Assessment of Safety, Tolerability, and Efficacy of Donanemab in Early Symptomatic Alzheimer's Disease
Phase: PHASE3
Conditions: Alzheimer Disease
Sponsor: Eli Lilly and Company

 
 I5T-MC-AACI Protocol Amendment (e)   
 
 
Assessment of Safety, Tolerability, and Efficacy of Donanemab in Early Symptomatic 
Alzheimer’s Disease 
 
NCT04437511 
 
Approval Date: 10-Nov-2022 
 
 

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I5T-MC-AACI(e) 
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Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of donanemab (LY3002813), unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: Assessment of Safety, Tolerability, and Efficacy of Donanemab in Early 
Symptomatic Alzheimer’s Disease
Protocol Number: I5T-MC-AACI 
Amendment Number: e 
Compound: Donanemab (LY3002813) 
Study Phase: Phase 3 
Short Title: Donanemab in Early Symptomatic Alzheimer’s Disease 
Acronym: TRAILBLAZER-ALZ 2  
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s): 
IND: 109157 
EudraCT: 2020-000077-25 
Approval Date: Protocol Amendment (e) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-074782 
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I5T-MC-AACI(e) 
 
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Medical Monitor Name and Contact Information will be provided separately. 
 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment d 
05-Oct-2021 
Amendment c 
03-Sep-2021 
Amendment b 
17-Feb-2021 
Amendment a 
14-Dec-2020 
Original Protocol 
30-Jan-2020 
Amendment [e]  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment 
The main rationale for the amendment is to remove Cohort 1 and Cohort 2 analyses and to 
update the analysis method for the primary objective. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Removed reference to 
amendment (d) 
Editorial.  
Removed reference to 
Cohorts 1 and 2 
Cohort analysis was not 
conducted. 
1.2 Schema 
Removed reference to 
Cohorts 1 and 2 
Cohort analysis was not 
conducted. 
1.3 Schedule of Activities (SoA) 
Added GFAP testing 
To evaluate potential disease 
modification. 
Updated “date” to 
“window” for MRI 
Clarification. 
Added text to extend 
window for flortaucipir 
F18 PET scan  
Improve feasibility. 
Updated notes for Vital 
signs and temperature to 
state that orthostatic BP 
and pulse will be 
measured at Visits 35, 38, 
41, EDb and unscheduled 
visits  
Correction. 
Updated footnote a to 
clarify the timing to 
Improve feasibility. 
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Section # and Name 
Description of Change 
Brief Rationale 
collect efficacy 
assessment 
Added footnote to extend 
collection of RUD-Lite 
and QOL-AD and permit 
collection by phone. 
Improve feasibility. 
2.1 Study Rationale 
Removed reference to 
amendment (d) 
Editorial. 
 
Added that the primary 
analysis will test low-
medium (intermediate) 
tau pathology population 
Clarification 
3 Objectives and Endpoints 
Added GFAP as 
tertiary/exploratory 
endpoint 
To evaluate potential disease 
modification. 
4.1.2 Double-Blind Period (Visit 2 
through 21) 
Removed reference to 
Cohort 1 
Cohort analysis was not 
conducted. 
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
Removed reference to 
Cohorts 1 and 2 
Cohort analysis was not 
conducted. 
6.4 Study Intervention 
Compliance 
Added text to clarify 
situation when a complete 
infusion can be avoided 
Clarification. 
7.1 Discontinuation of Study 
Intervention 
Added sentence to allow 
participants with MRI-
incompatible pacemakers 
who discontinue IP 
permanently to remain in 
study but not perform 
MRI. 
Allow continued observation 
of such participants in the 
study. 
7.2 Participant 
Discontinuation/Withdrawal from 
the Study  
Removed sentence to 
allow participants with 
MRI-incompatible 
pacemakers who 
discontinue study 
intervention permanently 
to remain in study but not 
perform MRI. 
Allow continued observation 
of such participants in the 
study. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.1 Efficacy Assessments 
Added text to clarify the 
timing for efficacy 
assessment collection 
Improve feasibility. 
8.1.1 Primary Efficacy 
Assessment 
Added description about 
iADRS 
Editorial. 
8.1.2.1 MMSE 
Added description about 
MMSE 
Editorial. 
8.1.2.3 CDR 
Updated description for 
CDR  
Editorial. 
8.6.1 Clearance of Amyloid 
Deposits 
Updated florbetapir F18 
PET to amyloid PET 
Clarification. 
9.1 Statistical Hypotheses 
Methodology for primary 
efficacy data updated 
from Bayesian Disease 
Progression Model to 
Natural Cubic Spline. 
Removed reference to 
Cohorts 2. 
Change from Bayesian 
analysis framework to 
frequentist analysis 
framework while 
maintaining high statistical 
power.  
9.2 Sample Size Determination 
Removed reference to 
Cohorts 1 and 2. Updated 
power to reflect Natural 
Cubic Spline model. 
Cohort analysis was not 
conducted. Reflected power 
for methodology. 
9.3 Populations for Analyses 
Removed Section 9.3.1 
related to Cohorts 1 and 
2. 
Cohort analysis was not 
conducted. 
9.4.1 General Considerations 
Removed reference to 
Cohorts 1 and 2. 
Cohort analysis was not 
conducted. 
9.4.3 Primary Endpoint(s) 
Methodology for primary 
efficacy data updated 
from Bayesian Disease 
Progression Model to 
Natural Cubic Spline. 
Change from Bayesian 
analysis framework to 
frequentist analysis 
framework while 
maintaining high statistical 
power. 
9.4.4 Secondary Endpoint(s) 
Minor updates. 
Editorial. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.5 Interim Analysis 
Removed reference to 
Cohorts 1 and 2. 
Cohort analysis was not 
conducted. 
10.1.6 Dissemination of Clinical 
Study data 
Removed reference to 
Cohort 1. 
Cohort analysis was not 
conducted 
10.2 Clinical Laboratory Tests 
Added GFAP testing 
To evaluate potential disease 
modification 
10.8 Appendix 8 
Update to interim 
analysis definition. 
Clarification. 
Added DSST to the list 
 
 
 
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Table of Contents 
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................14 
1.3. 
Schedule of Activities (SoA) ..........................................................................................15 
2. 
Introduction ...................................................................................................................33 
2.1. 
Study Rationale ...............................................................................................................33 
2.2. 
Background .....................................................................................................................33 
2.2.1. 
Donanemab Nonclinical Studies .....................................................................................34 
2.2.2. 
Donanemab Clinical Studies ...........................................................................................34 
2.3. 
Benefit/Risk Assessment ................................................................................................35 
3. 
Objectives and Endpoints ............................................................................................36 
4. 
Study Design ..................................................................................................................39 
4.1. 
Overall Design ................................................................................................................39 
4.1.1. 
Lead-In and Screening Period (Visits 601 and 1) ...........................................................39 
4.1.2. 
Double-Blind Period (Visits 2 through 21) .....................................................................40 
4.1.3. 
Extension Period (Visits 22 through 41) .........................................................................40 
4.1.4. 
Follow-Up (Visits 801 through 804)...............................................................................41 
4.2. 
Scientific Rationale for Study Design ............................................................................41 
4.3. 
Justification for Dose ......................................................................................................42 
4.4. 
End of Study Definition ..................................................................................................42 
5. 
Study Population ...........................................................................................................43 
5.1. 
Inclusion Criteria ............................................................................................................43 
5.2. 
Exclusion Criteria ...........................................................................................................45 
5.3. 
Lifestyle Considerations .................................................................................................47 
5.4. 
Screen Failures ................................................................................................................47 
6. 
Study Intervention ........................................................................................................48 
6.1. 
Study Intervention(s) Administered................................................................................48 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................48 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding ...........................................49 
6.4. 
Study Intervention Compliance ......................................................................................49 
6.5. 
Concomitant Therapy .....................................................................................................50 
6.5.1. 
Standard of Care for Alzheimer’s Disease......................................................................50 
6.5.2. 
Medications for Infusion Reactions ................................................................................50 
6.5.3. 
Excluded Medications .....................................................................................................51 
6.6. 
Dose Modification ..........................................................................................................51 
6.7. 
Intervention after the End of the Study ...........................................................................51 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................52 
7.1. 
Discontinuation of Study Intervention ............................................................................52 
7.1.1. 
Temporary Discontinuation ............................................................................................54 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................54 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................55 
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7.3. 
Lost to Follow-Up ...........................................................................................................55 
8. 
Study Assessments and Procedures.............................................................................56 
8.1. 
Efficacy Assessments .....................................................................................................56 
8.1.1. 
Primary Efficacy Assessment .........................................................................................56 
8.1.2. 
Secondary Efficacy Assessments ....................................................................................57 
8.2. 
Safety Assessments .........................................................................................................58 
8.2.1. 
Physical and Neurological Examinations .......................................................................59 
8.2.2. 
Vital Signs .......................................................................................................................59 
8.2.3. 
Electrocardiograms .........................................................................................................60 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................61 
8.2.5. 
Magnetic Resonance Imaging .........................................................................................62 
8.2.6. 
Hepatic Safety Monitoring ..............................................................................................62 
8.2.7. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................64 
8.3. 
Adverse Events and Serious Adverse Events .................................................................64 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................64 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................65 
8.3.3. 
Follow-Up of AEs and SAEs ..........................................................................................65 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................65 
8.3.5. 
Pregnancy ........................................................................................................................66 
8.3.6. 
Hypersensitivity, Including Infusion-Related Reactions ................................................66 
8.3.7. 
Amyloid-Related Imaging Abnormalities (ARIA-E and ARIA-H)................................67 
8.3.8. 
Adverse Events of Special Interest .................................................................................67 
8.3.9. 
Complaint Handling ........................................................................................................68 
8.4. 
Treatment of Overdose ...................................................................................................68 
8.5. 
Pharmacokinetics ............................................................................................................68 
8.6. 
Pharmacodynamics .........................................................................................................69 
8.6.1. 
Clearance of Amyloid Deposits ......................................................................................69 
8.6.2. 
Accumulation of Tau Deposits .......................................................................................69 
8.7. 
Genetics ..........................................................................................................................69 
8.7.1. 
Apolipoprotein E Genotyping .........................................................................................69 
8.7.2. 
Whole Blood Samples for Pharmacogenetic Research ...................................................69 
8.8. 
Biomarkers ......................................................................................................................70 
8.9. 
Immunogenicity Assessments.........................................................................................70 
8.10. 
Medical Resource Utilization and Health Economics ....................................................71 
8.10.1. Dependency Level (derived from ADCS-ADL) .............................................................71 
8.10.2. Resource Utilization in Dementia – Lite Version (RUD-Lite) .......................................71 
8.10.3. Quality of Life in Alzheimer’s Disease (QOL-AD) .......................................................72 
9. 
Statistical Considerations .............................................................................................73 
9.1. 
Statistical Hypotheses .....................................................................................................73 
9.2. 
Sample Size Determination ............................................................................................73 
9.3. 
Populations for Analyses ................................................................................................74 
9.4. 
Statistical Analyses .........................................................................................................74 
9.4.1. 
General Considerations ...................................................................................................74 
9.4.2. 
Treatment Group Comparability .....................................................................................76 
9.4.3. 
Primary Endpoint(s) ........................................................................................................77 
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9.4.4. 
Secondary Endpoint(s) ....................................................................................................78 
9.4.5. 
Tertiary/Exploratory Endpoint(s)....................................................................................79 
9.4.6. 
Other Safety Analyses.....................................................................................................79 
9.4.7. 
Other Analyses ................................................................................................................79 
9.5. 
Interim Analyses .............................................................................................................80 
9.6. 
Data Monitoring Committee ...........................................................................................81 
10. 
Supporting Documentation and Operational Considerations ..................................82 
10.1. 
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................82 
10.1.1. Regulatory and Ethical Considerations ...........................................................................82 
10.1.2. Financial Disclosure........................................................................................................82 
10.1.3. Informed Consent Process ..............................................................................................82 
10.1.4. Data Protection................................................................................................................83 
10.1.5. Committees Structure......................................................................................................83 
10.1.6. Dissemination of Clinical Study Data.............................................................................84 
10.1.7. Data Quality Assurance ..................................................................................................84 
10.1.8. Source Documents ..........................................................................................................86 
10.1.9. Study and Site Start and Closure ....................................................................................86 
10.1.10. Publication Policy ...........................................................................................................86 
10.1.11. Investigator Information .................................................................................................87 
10.2. 
Appendix 2:  Clinical Laboratory Tests ..........................................................................88 
10.3. 
Appendix 3:  Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting ........................................................91 
10.3.1. Definition of AE .............................................................................................................91 
10.3.2. Definition of SAE ...........................................................................................................92 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................................93 
10.3.4. Reporting of SAEs ..........................................................................................................95 
10.4. 
Appendix 4:  Liver Safety:  Suggested Actions and Follow-Up 
Assessments ....................................................................................................................96 
10.5. 
Appendix 5:  Flortaucipir F18 Tau PET Imaging ...........................................................97 
10.6. 
Appendix 6:  Florbetapir F18 Amyloid PET Imaging ....................................................99 
10.7. 
Appendix 7:  Removed .................................................................................................100 
10.8. 
Appendix 8:  Abbreviations ..........................................................................................101 
10.9. 
Appendix 9:  Protocol Amendment History .................................................................105 
11. 
References ....................................................................................................................122 
 
 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: Assessment of Safety, Tolerability, and Efficacy of Donanemab in Early 
Symptomatic Alzheimer’s Disease 
Short Title: Donanemab in Early Symptomatic Alzheimer’s Disease 
Rationale: 
Donanemab is an antibody directed at the pyroglutamate modification of the third amino acid of 
amyloid beta (N3pG Aβ) epitope that is present only in brain amyloid plaques. It is being studied 
for the treatment of Alzheimer’s disease (AD).  The mechanism of action of donanemab 
antibody is to target and remove deposited amyloid plaque, a key pathological hallmark of AD, 
via microglial-mediated clearance.  The clinical strategy for donanemab identifies early 
symptomatic AD patients with existing brain amyloid load, as measured using the amyloid 
plaque biomarker florbetapir F18 positron emission tomography (PET) imaging in conjunction 
with the presence of tau pathology in the brain.  This strategy is based on the amyloid hypothesis 
of AD, which postulates that the production and deposition of Aβ is an early and necessary event 
in the pathogenesis of AD (Selkoe 2000).  Clinical data supporting this hypothesis comes from 
the observation that parenchymal Aβ levels are elevated prior to the manifestation of AD 
symptoms, and further supported by genetic variants of AD that overproduce brain Aβ and 
genetic variants that protect against Aβ production (Jonsson et al. 2012; Fleisher et al. 2015).  
Furthermore, early in the disease, the presence of brain amyloid appears to increase the risk of 
conversion from mild cognitive impairment (MCI) to AD dementia (Doraiswamy et al. 2012).  
These data suggest that removal of deposited amyloid and clearance of Aβ can result in the 
slowing of AD progression. 
Study I5T-MC-AACI (AACI) is a Phase 3, double-blind, placebo-controlled study to evaluate 
the safety and efficacy of N3pG antibody (donanemab) in patients with early symptomatic AD 
(prodromal AD and mild dementia due to AD) with the presence of brain tau pathology.  Study 
AACI will assess whether removal of existing amyloid plaque can slow the progression of the 
disease as assessed by clinical outcomes for cognition and function, and by imaging biomarker 
measures of disease pathology and neurodegeneration over 76 weeks of double-blind 
observation.    
Study AACI expands the patient population compared to the prior Phase 2 study by including 
participants with high tau pathology.  The primary analysis will test the low-medium 
(intermediate) tau pathology population and the overall population (low-medium and high tau 
pathology).   
 
 
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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To assess the effect of donanemab versus 
placebo on clinical progression in participants 
with early symptomatic AD  
iADRS change from baseline through Week 
76 in at least one of  
 the low-medium tau pathology 
population or  
 the overall population 
Secondary 
 
To assess the effect of donanemab versus 
placebo on clinical progression in participants 
with early symptomatic AD  
Change from baseline through Week 76 in at 
least one of  
 the low-medium tau pathology 
population or 
 the overall population 
as measured by:   
 CDR-SB 
 ADAS-Cog13 score 
 ADCS-iADL score  
 MMSE score 
To assess the effect of donanemab versus 
placebo on brain amyloid deposition  
Change in brain amyloid plaque deposition 
from baseline through Week 76 as measured 
by florbetapir F18 PET scan 
To assess the effect of donanemab versus 
placebo on brain tau deposition 
Change in brain tau deposition from baseline 
through Week 76 as measured by flortaucipir 
F18 PET scan 
To assess the effect of donanemab versus 
placebo on brain region volumes  
Change in volumetric MRI measures from 
baseline through Week 76 
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Objectives 
Endpoints 
To evaluate safety and tolerability of 
donanemab 
Standard safety assessments:   
 Spontaneously reported AEs 
 Clinical laboratory tests 
 Vital sign and body weight 
measurements 
 12-lead ECGs 
 Physical and neurological 
examinations 
MRI (ARIA and emergent radiological 
findings) 
Infusion related reactions 
C-SSRS 
To assess peripheral PK and presence of 
anti-donanemab antibodies 
Plasma PK of donanemab 
ADAs against donanemab including  
 treatment-emergent ADAs  
 neutralizing antibodies 
Abbreviations:  AD = Alzheimer’s disease; ADA = anti-drug antibody; ADAS-Cog13 = Alzheimer’s Disease 
Assessment Scale – Cognitive subscale; ADCS-iADL = Alzheimer’s Disease Cooperative Study – instrumental 
Activities of Daily Living; AE = adverse event; ARIA = amyloid-related imaging abnormalities; CDR-SB = 
Clinical Dementia Rating Scale – Sum of Boxes; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = 
electrocardiogram; iADRS = integrated Alzheimer’s Disease Rating Scale; MMSE = Mini Mental State 
Examination; MRI = magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetics 
Overall Design 
Study AACI is a multicenter, randomized, double-blind placebo-controlled, Phase 3 study of 
donanemab in participants with early symptomatic AD.  Participants who meet entry criteria will 
be randomized in a 1:1 ratio to one of the following treatment groups:   
 Donanemab: 700 mg IV Q4W for first 3 doses and then 1400 mg IV Q4W  
 Placebo 
After 76 weeks, participants will be assigned to donanemab or placebo based on criteria 
described in Section 4.1.3.  
The maximum total duration of study participation for each participant, including screening and 
the post-treatment follow-up periods, is up to 205 weeks:   
 Lead-In:  any time prior to complete screening 
 Complete Screening:  up to 7 weeks 
 Double-Blind:  76 weeks 
 Extension:  78 weeks 
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 Follow-Up:  up to 44 weeks 
The maximum duration of treatment is 150 weeks.  
Scheduled Reduction of Donanemab to Placebo 
Participants whose amyloid plaque reduction as measured by florbetapir F18 PET scans at 
Visit 8 (Week 24), Visit 15 (Week 52), Visit 21 (Week 76), Visit 28 (Week 102), or Visit 35 
(Week 130) meets criteria will have a double-blind dose reduction of donanemab to IV placebo 
for the remaining duration of the study.   
These dose reduction rules are defined by the sponsor.   
Participant randomization will be stratified by investigative site and tau pathology (low-medium 
versus high). 
Disclosure Statement:  This is a parallel, double-blind treatment study with 2 treatment groups. 
Number of Participants: 
Approximately 1800 participants will be randomized in the trial.  
It is anticipated that approximately two-third of participants have low-medium tau and 
approximately one-third of participants have high tau pathology.  
External Data Monitoring Committee:  Yes 
 
 
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1.2. 
Schema 
 
Abbreviations: IP = investigational product; IV = intravenous; PET = positron emission tomography; Q4W = every 
4 weeks; V = Visit. 
a Dosing decisions are based on reduction in amyloid burden as determined by the florbetapir F18 PET scan at 
Weeks 24, 52, 76, 102, and 130.  
b Donanemab dosing schedule in the extension period is described in Section 4.1.3.   
c The follow-up period begins 12 weeks after the final administration of IP, and Visits 801 through 804 are 
scheduled as described in Section 4.1.4.  Investigator will be notified if participant is not required to complete all 
follow-up visits (V801-804). 
Notes: V601 is optional. For participants who do not complete V601, the procedures will be included in V1.   
 
Randomization occurs at V2. 
 
 
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1.3. 
Schedule of Activities (SoA) 
Screening 
LEAD-IN SCREENING 
COMPLETE SCREENING 
Notes 
Visit No.: 
601 
1 
V1 may be conducted over more than 1 day.  
V601 is optional.  If the participant’s initial visit is V1, then 
perform all V601 procedures in addition to V1 procedures. 
Day Relative to 
Randomization 
Can be done any time prior to 
complete screening 
-49 to -1 
Recommend screening to not extend past 63 days. Sponsor 
may strictly control toward end of study enrollment. 
Tolerance Interval for 
Visit (Days) 
Can be done at any time 
≤49 before V2 
 
Entry and Administrative 
Abbreviated (or Full) 
Informed 
Consent – participant and 
study partner 
X 
 
The Abbreviated Informed Consent grants consent only for 
procedures and assessments marked under V601. 
Study partner(s) are not required to complete the abbreviated 
Informed Consent. 
Full Informed Consent – 
participant and study 
partner 
 
X 
Do not collect if Full Informed Consent was collected at V601. 
Contact IWRS – register 
visit 
X 
X 
For all visits. 
Participant number assigned 
via IWRS 
X 
 
 
Demographics 
X 
 
 
Habits 
 
X 
 
Inclusion/exclusion review 
 
X 
 
Physical/neurological 
examination 
 
X 
 
Concomitant medications 
 
X 
 
Preexisting conditions 
 
X 
 
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LEAD-IN SCREENING 
COMPLETE SCREENING 
Notes 
Visit No.: 
601 
1 
V1 may be conducted over more than 1 day.  
V601 is optional.  If the participant’s initial visit is V1, then 
perform all V601 procedures in addition to V1 procedures. 
Day Relative to 
Randomization 
Can be done any time prior to 
complete screening 
-49 to -1 
Recommend screening to not extend past 63 days. Sponsor 
may strictly control toward end of study enrollment. 
Tolerance Interval for 
Visit (Days) 
Can be done at any time 
≤49 before V2 
 
Safety Assessments 
Vital signs 
 
X 
Sitting BP and pulse will be measured after approximately 5 
minutes in the sitting position only.   
Temperature will also be collected with sitting vitals. 
Height and weight 
 
X 
 
ECG 
 
X 
 
C-SSRS Baseline and 
Screening 
 
X 
 
Self-Harm Supplement 
Form 
 
X 
 
Self-Harm Follow-up Form  
 
X 
Required if triggered by the Self-Harm Supplement Form per 
instructions. 
Chemistry 
 
X 
 
Hematology 
 
X 
 
Entry Diagnostics 
MMSE 
X 
 
Participants who do not meet MMSE criteria are not to have 
any other screening procedures performed.  See Section 5.4 for 
rescreening criteria. 
See footnote a. 
P-tau 
X 
 
 
ApoE 
X 
 
Collect unless not allowed or unfeasible due to local 
regulations. 
The ApoE genotype sample may be collected at an alternative 
visit if it cannot be collected at screening. 
Pharmacogenetics sample 
X 
 
Collect unless not allowed or unfeasible due to local 
regulations. 
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LEAD-IN SCREENING 
COMPLETE SCREENING 
Notes 
Visit No.: 
601 
1 
V1 may be conducted over more than 1 day.  
V601 is optional.  If the participant’s initial visit is V1, then 
perform all V601 procedures in addition to V1 procedures. 
Day Relative to 
Randomization 
Can be done any time prior to 
complete screening 
-49 to -1 
Recommend screening to not extend past 63 days. Sponsor 
may strictly control toward end of study enrollment. 
Tolerance Interval for 
Visit (Days) 
Can be done at any time 
≤49 before V2 
 
Exploratory biomarker 
sample  
X 
 
Collect unless not allowed or unfeasible due to local 
regulations. 
Screening PET Scans and MRI 
Flortaucipir F18 PET scan 
 
X 
See footnote b. 
MRI 
 
X 
See footnote b. 
Florbetapir F18 PET scan 
 
X 
See footnote b. 
 
 
 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
18 
Visits 2 through 14 
 
After visit 5, visits without cognitive and functional scales are eligible to be conducted remotely, via mobile healthcare coordinated 
with and approved by the sponsor, if permitted by local regulations.     
 
Visit No.: 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Notes 
Week Relative to 
Randomization  
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Procedures for some visits may take more 
than 1 day. 
Tolerance 
Interval for Visit 
(Days) 
0 
7 to 
+10 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
 
Inclusion/ 
exclusion review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm that the participant has met all V1 
eligibility criteria before proceeding to V2 
procedures. 
Contact IWRS – 
register visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For all visits. 
Contact IWRS – 
dispensation of IP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For visits where IP will be dispensed. 
Physical/ 
neurological 
examination 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
V11 is a brief physical and neurological 
exam, as described in Section 8.2.1. 
Any clinically significant changes from 
baseline on physical/neurological 
examinations should be noted on the AE 
CRF. 
Previous/ 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Preexisting 
conditions/ 
adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IP administered 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administered by IV infusion.   
The participant should be observed for a 
minimum of 60 minutes following the end 
of each infusion. 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
19 
Visit No.: 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Notes 
Week Relative to 
Randomization  
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Procedures for some visits may take more 
than 1 day. 
Tolerance 
Interval for Visit 
(Days) 
0 
7 to 
+10 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
 
Efficacy Measures 
ADAS-Cog13 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
See footnote a. 
ADCS-ADL 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
See footnote a. 
CDR 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
See footnote a. 
MMSE 
 X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
See footnote a. 
DSST medicines 
version 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Collect via eCOA only when available. 
Safety Assessments 
C-SSRS since last 
visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
If visit is not conducted on site, may collect 
by phone. 
Self-Harm 
Supplement Form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
If visit is not conducted on site, may collect 
by phone. 
Self-Harm 
Follow-up Form 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Required if triggered by Self-Harm 
Supplement Form per instructions. 
If visit is not conducted on site, may collect 
by phone. 
Laboratory Tests and Sample Collectionsc 
Hematology 
X  
 
 
X 
 
 
X 
 
 
X 
  
 
 
 
Clinical 
Chemistry and 
eGFR (CKD-EPI) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
eGFR calculated by Lilly-designated lab. 
Urinalysis and 
Urinary 
protein/creatinine 
ratio (UPCR) 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
UPCR calculated by Lilly-designated lab. 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
20 
Visit No.: 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Notes 
Week Relative to 
Randomization  
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Procedures for some visits may take more 
than 1 day. 
Tolerance 
Interval for Visit 
(Days) 
0 
7 to 
+10 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
 
PK Samples 
(Predose) 
 
X 
X 
X 
X 
 
X 
 
  
X 
  
 
 
Do not collect if the last IP infusion was >6 
months prior to the scheduled visit. 
Predose collections may be collected from 
the IV site prior to the infusion. 
PK Samples 
(Postdose) 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Do not collect if the last IP infusion was >6 
months prior to the scheduled visit. 
Collect within 30 minutes of IP infusion 
completion.  
Collect from the arm that IP was not 
administered through. 
Immunogenicity 
(ADA) Samples 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
NfL/GFAP 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
P-tau 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
A  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Exploratory 
Biomarker 
Samples 
X 
  
  
X 
  
 
X 
  
  
X 
  
 
 
Collect unless not allowed or unfeasible due 
to local regulations.  
Other Safety Measures 
Weight 
X 
 
 
X 
 
 
X 
 
 
X 
  
 
 
 
Vital signs and 
temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sitting BP, pulse, and temperature will be 
measured at all visits.  
In addition, orthostatic BP and pulse will be 
measured at V2, V5, V8, V11, and 
unscheduled visits.   
ECG 
X 
 
 
 
 
 
X 
 
 
 
  
 
 
Perform prior to administration of IP. 
Unscheduled ECGs may be performed at the 
discretion of investigator. 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
21 
Visit No.: 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Notes 
Week Relative to 
Randomization  
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Procedures for some visits may take more 
than 1 day. 
Tolerance 
Interval for Visit 
(Days) 
0 
7 to 
+10 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
 
MRI 
 
X 
 
X 
 
 
X 
 
 
 
  
 
 
Perform at least 1 day prior to or after 
cognitive and functional tests, if applicable. 
MRI at V3 is to be performed and reviewed 
prior to V3 infusion and may occur no 
sooner than 21 days after the first infusion. 
If infusions are suspended after the first, 
second, or third dose, an MRI is to be 
performed and reviewed prior to the fourth 
infusion. 
MRI at V5 is to be performed and reviewed 
prior to V5 infusion.  MRI at V5 may occur 
up to 14 days before the scheduled visit 
window without protocol deviation. 
Unscheduled MRIs may be performed at the 
discretion of investigator, for example if 
titration is delayed due to temporary 
suspension of infusions. 
Additional Efficacy Measures 
Florbetapir F18 
PET scan 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
22 
Visits 15 through 21 and EDa  
Visits without cognitive and functional scales are eligible to be conducted remotely, via mobile healthcare coordinated with and 
approved by the sponsor, if permitted by local regulations.     
 
Visit No.: 
15 
16 
17 
18 
19 
20 
21 
EDa 
Notes 
End of Week Relative to 
Study Medication Start 
52 
56 
60 
64 
68 
72 
76 
 
If a participant discontinues before V21, perform EDa 
assessments, then the follow-up visits 12 weeks after the last 
dose received. 
Tolerance Interval for 
Visit (Days)
  
7 
7 
7 
7 
7 
7 
7 
  
 
Contact IWRS – register 
visit 
X 
X 
X 
X 
X 
X 
X 
X 
For all visits. 
Contact IWRS – 
dispensation of IP 
X 
X 
X 
X 
X 
X 
 
 
For visits where IP will be dispensed. 
Physical/neurological 
examination 
X 
 
 
X 
 
 
X 
X 
V18 is a brief physical and neurological exam, as described in 
Section 8.2.1.  
Any clinically significant changes from baseline on 
physical/neurological examinations should be noted on the AE 
CRF. 
Previous/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Preexisting 
conditions/adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
 
IP administered 
X 
X 
X 
X 
X 
X 
 
  
Administered by IV infusion.   
The participant should be observed for a minimum of 60 
minutes following the end of each infusion. 
Efficacy Measures 
ADAS-Cog13 
X 
 
 
X 
 
 
X 
X 
See footnote a. 
ADCS-ADL 
X 
 
 
X 
 
 
X 
X 
See footnote a. 
CDR 
X 
 
 
X 
 
 
X 
X 
See footnote a. 
MMSE 
X 
 
 
X 
 
 
X 
X 
See footnote a. 
DSST medicines version 
X 
 
 
X 
 
 
X 
X 
Collect via eCOA only when available. 
Safety Assessment 
C-SSRS since last visit 
X 
X 
X 
X 
X 
X 
X 
X 
If visit is not conducted on site, may collect by phone. 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
23 
Visit No.: 
15 
16 
17 
18 
19 
20 
21 
EDa 
Notes 
End of Week Relative to 
Study Medication Start 
52 
56 
60 
64 
68 
72 
76 
 
If a participant discontinues before V21, perform EDa 
assessments, then the follow-up visits 12 weeks after the last 
dose received. 
Tolerance Interval for 
Visit (Days)
  
7 
7 
7 
7 
7 
7 
7 
  
 
Self-Harm Supplement 
Form 
X 
X 
X 
X 
X 
X 
X 
X 
If visit is not conducted on site, may collect by phone. 
Self-Harm Follow-up Form 
X 
X 
X 
X 
X 
X 
X 
X 
Required if triggered by the Self-Harm Supplement Form per 
instructions. 
If visit is not conducted on site, may collect by phone. 
Laboratory Tests and Sample Collectionsc 
Hematology 
X 
 
 
X 
 
 
X 
X 
 
Clinical Chemistry and 
eGFR (CKD-EPI) 
X 
 
 
X 
 
 
X 
X 
eGFR calculated by Lilly-designated lab. 
Urinalysis and Urinary 
protein/creatinine ratio 
(UPCR) 
 
 
 
 
 
 
X 
X 
UPCR calculated by Lilly-designated lab. 
Pharmacokinetic (PK) 
Samples (Predose) 
X 
 
 
X 
 
 
 
 
Do not collect if the last IP infusion was >6 months prior to 
the scheduled visit. 
May be collected from the IV site prior to the infusion. 
Pharmacokinetic (PK) 
Samples (Postdose) 
X 
 
 
 
 
 
 
 
Do not collect if the last IP infusion was >6 months prior to 
the scheduled visit. 
Collect within 30 minutes of IP infusion completion.  Collect 
from the arm that IP was not administered through. 
PK Samples (Random) 
 
 
 
 
 
 
X 
X 
Do not collect if the last IP infusion was >6 months prior to 
the scheduled visit. 
Immunogenicity (ADA) 
Samples 
X 
 
 
 
 
 
X 
X 
 
NfL/GFAP 
X 
 
 
X 
 
 
X 
X 
 
P-tau 
X 
 
 
X 
 
 
X 
X 
 
A  
X 
 
 
X 
 
 
X 
X 
 
Exploratory Biomarker 
Samples 
X 
 
 
X 
 
 
X 
X 
Collect unless not allowed or infeasible due to local 
regulation. 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
24 
Visit No.: 
15 
16 
17 
18 
19 
20 
21 
EDa 
Notes 
End of Week Relative to 
Study Medication Start 
52 
56 
60 
64 
68 
72 
76 
 
If a participant discontinues before V21, perform EDa 
assessments, then the follow-up visits 12 weeks after the last 
dose received. 
Tolerance Interval for 
Visit (Days)
  
7 
7 
7 
7 
7 
7 
7 
  
 
Other Safety Measures 
Weight 
X 
 
 
X 
 
 
X 
X 
 
Vital signs and temperature 
X 
X 
X 
X  
X 
X 
X 
X 
Sitting BP, pulse, and temperature will be measured at all 
visits.  
In addition, orthostatic BP and pulse will be measured at visits 
15, 18, 21, EDa, and unscheduled visits.   
ECG 
X 
 
 
 
 
 
X 
X 
Perform prior to administration of IP. 
Unscheduled ECGs may be performed at the discretion of 
investigator. 
MRI 
X 
 
 
 
 
 
X 
X  
Perform at least 1 day prior to or after cognitive and functional 
tests, if applicable. 
Unscheduled MRIs may be performed at the discretion of 
investigator, for example if titration is delayed due to 
temporary suspension of infusions. 
Additional Efficacy Measures 
Flortaucipir F18 PET Scan 
  
 
 
 
 
 
X 
X 
Perform ≥16 hours apart from the florbetapir F18 PET scan, if 
applicable. 
Collect at EDa only if EDa occurs >36 weeks after 
randomization. 
V21 flortaucipir F18 PET scan may be performed at least 1 
day after completion of V20 through the end of the V21 
window. 
The flortaucipir F18 PET scan at V21 and EDa may become 
optional or regionally dependent at sponsor discretion. 
Florbetapir F18 PET scan 
X 
 
 
 
 
 
X 
X 
Perform ≥16 hours apart from the flortaucipir F18 PET scan, if 
applicable. 
Collect at EDa only if EDa occurs at ≥3 or more IP infusions 
after the last florbetapir F18 PET scan. 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
25 
 
Extension Period:  Visits 22 through 34 
After Visit 25, visits without cognitive and functional scales are eligible to be conducted remotely, via mobile healthcare coordinated 
with and approved by the sponsor, if permitted by local regulations.   
Visit No.: 
V22 
V23 
V24 V25 V26 V27 V28 V29 V30 V31 V32 V33 V34 
Notes 
Week Relative to 
Randomization  
78 
82 
86 
90 
94 
98 
102 
106 
110 
114 
118 
122 
126 Procedures for some visits may take more than 1 
day. 
Tolerance Interval for 
Visit (Days) 
7 7 to +10 7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
 
Contact IWRS – register 
visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For all visits. 
Contact IWRS – 
dispensation of IP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For visits where IP will be dispensed. 
Brief physical/neurological 
examination 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
As described in Section 8.2.1. 
Any clinically significant changes from baseline 
on physical/neurological examinations should be 
noted on the AE CRF. 
Previous/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Preexisting 
conditions/adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IP administered 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administered by IV at study site.   
The participant should be observed for a 
minimum of 60 minutes following the end of 
each infusion. 
Efficacy Measures 
ADAS-Cog13 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
See footnote a. 
ADCS-ADL 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
See footnote a. 
CDR 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
See footnote a. 
MMSE 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
See footnote a. 
DSST medicines version 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Collect via eCOA only when available. 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
26 
Visit No.: 
V22 
V23 
V24 V25 V26 V27 V28 V29 V30 V31 V32 V33 V34 
Notes 
Week Relative to 
Randomization  
78 
82 
86 
90 
94 
98 
102 
106 
110 
114 
118 
122 
126 Procedures for some visits may take more than 1 
day. 
Tolerance Interval for 
Visit (Days) 
7 7 to +10 7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
 
RUD-Lite 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Collect RUD-Lite at W78 only if not collected at 
W76 via AACI Addendum 4. 
See footnote e. 
QOL-AD 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Collect QOL-AD at W78 only if not collected at 
W76 via AACI Addendum 4. 
See footnote e. 
Safety Assessments 
C-SSRS since last 
assessment 
 
 
  
X 
 
 
X 
 
 
X 
 
 
 
 
Laboratory Tests and Sample Collections 
Hematology 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Clinical chemistry and 
eGFR (CKD-EPI) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
eGFR calculated by Lilly-designated lab. 
PK Samples (Predose) 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Do not collect if the last IP infusion was >6 
months prior to the scheduled visit. 
Predose collections may be collected from the 
IV site prior to the infusion. 
Immunogenicity (ADA) 
Samples 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
NfL/GFAP 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
P-tau 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
A  
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Exploratory Biomarker 
Samples 
 
  
  
X 
  
 
X 
  
  
X 
 
 
 
Collect unless not allowed or unfeasible due to 
local regulations.  
Other Safety Measures 
Weight 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
27 
Visit No.: 
V22 
V23 
V24 V25 V26 V27 V28 V29 V30 V31 V32 V33 V34 
Notes 
Week Relative to 
Randomization  
78 
82 
86 
90 
94 
98 
102 
106 
110 
114 
118 
122 
126 Procedures for some visits may take more than 1 
day. 
Tolerance Interval for 
Visit (Days) 
7 7 to +10 7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
7 
 
Vital signs and temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sitting BP, pulse, and temperature will be 
measured at all visits.  
In addition, orthostatic BP and pulse will be 
measured at V22, V25, V28, V31, and 
unscheduled visits.  
 
MRI 
 
X 
 
X 
 
 
X 
 
 
 
  
 
 
Perform at least 1 day prior to or after cognitive 
and functional tests, if applicable. 
MRI at V23 is to be performed and reviewed 
prior to V23 infusion and may occur no sooner 
than 21 days after the V22 infusion. If infusions 
are suspended after the first, second, or third 
dose of the extension period, an MRI is to be 
performed and reviewed prior to the fourth 
infusion. 
MRI at V25 is to be performed and reviewed 
prior to V25 infusion.  MRI at V25 may occur 
up to 14 days before the scheduled visit window 
without protocol deviation. 
Unscheduled MRIs may be performed at the 
discretion of investigator, for example if titration 
is delayed due to temporary suspension of 
infusions. 
Additional Efficacy Measures 
Florbetapir F18 PET scan 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
28 
Visits 35 through 41, EDb, and follow-up 
Visits without cognitive and functional scales are eligible to be conducted remotely, via mobile healthcare coordinated with and 
approved by the sponsor, if permitted by local regulations. 
Visit No.: 
V35 V36 V37 V38 V39 V40 V41 
EDb 
801-804 
Notes 
Week Relative to 
Randomization  
130 134 138 142 146 150 154 
 
d 
Procedures for some visits may take more than 1 day. 
If a participant discontinues after V21 and before V41, perform EDb 
assessments, then the follow-up visits 12 weeks after the last dose 
received. 
Tolerance Interval for Visit 
(Days) 
7 
7 
7 
7 
7 
7 
7 
 
14 
 
Contact IWRS – register visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For all visits. 
Contact IWRS – dispensation 
of IP 
X 
X 
X 
X 
X 
X 
 
 
 
For visits where IP will be dispensed. 
Brief physical/neurological 
examination 
X 
 
 
X 
 
 
X 
X 
 
As described in Section 8.2.1. 
Any clinically significant changes from baseline on physical/neurological 
examinations should be noted on the AE CRF. 
Previous/concomitant medications X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Preexisting conditions/adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IP administered 
X 
X 
X 
X 
X 
X 
 
 
 
Administered by IV at study site.   
The participant should be observed for a minimum of 60 minutes 
following the end of each infusion. 
Efficacy Measures 
ADAS-Cog13 
X 
 
 
X 
 
 
X 
X 
 
See footnote a. 
ADCS-ADL 
X 
 
 
X 
 
 
X 
X 
 
See footnote a. 
CDR 
X 
 
 
X 
 
 
X 
X 
 
See footnote a. 
MMSE 
X 
 
 
X 
 
 
X 
X 
 
See footnote a. 
DSST medicines version 
X 
 
 
X 
 
 
X 
X 
 
Collect via eCOA only when available. 
RUD-Lite 
X 
 
 
 
 
 
X 
X 
 
Collect at EDb only if EDb occurs at ≥12 weeks after the prior RUD-Lite 
assessment.  
See footnote e. 
QOL-AD 
X 
 
 
 
 
 
X 
X 
 
Collect at EDb only if EDb occurs at ≥12 weeks after the prior QOL-AD 
assessment. 
See footnote e. 
Approved on 10 Nov 2022 GMT

CONFIDENTIAL 
I5T-MC-AACI(e) 
 
29 
Visit No.: 
V35 V36 V37 V38 V39 V40 V41 
EDb 
801-804 
Notes 
Week Relative to 
Randomization  
130 134 138 142 146 150 154 
 
d 
Procedures for some visits may take more than 1 day. 
If a participant discontinues after V21 and before V41, perform EDb 
assessments, then the follow-up visits 12 weeks after the last dose 
received. 
Tolerance Interval for Visit 
(Days) 
7 
7 
7 
7 
7 
7 
7 
 
14 
 
Safety Assessments 
C-SSRS since last assessment 
X 
 
 
X 
 
 
X 
X 
X 
 
Self-Harm Supplement Form 
 
 
 
 
 
 
 
 
X 
If follow-up visit is not conducted on site, may collect by phone. 
Self-Harm Follow-up Form 
 
 
 
 
 
 
 
 
X 
Required if triggered by the Self-Harm Supplement Form per 
instructions. 
If follow-up visit is not conducted on site, may collect by phone. 
Hematology 
X  
 
 
 
 
 
X 
X 
 
 
Clinical Chemistry and eGFR 
(CKD-EPI) 
X 
 
 
 
 
 
X 
X 
 
eGFR calculated by Lilly-designated lab. 
PK Samples (Predose) 
X 
 
 
 
 
 
 
 
 
Do not collect if the last IP infusion was >6 months prior to the scheduled 
visit. 
Predose collections may be collected from the IV site prior to the 
infusion. 
PK (Random) 
 
 
 
 
 
 
X 
X 
X 
 
Immunogenicity (ADA) Samples 
X 
 
 
 
 
 
X 
X 
X 
 
NfL/GFAP 
X 
 
 
X 
 
 
X 
X 
 
 
P-tau 
X 
 
 
X 
 
 
X 
X 
 
 
A  
X 
 
 
X 
 
 
X 
X 
 
 
Exploratory Biomarker Samples 
X 
  
  
X 
  
 
X 
X 
 
Collect unless not allowed or unfeasible due to local regulations.  
Other Safety Measures 
Weight 
X 
 
 
X 
 
 
X 
X 
 
 
Vital signs and temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sitting BP, pulse, and temperature will be measured at all visits.  
In addition, orthostatic BP and pulse will be measured at Visits 35, 38, 
41, EDb and unscheduled visits.   
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Visit No.: 
V35 V36 V37 V38 V39 V40 V41 
EDb 
801-804 
Notes 
Week Relative to 
Randomization  
130 134 138 142 146 150 154 
 
d 
Procedures for some visits may take more than 1 day. 
If a participant discontinues after V21 and before V41, perform EDb 
assessments, then the follow-up visits 12 weeks after the last dose 
received. 
Tolerance Interval for Visit 
(Days) 
7 
7 
7 
7 
7 
7 
7 
 
14 
 
MRI 
X
 
 
 
 
 
 
X 
X 
 
Perform at least 1 day prior to or after cognitive and functional tests, if 
applicable. 
Unscheduled MRIs may be performed at the discretion of investigator, for 
example if titration is delayed due to temporary suspension of infusions. 
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Visit No.: 
V35 V36 V37 V38 V39 V40 V41 
EDb 
801-804 
Notes 
Week Relative to 
Randomization  
130 134 138 142 146 150 154 
 
d 
Procedures for some visits may take more than 1 day. 
If a participant discontinues after V21 and before V41, perform EDb 
assessments, then the follow-up visits 12 weeks after the last dose 
received. 
Tolerance Interval for Visit 
(Days) 
7 
7 
7 
7 
7 
7 
7 
 
14 
 
Flortaucipir F18 PET scan 
 
 
 
 
 
 
X 
X 
Perform ≥16 hours apart from the florbetapir F18 PET scan, if applicable. 
Collect at EDb only if EDb occurs >36 weeks after V22. 
V41 flortaucipir F18 PET scan may be performed at least 1 day after 
completion of V40 through the end of the V41 window. 
The flortaucipir F18 PET scan at V41 and EDb may become optional or 
regionally dependent at sponsor discretion. 
Florbetapir F18 PET scan 
X 
 
 
 
 
 
X 
X 
Perform ≥16 hours apart from the flortaucipir F18 PET scan, if 
applicable. 
Collect at EDb only if EDb occurs at ≥3 or more IP infusions after the last 
florbetapir F18 PET scan. 
Abbreviations:  A = amyloid beta; ADA = anti-drug antibody; ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognitive subscale; 
ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory; AE CRF = adverse event case report form; 
ApoE = Apolipoprotein E; BP = blood pressure; CDR = Clinical Dementia Rating Scale; CKD-EPI = chronic kidney disease epidemiology collaboration; 
C-SSRS = Columbia Suicide Severity Rating Scale; DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; eCOA = electronic Clinical Outcome 
Assessment; EDa = early discontinuation a; EDb = early discontinuation b; eGFR = estimated glomerular filtration rate; GFAP = glial fibrillary acidic protein; 
IP = investigational product; IWRS = interactive web-response system; IV = intravenous; MMSE = Mini Mental State Examination; MRI = magnetic 
resonance imaging; NfL = neurofilament light chain; No. = Number; PET = positron emission tomography; PK = pharmacokinetics; P-tau = phosphorylated 
tau; QOL-AD = Quality of Life in Alzheimer’s Disease; RUD-Lite = Resource Utilization in Dementia – Lite Version; UPCR = urinary protein/creatinine 
ratio; V = Visit. 
a Administer the ADAS-Cog13, ADCS-ADL, CDR, MMSE and DSST medicines version prior to medical procedures that could be stressful to the participant 
(blood draws, etc.).  These tests include the audio voice recording of the rater’s questions and the participant and study partner responses to assessment 
questions. If an efficacy assessment (ADAS-Cog13, ADCS-ADL, CDR, MMSE, or DSST medicines version) cannot be collected at the scheduled visit, it 
may be collected at the next opportunity, if within 30 days of the scheduled assessment. 
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b The participant should meet MMSE eligibility criteria before the screening flortaucipir F18 PET scan, MRI, and florbetapir F18 PET scan.  Perform the 
flortaucipir F18 and florbetapir F18 PET scans ≥16 hours apart from each other.  If results are received after the screening window, the participant remains 
eligible contingent on meeting the other eligibility criteria.  If the investigator feels it is necessary, a repeat of screening labs may be performed.  A historical 
florbetapir and/or flortaucipir PET scan may be submitted to be considered for eligibility if performed within 6 months of randomization.  The acceptance of a 
historical scan is at the discretion of the sponsor.   
c Unscheduled lab tests may be performed at the discretion of the investigator.  Collect labs prior to administration of IP, unless otherwise noted.  Record the 
date and times of sample collection on the Lab Requisition Form. 
d The follow-up period begins 12 weeks after the final administration of IP, and Visits 801 through 804 are scheduled as described in Section 4.1.4.   
e If RUD-Lite or QOL-AD cannot be collected at the scheduled visit, it may be collected at the next opportunity. If visit is not conducted on site, it maybe 
collected by phone. 
 
 
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2. 
Introduction 
2.1. 
Study Rationale 
Donanemab is an antibody directed at the pyroglutamate modification of the third amino acid of 
amyloid beta (N3pG Aβ) epitope that is present only in brain amyloid plaques.  It is being 
studied for the treatment of Alzheimer’s disease (AD).  The mechanism of action of donanemab 
antibody is to target and remove deposited amyloid plaque, a key pathological hallmark of AD, 
via microglial-mediated clearance.  The clinical strategy for donanemab identifies early 
symptomatic AD patients with existing brain amyloid load, as measured using the amyloid 
plaque biomarker florbetapir F18 positron emission tomography (PET) imaging in conjunction 
with the presence of tau pathology in the brain.  This strategy is based on the amyloid hypothesis 
of AD, which postulates that the production and deposition of Aβ is an early and necessary event 
in the pathogenesis of AD (Selkoe 2000).  Clinical data supporting this hypothesis comes from 
the observation that parenchymal Aβ levels are elevated prior to the manifestation of AD 
symptoms, and further supported by genetic variants of AD that overproduce brain Aβ and 
genetic variants that protect against Aβ production (Jonsson et al. 2012; Fleisher et al. 2015).  
Furthermore, early in the disease, the presence of brain amyloid appears to increase the risk of 
conversion from mild cognitive impairment (MCI) to AD dementia (Doraiswamy et al. 2012).  
These data suggest that removal of deposited amyloid and clearance of Aβ can result in the 
slowing of AD progression. 
Study I5T-MC-AACI (AACI) is a Phase 3, double-blind, placebo-controlled study to evaluate 
the safety and efficacy of N3pG antibody (donanemab) in Participants with early symptomatic 
AD (prodromal AD and mild dementia due to AD) with the presence of brain tau pathology.  
Study AACI will assess whether removal of existing amyloid plaque can slow the progression of 
the disease as assessed by clinical outcomes for cognition and function, and by imaging 
biomarker measures of disease pathology and neurodegeneration over 76 weeks of double-blind 
observation.   
Study AACI expands the Participant population compared to the prior Phase 2 study by 
including participants with high tau pathology.  The primary analysis will test low-medium 
(intermediate) tau pathology population and the overall population.    
2.2. 
Background 
Alzheimer’s disease is an age-related neurodegenerative disorder characterized by progressive 
decline in cognitive function and the ability to perform activities of daily living.  The amyloid 
hypothesis of AD postulates that the accumulation of Aβ is an early and necessary event in the 
pathogenesis of AD.  This hypothesis suggests that interventions that slow the accumulation of 
Aβ plaque in the brain or increase clearance of Aβ may be able to slow the progression of the 
AD clinical syndrome.  Another hallmark neuropathological lesion of AD is comprised of 
intraneuronal, neurofibrillary tangles consisting of tau proteins, which spread through the brain 
and mark disease progression (Braak and Braak 1996).  The relationship between these 2 
pathologies is still unclear, although the presence of both is necessary for the diagnosis of 
definite AD. 
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Converging evidence from both genetic at-risk and age at-risk cohorts suggests that the 
pathophysiological process of AD begins well more than a decade before the clinical stage now 
recognized as AD dementia, and that neurodegeneration is already apparent on magnetic 
resonance imaging (MRI) by the stage of MCI.  Like many disorders, AD occurs on a continuum 
from asymptomatic (preclinical) to MCI, and then to dementia in mild, moderate, and severe 
stages.  Recent clinical trial results in mild-to-moderate AD dementia, as well as evidence from 
transgenic animal experiments, suggest that treating AD during the earlier stages could have the 
greatest potential benefit on the disease and inhibiting progression, particularly when considering 
therapies targeted at Aβ reduction (Doody et al. 2014; Fleisher et al. 2015; Siemers et al. 2016). 
2.2.1. 
Donanemab Nonclinical Studies 
The safety of donanemab, a plaque-specific monoclonal antibody, was assessed in a 6-week 
toxicity study in cynomolgus monkeys, including evaluations of safety pharmacology and 
toxicokinetics.  The administration of donanemab in monkeys of up to a maximum dose of 100 
mg/kg/week (bolus intravenous [IV]) for 6 weeks resulted in no drug-related findings.  
Repeat-dose hazard identification studies of up to 6 months’ duration were conducted in the aged 
PDAPP (APPV717F) transgenic mouse model of Aβ deposition to investigate potential effects 
related to clearance of Aβ from the brain.  In addition, a specialized 3-month study to investigate 
the potential for cerebral amyloid angiopathy-associated microhemorrhages was conducted in 
aged PDAPP transgenic mice.  These studies in the PDAPP mouse were conducted with mE8c 
(LSN3026818), a murine analog antibody of donanemab, to avoid limitations due to potential 
immunogenicity from repeated administration of the humanized antibody to the mouse.  
No drug-related findings occurred in the hazard identification studies in PDAPP mice at mE8c 
doses of up to 100 mg/kg/week (the highest dose tested).  Treatment of PDAPP mice with mE8c 
at 12.5 mg/kg/week for 3 months did not exacerbate cerebral amyloid angiopathy-associated 
microhemorrhages at a dose that produced a maximum pharmacological response (reduction in 
deposited brain Aβ) in these animals.  
See the Investigator’s Brochure (IB) for additional details regarding nonclinical donanemab 
studies. 
2.2.2. 
Donanemab Clinical Studies 
Two Phase 1 studies (Study I5T-MC-AACC [AACC] and Study I5T-MC-AACD [AACD]) have 
been conducted in participants with MCI and mild-to-moderate AD. In both studies, rapid and 
sustained reduction in cerebral amyloid plaques were observed with donanemab doses 
10 mg/kg. 
One Phase 2 study (Study I5T-MC-AACG [AACG]) has been conducted in participants with 
early symptomatic AD and intermediate (low to medium) cerebral tau burden. Treatment with 
donanemab compared with placebo resulted in a significant slowing of disease progression, as 
measured by the integrated Alzheimer’s Disease Rating Scale (iADRS; Wessels et al. 2015) as 
well as deep and rapid reduction in amyloid plaque level. Safety findings observed in clinical 
development include ARIAs, IRRs, and the presence of ADAs (Mintun et al. 2021). 
See the IB for detailed safety and PK information regarding donanemab. 
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2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of donanemab can be found in the IB. 
 
 
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3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To assess the effect of donanemab versus 
placebo on clinical progression in participants 
with early symptomatic AD  
iADRS change from baseline through Week 
76 in at least one of  
 the low-medium tau pathology 
population or  
 the overall population 
Secondary 
 
To assess the effect of donanemab versus 
placebo on clinical progression in participants 
with early symptomatic AD  
Change from baseline through Week 76 in at 
least one of  
 the low-medium tau pathology 
population or 
 the overall population 
as measured by:   
 CDR-SB 
 ADAS-Cog13 score 
 ADCS-iADL score  
 MMSE score 
To assess the effect of donanemab versus 
placebo on brain amyloid deposition  
Change in brain amyloid plaque deposition 
from baseline through Week 76 as measured 
by florbetapir F18 PET scan 
To assess the effect of donanemab versus 
placebo on brain tau deposition 
Change in brain tau deposition from baseline 
through Week 76 as measured by flortaucipir 
F18 PET scan 
To assess the effect of donanemab versus 
placebo on brain region volumes  
Change in volumetric MRI measures from 
baseline through Week 76 
To evaluate safety and tolerability of 
donanemab 
Standard safety assessments:   
 Spontaneously reported AEs 
 Clinical laboratory tests 
 Vital sign and body weight 
measurements 
 12-lead ECGs 
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Objectives 
Endpoints 
 Physical and neurological 
examinations 
MRI (ARIA and emergent radiological 
findings) 
Infusion related reactions 
C-SSRS 
To assess peripheral PK and presence of 
anti-donanemab antibodies 
Plasma PK of donanemab 
ADAs against donanemab including  
 treatment-emergent ADAs  
 neutralizing antibodies 
Tertiary/Exploratory 
 
To assess the effect of donanemab versus 
placebo on blood-based biomarkers 
 
Plasma 
 NfL 
 GFAP 
 P-tau 
 A levels  
To assess the effect of donanemab versus 
placebo on cognition 
Change in DSST - Medicines Version from 
baseline through Week 76. 
To assess the efficacy of donanemab to 
prolong time in the current disease state 
CDR global score 
CDR-SB  
Extension Period  
To evaluate the clinical efficacy between 
early start participants versus delayed start 
participants treated with donanemab  
iADRS, CDR-SB, ADAS-Cog13, ADCS-
iADL, and MMSE score endpoint will be 
evaluated for the extension period following 
the approach outlined in Liu-Seifert et al. 
(2015) 
To evaluate if continued treatment with 
donanemab beyond 72 weeks results in 
amyloid clearance in participants who had not 
met dose reduction criteria during the double-
blind period 
Change in brain amyloid plaque deposition 
from baseline through Week 154 as measured 
by florbetapir F18 PET scan 
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To evaluate amyloid plaque re-accumulation 
in participants who met dose reduction criteria 
during double-blind and extension periods  
Change in brain amyloid plaque deposition 
from time of meeting dose reduction criteria 
through Week 154 as measured by florbetapir 
F18 PET scan 
To evaluate the quality of life, dependency 
level, healthcare resource utilization, and 
level of formal and informal care attributable 
to AD between early start participants versus 
delayed start participants treated with 
donanemab 
QOL-AD, dependency level (derived from 
ADCS-ADL), and RUD-Lite will be 
evaluated for the extension period following 
the approach outlined in Liu-Seifert et al. 
(2015) 
Abbreviations:  Aamyloid beta; AD = Alzheimer’s disease; ADA = anti-drug antibody; ADAS-Cog13 = 
Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-ADL = Alzheimer’s Disease Cooperative 
Study - Activities of Daily Living; ADCS-iADL = Alzheimer’s Disease Cooperative Study – instrumental 
Activities of Daily Living; AE = adverse event; ARIA = amyloid-related imaging abnormalities; CDR = Clinical 
Dementia Rating Scale; CDR-SB = Clinical Dementia Rating Scale – Sum of Boxes; C-SSRS = Columbia 
Suicide Severity Rating Scale; DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; GFAP = glial 
fibrillary acidic protein; iADRS = integrated Alzheimer’s Disease Rating Scale; MMSE = Mini Mental State 
Examination; MRI = magnetic resonance imaging; NfL = neurofilament light chain; PET = positron emission 
tomography; PK = pharmacokinetics; P-tau = phosphorylated tau; QOL-AD = Quality of Life in Alzheimer’s 
Disease; RUD-Lite = Resource Utilization in Dementia – Lite Version. 
 
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4. 
Study Design 
4.1. 
Overall Design 
Study AACI is a multicenter, randomized, double-blind placebo-controlled, Phase 3 study of 
donanemab in participants with early symptomatic AD.  Participants who meet entry criteria will 
be randomized in a 1:1 ratio to one of the following treatment groups:   
 Donanemab: 700 mg IV Q4W for first 3 doses and then 1400 mg IV Q4W  
 Placebo 
After 76 weeks, participants will be assigned to donanemab or placebo based on criteria 
described in Section 4.1.3.  
The maximum total duration of study participation for each participant, including screening and 
the post-treatment follow-up periods, is up to 205 weeks:   
 Lead-In:  any time prior to complete screening 
 Complete Screening: up to 7 weeks 
 Double-Blind: 76 weeks 
 Extension: 78 weeks 
 Follow-Up: up to 44 weeks 
The maximum duration of treatment is 150 weeks. 
Scheduled Reduction of Donanemab to Placebo 
Participants whose amyloid plaque reduction as measured by florbetapir F18 PET scans at 
Visit 8 (Week 24),Visit 15 (Week 52), Visit 21 (Week 76), Visit 28 (Week 102), or Visit 35 
(Week 130) meets dose reduction criteria will have a double-blind dose reduction of donanemab 
to IV placebo for the remaining duration of the study.   
These dose reduction rules are defined by the sponsor.   
4.1.1. 
Lead-In and Screening Period (Visits 601 and 1) 
At or before Visit 1, the study will be explained to the participant (and his or her legal 
representative, if applicable) and study partner.  Informed consent must be obtained before any 
study procedures are conducted.  The lead-in period (V601) is optional and may occur any time 
prior to Visit 1.  The screening period spans the time between Visit 1 to Visit 2.  
4.1.1.1. 
Visit 601 
For those who participate in V601, a preliminary screening informed consent may be obtained to 
conduct lead-in screening to collect demographics data, administer the Mini Mental State 
Examination (MMSE) and collect laboratory samples.  
Participants who do not meet the MMSE screening criteria are not to have imaging screening 
procedures performed.  For rescreening instructions, see Section 5.4.  All participants must sign 
the full informed consent to participate in Visit 1.   
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4.1.1.2. 
Visit 1 
Once the full informed consent is signed, 49 days are allowed for completion of the remaining 
Visit 1 screening assessments and procedures, as described in the SoA (Section 1.3).  
Participants who meet MMSE screening criteria may proceed to the remaining screening 
procedures.   
Although imaging may be the last screening procedures of the study, it is expected that the 
centrally read results will be available within the screening window.  However, it will not be a 
protocol deviation should the screening results not be available within the screening window. 
Participants whose screening imaging results are not available until after the screening window 
will remain eligible within Visit 1 until these results become available.   
Visit 1 is not considered complete until all screening procedures have been completed, results 
have been reviewed by the investigator or qualified designee, and the investigator or qualified 
designee has confirmed that the participant is eligible to be randomized.  Only then can the 
participant proceed to Visit 2.  
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 at Visit 1.  
Participants must meet all eligibility criteria (Sections 5.1 and 5.2) to continue to Visit 2.  
NOTE: The screening tolerance window is extended to 180 days at Visit 1 for participants in 
screening at the time of a temporary randomization pause. If such participants remain in 
screening for >90 days, chemistry, hematology, and ECG must be repeated to reassess eligibility 
criteria prior to Visit 2 (randomization). 
4.1.2. 
Double-Blind Period (Visits 2 through 21) 
The treatment period is a double-blind treatment phase beginning at Visit 2 (randomization).  At 
Visit 2, appointments should be made for all remaining visits and should be scheduled as close as 
possible to the target date, relative to Visit 2.  Participants who meet entry criteria will be 
enrolled and randomized to receive up to 72 weeks of treatment with donanemab or placebo 
during the double-blind period.   
During this double-blind period, participants will receive IV donanemab or IV placebo Q4W.  
Assessments and procedures will be performed as indicated in the SoA (Section 1.3).  Procedures 
for some visits may take more than 1 day.   
Final endpoint measures and safety assessments for the double-blind period will be performed at 
visit 21 (week 76) 4 weeks following the participant’s last dose of investigational product (IP).   
The study investigator and site clinical study team will not have access to any florbetapir F18 
and flortaucipir F18 follow-up PET results in order to maintain blinding to any potential changes 
in amyloid and tau deposition.   
4.1.3. 
Extension Period (Visits 22 through 41) 
Participants will be evaluated for amyloid plaque reduction by PET scan at V21. Dose reduction 
criteria for donanemab are defined by the sponsor.  
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 Participants randomized to donanemab during the double-blind period who do not meet 
dose reduction criteria by V21 will continue receiving donanemab.  
o Participants who remained on 700 mg during the double-blind period will have 
the opportunity to dose escalate to 1400 mg at V25 or after.  
 Participants randomized to donanemab during the double-blind period who meet dose 
reduction criteria by V21 will be assigned to receive placebo starting at V22.   
 Participants randomized to placebo during the double-blind period will be assigned to 
receive donanemab starting at V22, and will follow the same dose titration as participants 
during the double-blind period.  
All participants, by design, may have the opportunity to receive donanemab at some point in the 
study; however, assignment in the extension period is double-blind.  
After the extension period, participants will attend follow-up visits (V801 through V804) as 
described in Section 4.1.4.  
4.1.4. 
Follow-Up (Visits 801 through 804) 
Participants will have immunogenicity and safety follow-up visits (Visit 801 through Visit 804) 
beginning 12 weeks after their last dose of IP.  
Participants will continue to have quarterly immunogenicity and safety follow-up visits until the 
participant completes V804 or the site is notified that the participant is not required to complete 
all follow-up visits, whichever occurs first.  See the SoA (Section 1.3) for the timing of events 
and the measures to be assessed. 
Follow-up visits are not required if the participant meets release requirements determined by the 
sponsor. 
4.2. 
Scientific Rationale for Study Design 
Study AACI is a multicenter, randomized, double-blind, placebo-controlled, study of donanemab 
in patients with early symptomatic AD (where early symptomatic AD refers to the combination 
of 2 stages:  MCI-AD and mild AD dementia), MMSE 20-28, and with cerebral tau pathology 
that is elevated, as measured by flortaucipir.  The study is intended to further characterize the 
benefits and risks of treatment with donanemab versus placebo in participants with early 
symptomatic AD. 
Study AACI includes a placebo treatment arm and allows all participants to continue their 
symptomatic AD standard of care concomitant medications.  Inclusion of a placebo treatment 
arm is acceptable because there are no confirmed clinically  effective disease modifying 
treatments for AD; this approach is in agreement with the use of placebo described in the 
Declaration of Helsinki (WMA 2013).  The use of a placebo comparator in Study AACI is 
needed to determine the efficacy and safety of donanemab therapy.   
The study includes a screening visit, which can last up to 49 days (see exception in Section 4.1.1), 
at which participants are required to have flortaucipir F 18 PET imaging results consistent with 
elevated tau in order to be randomized to the double-blind period.  The duration of the double-
blind period of the study is 76 weeks and includes up to 72 weeks of treatment with endpoint 
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measures at the end of the double-blind period (Week 76), to assess the safety, tolerability, and 
efficacy of donanemab versus placebo. 
In addition to AE reporting, safety measures such as laboratory assessments, immunogenicity 
testing, vital signs and weight monitoring, electrocardiogram (ECG) monitoring, physical 
examinations, neurological examinations, MRI assessments, and assessments of suicidal ideation 
and behavior are included to facilitate a comprehensive safety evaluation. 
Amendment d adds a long-term extension period designed to further evaluate donanemab 
efficacy and safety over time.  
See Section 8.1 for descriptions of outcome measures.  In addition to clinical outcomes, imaging 
biomarkers will also be measured to assess the direct effect of donanemab on amyloid plaque 
removal, which is a known hallmark pathology of AD, and hypothesized to contribute to the 
cognitive and functional decline in people with AD.  Amyloid pathology is theorized to be a 
mediator for clinical decline and therefore it is hypothesized that the removal of amyloid may 
slow clinical decline. 
4.3. 
Justification for Dose 
Based on data presented in Section 2.2.2 as well as decreased participant burden with a Q4W 
dosing schedule compared with a Q2W dosing schedule and comparable safety (see Section 2), 
1400 mg Q4 week dosing was selected as the highest dose regimen for robust amyloid plaque 
lowering.  Safety data from AACD showed that the 1400 mg dose of donanemab had an 
acceptable safety profile based on the ability to monitor and manage AEs and AEs of special 
interest including amyloid-related imaging abnormalities (ARIA)-E, ARIA-H and 
hypersensitivity reactions, and the overall frequency, severity, and seriousness of AEs at this 
dose level.   
Protocol amendment (a) incorporated a titration schedule of 700 mg IV Q4W for the first 3 doses 
and then 1400 mg IV Q4W based on observation of two cases of symptomatic ARIA observed 
within their first 3 doses in this study. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all required 
phases of the study, including the last visit or the last scheduled procedure shown in the SoA. 
The end of the study for the primary outcome is defined as the date of the last visit of the double-
blind period in the study. 
End of the study is the date of the last visit or last scheduled procedure shown in the SoA for the 
last patient. 
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Type of Participant and Disease Characteristics 
1. 60 to 85 years of age inclusive, at the time of signing the informed consent. 
2. Gradual and progressive change in memory function reported by the participant or 
informant for ≥6 months. 
3. An MMSE score of 20 to 28 (inclusive) at Visit 601 or 1. 
4. Inclusion criterion 4 is removed.   
5. Meet flortaucipir F18 scan (central read) criteria (Section 8.1.2.5). 
6. Meet florbetapir F18 scan (central read) criteria (Section 8.1.2.5). 
7. Have a study partner who will provide written informed consent to participate, is in 
frequent contact with the participant (defined as at least 10 hours per week), and will 
accompany the participant to study visits or be available by telephone at designated 
times. 
A second study partner may serve as backup.  The study partner(s) is/are required to 
accompany the participant for signing consent.  One study partner is requested to be 
present or available by phone on all days the C-SSRS/Self-Harm Supplement Form is 
administered.  The study partner must be present on all days the cognitive and functional 
scales are administered.  If a participant has a second study partner, it is preferred that 1 
study partner be primarily responsible for the CDR and the Alzheimer’s Disease 
Cooperative Study – Activities of Daily Living Inventory (ADCS-ADL) assessments.  
Visits requiring the following assessments and scales must have a study partner available 
by telephone if not accompanying participant at a visit for the following assessments:   
 AEs and concomitant medications 
 Relevant portions of the C-SSRS/Self-Harm Supplement Forms 
 CDR, and 
 ADCS-ADL. 
If a study partner must withdraw from study participation, a replacement may be allowed 
at the investigator’s discretion.  The replacement will need to sign a separate informed 
consent on the first visit that he or she accompanies the participant.   
8. Have adequate literacy, vision, and hearing for neuropsychological testing in the opinion 
of the investigator at the time of screening. 
9. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures. 
10. Stable concomitant symptomatic AD medications and other medication that may impact 
cognition for at least approximately 30 days prior to randomization (does not apply to 
topical, as needed [prn], or discontinued medications). 
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Sex 
11. Males and females will be eligible for this study. 
a. Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
b. Male participants: 
i. 
Men, regardless of their fertility status, with non-pregnant women of 
childbearing potential (WOCBP) partners must agree to either remain 
abstinent (if this is their preferred and usual lifestyle) or use condoms as well 
as 1 additional highly effective (less than 1% failure rate) method of 
contraception (such as combination oral contraceptives, implanted 
contraceptives, or intrauterine devices) or effective method of contraception 
(such as diaphragms with spermicide or cervical sponges) for the duration of 
the study and until their plasma concentrations are below the level that could 
result in a relevant potential exposure to a possible fetus, predicted to be 90 
days following last dose of IP. 
A. Men and their partners may choose to use a double–barrier method of 
contraception.  (Barrier protection methods without concomitant use of 
a spermicide are not an effective or acceptable method of 
contraception.  Thus, each barrier method must include use of a 
spermicide.  It should be noted, however, that the use of male and 
female condoms as a double barrier method is not considered 
acceptable due to the high failure rate when these barrier methods are 
combined). 
B. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods), declaration of abstinence just for the duration of a 
trial, and withdrawal are not acceptable methods of contraception. 
ii. 
Men with pregnant partners should use condoms during intercourse for the 
duration of the study and until the end of estimated relevant potential exposure 
in WOCBP (90 days). 
iii. 
Men should refrain from sperm donation for the duration of the study and 
until their plasma concentrations are below the level that could result in a 
relevant potential exposure to a possible fetus, predicted to be 90 days 
following last dose of IP. 
iv. 
Men who are in exclusively same sex relationships (as their preferred and 
usual lifestyle) are not required to use contraception. 
c. Female participants: 
i. 
Women not of childbearing potential may participate and include those who 
are: 
A. infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
Mullerian agenesis; or 
B. post-menopausal – defined as either 
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a. 
A woman at least 40 years of age with an intact uterus, not on 
hormone therapy, who has cessation of menses for at least 1 year 
without an alternative medical cause, AND a follicle-stimulating 
hormone >40 mIU/mL; or 
b. 
A woman 55 or older not on hormone therapy, who has had at 
least 12 months of spontaneous amenorrhea; or 
c. 
A woman at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy. 
Informed Consent 
12. Capable of giving signed informed consent as described in Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
13. Significant neurological disease affecting the central nervous system other than AD, that 
may affect cognition or ability to complete the study, including but not limited to, other 
dementias, serious infection of the brain, Parkinson’s disease, multiple concussions, or 
epilepsy or recurrent seizures (except febrile childhood seizures). 
14. Current serious or unstable illnesses including cardiovascular, hepatic, renal, 
gastroenterologic, respiratory, endocrinologic, neurologic (other than AD), psychiatric, 
immunologic, or hematologic disease and other conditions that, in the investigator’s 
opinion, could interfere with the analyses in this study; or has a life expectancy of <24 
months. 
15. History of cancer within the last 5 years, with the exception of non-metastatic basal 
and/or squamous cell carcinoma of the skin, in situ cervical cancer, nonprogressive 
prostate cancer, or other cancers with low risk of recurrence or spread. 
16. Participants with any current primary psychiatric diagnosis other than AD if, in the 
judgment of the investigator, the psychiatric disorder or symptom is likely to confound 
interpretation of drug effect, affect cognitive assessment, or affect the participant’s ability 
to complete the study.  Participants with history of schizophrenia or other chronic 
psychosis are excluded. 
17. Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at 
significant risk for suicide. 
18. History of alcohol or drug use disorder (except tobacco use disorder) within 2 years 
before the screening visit. 
19. History of clinically significant multiple or severe drug allergies, significant atopy, or 
severe posttreatment hypersensitivity reactions (including but not limited to erythema 
multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, 
and/or exfoliative dermatitis). 
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Imaging, Vital Signs, Electrocardiograms, Laboratory Tests, and Physical Examination  
20. Have any clinically important abnormality at screening, as determined by investigator, in 
physical or neurological examination, vital signs, ECG, or clinical laboratory test results 
that could be detrimental to the participant, could compromise the study, or show 
evidence of other etiologies for dementia. 
21. Screening MRI which shows evidence of significant abnormality that would suggest 
another potential etiology for progressive dementia or a clinically significant finding that 
may impact the participant’s ability to safely participate in the study. 
22. Have any contraindications for MRI, including claustrophobia or the presence of 
contraindicated metal (ferromagnetic) implants/cardiac pacemaker. 
23. Have a centrally read MRI demonstrating presence of ARIA-E, >4 cerebral 
microhemorrhages, more than 1 area of superficial siderosis, any macrohemorrhage or 
severe white matter disease at screening. 
24. Sensitivity to florbetapir F18 or flortaucipir F18.   
25. Poor venous access. 
26. Contraindication to PET. 
27. Present or planned exposure to ionizing radiation that, in combination with the planned 
administration of study PET ligands, would result in a cumulative exposure that exceeds 
local recommended exposure limits. 
28. Alanine aminotransaminase (ALT) ≥2.5X the upper limit of normal (ULN) of the 
performing laboratory, aspartate aminotransferase (AST) ≥2.5X ULN, total bilirubin 
level (TBL) ≥1.5X ULN, or alkaline phosphatase (ALP) ≥2X ULN at screening. 
 
Note:  Participants with TBL ≥1.5X ULN are not excluded if they meet all of the 
following criteria for Gilbert syndrome:   
 Bilirubin is predominately indirect (unconjugated) at screening (direct bilirubin 
within normal limits). 
 Absence of liver disease. 
 ALT, AST, and ALP ≤1X ULN at screening. 
 Hemoglobin is not significantly decreased at screening. 
Prior/Concomitant Therapy 
29. Have had prior treatment with a passive anti-amyloid immunotherapy <5 half-lives prior 
to randomization. 
30. Have received active immunization against Aβ in any other study.  
31. Have known allergies to donanemab, related compounds, or any components of the 
formulation. 
Prior/Concurrent Clinical Study Experience 
32. Are currently enrolled in any other interventional clinical trial involving an IP or any 
other type of medical research judged not to be scientifically or medically compatible 
with this study. 
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33. Have participated, within the last 30 days (4 months for studies conducted in Japan; 3 
months for studies conducted in the United Kingdom), in a clinical trial involving an IP.  
If the previous IP is scientifically or medically incompatible with this study and has a 
long half-life, 3 months or 5 half-lives (whichever is longer) should have passed prior to 
screening (participation in observational studies may be permitted upon review of the 
observational study protocol and approval by the sponsor). 
34. Have previously completed or withdrawn from this study or received donanemab in any 
prior investigational study.  (This exclusion criterion does not apply to participants who 
are allowed to rescreen before randomization in this study). 
Other Exclusions 
35. Are investigator site personnel directly affiliated with this study and/or their immediate 
families.  Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted. 
36. Are Lilly employees or are employees of third-party organizations (TPOs) involved in study 
which requires exclusion of their employees, or have study partners who are Lilly employees 
or are employees of TPOs involved in a study which requires exclusion of their employees. 
5.3. 
Lifestyle Considerations 
Participants should refrain from donating blood or blood products from the time of their 
screening visit until 6 months following the last dose of IP. 
Participants should avoid excessive use of alcohol from the screening visit until the study ends.  
Excessive alcohol consumption is defined for men as consuming an average of more than 3 
drinks per day, or more than 21 drinks per week.  For women, excessive use of alcohol is defined 
as consuming an average of more than 2 drinks per day, or more than 14 drinks per week 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities.  Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened if the screen failure is due to non-eligible imaging results.  
If the screen failure is due to an MMSE score >28, then 1 rescreen will be allowed after 24 weeks. 
Other reasons for screen failure will require sponsor approval for rescreen. 
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6. 
Study Intervention 
Study intervention and IP are defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
trial protocol. 
6.1. 
Study Intervention(s) Administered 
Investigational products used in this study are: 
 Donanemab  
 Placebo  
Investigational product is administered by IV infusion over a minimum of 30 minutes.  Detailed 
instructions for administration, including reconstitution and infusion rate, can be found in the 
pharmacy preparation instructions.  
Note that at visits which require cognitive assessments be performed, all cognitive scales are to 
be administered before study medication is administered.   
Investigational product is to be administered once Q4W.  Investigational product must not be 
administered at a dosing interval of <21 days at any time in the study.  Based on permitted visit 
windows, it would appear that study medication could theoretically be administered at a 2-week 
interval.  However, administration of 2 doses within <21 days of each other will be a protocol 
deviation. 
See Section 6.5.2 for infusion-related reactions and premedication instructions, if applicable.   
Resuscitation equipment and rescue medications must be available wherever the IP is 
administered.  
Packaging and Labeling 
Clinical trial materials will be labeled according to the country’s regulatory requirements.  All 
IPs will be stored, inventoried, reconciled, and destroyed according to applicable regulations.  
Clinical trial materials are manufactured in accordance with current Good Manufacturing 
Practices (GMP). 
IP will be supplied in a vial.  Placebo will be provided as a solution.   
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all IP received and any discrepancies are reported and 
resolved before use of the IP. 
2. Only participants enrolled in the study may receive IP.  Only authorized study personnel 
may supply, prepare, or administer IP.  All IP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized study personnel. 
3. The investigator or authorized study personnel is responsible for IP accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition 
records). 
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4. Further guidance and information for the final disposition of unused IPs are provided by 
the sponsor. 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
This is a double-blind study, with design to maintain blinding to treatment.  To preserve the 
blinding of the study, a minimal number of Lilly personnel will see the randomization table and 
treatment assignments before the study is complete.   
The independent external data monitoring committee (DMC) is unblinded to randomization.  
Investigational product will be prepared by an unblinded pharmacist or other qualified unblinded 
personnel and will be administered by a blinded nurse or other qualified blinded personnel, as 
described in the pharmacy preparation instructions.  Authorized study personnel will confirm 
that they have located the correct packages by entering a confirmation number found on the label 
into the interactive web-response system (IWRS). 
Emergency unblinding at a participant level for AEs may be performed through the IWRS.  This 
option may be used ONLY if the subject’s well-being requires knowledge of the subject’s 
treatment assignment.  All unblinding events are recorded and reported by the IWRS. 
If an investigator, authorized study personnel performing assessments, or participant/partner is 
unblinded, the participant must be discontinued from the study.  In cases where there are ethical 
reasons to have the participant remain in the study, the investigator must obtain specific approval 
from a Lilly Medical Monitor for the participant to continue in the study. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event.  The 
participant’s safety must always be the first consideration in making such a determination.  If a 
participant’s treatment assignment is unblinded, Lilly must be notified immediately.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible. 
Participants who meet all criteria for enrollment will be assigned a study (participant) number at 
Visit 601 or Visit 1 and randomized to double-blind treatment at Visit 2.  Participants will be 
randomized to donanemab or Placebo in a 1:1 ratio.  
Participants who continue into the extension period will be assigned to placebo or donanemab, as 
described in Section 4.1.3. Assignment will be double-blind.   
For between-group comparability, participant randomization will be stratified by investigative 
site and tau pathology (low-medium versus high).  Assignment to treatment groups will be 
determined by a computer-generated random sequence using an IWRS.  Randomization into 1 
stratum may be discontinued at the discretion of the sponsor. 
6.4. 
Study Intervention Compliance 
IP will be administered under medical supervision by the investigator or designee. The dose of IP 
and study participant identification will be confirmed prior to the time of dosing.  The date and 
time of each dose administered will be recorded in the source documents and in the CRF.   
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Any infusion at which 75% (approximately 105 mL) or more of the infusion solution is given 
will be considered a complete infusion. 
If a participant attends a visit but does not receive a complete infusion (e.g., due to technical 
complications), every effort should be made to complete the infusion within 24 hours if possible 
except if an infusion reaction occurs that prevents rechallenge.  If less than 75% of the infusion 
solution is given, this must be recorded as an incomplete infusion on the CRF. 
Missed infusions should be recorded on the CRF.   
If at any time it is discovered that the participant has not completed proper dosing during the 
titration phase, the sponsor should be contacted prior to the subsequent infusions to discuss the 
possibility of completing a proper titration phase, if needed. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded in the CRF, along with any changes to dose.   
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants and their study partners will be instructed to consult the investigator or other 
appropriate study personnel at the site before initiation of any new medications or supplements 
and before changing dose of any current concomitant medications or supplements. 
6.5.1. 
Standard of Care for Alzheimer’s Disease 
To ensure standard of care for AD, use of approved symptomatic treatments for AD is permitted 
in this study.  The section below provides additional guidance on managing concomitant 
medication use. 
Use of approved or standard of care symptomatic treatments for AD is permitted during the 
study, provided that the dose has been unchanged for at least approximately 30 days before Visit 
2.  Doses of these medications should remain constant when possible throughout the double-
blind period and extension period (Visit 2 to Visit 41).  When medically indicated, initiation, 
increase or discontinuation of symptomatic treatments for AD is permitted. 
Nonmedication treatments for AD such as behavioral management are permitted but are subject 
to the same restrictions as medication treatment taken for AD. 
6.5.2. 
Medications for Infusion Reactions 
If an infusion reaction occurs, medications managing the reaction may be administered at the 
discretion of the investigator, according to local practice guidelines.  If the need for concomitant 
medication arises, inclusion or continuation of the participant may be at the discretion of the 
investigator .  Concomitant therapy administered to treat an infusion reaction or as premedication 
for infusions should be documented in addition to completion of the Hypersensitivity, 
Anaphylactic, and Infusion Related Reactions CRF. Also see Sections 8.3.6.1 and 8.3.6.2. 
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6.5.3. 
Excluded Medications 
Immunoglobulin G (IgG) therapy (also known as gamma globulin or intravenous 
immunoglobulin [IVIG]) is not allowed during the study.  See Section 7.2 for additional 
exclusions. 
Note: Concurrent use of passive anti-amyloid immunotherapies other than donanemab, such as 
gantenerumab, lecanemab, or aducanumab, is not permitted during the study. 
6.6. 
Dose Modification 
Dose modification of IP is not permitted in this study, except for participants whose amyloid 
plaque reduction meets dose reduction criteria, as described in Section 4.1, or as described 
below. 
The goal of the study is for the participant to be titrated to the target dose. For participants who 
develop ARIA during the titration period (that is, before the fourth infusion of study drug of the 
double-blind or of the extension period), the investigator may decide to  
 temporarily suspend dosing as described in Section 7.1.1.1, then determine if the 
participant should remain on the pre-suspension dose either temporarily beyond 
the first 3 doses or throughout the remainder of the treatment period, 
 continue the same dose either temporarily beyond the first 3 doses or throughout 
the remainder of the treatment period, or 
 continue the dosing schedule as outlined in Section 4.1. 
6.7. 
Intervention after the End of the Study 
Amendment d adds an extension period to Study AACI. 
No intervention will be provided after the end of the study. 
 
 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
Investigational product may be discontinued for a participant for the following reasons (details 
given below):   
 By request of the participant or participant’s designee (for example, legal guardian)  
 Clinical judgment  
 A hepatic event or liver test abnormality 
 C-SSRS results 
 ECG finding 
 ARIA 
 Systemic hypersensitivity reaction 
 Severe noncompliance  
 The participant requires an excluded therapeutic agent 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) IP.  If IP is definitively discontinued, the participant will remain in the study 
(following the SoA, except as noted below) to be evaluated for safety and efficacy.  
If IP infusion is permanently discontinued and the participant remains in the study. See 
Section 8.5 for PK sampling instructions. Participants who require a ferromagnetic implant or 
insertion of a cardiac pacemaker that is not MRI compatible will be permanently discontinued 
from IP and are not to have further MRIs. 
 
Clinical Judgment 
Adverse event or clinically significant laboratory value, ECG result, physical examination 
finding, MRI finding (such as symptomatic ischemic stroke), C-SSRS result, or vital sign 
measurement of such severity that, in the opinion of the investigator or sponsor-designated 
medical monitor, continued treatment is not in the best interest of the participant. 
Hepatic Event or Liver Test Abnormality 
Participants who are discontinued from IP due to a hepatic event or liver test abnormality should 
have additional hepatic safety data collected via the CRF. 
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a participant meets 1 of the following conditions after consultation with the sponsor-designated 
medical monitor:   
 
ALT or AST >8X ULN  
 
ALT or AST >5X ULN for more than 2 weeks  
 
ALT or AST >3X ULN and TBL >2X ULN or international normalized ratio (INR) 
>1.5   
 
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
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 
ALP >3X ULN  
 
ALP >2.5X ULN and TBL >2X ULN  
 
ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)  
C-SSRS  
In addition, IP may be discontinued if participants: 
 Answer “yes” to Question 4 or Question 5 on the “Suicidal Ideation” portion of the 
C-SSRS, or 
 Answer “yes” to any of the suicide-related behaviors on the Suicidal Behavior portion of 
the C-SSRS. 
A psychiatrist or appropriately trained professional may assist in the decision to discontinue the 
participant.   
ECG 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using QTcF) after enrollment, the investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant 
management is needed.  This review of the ECG printed at the time of collection must be 
documented.  Any new clinically relevant finding should be reported as an AE. 
ARIA 
Treatment with IP may be permanently discontinued in participants with treatment-emergent 
(TE) ARIA-E and/or ARIA-H at the discretion of the principal investigator (PI) depending on 
severity of clinical and radiologic findings (see Manual of Operations for permanent 
discontinuation guidance).  For temporary discontinuation for ARIA-related reasons, see 
Section 7.1.1.1. 
Systemic Hypersensitivity Reaction 
If the investigator, after consultation with the sponsor-designated medical monitor, determines 
that a systemic hypersensitivity suspicious for an anaphylactic reaction (see Section 8.3.6) has 
occurred related to IP administration, the participant should be permanently discontinued from 
the investigational drug. 
Severe Noncompliance 
Severe noncompliance to the study protocol, that results in a safety concern, in the judgment of 
the investigator, may be reason for discontinuing IP. 
Excluded Therapeutic Agent 
The participant, for any reason, requires a treatment with an excluded therapeutic agent 
(Section 6.5.3) and temporary discontinuation criteria cannot be met (see Section 7.1.1.2). 
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7.1.1. 
Temporary Discontinuation 
7.1.1.1. 
Due to ARIA 
The development of ARIA-E and/or ARIA-H (microhemorrhages and/or cortical superficial 
siderosis [cSS]) are expected events and occur more commonly on treatment with donanemab.  
The site PI may temporarily discontinue IP if the participant develops TE ARIA-H or ARIA-E to 
an extent deemed clinically significant by the site PI (see Manual of Operations for temporary 
discontinuation guidance). Dose modification considerations are described in Section 6.6. 
Reinitiating IP can be considered after resolution of ARIA-E and stabilization of ARIA-H  
imaging findings and the resolution of any associated symptoms.  
See Section 8.3.7 for details on adverse event reporting for ARIA-E and ARIA-H. 
In cases of new ARIA-E or ARIA-H, given the context of the severity of the imaging findings 
and symptoms, the site PI, at his/her clinical discretion, can elect to recommend discontinuing IP 
and then follow the participant with serial MRIs every 4 to 6 weeks (fluid attenuation inversion 
recovery [FLAIR] and T2* gradient-recall echo) and symptoms, to monitor stabilization or 
resolution.  Upon resolution of ARIA-E and stabilization of ARIA-H and the resolution of any 
associated symptoms, the participant can be considered for re-initiating IP.  There is no defined 
time duration for this monitoring period while off IP, and will be based on clinical judgment.  
Both the decision to stop and restart IP may be discussed with the sponsor-designated medical 
monitor (refer to Manual of Operations). 
7.1.1.2. 
Due to Reasons Other than ARIA 
Temporary discontinuation from IP treatment is allowed if a short-term treatment with an 
excluded medication is necessary, secondary to hospitalization, personal or exceptional 
circumstances or to evaluate the IP impact on an uncertain AE.  
Investigational product may be restarted at the next scheduled visit, at the investigator’s 
discretion.  
If temporary discontinuation is due to an AE, it should be reported to the sponsor-designated 
medical monitor.  Temporary treatment discontinuation and re-starting should be documented.  
Restarting treatment after a discontinuation period that is greater than 12 weeks should be 
discussed between the investigator and sponsor-designated medical monitor. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study:   
 
at any time at his/her own request  
 
at the request of his/her designee (for example, parents or legal guardian) 
 
at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 
if the participant becomes pregnant during the study  
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 
if the participant enrolls in any other clinical study involving an investigational 
medicinal product or enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study 
 
if the participant, for any reason, requires treatment with another disease-modifying 
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 
 
participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP). 
At the time of discontinuing from the study, if possible, an early discontinuation (ED) visit 
should be conducted, as shown in the SoA.  See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.  The 
participant will be permanently discontinued both from the IP and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  If a participant 
withdraws from the study, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants 
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, discussion should occur between the sponsor and investigator.  If the 
investigator and the sponsor-designated medical monitor agree it is medically appropriate to 
continue, the investigator must obtain documented approval from sponsor-designated medical 
monitor to allow the inadvertently enrolled participant to continue in the study with or without 
treatment with IP.  Safety follow up is as outlined in Section 1.3 (SoA), Section 8.2 (Safety 
Assessments), and Section 8.3 (AEs and SAEs) of the protocol. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 
Site personnel, or an independent third party, will attempt to collect the vital status of the participant 
within legal and ethical boundaries for all participants randomized, including those who did not get 
IP.  Public sources may be searched for vital status information.  If vital status is determined to be 
deceased, this will be documented, and the participant will not be considered lost to follow-
up.  Sponsor personnel will not be involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of regulatory, 
ethical, and trial oversight considerations in Section 10.1.9. 
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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA.  Protocol waivers or exemptions 
are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue IP. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
8.1. 
Efficacy Assessments 
Cognitive and functional testing will be administered using an electronic Clinical Outcome 
Assessment (eCOA) tablet.  The audio voice recordings of the rater’s questions and the 
participant’s and study partner’s responses will also be collected via the eCOA tablet during 
administration of the cognitive and functional testing for central monitoring of rater scale 
administration, where local guidelines permit.  Cognitive and functional testing for each 
participant should be performed at approximately the same time on each day, whenever possible, 
to reduce potential variability.  
Note that the CDR must be administered by a different rater than the ADAS-Cog13, MMSE, 
RUD-Lite, QOL-AD, and DSST medicines version. The ADCS-ADL should be administered by 
the same rater as the CDR. 
The CDR rater should be blinded to AEs to avoid bias in the CDR assessment.   
These 2 raters should continue administering the same scale whenever possible to the same 
participant throughout the study.  The PI has the responsibility of selecting the raters who will 
administer the instruments at the site and ensuring all training requirements have been met by 
those raters. 
When administered, cognitive and functional testing should be performed before medical 
procedures that could be stressful for the participant (for example, blood draws).  Note that 
procedures (for example, MRI, flortaucipir F18 PET tau imaging, florbetapir F18 PET amyloid 
imaging) can be conducted on other days within the visit window. If an efficacy assessment 
(ADAS-Cog13, ADCS-ADL, CDR, MMSE, or DSST medicines version) cannot be collected at 
the scheduled visit, it may be collected at the next opportunity, if within 30 days of the scheduled 
assessment. 
8.1.1. 
Primary Efficacy Assessment 
The integrated Alzheimer’s Disease Rating Scale (iADRS) assesses the impact of cognitive loss 
on the ability to conduct everyday activities and provides a measure of global AD severity as a 
single summary score. The iADRS comprises 2 underlying domains (“cognitive ability” and 
“functional ability”), with each representing related but separate concepts. The iADRS integrates 
the items that make up both domains into a single overall score that is conceptually distinct from 
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either domain assessed individually. The combination score of the iADRS captures 
commonalities across its domains, minimizing noise that exists within each domain individually. 
The iADRS captures clinical progression from MCI due to AD through moderate dementia due 
to AD, and treatment effects have been demonstrated across MCI and mild dementia due to AD 
(Honig et al. 2018; Wessels et al. 2020; Mintun et al. 2021). The iADRS has been validated 
(Wessels et al. 2015, 2018) and its statistical properties have been described. Minimal clinically 
important change estimates for the iADRS have been defined (Wessels et al. 2022b) and 
associations with meaningful outcomes of disease such as caregiver burden and quality of life 
have been demonstrated (Wessels et al. 2022a). 
The ADAS-Cog13 and the ADCS-ADL will be the actual scales administered to participants. 
8.1.2. 
Secondary Efficacy Assessments 
8.1.2.1. 
MMSE 
The Mini-Mental State Examination (MMSE) is a brief instrument used to assess cognitive 
function in participants (Folstein et al. 1975).  The instrument measures orientation, memory, 
and attention; the ability of the participant to name objects; follow verbal and written commands; 
write a sentence; and copy figures. The range for the total MMSE score is 0 to 30, with lower 
scores indicating greater level of impairment. The MMSE should whenever possible be 
administered by the same rater from visit to visit to reduce potential variability.  
8.1.2.2. 
ADAS-Cog13 
The Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog13) is a rater-
administered instrument that was designed to assess the severity of dysfunction in the cognitive 
and noncognitive behaviors characteristic of persons with AD (Rosen et al. 1984).  The ADAS-
Cog13 should, whenever possible, be administered by the same rater from visit to visit to reduce 
potential variability.  
The cognitive subscale of the ADAS, the ADAS-Cog13, consists of 13 items assessing areas of 
cognitive function that are the most typically impaired in AD:  orientation, verbal memory, 
language, praxis, delayed free recall, digit cancellation, and maze-completion measures (Mohs et 
al. 1997).  The ADAS-Cog13 scale ranges from 0 to 85, with higher scores indicating greater 
disease severity. 
8.1.2.3. 
CDR 
The CDR (Hughes et al. 1982; Morris 1993) is a global assessment tool that can be used to 
effectively evaluate both cognition and function. The tool was initially developed to measure 
dementia severity and covers 6 categories or “boxes”:  Memory, Orientation, Judgment and 
Problem Solving, Community Affairs, Home and Hobbies, and Personal Care.   
The CDR global ratings, calculated using an algorithm, range from 0 (no dementia) to 3 (severe 
dementia) while CDR-SB scores, calculated by adding the box scores, range from 0 to 18 (with 
higher scores indicative of more impairment).  Scoring is determined by a clinician through a 
semi-structured and in-depth interview with both the affected individual and their study partner. 
This scale demonstrates acceptable psychometric characteristics (Coley et al. 2011; Cedarbaum 
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et al. 2013) and has been shown to be sensitive enough to detect disease progression, even in 
populations with less advanced clinical disease (Williams et al. 2013; Wessels et al. 2015). 
The CDR should be administered whenever possible by the same rater from visit to visit to 
reduce potential variability.  The participant’s memory, orientation, judgment, and problem-
solving ability are assessed.  The study partner and participant must be interviewed separately. 
Note: The CDR may be administered to the participant and/or study partner by phone. 
Regardless of administration method, the CDR must be administered to the study partner prior to 
the participant. While the participant may complete the CDR by phone, other procedures and 
assessments may be required in person, as described in the SoA (Section 1.3). 
8.1.2.4. 
ADCS-ADL 
The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire that is to 
be answered by the participant’s study partner (Galasko et al. 1997, 2004).  The ADCS-ADL 
should be administered by the same rater from visit to visit to reduce potential variability.  
The ADCS-ADL subset of items (items 6a and 7 to 23) for iADLs will be used as a secondary 
efficacy measure.  The focus in the early symptomatic AD population is on the iADLs rather 
than the basic Activities of Daily Living (bADLs), which are thought to be affected in more 
severe stages of the disease.  The range for the iADL score is 0 to 59, with lower scores 
indicating greater disease severity.  
For each of the specific items, the study partner is first asked if the participant attempted the 
ADL during the past 4 weeks.  If the participant did attempt the ADL, the study partner is asked 
to rate the participant’s performance level based on a set of performance descriptions.  Scores for 
each item and the overall score for the tool are calculated.  The range for the total ADCS-ADL 
score is 0 to 78, with lower scores indicating greater level of impairment.  Separate scores for the 
bADLs (0 to 19) will also be computed. 
8.1.2.5. 
Biomarker Efficacy Measures 
Florbetapir F18 PET scan  
Change in amyloid burden (as assessed by florbetapir F18 PET) will be compared in donanemab- 
and placebo-treated participants. 
Flortaucipir F18 PET scan  
Change in tau pathology (as assessed by flortaucipir F18 PET) will be compared in donanemab- 
and placebo-treated participants.  
Volumetric MRI 
Volumetric magnetic resonance imaging (vMRI) of the brain will be performed according to the 
SoA (Section 1.3).  Donanemab- and placebo-treatment effects on vMRI will be assessed and 
compared to evaluate the loss of brain volume that occurs in AD participants. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
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8.2.1. 
Physical and Neurological Examinations 
Complete and brief physical examinations will be performed as indicated in the SoA 
(Section 1.3).  
The complete physical examination will include assessment of the following:   
 
general appearance;  
 
skin, head, and neck;  
 
lymph nodes;  
 
thyroid; 
 
abdomen (bowel sounds, liver and spleen palpation);  
 
back (costovertebral angle tenderness); and 
 
musculoskeletal, cardiovascular, and respiratory systems.  
The brief physical examination will include assessments of the following: 
 
skin,  
 
lungs,  
 
cardiovascular system, and  
 
abdomen (bowel sounds, liver and spleen palpation). 
Complete neurological examinations will be performed as indicated in the SoA (Section 1.3).  
The examinations will include a thorough assessment of the following: 
 
gait,  
 
balance,  
 
coordination,  
 
cranial nerves,  
 
sensory and motor systems, and 
 
reflexes.  
If necessary, given the training of the PI, a neurologist may be consulted in the event of 
significant new findings.  
If a clinically meaningful change in a MRI is noted during the study, an additional full 
neurological exam should be performed as soon as possible, along with any other medical 
follow-up deemed necessary by the investigator. 
8.2.2. 
Vital Signs 
Vital signs, including temperature, will be measured at all visits.   
Vital signs should be taken before administration of IP.  Vital signs may be repeated as needed.   
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8.2.2.1. 
Blood Pressure 
Sitting blood pressure and pulse will be measured after 5 minutes in the sitting position at all 
visits.  In addition, orthostatic blood pressure and pulse will be measured supine and standing at 
designated visits, as detailed in the SoA (Section 1.3). 
For orthostatic blood pressure monitoring, participants should be supine for at least 5 minutes 
and then stand for at least 3 minutes prior to taking the respective measurements.  If the subject 
feels unable to stand, only supine vital signs will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. 
Any clinically significant findings from vital sign measurements that result in a diagnosis and 
that occur after the participant receives the first dose of study treatment should be reported to 
Lilly or its designee as an AE via CRF/electronic data entry. 
8.2.2.2. 
Height, Weight, and Body Temperature 
Height and body weight will be measured.  Measurements should be taken, when possible, with 
the same scale for all measurements.  Body mass index will be calculated from the height and 
body weight.  
Temperature will be recorded using an oral or tympanic (or other acceptable route) thermometer. 
Any body weight data entered into the CRF will be used for the overall data analysis 
8.2.3. 
Electrocardiograms 
For each participant, 12-lead digital ECGs will be collected during the double-blind period, 
according to the SoA (Section 1.3).  Participants must be supine for approximately 5 to 10 
minutes before ECG collection and remain supine but awake during ECG collection. 
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs (replicates) than expected at a timepoint is allowed when needed to 
ensure high-quality records. 
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 participant is still present, to determine whether the subject meets entry criteria at the 
relevant visit(s) and for immediate participant management, should any clinically relevant 
findings be identified. 
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline or other clinically significant quantitative or qualitative change from baseline is 
identified, the participant will be assessed by the investigator for symptoms (e.g., palpitations, 
near syncope, syncope) and to determine whether the participant can continue in the study.  The 
investigator or qualified designee is responsible for determining if any change in participant 
management is needed.  The investigator or qualified designee must document his/her review of 
the ECG printed at the time of evaluation. 
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.  A report based on 
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data from this overread will be issued to the investigative site.  These data are not routinely 
reported back to the investigative site.  All data from the overreads will be placed in the Lilly 
database for analytical and study report purposes. 
When there are differences in 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 participant 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 the ECG printed at the 
time of collection, the final overread ECG report issued by the central ECG laboratory, and any 
alert reports. 
8.2.4. 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA for the 
timing and frequency. 
The investigator must review the laboratory results, document this review, and  report any 
clinically relevant changes occurring during the study in the AE section of the CRF.  The 
laboratory reports must be filed with the source documents.  Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study, or within the follow-up period after the last dose of IP, should be repeated until the 
values return to normal, baseline, or are no longer considered clinically significant by the 
investigator or medical monitor. 
1. If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified. 
2. All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the SoA and laboratory manual (or standard collection 
requirements, if applicable).  
3. If laboratory values from non-protocol-specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the investigator (for example, SAE, AE, or dose 
modification), then the results must be recorded in the CRF. Laboratory results from this 
laboratory must be retained with source documents unless a Source Document 
Agreement or comparable document cites an electronic location that accommodates the 
expected retention duration. 
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  
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Any clinically significant findings from laboratory tests that result in a new diagnosis and that 
occur after the participant receives the first dose of IP should be reported to Lilly or its designee 
as an AE via CRF/electronic data entry. 
8.2.5. 
Magnetic Resonance Imaging 
Magnetic resonance imaging of the brain will be performed according to the SoA (Section 1.3) 
and as clinically indicated.  Unscheduled MRIs may be performed at the discretion of 
investigator. 
This technology will be used to check for evidence of ARIA-H or ARIA-E, and other clinically 
relevant inclusion/exclusion and safety findings (vMRI will also be used to calculate brain 
volumes, as noted in Section 9.4.4). 
The MRI scans will be reviewed by the investigator or qualified designee for immediate 
participant management.  Any clinically significant findings noted at baseline that result in a 
diagnosis should be recorded as a preexisting condition or AE.  After the MRI scan is read 
locally, the MRI scans will be sent for analysis to a centralized MRI vendor designated by Lilly.  
Final MRI eligibility at screening will be determined by the centralized MRI vendor designated 
by Lilly and the MRI results will be reported to the site as “does” or “does not” meet MRI 
eligibility criteria.  
Specific analyses of the scans, including assessments of ARIA-H and ARIA-E and calculations 
of brain volumes, will be interpreted by the centralized MRI vendor for data analysis and report 
writing purposes.  
Results of centrally read MRIs regarding participant care/safety will be reported back to sites. 
8.2.6. 
Hepatic Safety Monitoring 
Close Hepatic Monitoring 
Laboratory tests (Section 10.4), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase (GGT), and creatine kinase (CK), should be repeated within 48 to 
72 hours to confirm the abnormality and to determine if it is increasing or decreasing, if 1 or 
more of these conditions occur: 
If a participant with baseline 
results of ...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with 
Gilbert’s syndrome) 
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Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, and history of alcohol 
drinking and other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize.  Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive Hepatic Evaluation   
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptoms*, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptoms*, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for participants with Gilbert’s syndrome)  
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for Prothrombin time and INR; tests for viral hepatitis 
A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (for example, 
ultrasound or computed tomography [CT] scan).  
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the sponsor-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
serum phosphatidylethanol.  Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy.   
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8.2.7. 
Suicidal Ideation and Behavior Risk Monitoring 
Participants should be monitored appropriately and observed closely for suicidal ideation and 
behavior or any other unusual changes in behavior, especially at the beginning and end of the 
course of intervention or at the time of dose changes, either increases or decreases.  
Consideration should be given to discontinuing the study medication in subjects who experience 
signs of suicidal ideation or behavior, following a risk assessment.  
Families and caregivers of participants should be alerted about the need to monitor participants 
for the emergence of unusual changes in behavior, as well as the emergence of suicidal ideation 
and behavior and to report such symptoms immediately to the study investigator. 
Baseline assessment of suicidal ideation and behavior and intervention-emergent suicidal 
ideation and behavior will be monitored during Study AACI using the C-SSRS.  
C-SSRS 
Columbia Suicide-Severity Rating Scale is a scale that captures the occurrence, severity, and 
frequency of suicidal ideation and behavior during the assessment period via a questionnaire.  
The scale was developed by the National Institute of Mental Health (NIMH) trial group for the 
purpose of being counterpart to the Columbia Classification Algorithm of Suicide Assessment 
(C-CASA) categorization of suicidal events. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of the following events can be found in Section 10.3: 
 Adverse events (AEs) 
 Serious adverse events (SAEs) 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, study 
partner, surrogate, or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE, and remain responsible for following 
up on AEs that are serious, considered related to the IP or study procedures, or that caused the 
participant to discontinue the IP (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the ICF through the time points specified in the 
SoA (Section 1.3). 
All AEs will be collected from the signing of the ICF through the time points specified in the 
SoA. 
Medical occurrences that begin before the start of IP but after signing of the ICF will be recorded 
on the AE CRF. 
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to sponsor begins after the participant has signed the ICF and has received IP or 
PET tracer.  However, if an SAE occurs after signing the ICF, but prior to receiving IP or PET 
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tracer, it needs to be reported ONLY if it is considered reasonably possibly related to study 
procedures. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3.  The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available.   
Investigators are not obligated to actively seek AEs or SAEs after conclusion of study 
participation.  However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the IP or study participation, the investigator must promptly notify the sponsor. 
8.3.1.1. 
Adverse Event Monitoring with a Systematic Questionnaire 
Nonleading AE collection should occur prior to the collection of the C-SSRS.   
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form.   
If an AE is serious or leads to discontinuation, it needs to be included on the AE form and the 
process for reporting SAEs is followed. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs, and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-Up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs, and AEs of special interest (as defined in Section 8.3.8), 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3).  Further information on follow-up procedures is 
provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of an IP 
under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IP under clinical investigation.  The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), 
and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (for example, summary or listing of SAEs) from the sponsor will review and 
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then file it along with the IB, and will notify the IRB/IEC if appropriate according to local 
requirements. 
8.3.5. 
Pregnancy 
Women of childbearing potential are excluded from Study AACI.  Therefore, pregnancy is not 
expected to occur.  However, if pregnancy does occur, follow the instructions below. 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of IP and until 90 days after the last dose of IP 
received. 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy. 
Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6. 
Hypersensitivity, Including Infusion-Related Reactions 
8.3.6.1. 
Management of Infusion-Related Reactions 
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions.  If such a reaction occurs, additional data describing each sign or symptom should be 
provided to the sponsor in the Hypersensitivity, Anaphylactic, and Infusion Related Reactions 
CRF. 
Locations where study participants are receiving IP should have appropriately trained medical 
staff and appropriate medical equipment and rescue medications available.  It is recommended 
that participants who experience a systemic hypersensitivity reaction be treated per the local 
standard of care. 
If a participant experiences a systemic hypersensitivity reaction or infusion related reaction either 
involving two or more organ systems (e.g. mucocutaneous, respiratory, cardiovascular, or 
gastrointestinal systems), or that is severe, additional blood and urine samples should be 
collected as close to the event as possible, as described in Section 10.2 (IRR kit).  Tryptase and 
when applicable urine N-methylhistamine should be repeated in approximately 4 weeks to obtain 
post-event baseline.  Laboratory results are provided to the sponsor via the central laboratory. 
8.3.6.2. 
Dosing rechallenge and premedication for infusions 
Premedication for dosing is not planned.  
Dosing rechallenge is contraindicated in participants that have experienced a suspected or 
possible anaphylactic reaction (e.g. reaction involving two or more organ systems [for example, 
mucocutaneous, respiratory, cardiovascular, or gastrointestinal systems] occurring in close 
proximity to dosing), in a prior dose (Sampson et al 2006).  For infusion related reactions which 
are not suspicious for anaphylaxis, after review of the data, and at the investigator’s discretion, 
the participant may be rechallenged.  If rechallenge is planned, the participant may be 
premedicated for subsequent doses at the investigator discretion and according to local practice 
guidelines.  
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Prior to initiating premedication, the investigator may consult with the sponsor.   
Any premedication given will be documented as a concomitant therapy (Section 6.5.2). 
8.3.7. 
Amyloid-Related Imaging Abnormalities (ARIA-E and ARIA-H) 
While most cases of ARIA are asymptomatic, serious cases have been reported. Available data 
suggests serious cases are most likely to occur early in dosing, after the first, second, or third 
infusion. 
When symptoms are present in association with these imaging abnormalities, they have been 
reported to include, but may not be limited to, headache, vomiting, unsteadiness, dizziness, 
tremor, confusion, visual disturbances, speech disturbances, worsening cognitive function, 
alteration of consciousness, and seizures (Ostrowitzki et al. 2012; Sperling et al. 2012; 
VandeVrede et al. 2020; Mintun et al. 2021; Swanson et al. 2021). 
If a participant simultaneously develops more than 1 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 a MRI. 
If the above-mentioned symptoms are reported, and:  
 
ARIA-E is suspected, then the abnormality is best detected by FLAIR sequences on 
MRI, while 
 
ARIA-H is best detected with the T2* gradient-recalled echo on MRI. 
An unscheduled MRI with these imaging sequences should be obtained upon suspicion of ARIA.  
If ARIA is present, it is recommended to repeat MRIs with these sequences every 4 to 6 weeks 
until resolution of ARIA-E or stabilization of ARIA-H is documented.  For asymptomatic or 
mild symptoms, the participant can be observed; for moderate symptoms associated with ARIA-
E, the use of oral or IV steroids can be considered.  In the case of severe symptoms associated 
with ARIA-E, it is recommended to hospitalize the participant for close observation and consider 
the use of IV steroids such as high-dose dexamethasone or a similar agent (see Manual of 
Operations for more detail). 
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 (Section 8.2.5).  
For procedure to follow in the event of ARIA-E or ARIA-H, see Section 7.1.1.1.   
In the event of a finding of ARIA-E on MRI, the investigator is to complete the ARIA-E Related 
Events CRF regarding the presence or absence of symptoms related to the ARIA-E, and ARIA-E 
should be reported as an adverse event in the Adverse Events CRF. 
8.3.8. Adverse Events of Special Interest  
Specific safety topics of interest for this study include, but are not limited to, the following:   
 
ARIA-E 
 
ARIA-H 
 
Hypersensitivity, immediate and non-immediate, including infusion-related reactions 
and anaphylaxis 
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The topics listed above, as well as other topics which may be subsequently determined by the 
sponsor, will be subject to enhanced surveillance activities.  Additionally, the topics above will 
be analyzed for presentation in the Clinical Study Report in accordance with the Study SAP. 
8.3.9. 
Complaint Handling 
Lilly collects product complaints on investigational medicinal products or investigational devices 
used in clinical trials in order to ensure the safety of study participants, to monitor quality, and to 
facilitate process and product improvements. 
Study participants will be instructed to contact the investigator as soon as possible if they have a 
complaint or problem with the investigational medicinal product so that the situation can be 
assessed. 
8.4. 
Treatment of Overdose 
In the event of an overdose, the investigator or treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Obtain a plasma sample for PK analysis of IP if requested by the Medical Monitor 
(determined on a case-by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
Pharmacokinetics 
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine the serum concentrations of donanemab.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sampling will be recorded. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
A maximum of 3 blood samples per participant may be drawn at additional time points during 
the study, if warranted and agreed upon between both the investigator and sponsor.  Instructions 
for the collection and handling of blood samples will be provided by the sponsor. 
If IP infusion is permanently discontinued but the participant remains in the study, 1 PK sample 
should be collected at the soonest scheduled visit regardless if  PK sample collection is on the 
SoA at that visit.  Dosing dates and times should be collected.  Subsequent PK sample collection 
should follow the protocol SoA unless the scheduled visit exceeds 6 months since 
discontinuation of infusions.  No additional PK sample collection is required once the participant 
exceeds 6 months since discontinuation of infusions. 
Bioanalytical samples collected to measure donanemab concentrations will be retained for a 
maximum of 1 year following last subject visit for the study.  During this time, samples 
remaining after the bioanalyses may be used for exploratory analyses such as metabolism, protein 
binding, or bioanalytical method development/validation work. 
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8.6. 
Pharmacodynamics 
8.6.1. 
Clearance of Amyloid Deposits  
Amyloid PET provides quantitative assessment of amyloid plaque deposition in the brain and 
can serve as a PD biomarker of clearance of amyloid deposits. 
Clearance of amyloid deposits (as assessed by florbetapir F18 PET and/or florbetaben F18 PET 
signal) will be compared in donanemab- and placebo-treated participants for those participants 
who undergo amyloid PET scans as described in the SoA (Section 1.3). 
8.6.2. 
Accumulation of Tau Deposits 
Flortaucipir F18 PET provides quantitative assessment of tau deposition in the brain and can 
serve as a PD biomarker of accumulation of tau deposits as AD progresses. 
Accumulation of tau deposits (as assessed by flortaucipir F18 PET signal) will be compared in 
donanemab- and placebo-treated participants for those participants who undergo flortaucipir F18 
PET scans as described in the SoA (Section 1.3). 
8.7. 
Genetics 
8.7.1. 
Apolipoprotein E Genotyping 
Apolipoprotein E (ApoE) genotyping is a mandatory part of this study, unless country-specific 
laws and regulations prohibit this type of testing.  Blood sampling for ApoE genotyping will be 
performed as shown in the SoA (Section 1.3).  Neither participants nor investigators will receive 
the genotype results unless there is a country-specific law or regulation that requires notification 
of the results.  
Failure to collect samples for ApoE will not be considered a protocol deviation if country-
specific regulations prohibit the testing of genetic material or transportation of such material 
outside of the country. 
8.7.2. 
Whole Blood Samples for Pharmacogenetic Research 
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3) where local regulations allow. 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to donanemab and to 
investigate genetic variants thought to play a role in AD or other neurological conditions.  
Assessment of variable response may include evaluation of AEs or differences in efficacy. 
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
ERBs/investigational review boards (IRBs) impose shorter time limits.  This retention period 
enables use of new technologies, response to regulatory questions, and investigation of variable 
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response that may not be observed until later in the development of donanemab or after 
donanemab becomes commercially available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section. 
8.8. 
Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), proteins, lipids, and other cellular elements. 
Serum, plasma, and whole blood RNA samples for biomarker research will be collected at the 
times specified in the SoA (Section 1.3) where local regulations allow. 
Samples will be used for research on the drug target, disease process, variable response to 
donanemab, pathways associated with AD, mechanism of action of donanemab, and/or research 
method or in validating diagnostic tools or assay(s) related to AD or other neurological 
conditions. 
All samples will be coded with the participant number.  These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of donanemab or after donanemab becomes commercially available. 
8.9. 
Immunogenicity Assessments 
Where local regulations and ERBs allow, at the visits and times specified in the SoA 
(Section 1.3), venous blood samples will be collected to determine antibody production against 
donanemab.  To interpret the results of immunogenicity, a venous blood sample will be 
collected, if warranted, at the same time points to determine the serum concentrations of 
donanemab.  All samples for immunogenicity should be taken predose when applicable and 
possible. 
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of donanemab at a laboratory approved by the sponsor.  Antibodies may be further characterized 
and/or evaluated for their ability to neutralize the activity of donanemab.  The testing paradigm is 
outlined in Section 9.4.7.1. 
Treatment-emergent ADAs are defined in Section 9.4.7.1.  If the immunogenicity sample at the 
last scheduled assessment or discontinuation visit is TE ADA positive, additional samples may 
be taken for up to approximately 1 year after last dose.   
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Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and ERBs allow, at a facility selected by the sponsor.  The 
duration allows the sponsor to respond to future regulatory requests related to donanemab.  Any 
samples remaining after 15 years will be destroyed. 
8.10. 
Medical Resource Utilization and Health Economics 
8.10.1. 
Dependency Level (derived from ADCS-ADL) 
Dependence, or the level of assistance required by a participant, has been suggested as a 
construct for assessing the effect of AD treatment.  The process of increasing dependence on 
others is intended as a complementary measure to existing clinical measures in order to help 
explain the impact of AD on economic issues such as the risk of institutionalization and 
caregiver burden (McLaughlin et al. 2010; Spackman et al. 2013).  
The ADCS-ADL scores were used to map individuals into 1 of 6 dependence levels (0 to 5):   
 
Level 0 – No iADL/bADL impairment;  
 
Level 1 – Some supervision needed on isolated iADLs;  
 
Level 2 – Supervision on multiple iADLs or loss of at least 1 household activity;  
 
Level 3 – Supervision on all types of iADLs or homebound;  
 
Level 4 – Supervision on some bADLs; and  
 
Level 5 – Impaired transfer or complete incontinence (Kahle-Wrobleski et al. 2015).  
An approach to transforming continuous functional scale scores into discrete levels of 
dependence was examined previously in a longitudinal observational study, with preliminary 
results suggesting acceptable validity and progression in dependence level over time 
(Kahle-Wrobleski et al. 2017).  At baseline, 49.6% of those with mild AD dementia were 
dependence level 2 and 42.7% were at levels 3 or 4.  At 18 months, the proportion of participants 
at level 2 declined to 31.2% while that at levels 3 and 4 rose to 58.8%.  
Analyses will be conducted to examine changes in dependence levels across the trial population 
as well as potential differences on dependence level by treatment group assignment. 
8.10.2. 
Resource Utilization in Dementia – Lite Version (RUD-Lite) 
The RUD-Lite is designed to assess the healthcare resource utilization of patients and their 
caregivers and to determine the level of formal and informal care attributable to AD (Wimo et al. 
2013).  The data are collected through a structured interview with the study partner.  Information 
on both caregivers (caregiving time and work status) and participants (accommodation and 
healthcare resource utilization) is gathered from the baseline and follow-up interviews. 
Caregivers will be asked to provide data on time spent assisting participants’ basic Activities of 
Daily Living (ADLs), such as using the toilet, eating, dressing, grooming, walking, and bathing; 
assisting participants’ instrumental ADLs, such as shopping, cooking, housekeeping, laundry, 
transportation, taking medication, and managing finances; and providing supervision.  The 
resource utilization quantified by the RUD-Lite can be used for calculating cost offsets and in 
cost-effectiveness models. 
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8.10.3. 
Quality of Life in Alzheimer’s Disease (QOL-AD) 
The QoL-AD is a valid, reliable, and disease-specific measure of quality of life for an AD 
population (Logsdon et al. 1999, 2002; Thorgrimsen et al. 2003). It includes 13 items, each rated 
on a 4-point scale. Summing the items provides an overall score to index the participant’s quality 
of life. The QoL-AD is administered to the participant by a rater and asks the participant to 
provide ratings on mood, relationships, memory, finances, etc. The participant’s primary 
caregiver also is asked to complete the same measure. 
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9. 
Statistical Considerations 
The primary efficacy objective of Study AACI is to demonstrate donanemab slows the cognitive 
and/or functional decline in AD versus placebo as measured by the iADRS through 76 weeks in 
the population of participants with low-medium tau pathology or the overall population. This 
study includes high tau participants, a population not studied in Study AACG. The overall 
population will include all enrolled early symptomatic AD participants with a low-medium 
(intermediate) or high tau pathology at baseline.   
9.1. 
Statistical Hypotheses 
The primary efficacy objective will be assessed using a Natural Cubic Spline (NCS) model with 
2 degrees of freedom of the primary outcome iADRS at Month 18.  
The primary efficacy analysis will be conducted on two populations: the intermediate tau 
population at baseline and the overall population. The hypothesis will be tested with a control of 
family wise 2-sided type I error rate of 5% following the chain procedure (Millen and 
Dmitrienko 2011). 
The testing scheme, and a graphic testing procedure that will be used to control the overall false 
positive rate for the primary endpoint and major secondary endpoints will be described in the 
Study SAP. 
Major secondary hypotheses defined in a similar manner are that donanemab is superior to 
placebo with regard to: 
 
Clinical progression in participants with early symptomatic AD through Week 76, as 
measured by MMSE, ADAS-Cog13, CDR-SB, and ADCS-iADL 
 
Brain amyloid deposition at Week 76 measured by florbetapir F18 PET scan 
 
Brain tau deposition at Week 76 measured by flortaucipir F18 PET scan 
 
Brain region volumes at Week 76 measured by vMRI 
9.2. 
Sample Size Determination 
Approximately 1800 participants will be randomly assigned in the study. It is anticipated that 
approximately two-third of participants have low-medium tau and approximately one-third of 
participants have high tau pathology. 
The powering and sample size determination of the trial is based on the low-medium tau 
pathology population. The assumptions for the power calculation were based on the results of the 
Study AACG data. The mean progression levels in the placebo and donanemab arms from the 
MMRM analysis on iADRS were -10.06 and -6.86 points (approximately 32% slowing) over 18 
months, respectively, with a standard deviation of 11.06. The assumed discontinuation rate of 
AACI is 30%. Multiple longitudinal datasets were simulated, and the NCS model with 2 degrees 
of freedom was fit to each sample to determine the power. With a sample size of approximately 
1000 randomized participants in the low-medium tau pathology population, the NCS model with 
2 degrees of freedom provides greater than 95% power to achieve statistical significance at a 1-
sided 0.025 level for the treatment difference relative to placebo, as measured by iADRS at 
Month 18. If both treatment arms are placebo-like with no efficacy, the type I error is 2.5%. 
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9.3. 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Entered 
All participants who sign the ICF. 
Enrolled/Intent-to-Treat 
All participants assigned to treatment, regardless of whether they 
take any doses of study treatment, or if they took the correct 
treatment.  Participants will be analyzed according to the 
treatment group to which they were assigned. 
Efficacy Evaluable  
All participants with a complete baseline assessment and at least 
1 complete post-baseline assessment.*  Participants will be 
grouped according to randomized treatment assignment 
(donanemab or placebo), even if the participant does not take the 
assigned treatment, does not receive the correct treatment, or 
otherwise does not follow the protocol.   
Safety 
All participants randomly assigned to IP and who take at least 1 
dose of IP. 
Abbreviations:  ICF = informed consent form; IP = investigational product. 
* For each assessment, the efficacy evaluable population will be defined as all participants with a baseline 
measurement and at least 1 complete post-baseline measurement for that respective assessment.   
9.4. 
Statistical Analyses 
9.4.1. General Considerations 
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 
Unless otherwise noted, all pairwise tests of treatment effects will be conducted at a 2-sided 
alpha level of 0.05 (or equivalently, a 1-sided 0.025 alpha level); 2-sided 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. 
Details on the testing strategy for the primary and key secondary analyses will be specified in the 
Study SAP. 
All efficacy analyses will follow the intent-to-treat (ITT) principle unless otherwise specified.  
An ITT analysis is an analysis of data by the groups to which subjects are assigned by random 
allocation, even if the subject does not take the assigned treatment, does not receive the correct 
treatment, or otherwise does not follow the protocol. 
When change from baseline is assessed, subjects will be included in the analysis only if both a 
baseline and a postbaseline measure are available.  Unless otherwise defined, a baseline measure 
is the last nonmissing observation collected prior to the first administration of study medications.  
Endpoint is the last nonmissing postbaseline measurement. 
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For MMRM models, observations collected at nonscheduled visits will not be included in the 
analyses. 
A database lock for the double-blinded phase primary efficacy analysis is expected to occur after 
all randomized subjects have had a chance to complete the double-blind period of the study.  
Efficacy and safety analyses will be conducted based on data collected during the double-blind 
period.  Additional database lock(s) may occur.  Additional efficacy and safety analyses will be 
conducted based on data collected during the extension period.  Data collected during the 
immunogenicity and safety follow-up period will be summarized and analyzed separately.  
The study will include several separate SAPs:  a main study SAP (referred to as Study SAP) 
which will detail the analyses for the objectives for double-blinded, placebo-controlled phase, 
and a long-term extension (LTE) SAP which will detail analyses for the objectives of LTE phase. 
The analyses for any addenda such as analyses for open-label safety cohort will be included in a 
separate addendum-specific SAP. 
The main Study SAP will be finalized prior to unblinding of all participants in the placebo-
controlled phase. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints and a more technical and 
detailed description of the statistical analyses will be described in the SAPs.  
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the Study SAP and the clinical study report.  Additional exploratory analyses of the data will 
be conducted as deemed appropriate. 
9.4.1.1. 
Handling of Missing Items for Scales 
If any of the individual items for ADAS-Cog13 or ADCS-ADL are missing or unknown, every 
effort will be made to obtain the score for the missing item or items.  For ADAS-Cog13, if 4 or 
fewer of a total of 13 items are missing, the total score (maximum = 85) will be imputed as 
follows:  the total from remaining items will be multiplied by a factor that includes the maximum 
score for the missing items.  For example, if the first item, “Word-Recall Task,” which ranges 
from a score of 0 through 10 (maximum = 10), is missing, and the second item “Commands,” 
which ranges from a score of 0 to 5 (maximum = 5), is missing, then the multiplication factor = 
85/(85 - [10 + 5]) = 85/70 = 1.21.  Thus, the total score for this example will be the sum of the 
remaining 11 items multiplied by 1.21.  The imputed number will be rounded up to the nearest 
integer.  If more than 4 items are missing, the total score for ADAS-Cog13 at that visit will be 
considered missing. 
For the ADCS-iADL, if <30% of the items are missing, the total score will be imputed.  The sum 
of the nonmissing items will be prorated to the sum of total items.  The imputed number will be 
rounded up to the nearest integer.  If the nearest integer is greater than the maximum possible 
score, the imputed score will be equal to the maximum score.  If >30% of the items are missing, 
the total score for ADCS-iADL at that visit will be considered missing.  The same imputation 
technique will be applied to the ADCS-ADL total score.  Note that, depending on the specific 
item responses that are missing, it is possible to have an imputed total score for both the 
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DCS-iADL and the ADCS-ADL, an imputed total score for 1 but not the other, or both total 
scores missing. 
The same imputation technique will be applied to the CDR-SB.  If only 1 box (of 6) of the CDR 
is missing, the sum of the boxes will be imputed by prorating the sum from the other 5 boxes.  If 
the score from more than 1 box is not available, the CDR-SB at that visit will be considered 
missing. 
The iADRS score is calculated as:  
ADCS-iADL score-ADAS-Cog13 score + 85.   
If either ADAS-Cog13 or ADCS-iADL is missing, iADRS score will be considered missing. 
For all other scales, if any item is missing, any total or sum involving that item will be 
considered missing. 
9.4.2. 
Treatment Group Comparability 
9.4.2.1. 
Participant Disposition 
All participants who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will be 
given. 
The reasons for discontinuation will be collected when the participant’s participation in the study 
ends and will be summarized by treatment group for all randomized subjects.  The percentage of 
subjects discontinuing from each treatment group will be compared between groups using 
Fisher’s exact test.  The comparisons will be done for the overall percentage of participants who 
discontinue and for select specific reasons for discontinuation. 
9.4.2.2. 
Participant Characteristics 
The participant’s age, sex, race, height, body weight, body mass index (weight (kg) / [height 
(m)]2), tobacco use, alcohol use, caffeine use, years of education, work status, time since onset 
of first AD symptoms, time since diagnosis, baseline MMSE, ApoE genotype (E4 carrier versus 
non-carrier), having 1 or more first degree relatives with AD, and acetylcholinesterase inhibitor 
(AChEI) and/or memantine use at baseline will be recorded. 
Baseline characteristics will be summarized by treatment group and overall.  Summaries will 
include descriptive statistics for continuous and categorical measures.  Fisher’s exact test or 
Pearson’s chi-square test will be used for treatment-group comparisons of categorical data.  For 
continuous data, analysis of variance (ANOVA), with independent factors for treatment and 
investigator, will be used. 
9.4.2.3. 
Prior and Concomitant Therapy 
Prior medications are defined as those that stop before randomization (Visit 2).  Concomitant 
medications are defined as those being taken on or after randomization (Visit 2).  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.  
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If the start or stop dates of therapies are missing or partial to the degree that determination cannot 
be made of whether the therapy is prior or concomitant, the therapy will be deemed concomitant. 
Prior and concomitant medications will be listed. 
Summary tables will also be provided for concomitant anticholinergics that affect cognitive 
function and AChEI/memantine medications. 
Medications will be coded using the World Health Organization drug dictionary. 
9.4.2.4. 
Treatment Compliance 
Summary statistics for treatment compliance will be provided for the total number of complete 
infusions received, duration of complete infusion, and volume of complete infusion by treatment 
group. 
Frequencies and percentages of reasons why infusion was stopped will also be presented.  
9.4.3. 
Primary Endpoint(s) 
The primary objective of this study is to test the hypothesis that IV infusion of donanemab will 
slow the cognitive and/or functional decline of AD as measured by iADRS score compared with 
placebo in the population of participants with intermediate tau pathology at baseline and the 
overall population. 
A NCS analysis (Chambers and Hastie 1992) with 2 degrees of freedom (DF) will be used to 
assess the difference between treatment groups in iADRS score at Week 76. The NCS model 
provides a type of smoothing function to the data and can adequately estimate longitudinal 
trajectories under a variety of shapes (for example, linear and quadratic) for each treatment 
group. The degrees of freedom of the model can be prespecified to establish the level of 
smoothing of the data. The number and location of the “knots” is utilized to parse out different 
time periods where the data may transition from one shape to another to provide an adequate fit 
and the location of the knots will be provided in the SAP. 
The iADRS score at baseline and at each of the postbaseline visits will be included in model as a 
dependent variable. Study visit will be treated as a continuous variable with values equal to 
weeks between baseline and postbaseline exam dates. The model will include these fixed effects: 
NCS basis expansion terms (2 terms), NCS basis expansion term-by-treatment interaction (2 
terms), baseline age, concomitant AChEI and/or memantine use at baseline (yes/no), and 
potentially other covariates will be included in the model and specified in the Study SAP. An 
unstructured variance-covariance structure matrix will be used to adjust for intra-subject 
correlation. If the unstructured variance-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 primary time point for treatment comparison will be at Week 76.  
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The primary efficacy analysis may be modified to use an alternative statistical model based on 
interactions with regulatory agencies and/or internal decision making, and if modified, the model 
will be outlined in the Study SAP prior to unblinding of the placebo-controlled phase. 
As a sensitivity analysis,  a Bayesian Disease Progression Model (DPM) on the iADRS will 
evaluate possible slowing of disease progression with treatment of donanemab relative to 
placebo. The primary purpose of the DPM is to estimate a quantity known as the disease 
progression ratio (DPR), which measures the proportion of disease progression in donanemab-
treated participants relative to placebo-treated participants.  
The MMRM analysis will also be assessed for the iADRS. The change from baseline score on 
the iADRS at each scheduled postbaseline visit (according to the SoA) during the treatment 
period will be the dependent variable.  The model for the fixed effects will include the following 
terms:  baseline score, pooled investigator, treatment, visit, treatment-by-visit interaction, 
baseline-by-visit interaction, concomitant AChEI and/or memantine use at baseline (yes/no), and 
age at baseline.  Visit will be considered a categorical variable.  The null hypothesis is that the 
contrast between the donanemab group versus placebo at the last visit equals 0.  An unstructured 
covariance matrix will be used to model the within-subject variance-covariance errors.  If the 
unstructured covariance structure matrix results in a lack of convergence, the following tests will 
be used in sequence: 
 
heterogeneous Toeplitz covariance structure 
 
heterogeneous autoregressive covariance structure 
 
heterogeneous compound symmetry covariance structure  
 
compound symmetry covariance structure 
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. 
The primary time point for treatment comparison will be at Week 76.  The treatment group 
contrast in least-squares mean progression and its associated p-value and 95% CI will be 
calculated for the treatment comparison of donanemab versus placebo using the MMRM model 
specified above. 
All analyses as described above, including the NCS with 2 DF, DPM, and MMRM models on 
iADRS will be assessed in the intermediate tau population and overall population. 
Details about these analyses, as well as other sensitivity analyses including NCS with 3 degree of 
freedom, and quadratic models will be described in the SAP. 
9.4.4. 
Secondary Endpoint(s) 
Similar to the primary endpoint of iADRS, each of the secondary efficacy outcomes will be 
assessed using NCS with 2 DF, DPM, and MMRM analyses for the intermediate tau population 
and overall population. These secondary efficacy outcomes include ADAS-Cog13, ADCS-iADL, 
CDR-SB, and MMSE.   
Longitudinal changes from baseline in amyloid plaque (as measured by florbetapir F18 PET 
scan) will be analyzed using MMRM including the following terms in the model:  baseline 
biomarker value, treatment, visit, treatment-by-visit interaction, and baseline-by-visit interaction.  
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The change from baseline to endpoint in tau deposition (as measured by flortaucipir PET scan) 
will be analyzed using an analysis of covariance (ANCOVA) model with terms of baseline value 
and treatment.  Atrophy in vMRI parameters will be analyzed using MMRM including the 
following terms in the model:  treatment, visit, treatment-by-visit interaction, baseline vMRI, 
intracranial volume, and age at baseline.  
Any additional analyses of secondary efficacy outcomes and biomarkers will be specified in the 
Study SAP. 
9.4.5. 
Tertiary/Exploratory Endpoint(s) 
Efficacy analyses will be conducted to evaluate the hypotheses of delayed start disease 
modification by donanemab on clinical progression as measured by iADRS, CDR-SB, ADCS-
iADL, ADAS-Cog13, and MMSE. The statistical method outlined in Liu-Seifert et al. (2015) will 
be used to analyze each clinical endpoint to compare the treatment efficacy between the early 
start participants (randomized to donanemab at the beginning of AACI) and delayed start 
participants (receiving donanemab for the first time in the extension period). The analysis will 
follow the intent-to-treat (ITT) principle unless otherwise specified. The details of the analyses 
will be described in the SAP. 
Change in brain amyloid plaque deposition (as measured by florbetapir F18 PET) will be 
evaluated through Week 154 for the participants who had not met dose reduction criteria during 
the double-blind period. The brain amyloid plaque deposition (as measured by florbetapir F18 
PET) will also be assessed in participants who met dose reduction criteria during double-blind 
and extension period to evaluate amyloid plaque re-accumulation. 
Additional exploratory and extension period endpoints and their respective analyses will be 
described in the Study SAP. 
9.4.6. 
Other Safety Analyses 
All safety analyses will be made on the Safety Population.  Refer to the Study SAP for additional 
details. 
9.4.7. 
Other Analyses  
9.4.7.1. 
Evaluation of Immunogenicity 
Subject samples will be analyzed using a 4-tiered approach.  All samples will be assessed in Tier 
1 (screening) for the possible presence of ADAs.  Samples found to produce a signal above or 
equal to the screening cut point will be assessed in Tier 2 to confirm specificity to donanemab 
(confirmation).  Any samples confirmed as specific for anti-donanemab antibodies will be 
reported as “detected.”  All samples below the screening cut point (Tier 1) or not confirmed (Tier 
2) will be reported as “not detected.”  Any “detected” sample in Tier 2 will be assessed in Tier 3 
(titer assessment) and Tier 4 (neutralizing antibodies).  Anti-drug antibody titer values will be 
reported from Tier 3 titer assessment.  Any samples above the Tier 4 assay cut point will be 
reported as “detected for neutralizing antibodies”; samples below the assay cut point in Tier 4 
will be reported as “not detected for neutralizing antibodies.” 
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The frequency and percentage of subjects with preexisting (baseline) ADAs, ADAs at any time 
after baseline, and TE ADAs to donanemab will be tabulated.  If no ADAs are detected at 
baseline, TE ADAs are defined as those with a titer 2-fold (1 dilution) greater than the minimal 
required dilution of the assay.  For samples with ADAs detected at baseline, TE ADAs are 
defined as those with a 4-fold (2 dilutions) increase in titer compared to baseline.  For the TE 
ADA subjects, the distribution of maximum titers will be described.  The frequency of 
neutralizing antibodies may also be tabulated.  The relationship between the presence of 
antibodies to donanemab and PK, PD, safety, and/or efficacy assessment may be assessed. 
9.4.7.2. 
Pharmacokinetic/Pharmacodynamic Analyses 
Compartmental modeling of donanemab PK data using nonlinear mixed effects modeling or 
other appropriate software may be explored, and population estimates for clearance and central 
volume of distribution may be reported.  Depending on the model selected, other PK parameters 
may also be reported.  Exploratory graphical analyses of the effect of dose level or demographic 
factors on PK parameters may be conducted.  If appropriate, data from other studies of 
donanemab may be used in this analysis. 
The PK/PD relationships between plasma donanemab concentration and SUVr, cognitive 
endpoints, ARIA incidence rate, or other markers of PD activity may be explored graphically.  
The relationship between the presence of antibodies to donanemab and PK, PD, safety, and/or 
efficacy may be assessed graphically. 
To facilitate this modeling, and to ensure that exposure estimates from this study are available at 
the end of the trial, it is intended that the PK data will be locked after all participants complete 
Visit 18 (64 weeks of treatment), to allow PK modeling to begin before the end of the trial. No 
safety or efficacy data will be included in the 64-week PK lock.  
An Early PK Lock Plan will be developed and implemented prior to this lock, which will specify 
the safeguards to be taken to ensure the integrity of the study. It is intended that the results of the 
PK analysis will be provided in a separate report. 
Additional modeling may be performed based on the results of the graphical analyses. 
9.4.7.3. 
Analysis of C-SSRS Data 
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide 
(CIUMC 2016). 
9.5. 
Interim Analyses  
Interim analyses may be conducted for Study AACI. Interims potentially executed include 
futility, early efficacy, and sample size re-estimation. Operational details and a quantitative 
framework to provide information for these decisions will be documented in the SAP prior to 
execution of interim(s).  
Unblinded interims will be executed through the external DMC. Study sites will receive 
information about interim results only if they need to know for the safety of their participants or 
changes to the protocol. For interims that stop the trial early, subjects will proceed to their early 
discontinuation visit.  
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Unblinding details are specified in the unblinding plan section of the SAP or a separate 
unblinding plan document.  
The SAP will describe the interim analyses in greater detail, if any are planned.  
9.6. 
Data Monitoring Committee 
For details on the DMC, refer to Section 10.1.5. 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with the following: 
o consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
o applicable International Council for Harmonisation (ICH) GCP Guidelines, and 
o applicable laws and regulations. 
 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
 
The investigator will be responsible for the following: 
o providing written summaries of the status of the study to the IRB/IEC annually, or 
more frequently, in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, and 
o providing oversight of study conduct for participants under their responsibility and 
adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
 
The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant or his/her legally authorized representative and 
answer all questions regarding the study. 
 
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed 
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consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. 
 
As used in this protocol, the term “informed consent” includes all consent and assent 
given by the participant or their legal representatives and by study partners. 
 
The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF. 
 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and must be kept on file. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
 
Participants will be assigned a unique identifier by the sponsor.  Any participant 
records, datasets, or tissue samples that are transferred to the sponsor will contain the 
identifier only; participant names or any information which would make the participant 
identifiable will not be transferred. 
 
The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law.  The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent.  
 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Committees Structure 
A DMC consisting of members external to Lilly will be established.  The purpose of the DMC is 
to conduct periodic monitoring of clinical trial data for Study AACI.  The DMC will consist of a 
minimum of 3 members, including a physician with expertise in AD and a statistician. 
No member of the DMC will influence study sites.  A statistical analysis center (SAC) will 
prepare and provide unblinded data to the DMC.  The SAC members will not be Lilly 
employees, but will come from TPOs designated by Lilly.  The SAC members will have no 
contact with sites and no privileges to influence changes to the ongoing studies.  The timing and 
frequency of the periodic clinical trial data review by the DMC will be detailed in a DMC 
charter. 
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The DMC is authorized to evaluate unblinded interim and safety analyses.  In addition, the DMC 
may request key efficacy data to put safety observations into context and to assess a reasonable 
benefit/risk profile for ongoing participants in the study.  The DMC will make recommendation 
to the Lilly Research Laboratories Senior Management Designee, who may order the immediate 
implementation of the DMC recommendation, or may convene an internal review committee, 
which is independent from the study team, to review the recommendation according to standard 
Lilly policy.  Study sites will receive information about interim results ONLY if it is required for 
the safety of their participants or change in protocol. 
10.1.6. 
Dissemination of Clinical Study Data 
Reports  
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation.    
Data   
The sponsor provides access to all individual participant data collected during the trial and after 
anonymization, with the exception of PK, images, or genetic data.  Data are available for request 
6 months after the indication studied has been approved in the US and EU, and after primary 
publication acceptance, whichever is later.  No expiration date of data requests is currently set 
once data are made available.    
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement.  Data and 
documents, including the study protocol, and Study SAPs, clinical study report, and blank or 
annotated CRFs, will be provided in a secure data sharing environment for up to 2 years per 
proposal.    
For details on submitting a request, see the instructions provided at 
www.clinicalstudydatarequest.com. 
10.1.7. 
Data Quality Assurance 
 
All participant data relating to the study will be recorded on a printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data).  The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques, are provided in the Monitoring Plan. 
 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
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 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents, that the safety and rights of participants are being protected, 
and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may 
be destroyed during the retention period without the written approval of the sponsor.  
No records may be transferred to another location or party without written notification 
to the sponsor. 
 
In addition, the sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site.  The study may be 
audited by the sponsor or its representatives and/or regulatory agencies at any time.  
Investigators will be given notice before an audit occurs.   
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Additionally, COA data (participant-focused outcome instrument) will be collected by the 
participant/partner and/or authorized study personnel via a paper source document and will be 
transcribed by authorized study personnel into the EDC system. 
Additionally, eCOA data (participant-focused outcome instrument) will be directly recorded by 
authorized study personnel into an instrument (for example, tablet).  The eCOA data will serve 
as the source documentation and the investigator will not maintain a separate, written or 
electronic, record of these data.   
Data collected via the sponsor-provided data capture system will be stored at a third-party.  The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
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and retention.  Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.8. 
Source Documents 
 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available. 
10.1.9. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
 
failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
 
inadequate recruitment of participants by the investigator, and 
 
discontinuation of further IP development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements.  The investigator shall promptly inform the participant and should 
assure appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy 
The publication policy for Study AACI is described in the Clinical Trial Agreement. 
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10.1.11. 
Investigator Information 
Physicians with a specialty in neurology, geriatrics, or psychiatry will participate as investigators 
in this clinical trial.  In addition, licensed clinicians who have clearly documented experience in 
AD may participate as investigators in this clinical study. 
 
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10.2. 
Appendix 2:  Clinical Laboratory Tests 
 
The tests detailed in the table below will be performed by the central laboratory (unless 
specified otherwise below).   
 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or as required by local regulations. 
 
In circumstances where the sponsor approves local laboratory testing in lieu of central 
testing (in the table below), the local laboratory must be qualified in accordance with 
applicable local regulation. 
Investigators must document their review of the laboratory safety results. 
Laboratory analyte results denoted below that could unblind the study will not be reported to 
investigative sites or other blinded personnel. 
 
Clinical Laboratory Tests  
Comments   
Hematology 
Assayed by Lilly-designated laboratory 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Leukocytes (WBCs)  
  
Differential 
  
   Neutrophils, segmented 
  
   Lymphocytes 
  
   Monocytes 
  
   Eosinophils 
  
   Basophils 
  
Platelets 
  
Cell morphology (RBC and WBC) 
  
  
  
Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
Total bilirubin 
  
Direct bilirubin 
  
ALP 
  
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ALT 
  
AST 
  
GGT 
  
BUN 
  
Creatinine  
  
CK 
  
Uric acid 
  
Albumin 
  
Calcium 
  
Glucose 
  
Cholesterol  
  
 
 
Urinalysis 
 
Specific gravity 
  
pH 
 
Protein 
 
Glucose 
 
Ketones 
 
Blood 
 
Urine leukocyte esterase 
 
 
 
Calculations 
Generated by Lilly-designated laboratory. 
eGFR (CKD-EPI) 
 
Urinary protein/creatinine ratio (UPCR) 
 
 
 
PK Samples – donanemab concentration 
Assayed by Lilly-designated laboratory.  Results 
will not be provided to the investigative sites. 
  
  
Biomarkers 
Assayed by Lilly-designated laboratory.  Results 
will not be provided to the investigative sites. 
ApoE 
 
NfL/GFAP 
 
P-tau 
 
A  
 
 
 
Pharmacogenetics sample 
Assayed by Lilly-designated laboratory.  Results 
will not be provided to the investigative sites. 
  
  
Stored Samples 
Assayed by Lilly-designated laboratory.  Results 
will not be provided to the investigative sites. 
Exploratory storage samples:   
All samples will be collected at all visits except for 
the Lead-In Screening.  Plasma only will be 
collected at the Lead-In Screening Visit.  
   Serum 
  
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   Plasma (EDTA) 
  
   Paxgene RNA tube 
  
Immunogenicity Samples 
Assayed by Lilly-designated laboratory.  Results 
will not be provided to the investigative sites. 
   Anti-donanemab antibodies  
  
   Anti-donanemab antibodies neutralization 
  
  
  
Hypersensitivity Tests (IRR kit) 
Selected tests may be obtained in the event of 
infusion related reaction, anaphylaxis or systemic 
allergic/hypersensitivity reactions.  These should be 
collected as soon after the event as possible 
(optimally 30 minutes to 2 hours after the start of the 
event and after participant has been stabilized as 
necessary).  Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative 
sites. 
  Anti-donanemab antibodies 
(Immunogenicity) 
  
  Donanemab Concentrations (PK) 
  
   Tryptase 
Optimally collected between 30 minutes to 2 hours 
after the start of the event. Do not collect if >12 
hours have passed since the hypersensitivity event. 
Collect and repeat in approximately 4 weeks for post 
event baseline 
  Urine N-methylhistamine (NMH) 
Obtain only if tryptase sample was collected >2 
hours after the hypersensitivity event.  Collect and 
repeat in approximately 4 weeks for a post event 
baseline. 
  IgE 
 
   Basophil Activation Test 
Will be performed if a validated assay is available. 
   Complement (C3a and C5a) 
  
   Cytokine Panel 
  
Abbreviations:  A = amyloid beta; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
ApoE = apolipoprotein E; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatine kinase; 
EDTA = Ethylenediaminetetraacetic acid; GFAP = glial fibrillary acidic protein; GGT = gamma-glutamyl 
transferase; IgE = immunoglobulin E; NfL = neurofilament light chain; NMH = N-methylhistamine; RBC = red 
blood cell; PK = pharmacokinetics; P-tau = phosphorylated tau; RNA = ribonucleic acid; WBC = white blood 
cells. 
 
 
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10.3. 
Appendix 3:  Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of IP, whether or not considered related 
to the IP. 
 NOTE:  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of IP. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, or vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition. 
 New condition(s) detected or diagnosed after IP administration, even though it may 
have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either IP or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it 
is an intentional overdose taken with possible suicidal/self-harming intent.  Such 
overdoses should be reported regardless of sequelae. 
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE/SAE.  Such instances will be captured in the efficacy assessments.  
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as an AE/SAE if they fulfill the definition of an AE/SAE. 
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
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 Medical or surgical procedure (e.g., endoscopy, appendectomy):  the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE, even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease). 
An SAE is defined as any untoward medical occurrence that at any dose: 
a. Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to the 
hospital for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious.  When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle), which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 
 
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f. 
Other situations: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These events should usually be considered 
serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
 The investigator will then record all relevant AE/SAE information in the CRF. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE CRF page. 
 There may be instances when copies of medical records for certain cases are requested 
by the sponsor or designee.  In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:   
 Mild:  An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities. 
 Moderate:  An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
 Severe:  An event that prevents normal everyday activities.  An AE that is assessed as 
severe should not be confused with an SAE.  Severe is a category utilized for rating the 
intensity of an event, and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
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Assessment of Causality 
 The investigator is obligated to assess the relationship between IP and each occurrence 
of each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to IP administration will be 
considered and investigated. 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor or designee.  
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the sponsor 
or designee. 
 The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
or designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
postmortem findings, including histopathology.  
 New or updated information will be recorded in the originally completed CRF. 
 The investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of receipt of the information. 
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10.3.4. 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
 SAE reporting is done through the eCRF. 
 
SAE Reporting via Paper CRF 
 Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor. 
 In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found on the paper CRF. 
 
 
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10.4. 
Appendix 4:  Liver Safety:  Suggested Actions and Follow-Up 
Assessments  
Selected tests may be obtained in the event of a TE hepatic abnormality and may be required in 
follow-up with participants in consultation with the sponsor-designated medical Monitor. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented 
 
Lymphocytes 
Hepatic Serologiesa,b 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Antinuclear antibodya 
AST 
 
GGT 
Alkaline Phosphatase Isoenzymesa 
CK 
 
 
Anti-smooth muscle antibody (or anti-actin antibody)a 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; GGT = 
gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cells; 
WBC = white blood cells. 
a Assayed by the sponsor-designated laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 
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10.5. 
Appendix 5:  Flortaucipir F18 Tau PET Imaging  
Flortaucipir F18 PET scans will be performed as part of the study eligibility criteria and as 
indicated in the SoA (Section 1.3). 
For inclusion and exclusion criteria related to the flortaucipir F18 PET scans, refer to 
Sections 5.1 and 5.2. 
Site investigators, participants, and study partners will only be informed of the eligibility results 
of PET scans obtained prior to randomization, as they relate to the study, and will not be 
informed of scan results obtained post randomization.  Any significant findings that may be of 
potential medical concern will be provided for appropriate follow-up.   
PET Scan-Specific Information 
PET Scan Procedures 
Specific imaging acquisition protocols designed to ensure consistency across sites will be 
provided in a PET Imaging Manual.  
Scan Safety 
The primary risk related to flortaucipir F18 PET is radiation exposure.  Details on the amount of 
exposure estimated to occur on each imaging occasion and cumulatively are shown in the table 
below and will be provided in the ICF. The safety profile of flortaucipir F18 has been well-
characterized in clinical studies and is considered acceptable for a diagnostic 
radiopharmaceutical. Details on the clinical information to date regarding flortaucipir F18 
exposure will be provided in the ICF.  More detailed information about the known and expected 
benefits and risks of flortaucipir F18 can be found in the IB. 
Participants must minimize movement during each PET procedure, which can last 10 to 30 
minutes for each scan.  Most state-of-the-art imaging systems are designed to reduce head 
motion and participant discomfort. 
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The table below shows the effective radiation dose of the Study AACI’s PET scans. 
 
Effective 
Dose 
(mSv) 
per 
Scan* 
Number 
of 
Scans 
in First 
Year** 
Effective 
Dose 
(mSv) 
for 
Scans in 
First 
Year 
Number 
of 
Scans 
in 
Second 
Year** 
Effective 
Dose 
(mSv) 
for 
Scans in 
Second 
Year 
Number 
of 
Scans 
in Third 
Year** 
Effective 
Dose 
(mSv) 
for 
Scans in 
Third 
Year 
Number 
of 
Scans 
in 
Fourth 
Year** 
Effective 
Dose 
(mSv) 
for 
Scans in 
Fourth 
Year 
Sum of 
Effective 
Dose 
(mSv) 
for 
Years 1, 
2, 3, and 
4 
Flortaucipir 
F18 Scan 
(10 mCi 
IV) 
9.10 
1 
9.10 
1 
9.10 
0 
0 
1 
9.10 
27.30 
Florbetapir 
F18 Scan 
(10 mCi 
IV) 
7.43 
2 
14.86 
2 
14.86 
2 
14.86 
1 
7.43 
52.01 
Total 
 
3 
23.96 
3 
23.96 
2 
14.86 
2 
16.53 
79.31 
Abbreviations:  CT = computerized tomography; ED = early discontinuation; IV = intravenous infusion; PET = positron emission tomography. 
*Dose shown includes radiation exposure from the radiotracer and assumes a nonclinical CT scan is obtained (estimated at 0.4 mSv) as part of the PET scan 
attenuation correction process when the scan is done on a PET/CT scanner.  A clinical CT scan is not needed during the PET scan session and, because it will 
add additional radiation exposure, it is not recommended. 
** In the event of an ED scan, up to 1 additional flortaucipir F18 and/or 1 additional florbetapir F18 scan may be received in 1 year.   
Note:  In the event a repeat scan is required (for example, the scan is not analyzable), 1 additional flortaucipir F18 and/or 1 additional florbetapir F18 scan may 
be received in 1 year.  
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10.6. 
Appendix 6:  Florbetapir F18 Amyloid PET Imaging 
Florbetapir F18 PET scans will be performed as part of the study eligibility criteria to determine 
participant eligibility for participation in Study AACI.  Additional florbetapir F18 PET scans will 
be performed as indicated in the SoA (Section 1.3).  Specific instructions for the florbetapir F18 
PET scan itself will be provided in the PET Imaging Manual. 
For inclusion and exclusion criteria related to florbetapir F18 PET imaging, see Sections 5.1 
and 5.2.   
Site investigators, participants, and study partners will not be informed of the results of PET 
scans obtained following randomization as they relate to the study.  Any findings that may be of 
potential medical concern will be provided for appropriate follow-up. 
PET Scan-Specific Information 
PET Scan Procedures 
Specific imaging acquisition protocols designed to ensure consistency across sites will be 
provided in a PET Imaging Manual.  
PET Scan Safety 
The primary risk related to florbetapir F18 PET is radiation exposure.  Details on the amount of 
exposure estimated to occur on each imaging occasion and cumulatively are presented in the 
table above (Section 10.5) and will be provided in the ICF.  Details on the clinical information to 
date regarding florbetapir F18 exposure will be provided in the ICF.  More detailed information 
about the known and expected benefits and risks of florbetapir F18 can be found in the United 
States Package Insert for florbetapir F18 Injection (AmyvidTM package insert, 2012). 
Participants must minimize movement during each PET procedure, which can last 10 to 30 
minutes for each scan.  Most state-of-the-art imaging systems are designed to reduce head 
motion and participant discomfort. 
 
 
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10.7. 
Appendix 7:  Removed 
Appendix 7 is removed. 
 
 
 
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10.8. 
Appendix 8:  Abbreviations 
Term 
Definition 
Aβ 
amyloid beta 
AChEI 
acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADA 
anti-drug antibody 
ADAS-Cog13 
Alzheimer’s Disease Assessment Scale – Cognitive subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory 
ADCS-iADL 
Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
analysis of variance 
ApoE 
apolipoprotein E 
ARIA 
amyloid-related imaging abnormalities 
AST 
aspartate aminotransferase 
bADL 
basic Activities of Daily Living 
blinding/masking 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment, but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment, but the investigator and/his staff and the participant are not. 
A double-blind study is one in which neither the participant 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. 
BMI 
body mass index 
C-CASA 
Columbia Classification Algorithm of Suicide Assessment 
CDR 
Clinical Dementia Rating Scale 
CDR-SB 
Clinical Dementia Rating Scale – Sum of Boxes 
CK 
Creatine kinase 
CIOMS 
Council for International Organizations of Medical Sciences 
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Companion 
diagnostic  
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product 
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 study-related, GCP, and applicable regulatory requirements. 
CRF 
case report form 
CRP 
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
cSS 
cortical superficial siderosis 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT 
Computed tomography 
Device Deficiencies 
Equivalent to product complaint 
DMC 
data monitoring committee 
DSST 
Digit symbol substitution test 
ECG 
electrocardiogram 
eCOA 
electronic Clinical Outcome Assessment  
eCRF 
electronic case report form 
ED 
early discontinuation 
EDC 
electronic data capture 
enroll 
The act of assigning a participant to a treatment.  Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
Enter 
Participants entered into a study are those who sign the ICF directly or through their 
legally acceptable representatives. 
FLAIR 
fluid attenuation inversion recovery 
GCP 
good clinical practice 
GGT 
Gamma-glutamyl transferase 
iADRS 
integrated Alzheimer’s Disease Rating Scale 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
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ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
Informed consent 
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate.  Informed consent is 
documented by means of a written, signed and dated ICF. 
INR 
international normalized ratio 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the complete reporting database for the primary outcome is 
created/locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IP 
investigational product 
IRR 
infusion-related reaction 
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 participant (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that participant 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. 
IV 
intravenous 
IVIG 
Intravenous immunoglobulin 
IWRS 
interactive web-response system 
MAD  
Multiple-ascending dose 
MCI 
mild cognitive impairment 
MMSE 
Mini Mental State Examination 
MRI 
magnetic resonance imaging 
NCS 
Natural Cubic Spline 
N3pG Aβ 
Pyroglutamate modification of the third amino acid of amyloid beta 
NIMH 
National Institute of Mental Health 
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participant 
Equivalent to CDISC term “subject”:  an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PD 
pharmacodynamics 
PET 
positron emission tomography 
PI 
principal investigator 
PK 
pharmacokinetics 
PRN 
As needed 
PRO 
patient-reported outcomes 
P-tau 
phosphorylated tau 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QTc 
corrected QT interval 
QTcF 
Fridericia’s formula 
RNA 
ribonucleic acid 
SAC 
statistical analysis center 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SUSARs 
suspected unexpected serious adverse reactions 
SUVr 
Standardized Uptake Value ratio 
TBL 
total bilirubin level 
TE 
treatment-emergent 
TEAE 
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
TPO 
third-party organization 
ULN 
upper limit of normal 
vMRI 
volumetric magnetic resonance imaging 
WOCBP 
women of childbearing potential 
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10.9. 
Appendix 9:  Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the scientific value of the trial.  
Overall Rationale for the Amendment: 
This amendment adds a long-term extension phase to Study AACI.  The extension period is 
designed to further evaluate donanemab efficacy and safety over time. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Aligned to changes in text of 
the body. 
Rationale for each change described 
below. 
1.2. Schema 
Added extension period to 
figure. 
Alignment with addition of extension 
period. 
1.3. Schedule of 
Activities 
Added “Contact IWRS – 
register visit” procedure for 
all visits. 
Clarification. All visits must be 
registered with IWRS regardless of IP 
dispensation. 
 
Added note for “Contact 
IWRS – dispensation of IP” 
that this procedure is for 
visits where IP will be 
dispensed.  
Clarification. 
 
Added eGFR (CKD-EPI) to 
clinical chemistry. 
Clarification. 
 
Added UPCR to urinalysis. 
Clarification. 
 
Modified note for postdose 
PK: “Collect within 30 
minutes of IP administration 
infusion completion.” 
Clarification. 
 
Added MRI at V3. Added 
text to Comment field about 
MRI at V3, including text 
about MRI timings relative to 
the first and fourth infusions. 
To allow for better characterization 
of the incidence and severity of 
ARIA at an earlier time point. 
 
Changed V3 tolerance 
interval from “±7” days to 
“7 to +10” days. 
To provide additional time to perform 
and review MRI prior to infusion. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Added MRI at V23. Added 
text to Comment field about 
MRI at V23, including text 
about MRI timings relative to 
V22 infusion and fourth 
extension period infusion. 
To allow for better characterization of 
the incidence and severity of ARIA at 
an earlier time point. 
 
Changed V23 tolerance 
interval from “±7” days to 
“7 to +10” days. 
To provide additional time to 
perform and review MRI prior to 
infusion. 
 
Moved follow-up column 
(V801-804) to extension 
phase table.   
Added footnote describing 
follow-up visits as occurring 
12 weeks after the last dose 
of IP.  
Organization.  
 
Clarification. 
 
Renamed ED visit as EDa. 
Clarification. The extension phase has a 
separate ED visit, named EDb.  
 
Added SoA table for 
extension period. 
Extension period added to study. 
 
Modified footnote b: “The 
participant should meet all 
other MMSE eligibility 
criteria before the screening 
flortaucipir F18 PET scan, 
MRI, and florbetapir F18 
PET scan.” 
Correction. 
 
Added footnote d, which 
describes follow-up visits 
801 through 804. 
Clarification. 
2.1. Study Rationale Modified description of 
primary endpoint. 
Added rationale for addition 
of long-term extension 
period. 
Alignment with change to primary 
endpoint. 
 
Extension period added to study. 
2.2.2. Donanemab 
Clinical Studies 
Updated section. 
Update to reflect new information. 
3. Objectives and 
Endpoints 
Modified the primary 
endpoint to include the 
overall population.   
Opportunity to test the overall 
population.   
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Section # and Name 
Description of Change 
Brief Rationale 
 
Combined 2 of the secondary 
objective/endpoints. (High 
tau population will be 
described in the SAP as an 
exploratory objective.) 
Organization.  
 
Added objectives and 
endpoints for the extension 
period. 
Extension period added to study. 
4.1. Overall Design 
4.1.3. Extension 
Period (Visits 22 
through 41) 
Added design details for the 
extension period. 
Extension period added to study. 
4.1.2. Double-Blind 
Period (Visits 2 
through 21) 
Modified text: Participants 
who meet entry criteria will 
be enrolled and randomized 
to … donanemab or placebo 
during the double-blind 
period.” 
Clarification. 
4.1.4. Follow-Up 
(Visits 801 through 
804) 
Moved from 4.1.3. to 4.1.4. 
Removed references to week 
numbers for the follow-up 
period. 
 
Removed text related to an 
extension protocol.   
Added a note that follow-up 
may not be required for some 
participants. 
Organization. 
Clarification.  Follow-up will occur 12 
weeks after the final dose of IP is 
administered. 
Extension period added to study.  
 
Clarification. 
4.2. Scientific 
Rationale for Study 
Design 
Modified text: “Inclusion of a 
placebo treatment arm is 
acceptable because there are 
no confirmed clinically 
currently effective disease 
modifying treatments for 
AD;…”. 
Clarification. 
 
Added rationale for the long-
term extension period. 
Extension period added to study. 
4.4. End of Study 
Definition 
Added definition for end of 
the study. 
Extension period added to study. 
Added definition for clarity.  
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Section # and Name 
Description of Change 
Brief Rationale 
5.1. Inclusion 
Criteria 
Modified Inclusion Criterion 
7: added CDR and ADCS-
ADL to the list of study 
partner assessments that may 
be conducted by phone. 
Add flexibility. 
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Added assignment and 
blinding information for the 
extension period. 
Extension period added to study. 
6.5.1. Standard of 
Care for 
Alzheimer’s 
Disease 
Added clarification that 
standard of care medications 
“should remain constant 
when possible throughout the 
double-blind period and 
extension period (Visit 2 to 
Visit 2141). 
Extension period added to study. 
6.5.3. Excluded 
Medications 
Added note concerning 
concurrent use of passive 
anti-amyloid 
immunotherapies. 
Clarification. 
6.6. Dose 
Modification 
Added text: “For participants 
who develop ARIA during 
the titration period (that is, 
before the fourth infusion of 
study drug of the double-
blind or of the extension 
period), the investigator may 
decide to…”. 
Extension period added to study. 
Added text for clarity.  
 
Modified text: “continue the 
same pre-suspension 
dose…”. 
Clarification. 
 
Added “or as described 
below” in first sentence. 
Clarification. 
6.7. Intervention 
after the End of the 
Study 
Updated subsection to reflect 
addition of the extension 
period. 
Extension period added to study. 
7.1. Discontinuation 
of Study 
Intervention 
Added cross-reference to the 
Manual of Operations 
regarding information about 
permanent discontinuation 
guidance. 
To provide further guidance. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.1.1. Due to 
ARIA 
Added 2 cross-references to 
the Manual of Operations 
regarding information about 
temporary discontinuation 
guidance. 
Modified text (2 instances) 
regarding considering 
reinitiating IP. 
To provide further guidance. 
 
 
 
Recommendation of DMC 
8.1. Efficacy 
Assessments 
Specified that RUD-Lite and 
QOL-AD must be 
administered by a different 
rater than the CDR. 
Addition of RUD-Lite and QOL-AD as 
described below for Section 8.10. 
8.1.2.3. CDR 
Added note regarding 
administering the CDR by 
phone. 
Clarification. 
8.2.5. Magnetic 
Resonance Imaging 
Added text to allow 
performance of unscheduled 
MRIs 
Clarification. 
8.3.1. Time Period 
and Frequency for 
Collecting AE and 
SAE Information 
Added text:  “but prior to 
receiving IP or PET 
tracer…”. 
Clarification. 
8.3.7. Amyloid-
Related Imaging 
Abnormalities 
(ARIA-E and 
ARIA-H) 
Added text regarding the 
likely timing of serious ARIA 
cases based on available data. 
Added cross-reference to the 
Manual of Operations 
regarding management of 
participants. 
Updated symptoms and 
citations. 
To provide additional insight into 
timing of ARIA. 
 
To provide further guidance. 
 
 
Update to align with IB. 
8.10. Medical 
Resource Utilization 
and Health 
Economics 
Added subheader 8.10.1. 
Added subheader 8.10.2 and 
description of RUD-Lite. 
Added subheader 8.10.3 and 
description of QOL-AD. 
Organization. Text not modified. 
RUD-Lite and QOL-AD are 
assessments of interest for the 
extension period.  
9. Statistical 
Considerations 
Added text, “…or the overall 
population.” 
Alignment with change to primary 
endpoint. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.1 Statistical 
Hypotheses 
Modified subsection to add 
changes to primary endpoint 
and add description of 
primary endpoint analysis. 
 
9.2 Sample Size 
Determination 
Added clarifying text 
regarding the number of 
participants in Cohort 1. 
Clarification. 
9.4.1. General 
Considerations 
Added, “Additional efficacy 
and safety analyses will be 
conducted based on data 
collected during the 
extension period.”  
Also added, “The analyses 
for any addenda will be 
included in the Study SAP or 
an additional addendum-
specific SAP. 
Clarification. 
9.4.1.1. Handling of 
Missing Items for 
Scales 
Modified text: “Thus, the 
total score for this example 
will be the sum of the 
remaining 112  items 
multiplied by 1.21.” 
Correction. 
9.4.3. Primary 
Endpoint(s) 
Added population description 
to description of the primary 
endpoint. 
Alignment with change to primary 
endpoint. 
 
Added details related to the 
quadratic model. 
Clarification.  
 
Modified text, “…the mean 
for each treatment group over 
the entire double-blind 
duration period of the 
study…”. 
Clarification. 
9.4.4. Secondary 
Endpoint(s) 
Added details related to the 
quadratic model. 
Clarification.  
9.4.5. 
Tertiary/Exploratory 
Endpoint(s) 
Added details related to the 
objectives and endpoints for 
the extension period. 
Extension period added to study. 
10.2. Appendix 2:  
Clinical Laboratory 
Tests 
Arranged CKD-EPI and 
UPCR under “Calculations” 
group. 
Organization. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.5. Appendix 5:  
Flortaucipir F18 
Tau PET Imaging 
Updated effective radiation 
dose table. 
Extension period added to study. 
Throughout 
Minor editorial changes. 
Corrected instances of CDR-
SB to CDR. 
Minor, therefore, not described. 
Correction. CDR is the assessment.  
CDR-SB is a calculation based on the 
assessment.   
 
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Amendment:  c (03-Sep-2021) 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the conduct or management of the trial. 
Overall Rationale for the Amendment: 
This amendment increases the sample size by approximately 300 participants and defines an 
approximately equivalent number of early enrolled participants as Cohort 1.  Cohort 1 will be 
unblinded to the sponsor, but remain blinded at site, participant, and study partner level, at a 
prespecified timepoint and analyzed prior to the end of the study.  Cohort 1 data will be utilized 
to inform analyses of safety and efficacy of donanemab and planning future studies in 
Alzheimer’s disease.  Cohort 2 will remain double-blinded for the duration of the study. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Modified Number of Participants Alignment with changes made in Section 
9.2. 
1.2. Schema 
Added note related to Cohorts 1 
and 2. 
Clarification. 
4.1.2. Double-
Blind Period 
(Visits 2 
through 21) 
Added note that Cohort 1 will be 
sponsor unblinded, as described 
in Section 9.3.1. 
Amendment defines Cohort 1. 
6.3. Measures to 
Minimize Bias:  
Randomization 
and Blinding 
Added description of blinding 
for Cohorts 1 and 2.  
Amendment defines Cohort 1, which will 
be unblinded to the sponsor.   
 
Moved sentence about the DMC 
being unblinded to 
randomization. 
Organization. 
9.2. Sample 
Size 
Determination 
Increased total study sample size 
to 1800 (from 1500).   
Amendment defines Cohort 1 of 300 
randomized participants. 
 
Added and defined Cohorts 1 
and 2.  
Regulatory feedback. 
 
Specified that the power of the 
study is based on Cohort 2. 
The primary analysis will be composed of 
Cohort 2 only; it will not include Cohort 
1. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.3.1. Cohorts 1 
and 2 
Added subsection.  Provided 
details related to Cohorts 1 and 
2.  
To clarify the purpose of Cohort 1, and 
how the data from Cohort 1 will be used. 
9.4.1. General 
Considerations 
Added “Additional database 
lock(s) may occur.” 
To accommodate analyses of Cohort 1.   
 
Added details related to the 
Cohort 1 SAP and Study SAP.   
Clarification.   
 
Moved paragraph related to 
change in the data analysis 
methods.  
Organization.  
9.5. Interim 
Analyses 
Added safety as a potential 
reason for conducting an interim 
analysis. 
Cohort 1 analysis will include, but not be 
limited to, safety.   
 
Added “Interim analyses of 
Cohort 1 will be conducted by 
Lilly.”  Specified that other 
interim analyses involving 
Cohort 2 will be executed 
through the external DMC. 
Only Cohort 1 will be unblinded to 
sponsor.  Cohort 2 will not be unblinded 
to sponsor prior to data lock.   
Throughout 
Minor editorial corrections. 
Minor clarifying changes (for 
example, clarify between Cohort 
1 SAP and Study SAP). 
Minor, therefore, not described. 
 
 
 
 
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Amendment:  b (17-Feb-2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
 
Overall Rationale for the Amendment: 
This amendment adapts Protocol AACI as a Phase 3 study.  The goal of the study is to confirm 
Phase 2 results.   
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
2.1 Study Rationale 
Updated study to Phase 3 
To reproduce and confirm Study I5T-
MC-AACG (TRAILBLAZER-ALZ) 
data. 
1.1 Synopsis 
Updated to reflect changes in 
body of protocol. 
Rationale described per section. 
 
Removed text under 
“Intervention Groups and 
Duration”. 
Text repeats information under 
“Overall Design” in synopsis. 
1.2 Schema 
1.3 Schedule of 
Activities 
Updated screening window 
and follow up. 
 
Removed P-tau as an eligibility 
criterion and step in screening. Follow 
up timing corrected to align with 
timing described in Section 4.1.3.  
1.3 Schedule of 
Activities 
Removed notes for P-tau 
assay. 
 
P-tau no longer required for inclusion, 
therefore notes were no longer 
applicable. 
 
Added note for 
pharmacogenetics and 
exploratory biomarker sample: 
“collect unless not allowed or 
unfeasible due to local 
regulations. 
Clarification. 
 
 
Added language to allow for 
some visits to be conducted 
remotely.  
Add flexibility and decrease 
participant burden. 
 
Removed DSST. 
Decrease participant burden. 
 
Added note for C-SSRS-
related assessments collection 
for remote visits. 
Add flexibility. 
 
Removed hematology and 
clinical chemistry collection at 
V3 and V4. 
Decrease participant burden.  Phase 2 
data supports collecting less 
frequently. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Removed urinalysis at V15. 
Decrease participant burden. 
 
Added PK Sample collection 
(predose) at V5 and V8. 
Predose concentration necessary to 
interpret results of ADA sample. 
 
Removed PK Sample 
collection (postdose) at V20. 
Decrease participant burden. Phase 2 
data supports not collecting at this 
visit. 
 
Removed ECG at V3, V4, V5, 
V11. Added note that ECG 
may be collected at the 
discretion of the investigator. 
Decrease participant burden. Adequate 
sampling at this timepoint. 
 
Added notes for MRI 
Reminder/clarification. 
 
Added note for Flortaucipir 
F18 PET scan regarding V21. 
Clarification/flexibility depending on 
regional availability and sponsor 
discretion.  
 
Updated footnote a to include 
DSST medicines version. 
Reminder/clarification. 
 
2.1 Study Rationale Updated assessment and 
analysis population.  
Aligned with changes in Section 9 
Statistical Considerations. 
2.2.2 Donanemab 
Clinical Studies 
Updated description of Study 
AACG. 
Update. 
3. Objectives and 
Endpoints 
 
Changed primary analysis 
from CDR-SB in overall 
population or low-medium tau 
population to iADRS in the 
low-medium tau population. 
Adapting as a Phase 3 study, therefore 
updating primary endpoint to confirm 
Phase 2 results. 
 
Added CDR-SB, removed 
iADRS as secondary endpoints 
in low-medium tau population. 
Update per change to primary 
endpoint. 
 
Defined populations for 
secondary endpoints: iADRS, 
CDR-SB-ADAS-Cog13, 
ADCS-iADL, and MMSE. 
Adding specificity. 
 
Removed DSST from 
exploratory endpoints. 
DSST no longer collected 
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Section # and Name 
Description of Change 
Brief Rationale 
4.1 Overall Design 
Updated total duration of 
study, screening duration, and 
follow up. 
Alignment with Section 1.2 Schema 
and Section 1.3 Schedule of Activities.  
See rationale above. 
4.1.1 Lead-In and 
Screening Period 
(Visits 601 and 1) 
Removed the P-tau assay as a 
screening assessment for 
eligibility. 
P-tau assay removed as a step in 
screening and eligibility criterion. 
4.1.1.1 Visit 601 
4.1.1.2 Visit 1 
Created subsections. 
Reorganized text to discuss 
Visits 1 and 601 separately. 
Clarity and organization. 
4.1.3 Follow-Up 
(Visits 801 through 
804) 
Removed list of specific 
assessments. 
Detailed in the Schedule of Activities. 
 
Added statement describing 
when follow up visits may not 
be necessary. 
Follow up visits may not be necessary 
for participants who enroll in an 
extension study that includes these 
assessments. 
4.2 Scientific 
Rationale for Study 
Design 
“…there are no currently 
effective available disease 
modifying treatments for 
AD…” 
Clarification. 
 
Removed sentence describing 
provision for if donanemab 
meets success factors for late-
stage clinical development. 
Scenario described in Section 6.7. 
 
Removed description of CDR-
SB 
Alignment with updated primary 
endpoint. 
4.3 Justification for 
Dose 
Removed text related to 
clinical data described in 
Section 2.2.2. 
Text was redundant with prior section. 
 
Changed description of safety 
data from Study AACD. 
Safety data no longer preliminary. 
4.4 End of Study 
Definition 
Added definition for end of the 
study. 
Clarification. 
5.1 Inclusion 
Criteria 
Criterion 4 removed, which 
required P-tau assay results for 
screening. 
P-tau results or historical positive AD 
pathology is no longer required for 
progression to imaging assessments. 
 
Criterion 7:  added ‘or 
available by phone’ for study 
partner.   
Added flexibility. 
 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Modified language related to 
assessments requiring a study 
partner be available by 
telephone. 
 
Criterion 10:  modified 
criterion to specify 
concomitant medications for 
symptomatic AD or 
medications that may impact 
cognition.  Changed time point 
from 1 month to approximately 
30 days. 
Add flexibility.   
6.1 Study 
Intervention(s) 
Administered 
Updated where detailed 
instructions for administration 
is found. 
Clarification. 
 
Added requirement for 
resuscitation equipment and 
rescue medications to be 
available wherever the IP is 
administered. 
Added instructions for safety. 
6.4 Study 
Intervention 
Compliance 
Updated language to be 
inclusive of visits not at the 
site.  
Clarification and added flexibility. 
6.5.1 Standard of 
Care for 
Alzheimer’s 
Disease 
Modified time point for 
unchanged dose of 
symptomatic treatments for 
AD. 
Added statement describing 
that modification of 
symptomatic treatments for 
AD is permitted when 
medically indicated.  
Alignment with Inclusion Criterion 10. 
 
 
Clarification. 
6.5.2 Medications 
for Infusion 
Reactions 
Removed ‘after consultation 
with a Lilly Medical Monitor’. 
Inclusion or continuation of the 
participant is at the discretion of the 
investigator. 
 
Added reminder for 
completing the related CRF. 
Reminder/Clarification. 
6.6 Dose 
Modification 
Updated language to more 
clearly outline investigator 
options for participants who 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
develop ARIA during the 
titration period. 
6.7 Intervention 
after the End of the 
Study 
Modified language describing 
potential for participants to 
enroll in an extension protocol. 
Added details.  
7.1 Discontinuation 
of Study 
Intervention 
Removed redundant text 
related to PK sampling. 
Redundant with text in Section 8.5.  
 
Added language related to 
systemic hypersensitivity 
reaction. 
Safety: added details. 
7.1.1.1 Due to 
ARIA 
Updated language describing 
ARIA events. 
Alignment with current safety data. 
 
Removed requirement that 
discontinuation and re-
initiation must be discussed 
with the sponsor. 
These decisions are at the discretion of 
the investigator.  Investigator may 
discuss decision with sponsor if 
desired. 
 
Moved text related to AE 
reporting to 8.3.7.  Added 
cross reference. 
Organization of information within 
document. 
7.1.1.2. Due to 
Reasons Other than 
ARIA 
Added ‘exceptional 
circumstances’ as a potential 
reason to temporarily 
discontinue IP. 
Allowance for exceptional 
circumstances. 
8.1 Efficacy 
Assessments 
Added ‘where local guidelines 
permit’ for audio voice 
recordings. 
Clarification. 
 
Modified note language 
concerning which assessments 
must or should be administered 
by a different rater. 
Clarification. 
 
Minor edit to describe that any 
procedure can be conducted on 
other days within the visit 
window. 
Clarification. 
8.1.1 Primary 
Efficacy 
Assessment 
8.1.2.3 CDR-SB 
Switched text between the 
subsections. 
Alignment with change of primary 
efficacy assessment. 
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119 
Section # and Name 
Description of Change 
Brief Rationale 
8.1.2.5 Biomarker 
Efficacy Measures 
Removed scheduling language. Not relevant to section. Scheduling 
described in Section 1.3.  
8.2.4 Clinical 
Safety Laboratory 
Assessments 
Modified language to 
instructions. 
Clarification of instructions. 
8.2.7 Suicidal 
Ideation and 
Behavior Risk 
Monitoring 
Modified language, 
“Participants being treated 
with donanemab should be…” 
Study is double blinded. Therefore, all 
participants should be monitored 
appropriately. 
8.3 Adverse Events 
and Serious 
Adverse Events 
Removed language related to 
experimental devices. 
The P-tau assay is no longer being 
used as a screening step. 
8.3.6.1 
Management of 
Infusion-Related 
Reactions 
8.3.6.2. Dosing 
rechallenge and 
Premedication for 
Infusions 
Updated language and 
instructions based on current 
safety data.  
Safety: updated to expand reasons for 
sample collection. 
8.3.7 Amyloid-
Related Imaging 
Abnormalities 
(ARIA-E and 
ARIA-H) 
Moved text related to AE 
reporting from Section 7.1.1.1. 
Clarification. Organization of 
information in document. 
8.3.9 Medical 
Device 
Deficiencies 
Removed section and related 
subsections. 
The P-tau assay is no longer being 
used as a screening step.  
8.5 
Pharmacokinetics 
Modified language to be 
inclusive of placebo.  
Clarification.  
9 Statistical 
Considerations 
Updated section and associated 
subsections to reflect changes 
to study phase and endpoints. 
Alignment with study design changes 
detailed above. 
9.1 Statistical 
Hypotheses 
Removed examples and 
calculations better described in 
the SAP to reflect low-medium 
tau as the primary population. 
Clarity, organization of information 
across documents. 
9.2 Sample Size 
Determination 
Increased sample size to 1500 
participants. Updated 
To confirm results from Study AACG, 
and to reflect the phase 3 sample size. 
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Section # and Name 
Description of Change 
Brief Rationale 
associated calculations to 
reflect a change to the iADRS. 
9.4.7.2 
Pharmacokinetic/ 
Pharmacodynamic 
Analyses 
Added information regarding 
PK data lock (no safety or 
efficacy data included).  
To facilitate PK modeling. 
9.5 Interim 
Analyses 
Modified language describing 
interim analyses. 
Clarification. 
10.1.5 Committees 
Structure 
Modified DMC members 
description. 
Correction. 
10.2 Appendix 2:  
Clinical Laboratory 
Tests 
Added requirements for when 
the sponsor approves local lab 
testing in lieu of central 
testing. 
Clarification of requirements. 
 
Added eGFR (CKD-EPI) and 
spot urine protein/creatinine. 
Safety: proactively monitoring of renal 
parameters.  
 
Updated language and 
instructions for 
Hypersensitivity Tests (IRR 
kit) based on current safety 
data.  
Safety: updated to expand reasons and 
timing of sample collection. 
10.5 Appendix 5:  
Flortaucipir F18 
Tau PET Imaging 
Updated language related to 
the safety profile of 
flortaucipir. 
Updated to reflect data available. 
10.7 Appendix 7:  
Medical Device 
Adverse Events 
(AEs), Adverse 
Device Effects 
(ADEs), Serious 
Adverse Events 
(SAEs) and Device 
Deficiencies: 
Definition and 
Procedures for 
Recording, 
Evaluating, Follow-
up, and Reporting 
Removed appendix. 
P-tau is no longer a step in the 
screening process. 
Throughout 
document 
Minor editorial changes. 
Minor, therefore, not described. 
 
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Amendment:  a (14-Dec-2020) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
 
Overall Rationale for the Amendment: 
This amendment adds a titration period in response to safety concerns. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.2 Schema  
4.1 Overall Design 
Added titration period of 700 mg 
for first 3 doses. 
Safety. 
1.3 Schedule of 
Activities 
4.1.1 Lead-In and 
Screening Period 
(Visits 601 and 1) 
Changed extra days added to the 
tolerance interval when P-tau 
results are needed from V1 from 7 
to 10. 
Operational considerations: 
result turnaround time longer 
than initially anticipated.  
1.3 Schedule of 
Activities 
3 Objectives and 
Endpoints 
Corrected abbreviation for DSST. 
Correction. 
4.1.1 Lead-In and 
Screening Period 
(Visits 601 and 1) 
Added exception for the screening 
tolerance window for temporary 
randomization pauses. 
Operational considerations. 
4.3 Justification for 
Dose 
Added justification for titration 
doses. 
Addition of titration schedule. 
6.4 Study Intervention 
Compliance 
Added instructions for when a 
participant does not complete the 
titration phase. 
Safety. 
6.6 Dose Modification Added instructions for when a 
participant develops ARIA.  
Safety.  
8.1.2.4 ADCS-ADL 
Corrected description of scores, 
“…higher lower scores indicating 
greater level of impairment.” 
Correction. 
9.4.1.1 Handling of 
Missing Items for 
Scales 
Corrected iADRS score calculation. Correction. 
Throughout  
Editorial changes 
Minor editorial changes, 
therefore, not described. 
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