive 800 mg until such time that the MRI central read is available, which will not be considered a protocol deviation.  If a study MRI is 
scheduled within ±2 months of the dose escalation MRI, the MRI should be conducted according the dose escalation schedule as a substitute for the MRI 
specified in the main study schedule; an exception is the MRI at endpoint (Visit 66), which should be done according to the Study Schedule regardless of 
timing relative to dose escalation. 
c 
Infusion occurs after all other procedures at each visit. 
d 
Dosing at 1600 mg every 4 weeks to continue through the remaining duration of the study. 
 
 
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Study Schedule, A4 Protocol, Visits 66 through 117 (Open-Label Extension Period) 
Category   
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early 
Terma 
Visit Nob.: V66 V69 V72 V75 V78 V81 V84 V87 V90 V93 V96 V99 V102 V105 V108 V111 V114 V117 
 
Week: 240 252 264 276 288 300 312 324 336 348 360 372 384 396 408 420 432 444 
 
Tolerance Interval for Visit (days)c 
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 
 
Informed Consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infusion (every 4 weeks) 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRSe 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
MRIf 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy and Health Outcomes 
Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PACC (version A or B, as shown)g 
 
 
B 
 
A 
 
B 
 
A 
 
B 
 
A 
 
B 
 
A 
 
Xg 
CDRh 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
CFI (self and study partner)h 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
C3h,i 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
ADCS-ADL Prevention Questionnaire 
(self and study partner)h 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
RUI-Bh 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Clinician Diagnostic Impression 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Abbreviations:  AD = Alzheimer’s disease; ADCS-ADL Prevention Questionnaire = Alzheimer’s Disease Cooperative Study – Activities of Daily Living 
Prevention Questionnaire; PACC = Preclinical Alzheimer’s Cognitive Composite; AE = adverse event; CFI = Cognitive Function Index; C-SSRS = Columbia 
Suicide Severity Rating Scale; MRI = magnetic resonance imaging; V = Visit. 
a Depending on the timing of the most recent visit, not all procedures/tests may be required at early termination.  Consult medical monitor for early 
terminations.  If the open-label period is ended early because of lack of efficacy in the placebo-controlled period, all participants should have an early 
termination visit within 3 months of site notification. 
b The open-label period uses a common close design such that subjects will complete the study period at approximately the same time, up to V117 (444 weeks) 
or when primary analyses of the A4 study placebo-controlled period are completed and reviewed, whichever comes first.  At all visits not shown on the table 
(Visits 67, 68, 70, 71, 73, 74, 76, 77, 79, 80, 82, 83, 85, 86, 88, 89, 91, 92, 94, 95, 97, 98, 100, 101, 103, 104, 106, 107, 109, 110, 112, 113, 115, and 116), 
infusion and collection of AE information will occur. 
c Visit intervals are every 4 weeks ±10 days throughout the trial.  In addition, there are to be a minimum of 14 days between infusions. 
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d Prior to administration of study drug, confirm approval from the coordinating center has been granted, that the open-label period informed consent has been 
obtained, and that all V66 (Week 240) assessments, including MRI and florbetapir PET, have been completed.  Consent may be obtained any time before the 
V66 infusion.  Subjects may enter the open-label period of the study and receive their first open-label infusion of study drug up to 12 weeks following 
completion of the placebo-controlled period Visit 66 assessments and procedures.  
e If C-SSRS indicates suicide-related behavior has occurred, the Lilly Self Harm Form is to be completed and follow-up must occur by a site clinician. 
f The MRI and florbetapir and flortaucipir (if applicable) PET scans at V66 must be completed before the infusion and can be completed up to 4 weeks before 
V66. 
g The PACC should be administered before all other procedures on the same day.  PACC version at the early term visit should be the next version in series (not 
including SC).  If the PACC is not collected at the scheduled visit, the missed version should be collected at the next possible subsequent visit within 8 weeks 
of the scheduled visit window.  
h If the CDR-SB, CFI, C3, ADCS-ADL Prevention Questionnaire, or RUI-B is not collected at the scheduled visit, the assessment may be collected at a 
subsequent visit within 8 weeks of the scheduled visit window. 
i 
The C3 will be optional in Japan. 
 
 
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Attachment 2. A4 Protocol Clinical Laboratory Tests 
Clinical Laboratory Tests for A4 Protocol 
Hematology
a,b,c 
Clinical Chemistry
a,c Serum Concentrations of: 
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count 
Chloride 
MCV 
Total bilirubin
d 
MCHC 
Direct bilirubin 
Leukocytes (WBC) 
Alkaline phosphatase 
Neutrophils, segmented 
ALT/SGPT
d 
Lymphocytes 
AST/SGOT
d 
Monocytes 
GGT 
Eosinophils 
BUN 
Basophils 
Creatinine 
Plateletsa,e 
Uric acid 
 
Phosphorus 
Coagulation Panelc,e 
Calcium 
PT 
Glucose, nonfasting or fasting 
INR 
Total protein 
PTT 
Albumin 
 
Cholesterol 
CSFf,g 
CK 
Glucose 
 
Protein 
 
Cell count with differential 
 
Urinalysis
a,c 
Other Tests 
Color 
Urine pregnancyh 
Specific gravity 
APOE genotypinga,c,i 
pH 
Serologies if neededc,d 
Protein 
  C-reactive proteinc 
Glucose 
  HbA1c
a 
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Ketones 
 
Blood 
 
Leukocyte esterase 
 
Clinical Laboratory Tests for A4 Protocol Abbreviations and Footnotes 
Note:  Laboratory tests may be ordered by the primary investigator at any time during the study when they are deemed clinically indicated. 
Abbreviations:  APOE = Apolipoprotein E gene; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; BUN = blood urea nitrogen; CK = 
creatine kinase; CSF = cerebrospinal fluid; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c;  hCG = human chorionic gonadotropin; 
INR = International Normalized Ratio; MCHC = mean cell hemoglobin concentration; MCV = Mean cell volume; PT = Prothrombin Time; PTT = Partial 
Thromboplastin Time; SGOT = serum glutamic oxalo-acetic transaminase; SGPT= serum glutamic pyruvate transaminase; ULN = upper limit of normal; 
WBC = white blood cells. 
a Assayed by central laboratory. 
b Reflex assessment of cell morphology by peripheral smear will be performed when predefined hematology limits are exceeded. 
c 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. 
d If a study subject experiences elevated ALT or AST >3X ULN or elevated total bilirubin >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 subject safety 
and comply with regulatory guidance, the investigator is to consult with the Medical Monitor regarding collection of specific recommended clinical 
information and follow-up laboratory tests. 
e Optional, for subjects who undergo a lumbar puncture.  If desired, coagulation profile (including PT/INR and PTT) and platelet count are obtained from a 
local laboratory up to 4 weeks before the lumbar puncture. 
f 
Assayed by local laboratory. 
g Cerebrospinal fluid samples are only collected from subjects undergoing LP. 
h Urine pregnancy tests are ordinarily required on the day of florbetapir PET imaging in females of childbearing potential to rule out pregnancy.  Because such 
females are excluded from participation by exclusion criterion [24], this is not routinely necessary in this study.  However, if there is any concern that a 
subject is not fully menopausal (for example, has had suspected menses in the past 12 months), conduct a pregnancy test; this test must be negative in order to 
proceed with florbetapir dose administration. 
i 
Neither subjects nor investigators will receive the genotype results unless there is a country-specific law or regulation that requires notification of the results. 
 
 
 
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Attachment 3. Development of the PACC Measure 
Based on review of the literature from cohort studies data from “normal controls” who progressed to mild cognitive impairment or AD 
dementia, we determined that a composite measure sensitive to change in preclinical AD would likely require assessment of these key 
domains:  episodic memory, executive function, and orientation.  Previous studies have reported evidence that both list learning and 
paragraph recall measures of episodic memory decline 7 to 10 years prior to the diagnosis of MCI or AD dementia (Elias et al. 2000; 
Grober et al. 2008; Derby et al. 2013).  Recent data from amyloid imaging studies have reported decline in multiple cognitive domains 
looking retrospectively at cognitive trajectories over 8 to 10 years prior to PET amyloid imaging (Resnick et al. 2010; Landau et al. 
2012; Snitz et al. 2013) and prospectively over 1- to 3-year longitudinal follow-up (Morris et al. 2009; Doraiswamy et al. 2012; 
Knopman et al. 2012; Lim et al. 2012b; Kawas et al. 2013). 
In order to test the hypothesis that a composite measure including episodic memory measures, timed executive function and a global 
measure would be sensitive to detect decline from clinically normal to the stage of mild cognitive impairment, we tested several 
combinations of measures using data from longitudinal studies in clinically normal populations, including the Alzheimer’s Disease 
Neuroimaging Initiative (ADNI); the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL); and the ADCS-
PI trial. 
Evidence Supporting Use of the Proposed Composite.  We examined whether the proposed combination of measures (memory, timed 
executive function, and global) would demonstrate greater decline in individuals progressed to MCI (CDR 0.5) compared with those 
who remained normal (CDR 0) in two datasets: the ADCS-PI and ADNI. 
Figure A4.3 illustrates the 3-year change in the proposed composite (PACC) among those who declined from Normal (defined as 
CDR 0) to MCI (CDR 0.5 plus cognitive decline) as compared with those whose CDR score remained stable at 0 in the ADCS-PI 
trial.  Figure A4.4 shows ADNI data from a very similar composite cognitive measure for Normals who remained stable compared 
to those who progressed to a diagnosis of MCI over 3 years.  Both datasets demonstrate the sensitivity of a composite that included 
episodic memory, timed executive function, and global measures (including orientation) to detect cognitive decline in individuals 
who demonstrate clinical decline to the stage of MCI. 
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ADCS Prevention Instrument Study  
Comparing Stable Normals to Progressors to MCI on PACC 
 
The shaded regions represent 95% confidence intervals for the estimates at each time point. CDR-G stable refers to subjects whose 
global CDR score remained at 0 throughout the trial; [C]DR-G progressors were those whose global CDR score changed from 0 to 
0.5. 
* p<0.05 For the test of the group difference at the indicated time. 
Abbreviations:  ADCS = Alzheimer Disease Cooperative Study; CDR-G = Clinical Dementia Rating – Global score. 
Figure A4.3. 
MMRM estimates of change on the ADCS Preclinical Alzheimer Cognitive Composite, controlling for 
age, for stable and progressing subjects from the ADCS Prevention Instrument (PI) study. 
 
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Alzheimer’s Disease Neuroimaging Initiative (ADNI) study 
Comparing Stable Normals to Progressors to MCI on a Similar Cognitive Composite 
The shaded regions represent 95% confidence intervals for the estimates at each time point.  
* p<0.05 For the test of the group difference at the indicated time. 
Abbreviations:  ADNI = Alzheimer’s Disease Neuroimaging Initiative; LMIIa = Logical Memory test, part IIa; MCI = mild 
cognitive impairment; MMRM = mixed model repeated-measure; NL=normal; RAVLT = Rey Auditory Verbal Learning Test. 
Figure A4.4. 
MMRM estimates of change on the ADNI data, using a similar Composite (RAVLT for list learning, 
LMIIa, Digit Symbol, and MMSE), controlling for age, comparing for stable NL subjects versus NL 
subjects who progressed to MCI in ADNI. 
 
Data from normal controls with elevated brain amyloid deposition and normal controls without elevated brain amyloid deposition 
were compared in the ADNI and AIBL datasets.  For these power analyses, we only considered clinically normal older individuals 
(CDR 0) with baseline Logical Memory Delayed Recall scores of less than 15 to capture individuals at the highest risk of imminent 
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cognitive decline.  In the ADCS Prevention Instrument study, biomarkers of amyloid were not collected.  Therefore, we considered 
APOE ε4 carriers (at least one allele) versus noncarriers in the ADCS-PI trial (see Figure A4.5). 
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ADNI Aβ+ vs. Aβ– 
AIBL Aβ+ vs. Aβ– 
 
 
ADCS Prevention Instrument Study APOE-e4 carrier vs. noncarrier 
 
The shaded regions represent 95% confidence intervals for the estimates at each time point.  
* p<0.05 For the test of the group difference at the indicated time. 
Abbreviations:  Aβ = amyloid-β peptide; ADCS = Alzheimer Disease Cooperative Study; ADNI = Alzheimer’s Disease 
Neuroimaging Initiative; AIBL = Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. 
Figure A4.5. 
MMRM estimates of change on the ADCS Preclinical Alzheimer Cognitive Composite, controlling for 
age, from ADNI, AIBL, and the ADCS Prevention Instrument (PI) study. 
 
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The Harvard Aging Brain Study (HABS) is a longitudinal study of aging and preclinical Alzheimer’s disease.  The HABS is following 
approximately 300 clinically normal older (CDR=0; 73.5±6.0 years) individuals, characterized on the basis of baseline amyloid PET 
imaging.  In a recent study (Mormino et al. 2017), we investigated amyloid-beta (Aβ)-related longitudinal cognitive change, 
examining several variations of the Preclinical Alzheimer Cognitive Composite (PACC).  Aβ+ CN demonstrated longitudinal decline 
on all individual PACC components, and all PACC variations.  Aβ group differences emerged after 1 to 2 years when both Free and 
Total Recall FCSRT scores were included in the PACC (see Figure A4.6).  Decline in PACC was also associated with progression to 
CDR 0.5.  These results confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages 
of AD, which may prove advantageous in prevention trial design. 
 
 
Abbreviations:  HABS = Harvard Aging Brain Study; PACC = preclinical Alzheimer cognitive composite. 
Source:  Mormino et al. (2017). 
Figure A4.6. 
Longitudinal change by Aβ status for the PACC and individual components tests in HABS 
participants.  Aβ-related decline is significant for the PACC4-96 (A) as well as on all individual 
components (B–G).  Z-scores are shown on the y-axis for all tests. 
 
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Development of the PACC composite measure for the A4 trial has been publicly presented at an AlzForum webinar (Developing 
Outcome Measures for Pre-Dementia Trials – 28 February 2013) and published in 2014 (Donohue et al. 2014).  This combination of 
tests measuring word list learning, paragraph recall, timed executive function and global cognition, including orientation to time, is 
also strongly supported by work done for the Alzheimer’s Prevention Initiative (API) by Drs. Suzanne Hendrix and Jessica Langbaum, 
using longitudinal cohorts from Rush University and the Colombian PS-1 kindred data (Langbaum et al. 2011).  These data were also 
presented by Dr. Hendrix in the AlzForum webinar (Developing Outcome Measures for Pre-Dementia Trials – 28 February 2013).  
Further description of development of the PACC has been reported by Mormino and colleagues (2017). 
Evidence Supporting Selection of Individual Components. 
 
Episodic Memory.  Across multiple datasets (ADNI, AIBL, ADCS-PI, and summary data from Washington University), we 
found evidence that a combination of a list learning memory measure and paragraph recall consistently provided the greatest 
sensitivity to detect decline in elevated brain amyloid (or APOE 4) individuals.  Although the available datasets used 
different list-learning measures, the results were quite consistent.  We chose to use the FCSRT for the list-learning test for the 
A4 study, as this measure was particularly powerful in detecting decline in individuals who progressed to MCI during the 
ADCS-PI trial (Salmon et al. in press), 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).  In addition, 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).  The Delayed Paragraph Recall score on the Logical Memory IIa was chosen as the paragraph recall test 
because there is extensive data using this measure in ADNI and other cohorts (Crane et al. 2012; Derby et al. 2013). 
 
Executive Function.  We also found that the addition of a timed executive function measure, such as Digit-Symbol, added 
power to detect decline, consistent with previous reports that slowing of processing speed and executive dysfunction are seen 
in very early AD (Albert 1996; Storandt et al. 2009). 
 
Orientation/Other Cognitive Domains.  Although the MMSE has not been typically thought of as a sensitive measure for early 
detection, the MMSE score (or the Modified MMSE [Teng and Chui 1987]) consistently added power to detect decline in all 
of the cohorts that have been examined. 
Attachment 3 references that are not contained in earlier reference list: 
Albert MS. Cognitive and neurobiologic markers of early Alzheimer disease. Proc Natl Acad Sci U S A. 1996;93(24):13547-51. 
Amieva H, Le Goff M, Millet X, Orgogozo JM, Pérès K, Barberger-Gateau P, Jacqmin-Gadda H, Dartigues JF. Prodromal 
Alzheimer’s disease: successive emergence of the clinical symptoms. Ann Neurol. 2008;64(5):492-498. 
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Crane PK, Carle A, Gibbons LE, Insel P, Mackin RS, Gross A, Jones RN, Mukherjee S, Curtis SM, Harvey D, Weiner M, Mungas D, 
Alzheimer’s Disease Neuroimaging Initiative. Development and assessment of a composite score for memory in the Alzheimer’s 
Disease Neuroimaging Initiative (ADNI). Brain Imaging Behav. 2012;6(4):502-516. 
Derby CA, Burns LC, Wang C, Katz MJ, Zimmerman ME, L’italien G, Guo Z, Berman RM, Lipton RB. Screening for predementia 
AD: Time-dependent operating characteristics of episodic memory tests. Neurology. 2013;80(14):1307-1314. 
Donohue MC, Sperling RA, Salmon DP, Rentz DM, Raman R, Thomas RG, Weiner M, Aisen PS; Australian Imaging, Biomarkers, 
Lifestyle Flagship Study of Ageing; Alzheimer's Disease Neuroimaging Initiative; and Alzheimer’s Disease Cooperative, Study. 
The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 2014;71(8):961-970. 
Elias MF, Beiser A, Wolf PA, Au R, White RF, D’Agostino RB. The preclinical phase of Alzheimer disease: A 22-year prospective 
study of the Framingham Cohort. Arch Neurol. 2000; 57(6):808–813. 
Kawas CH, Greenia DE, Bullain SS, Clark CM, Pontecorvo MJ, Joshi AD, Corrada MM. Amyloid imaging and cognitive decline in 
nondemented oldest-old: the 90+ Study. Alzheimers Dement. 2013;9(2):199-203. 
Landau SM, Mintun MA, Joshi AD, Koeppe RA, Petersen RC, Aisen PS, Weiner MW, Jagust WJ; Alzheimer’s Disease 
Neuroimaging Initiative. Amyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol. 2012;72(4):578-
586. 
Langbaum JB, Hendrix S, Ayutyanont N, Tariot P, Fleisher A, Caselli R, Chen K, Langlois C, Bennett D, Reiman EM. Composite 
cognitive endpoints with improved power to detect presymptomatic Alzheimer’s disease treatment effects in APOE4 carriers: 
Findings from the Alzheimer’s Prevention Initiative.  Presented at: Alzheimer’s Association International Conference on 
Alzheimer’s Disease 2011; Paris, France. 
Mormino E, Papp KV, Rentz DM, Donohue MC, Amariglio R, Quiroz YT, Chhatwal J, Marshall GA, Donovan N, Jackson J, Gatchel 
JR, Hanseeuw BJ, Schultz AP, Aisen PS, Johnson KA, Sperling RA. Early and late change on the preclinical Alzheimer’s cognitive 
composite in clinically normal older individuals with elevated betaamyloid. Alzheimers Dement. 2017. pii:S1552-5260(17)30044-4. 
doi:10.1016/j.jalz.2017.01.018. [Epub ahead of print]. 
Resnick SM, Sojkova J, Zhou Y, An Y, Ye W, Holt DP, Dannals RF, Mathis CA, Klunk WE, Ferrucci L, Kraut MA, Wong DF. 
Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB. Neurology. 2010;74(10):807-815. 
Salmon et al. in press. 
Snitz BE, Weissfeld LA, Lopez OL, Kuller LH, Saxton J, Singhabahu DM, Klunk WE, Mathis CA, Price JC, Ives DG, Cohen AD, 
McDade E, Dekosky ST. Cognitive trajectories associated with β-amyloid deposition in the oldest-old without dementia. Neurology. 
2013;80(15):1378-1384. 
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Storandt M, Mintun MA, Head D, Morris JC. Cognitive decline and brain volume loss as signatures of cerebral amyloid-beta peptide 
deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta deposition. Arch Neurol. 
2009;66(12):1476-1481. 
Teng EL, Chui HC. Modified Mini Mental State (3MS) examination. J Clin Psychiatry. 1987;48:314-318. 
 
 
 
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Approval
Statistician
09-Aug-2022 18:30:07 GMT+0000
Approval
Medical Director
09-Aug-2022 20:31:18 GMT+0000
Approved on 09 Aug 2022 GMT
PPD
PPD