A Phase 3, Open-Label, Parallel-Group, 2-Arm Study to Investigate Amyloid Plaque Clearance With Donanemab Compared With Aducanumab-avwa in Participants With Early Symptomatic Alzheimer's Disease
Phase: PHASE3
Conditions: Mild Cognitive Impairment (MCI), Alzheimer Disease
Sponsor: Eli Lilly and Company

Protocol I5T-MC-AACN(b) 
A Phase 3, Open-Label, Parallel-Group, 2-Arm Study to Investigate Amyloid Plaque Clearance 
with Donanemab Compared with Aducanumab-avwa in Participants with Early Symptomatic 
Alzheimer’s Disease 
NCT05108922 
Approval Date: 17-May-2022 

CONFIDENTIAL 
Protocol number I5T-MC-AACN(b) 
1 
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:  
A Phase 3, Open-Label, Parallel-Group, 2-Arm Study to Investigate Amyloid Plaque Clearance 
with Donanemab Compared with Aducanumab-avwa in Participants with Early Symptomatic 
Alzheimer’s Disease 
Protocol Number: I5T-MC-AACN 
Amendment Number: b  
Compound: donanemab (LY3002813) 
Brief Title:  
A Study to Investigate Amyloid Plaque Clearance with Donanemab Compared with 
Aducanumab-avwa in Participants with Early Symptomatic Alzheimer’s Disease 
Study Phase: 3 
Acronym: TRAILBLAZER-ALZ 4 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 109157 
Document ID: VV-CLIN-059456 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below.  
 
 

CONFIDENTIAL 
Protocol number I5T-MC-AACN(b) 
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Medical Monitor Name and Contact Information will be provided separately. 

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Protocol number I5T-MC-AACN(b) 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment a 
11-Oct-2021 
Original Protocol 
17-Aug-2021 
Amendment b  
Overall Rationale for the Amendment: 
This amendment adds an MRI at Visit 10 due to a recent label update to aducanumab-avwa. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
Added an MRI to Visit 10. 
Align with label update to aducanumab-
avwa 
7.1.3 Amyloid-
Related Imaging 
Abnormalities 
(ARIA) 
Clarified the timing of ARIA 
or donanemab v aducanumab-
avwa.  
Minor clarification.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol number I5T-MC-AACN(b) 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities (SoA) ..........................................................................................13 
2. 
Introduction ...................................................................................................................23 
2.1. 
Study Rationale ...............................................................................................................23 
2.2. 
Background .....................................................................................................................23 
2.3. 
Benefit/Risk Assessment ................................................................................................24 
3. 
Objectives, Endpoints, and Estimands .......................................................................25 
4. 
Study Design ..................................................................................................................28 
4.1. 
Overall Design ................................................................................................................28 
4.2. 
Scientific Rationale for Study Design ............................................................................28 
4.3. 
Justification for Dose ......................................................................................................29 
4.4. 
End of Study Definition ..................................................................................................29 
5. 
Study Population ...........................................................................................................30 
5.1. 
Inclusion Criteria ............................................................................................................30 
5.2. 
Exclusion Criteria ...........................................................................................................31 
5.3. 
Lifestyle Considerations .................................................................................................32 
5.4. 
Screen Failures ................................................................................................................33 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................33 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................34 
6.1. 
Study Intervention(s) Administered................................................................................34 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................34 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................35 
6.4. 
Study Intervention Compliance ......................................................................................35 
6.5. 
Dose Modification ..........................................................................................................36 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................36 
6.7. 
Treatment of Overdose ...................................................................................................36 
6.8. 
Concomitant Therapy .....................................................................................................36 
6.8.1. 
Medications for Alzheimer’s Disease .............................................................................37 
6.8.2. 
Medications for Infusion Reactions ................................................................................37 
6.8.3. 
Excluded Medications .....................................................................................................37 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................38 
7.1. 
Discontinuation of Study Intervention ............................................................................38 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................38 
7.1.2. 
QTc Stopping Criteria .....................................................................................................39 
7.1.3. 
Amyloid-Related Imaging Abnormalities (ARIA) .........................................................39 
7.1.4. 
Temporary Discontinuation ............................................................................................40 

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Protocol number I5T-MC-AACN(b) 
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7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................40 
7.3. 
Lost to Follow up ............................................................................................................41 
8. 
Study Assessments and Procedures.............................................................................42 
8.1. 
Efficacy Assessments .....................................................................................................42 
8.1.1. 
Biomarker Efficacy Measures.........................................................................................42 
8.2. 
Safety Assessments .........................................................................................................42 
8.2.1. 
Vital Signs .......................................................................................................................42 
8.2.2. 
Electrocardiograms .........................................................................................................42 
8.2.3. 
Clinical Safety Laboratory Tests ....................................................................................43 
8.2.4. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................43 
8.2.5. 
Magnetic Resonance Imaging .........................................................................................44 
8.2.6. 
Hepatic Safety Monitoring ..............................................................................................44 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................46 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................47 
8.3.2. 
Pregnancy ........................................................................................................................49 
8.3.3. 
Hypersensitivity Including Infusion-Related Reactions .................................................50 
8.3.4. 
Adverse Events of Special Interest .................................................................................51 
8.4. 
Pharmacokinetics ............................................................................................................51 
8.5. 
Pharmacodynamics .........................................................................................................51 
8.6. 
Genetics ..........................................................................................................................51 
8.6.1. 
Apolipoprotein E Genotyping .........................................................................................51 
8.6.2. 
Whole Blood Samples for Pharmacogenetic Research ...................................................51 
8.7. 
Biomarkers ......................................................................................................................52 
8.8. 
Immunogenicity Assessments.........................................................................................52 
8.9. 
Health Economics ...........................................................................................................52 
9. 
Statistical Considerations .............................................................................................53 
9.1. 
Statistical Hypotheses .....................................................................................................53 
9.2. 
Analyses Sets ..................................................................................................................53 
9.3. 
Statistical Analyses .........................................................................................................54 
9.3.1. 
General Considerations ...................................................................................................54 
9.3.2. 
Treatment Group Comparability .....................................................................................55 
9.3.3. 
Primary Analyses ............................................................................................................56 
9.3.4. 
Secondary Analyses ........................................................................................................56 
9.3.5. 
Other Safety Analyses.....................................................................................................57 
9.3.6. 
Other Analyses ................................................................................................................58 
9.4. 
Interim Analysis ..............................................................................................................58 
9.5. 
Sample Size Determination ............................................................................................58 
10. 
Supporting Documentation and Operational Considerations ..................................60 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................60 
10.1.1. Regulatory and Ethical Considerations ...........................................................................60 
10.1.2. Financial Disclosure........................................................................................................60 
10.1.3. Informed Consent Process ..............................................................................................61 
10.1.4. Data Protection................................................................................................................61 

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Protocol number I5T-MC-AACN(b) 
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10.1.5. Committees Structure......................................................................................................61 
10.1.6. Dissemination of Clinical Study Data.............................................................................62 
10.1.7. Data Quality Assurance ..................................................................................................62 
10.1.8. Source Documents ..........................................................................................................64 
10.1.9. Study and Site Start and Closure ....................................................................................64 
10.1.10. Publication Policy ...........................................................................................................65 
10.1.11. Investigator Information .................................................................................................65 
10.1.12. Sample Retention ............................................................................................................65 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................66 
10.2.1. Clinical Laboratory Tests for Hypersensitivity Events ...................................................67 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................70 
10.3.1. Definition of AE .............................................................................................................70 
10.3.2. Definition of SAE ...........................................................................................................71 
10.3.3. Definition of Product Complaints ...................................................................................72 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................72 
10.3.5. Reporting of SAEs ..........................................................................................................74 
10.3.6. Regulatory Reporting Requirements ...............................................................................75 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................76 
10.4.1. Definitions.......................................................................................................................76 
10.4.2. Contraception Guidance..................................................................................................76 
10.5. 
Appendix 5: Genetics......................................................................................................77 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................78 
10.7. 
Appendix 7: Flortaucipir F18 PET Imaging ...................................................................80 
10.8. 
Appendix 8:  Florbetapir F18 PET Imaging ...................................................................82 
10.9. 
Appendix 9:  CDR and MMSE .......................................................................................83 
10.9.1. CDR ................................................................................................................................83 
10.9.2. MMSE .............................................................................................................................83 
10.10. 
Appendix 10: Abbreviations and Definitions .................................................................84 
11. 
References ......................................................................................................................90 
 

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Protocol number I5T-MC-AACN(b) 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
A Phase 3, Open-Label, Parallel-Group, 2-Arm Study to Investigate Amyloid Plaque Clearance 
with Donanemab Compared with Aducanumab-avwa in Participants with Early Symptomatic 
Alzheimer’s Disease 
Brief Title:  
A Study to Investigate Amyloid Plaque Clearance with Donanemab Compared with 
Aducanumab-avwa in Participants with Early Symptomatic Alzheimer’s Disease 
Rationale: 
Study I5T-MC-AACN (AACN) is a Phase 3, open-label, head-to-head study to evaluate the 
superiority of donanemab to aducanumab in participants with Early Symptomatic AD. 
The amyloid hypothesis of AD postulates that the production and deposition of Aβ is an early 
and necessary event in the pathogenesis of AD (Selkoe 2000). Both donanemab and aducanumab 
have previously demonstrated the ability to reduce brain amyloid plaque burden and potentially 
slow clinical decline (Sevigny et al 2016; Mintun et al 2021; Aducanumab USPI, 2021). 
Recently, the FDA approved aducanumab, in the US, under accelerated approval for the 
treatment of AD based on its ability to reduce amyloid plaque burden (Aducanumab USPI, 
2021). The current study aims to evaluate the superiority of donanemab to aducanumab on 
amyloid plaque clearance in participants with early symptomatic AD. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Co-Primary 
 
To assess the superiority of donanemab 
versus aducanumab on complete brain 
amyloid plaque clearance in participants with 
early symptomatic AD. 
Superiority of percentage of participants who 
reach complete amyloid plaque clearance on 
florbetapir F18 PET scan on donanemab 
versus aducanumab at 6 months. 
To assess the superiority of donanemab 
versus aducanumab on complete brain 
amyloid plaque clearance in the intermediate 
tau subpopulation of participants with early 
symptomatic AD. 
Superiority of percentage of participants who 
reach complete amyloid plaque clearance on 
florbetapir F18 PET scan in the intermediate 
tau subpopulation on donanemab versus 
aducanumab at 6 months. 

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Protocol number I5T-MC-AACN(b) 
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Key Secondary 
 
To assess the superiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction. 
Superiority of mean absolute change from 
baseline in brain amyloid plaque on 
florbetapir F18 PET scan for donanemab 
versus aducanumab at: 
 6 months 
 12 months, and 
 18 months. 
To assess the superiority of donanemab 
versus aducanumab in time to reach complete 
amyloid plaque clearance. 
Time to reach complete amyloid plaque 
clearance on donanemab versus aducanumab. 
Other Secondary 
 
To assess the superiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction. 
Superiority of mean percent change from 
baseline in brain amyloid plaque on 
florbetapir F18 PET scan for donanemab 
versus aducanumab at: 
 6 months 
 12 months, and 
 18 months. 
To assess the non-inferiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction. 
Non-inferiority of mean absolute change from 
baseline in brain amyloid plaque on 
florbetapir F18 PET scan at: 
 donanemab 6 months vs aducanumab 
12 months, and 
 donanemab 6 months vs aducanumab 
18 months. 
To assess the superiority of donanemab 
versus aducanumab on complete brain 
amyloid plaque clearance. 
Superiority of percentage of participants who 
reach complete amyloid plaque clearance on 
florbetapir F18 PET scan on donanemab 
versus aducanumab at: 
 12 months, and 
 18 months. 

CONFIDENTIAL 
Protocol number I5T-MC-AACN(b) 
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To assess the superiority of donanemab 
versus aducanumab on complete brain 
amyloid plaque clearance in the intermediate 
tau subpopulation. 
Superiority of percentage of participants who 
reach complete amyloid plaque clearance on 
florbetapir F18 PET scan in the intermediate 
tau subpopulation on donanemab versus 
aducanumab at: 
 12 months, and 
 18 months. 
To assess the superiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction in the intermediate 
tau subpopulation. 
Superiority of mean absolute change from 
baseline in brain amyloid plaque on 
florbetapir F18 PET scan in the intermediate 
tau subpopulation for donanemab vs 
aducanumab at:  
 6 months 
 12 months, and 
 
18 months. 
To assess the superiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction. 
Superiority of change from baseline in brain 
amyloid plaque reduction on florbetapir F18 
PET scan for donanemab 6 months vs 
aducanumab 12 months. 
To evaluate the safety and tolerability of 
donanemab vs aducanumab 
Characterization of standard safety 
assessments: 
 Spontaneously reported AEs 
 Clinical laboratory tests 
 MRI (ARIA and emergent radiological 
findings) 
 Serious hypersensitivity reactions 
 C-SSRS 
Abbreviations: AD = Alzheimer's disease; AE = adverse event; ARIA = amyloid-related imaging abnormalities; C-
SSRS = Columbia Suicide-Severity Rating Scale; MRI = magnetic resonance imaging; PET = positron emission 
tomography. 
NOTE: Other pre-specified, non-gated endpoints not listed will be detailed in the SAP. 
Overall Design 
Study I5T-MC-AACN (AACN) is a Phase 3, open-label, head-to-head study to evaluate the 
superiority of donanemab to aducanumab in participants with early symptomatic AD. 
Brief Summary: 
Study AACN is a multicenter, randomized, open-label, head-to-head, Phase 3 study of 
donanemab compared to aducanumab in participants with early symptomatic AD. 
Participants who meet entry criteria will be randomized in a 1:1 ratio to 1 of the following 
treatment groups: 

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Protocol number I5T-MC-AACN(b) 
10 
 donanemab: 700 mg IV Q4W for first 3 doses and then 1400 mg IV Q4W 
 aducanumab: Refer to PI/routine clinical practice 
The maximum total duration of study participation for each participant, including screening and 
the post-treatment follow-up periods, is up to 127 weeks: 
 Lead-In:  any time prior to complete screening 
 Complete Screening:  up to 7 weeks 
 Open-label study period:  76 weeks 
 Follow-Up:  up to 44 weeks 
The maximum duration of treatment is 72 weeks. 
Scheduled Reduction of Donanemab 
Participants randomized to donanemab whose amyloid plaque reduction as measured by 
florbetapir F18 PET scans at Visit 8 (Week 24) or Visit 15 (Week 52) meets criteria will stop 
donanemab infusions but continue all other assessments for the remaining duration of the open-
label period and short-term follow-up period. These dose reduction rules are defined by the 
sponsor. 
Participants randomized to aducanumab will continue monthly infusions throughout the open-
label period, regardless of amyloid plaque reduction on florbetapir F18 PET scans. 
Participant randomization will be stratified by amyloid burden at baseline and ApoE ε4 status 
(noncarrier/heterozygous/homozygous). 
Number of Participants: 
Approximately 200 participants will be randomly assigned to study intervention.  

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Protocol number I5T-MC-AACN(b) 
11 
Intervention Groups and Duration: 
Intervention Name 
donanemab 
aducanumab 
Dosage Level(s) 
700 mg IV Q4W for 
first 3 doses and 
then 1400 mg IV 
Q4Wa 
Refer to PI/routine 
clinical practice 
Route of 
Administration 
IV infusion 
IV infusion 
Use 
experimental 
active-comparator 
Abbreviations: IV = intravenous; PI = package insert; Q4W = once every 4 weeks. 
a Participants randomized to donanemab whose amyloid plaque reduction as measured by florbetapir F18 PET scans 
at Visit 8 (Week 24) or Visit 15 (Week 52) meets criteria will stop donanemab infusions but continue all other 
assessments for the remaining duration of the open-label period and short-term follow-up period. These dose 
reduction rules are defined by the sponsor. 
Data Monitoring Committee: Yes 

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Protocol number I5T-MC-AACN(b) 
12 
1.2. 
Schema 
  
  
Abbreviations: IV = intravenous; mg = milligrams; Q4W = every 4 weeks. 
Note: V601 is optional. For participants who do not complete V601, procedures will be included in V1. 
Randomization occurs at V2. 
a Participants whose amyloid plaque reduction as measured by florbetapir F18 PET scans at Visit 8 (Week 24) or Visit 15 (Week 52) meets criteria will stop 
donanemab infusions but continue all other assessments for the remaining duration of the open-label period and short-term follow-up period. These dose 
reduction rules are defined by the sponsor. 

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Protocol number I5T-MC-AACN(b) 
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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 
 
Tolerance Interval for 
Visit (Days) 
Can be done at any time 
≤49 before V2 
 
Entry and Administrative 
Abbreviated (or Full) 
Informed 
Consent – participant  
X 
 
The Abbreviated Informed Consent 
grants consent only for procedures and 
assessments marked under V601. 
Full Informed Consent – 
participant  
 
X 
Do not collect if Full Informed Consent 
was collected at V601. 
Full Informed Consent –
study partner 
X 
 
Study partner(s) are not required to 
complete the abbreviated Informed 
Consent. 
Participant number assigned 
via IWRS 
X 
 
Demographics 
X 
 
Inclusion/exclusion review 
 
X 
Physical/neurological 
examination 
 
X 
As described in the Manual of 
Operations. 
Concomitant medications 
 
X 
Preexisting conditions 
 
X 
Assessments 
Height and weight 
 
X 
 

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Protocol number I5T-MC-AACN(b) 
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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 
 
Tolerance Interval for 
Visit (Days) 
Can be done at any time 
≤49 before V2 
 
ECG 
 
X 
Single, locally-read ECG. 
Unscheduled ECGs may be performed at 
the discretion of investigator. 
Chemistry 
X 
Blood draw can be performed at either at 
V601 or V1.  
Collect all blood draws for screening at 
the same time.  
Hematology 
X 
ApoE 
X 
Blood draw can be performed at either at 
V601 or V1.  
Collect all blood draws for screening at 
the same time.   
Entry Diagnostics 
MMSE 
X 
 
Participants who do not meet MMSE 
criteria are not to have any other 
screening procedures performed.   
Administer the MMSE prior to medical 
procedures that could be stressful to the 
participant (blood draws, etc.).   
CDR 
X 
 
Administer the CDR prior to medical 
procedures that could be stressful to the 
participant (blood draws, etc.).   

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Protocol number I5T-MC-AACN(b) 
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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 
 
Tolerance Interval for 
Visit (Days) 
Can be done at any time 
≤49 before V2 
 
Screening PET Scans and MRI 
Florbetapir F18 PET scan 
 
X 
The participant should meet all other 
non-imaging eligibility criteria before 
the screening florbetapir F18 PET scan. 
Previous florbetapir F18 PET scans 
within 3 months of randomization may 
be acceptable. The acceptance of a 
historical scan is at the discretion of the 
sponsor. 
MRI 
 
X 
The participant should meet all other 
non-imaging eligibility criteria before 
the screening MRI.   
Abbreviations: ApoE = apolipoprotein E; CDR = Clinical Dementia Rating; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; 
IWRS = interactive web response system; MMSE = Mini-Mental State Exam; MRI = magnetic resonance imaging; PET = positron emission tomography; V = 
visit. 
 
 
 

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Protocol number I5T-MC-AACN(b) 
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Visits 2 through 11 
 
Open-Label Study Period 
Comments 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Weeks relative to first 
infusion 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
 
Visit interval tolerance 
(days) 
 
-7 to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Entry and Administrative 
 
Inclusion and exclusion 
criteria, review and 
confirm 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria should be confirmed at V2, prior to 
randomization and administration of the first dose of study 
intervention. 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
Brief 
Physical/Neurological 
Exam 
X 
 
 
X 
 
 
X 
 
 
X 
As described in the Manual of Operations. 
Any clinically significant changes from baseline on brief 
physical/neurological examinations should be noted on the AE CRF. 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Any events that occur after signing the informed consent are 
considered AEs as defined in Section 10.3. 
C-SSRS 
screening/baseline 
X 
 
 
 
 
 
 
 
 
  
 
C-SSRS since last 
assessment  
 
 
X 
 
X 
 
X 
 
X 
 
 
Administer study 
intervention 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
See Section 6.1. 
Administration of study intervention (and treatment-related activities 
conducted in person) outside of the visit window is not a protocol 
deviation, unless 2 doses are administered within <21 days of each 
other. 
The participant should be observed for a minimum of 30 minutes 
following the end of each infusion. 

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Protocol number I5T-MC-AACN(b) 
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Open-Label Study Period 
Comments 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Weeks relative to first 
infusion 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
 
Visit interval tolerance 
(days) 
 
-7 to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Vital signs include pulse rate, blood pressure, and temperature. Vitals 
should be measured after participant has been sitting for at least 
5 minutes. 
Vital signs are measured prior to and within 30 minutes after infusion 
for clinical management, and not recorded in the CRF. 
Weight (for aducanumab 
participants only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight is measured prior to dosing with aducanumab only and is not 
recorded in the CRF.   
MRI  
 
  
 X 
 
X 
  
 
X 
  
X  
  
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. The 
MRI should occur at least 14 days after infusion at V4 is 
administered, and may occur outside of the visit windows. 
MRI at V8 is to be performed and reviewed prior to V8 infusion. The 
MRI should occur at least 14 days after infusion at V7 is 
administered, and may occur outside of the visit windows. 
MRI at V10 is to be performed and reviewed prior to V10 infusion. 
The MRI should occur at least 14 days after infusion at V9 is 
administered, and may occur outside of the visit windows. 
 
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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Protocol number I5T-MC-AACN(b) 
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Open-Label Study Period 
Comments 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Weeks relative to first 
infusion 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
 
Visit interval tolerance 
(days) 
 
-7 to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Flortaucipir F18 PET 
scan 
X 
 
 
 
 
 
 
 
 
 
Will not be used for eligibility. Participants have +/- 3 months from 
randomization to obtain flortaucipir results (either from pre-existing 
scan or new scan). 
PET scans must be performed ≥16 hours apart from each other. 
Previous flortaucipir F18 PET scans may be acceptable. The 
acceptance of a historical scan is at the discretion of the sponsor. 
Florbetapir F18 PET scan 
 
 
 
 
 
 
X 
 
 
 
PET scans must be performed ≥16 hours apart from each other. 
Laboratory Tests and 
Sample Collections 
In the event that study intervention is delayed, all laboratory collections should occur on the same day as study intervention 
infusion – and should be collected prior to infusion. 
Hematology and clinical 
chemistry 
 
 
 
 
 
 
X 
 
 
 
Collect prior to infusion. 
PK sample   
 
  
  
  
 
  
X 
  
  
 
Collect prior to infusion. Predose collections may be collected from 
the IV site prior to the infusion. 
 
Immunogenicity (ADA) 
samples 
X 
  
  
  
 
  
X 
  
  
 
Collect prior to infusion. 
Stored Samples 
 
 
 
 
 
 
 
 
 
 
 
Genetics sample 
X 
  
  
  
  
  
  
 
  
  
Collect prior to infusion. 
Exploratory biomarker 
samples  
X 
  
  
  
  
  
 X 
 
  
  
Collect prior to infusion. 
Abbreviations: ADA = anti-drug antibody; AEs = adverse events; CRF = case reporting form; C-SSRS = Columbia-Suicide Severity Rating Scale; MRI = 
magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetic; V = visit. 
 
 
 

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Protocol number I5T-MC-AACN(b) 
19 
Visits 12 through 21 and Follow-Up 
 
 
Open-Label Treatment 
Short-term 
Follow-up 
Comments 
Visit Number 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
ET 
801-804^ 
^Visit 801 to 804 may be used for 
return to baseline ADA monitoring 
and other safety assessments at 
discretion of the sponsor and may be 
requested within the time period 
listed. 
Weeks relative to first 
infusion 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
- 
84-120 
 
Visit interval tolerance 
(days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
±14 
 
Entry and Administrative 
 
Brief 
Physical/Neurological 
Exam 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
As described in the Manual of 
Operations.  
Any clinically significant changes 
from baseline on brief 
physical/neurological examinations 
should be noted on the AE CRF. 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Any events that occur after signing 
the informed consent are 
considered AEs as defined in 
Section 10.3. 
C-SSRS since last 
assessment  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 

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Protocol number I5T-MC-AACN(b) 
20 
 
Open-Label Treatment 
Short-term 
Follow-up 
Comments 
Visit Number 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
ET 
801-804^ 
^Visit 801 to 804 may be used for 
return to baseline ADA monitoring 
and other safety assessments at 
discretion of the sponsor and may be 
requested within the time period 
listed. 
Weeks relative to first 
infusion 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
- 
84-120 
 
Visit interval tolerance 
(days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
±14 
 
Administer study 
intervention 
X 
X 
X 
X 
X 
X 
X 
X  
X 
 
 
 
See Section 6.1. 
Administration of study 
intervention (and treatment-related 
activities conducted in person) 
outside of the visit window is not a 
protocol deviation, unless 2 doses 
are administered within <21 days 
of each other. 
The participant should be observed 
for a minimum of 30 minutes 
following the end of each infusion. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
Vital signs include pulse rate, 
blood pressure, and temperature. 
Vitals should be measured after 
participant has been sitting for at 
least 5 minutes. 
Vital signs are measured prior to 
and within 30 minutes after 
infusion for clinical management, 
and not recorded in the CRF. 
Weight (for aducanumab 
participants only) 
X 
X 
X 
X 
X 
X 
X 
X  
X 
 
 
 
Weight is measured prior to dosing 
with aducanumab only and is not 
recorded in the CRF.  

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Protocol number I5T-MC-AACN(b) 
21 
 
Open-Label Treatment 
Short-term 
Follow-up 
Comments 
Visit Number 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
ET 
801-804^ 
^Visit 801 to 804 may be used for 
return to baseline ADA monitoring 
and other safety assessments at 
discretion of the sponsor and may be 
requested within the time period 
listed. 
Weeks relative to first 
infusion 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
- 
84-120 
 
Visit interval tolerance 
(days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
±14 
 
MRI  
  
X  
 
 
 
  
  
  
  
  
 
 
MRI at V13 is to be performed and 
reviewed prior to V13 infusion. 
The MRI should occur at least 14 
days after infusion at V12 is 
administered, and may occur 
outside of the visit windows. 
 
Unscheduled MRIs may be 
performed at the discretion of 
investigator, for example, if 
titration is delayed due to 
temporary suspension of infusions. 
Florbetapir F18 PET 
scan 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Collect at ET only if ET occurs at 
3 or more IP infusions after the last 
florbetapir F18 PET scan. 
Laboratory Tests and 
Sample Collections 
In the event that study intervention is delayed, all laboratory collections should occur on the same day as study 
intervention infusion - and should be collected prior to infusion. 
Hematology and clinical 
chemistry 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Collect prior to infusion. 
PK sample 
 
  
  
X 
 
  
  
  
  
X 
X 
X 
Collect prior to infusion. Predose 
collections may be collected from 
the IV site prior to the infusion. 
Immunogenicity (ADA) 
samples  
 
  
  
X 
 
  
  
  
  
X 
X 
X 
Collect prior to infusion. 

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Protocol number I5T-MC-AACN(b) 
22 
 
Open-Label Treatment 
Short-term 
Follow-up 
Comments 
Visit Number 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
ET 
801-804^ 
^Visit 801 to 804 may be used for 
return to baseline ADA monitoring 
and other safety assessments at 
discretion of the sponsor and may be 
requested within the time period 
listed. 
Weeks relative to first 
infusion 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
- 
84-120 
 
Visit interval tolerance 
(days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
±14 
 
Stored Samples 
 
Exploratory biomarker 
samples  
 
  
  
X 
  
  
  
 
  
X  
X 
 
Collect prior to infusion. 
Abbreviations: ADA = anti-drug antibody; AEs = adverse events; CRF = electronic case reporting form; C-SSRS = Columbia-Suicide Severity Rating Scale; ET 
= early termination; MRI = magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetic; V = visit. 
 
 
 

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Protocol number I5T-MC-AACN(b) 
23 
2. 
Introduction 
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 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. 
Aducanumab is a human anti-Aβ monoclonal antibody that selectively targets aggregated forms 
of Aβ, including soluble oligomers and insoluble fibrils (Ferrero et al 2016). It was recently 
approved, in the US, under accelerated approval for the treatment of AD (Aducanumab USPI, 
2021). 
2.1. 
Study Rationale 
Study I5T-MC-AACN (AACN) is a Phase 3, open-label, head-to-head study to evaluate the 
superiority of donanemab to aducanumab in reaching amyloid plaque clearance in participants 
with early symptomatic AD. 
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 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. Both donanemab and aducanumab have previously demonstrated 
the ability to reduce brain amyloid plaque burden and potentially slow clinical decline (Sevigny 
et al 2016; Mintun et al 2021; Aducanumab USPI, 2021). Recently, the FDA approved 
aducanumab for clinical use based on its ability to reduce amyloid plaque burden (Aducanumab 
USPI, 2021). The current study aims to evaluate the superiority of donanemab to aducanumab in 
reaching amyloid plaque clearance. 
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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Protocol number I5T-MC-AACN(b) 
24 
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 MRI by the stage 
of MCI (Jack et al 2010). 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). 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of donanemab may be found in the IB, Participant Information Leaflet, 
Package Insert, or Development Safety Update Report or Summary of Product Characteristics. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of aducanumab may be found in the Participant Information Leaflet, 
Package Insert, or Summary of Product Characteristics. 

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Protocol number I5T-MC-AACN(b) 
25 
3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Co-Primary 
 
To assess the superiority of donanemab 
versus aducanumab on complete brain 
amyloid plaque clearance in participants with 
early symptomatic AD. 
Superiority of percentage of participants who 
reach complete amyloid plaque clearance on 
florbetapir F18 PET scan on donanemab 
versus aducanumab at 6 months. 
To assess the superiority of donanemab 
versus aducanumab on complete brain 
amyloid plaque clearance in the intermediate 
tau subpopulation of participants with early 
symptomatic AD. 
Superiority of percentage of participants who 
reach complete amyloid plaque clearance on 
florbetapir F18 PET scan in the intermediate 
tau subpopulation on donanemab versus 
aducanumab at 6 months. 
Key Secondary 
 
To assess the superiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction. 
Superiority of mean absolute change from 
baseline in brain amyloid plaque on 
florbetapir F18 PET scan for donanemab 
versus aducanumab at: 
 6 months 
 12 months, and 
 18 months. 
To assess the superiority of donanemab 
versus aducanumab in time to reach complete 
amyloid plaque clearance. 
Time to reach complete amyloid plaque 
clearance on donanemab versus aducanumab. 
Other Secondary 
 
To assess the superiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction. 
Superiority of mean percent change from 
baseline in brain amyloid plaque on 
florbetapir F18 PET scan for donanemab 
versus aducanumab at: 
 6 months 
 12 months, and 
 18 months. 

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Protocol number I5T-MC-AACN(b) 
26 
Objectives 
Endpoints 
To assess the non-inferiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction. 
Non-inferiority of mean absolute change from 
baseline in brain amyloid plaque on 
florbetapir F18 PET scan at: 
 donanemab 6 months vs aducanumab 
12 months, and 
 donanemab 6 months vs aducanumab 
18 months. 
To assess the superiority of donanemab 
versus aducanumab on complete brain 
amyloid plaque clearance. 
Superiority of percentage of participants who 
reach complete amyloid plaque clearance on 
florbetapir F18 PET scan on donanemab 
versus aducanumab at: 
 12 months, and 
 18 months. 
To assess the superiority of donanemab 
versus aducanumab on complete brain 
amyloid plaque clearance in the intermediate 
tau subpopulation. 
Superiority of percentage of participants who 
reach complete amyloid plaque clearance on 
florbetapir F18 PET scan in the intermediate 
tau subpopulation on donanemab versus 
aducanumab at:  
 12 months, and 
 18 months. 
To assess the superiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction in the intermediate 
tau subpopulation. 
Superiority of mean absolute change from 
baseline in brain amyloid plaque on 
florbetapir F18 PET scan in the intermediate 
tau subpopulation for donanemab vs 
aducanumab at:  
 6 months 
 12 months, and 
 
18 months. 
To assess the superiority of donanemab 
versus aducanumab on degree of brain 
amyloid plaque reduction. 
Superiority of change from baseline in brain 
amyloid plaque reduction on florbetapir F18 
PET scan for donanemab 6 months vs 
aducanumab 12 months. 

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Protocol number I5T-MC-AACN(b) 
27 
Objectives 
Endpoints 
To evaluate the safety and tolerability of 
donanemab vs aducanumab. 
Characterization of standard safety 
assessments: 
 Spontaneously reported AEs 
 Clinical laboratory tests 
 MRI (ARIA and emergent radiological 
findings) 
 Serious hypersensitivity reactions 
 C-SSRS 
Abbreviations: AD = Alzheimer's disease; AE = adverse event; ARIA = amyloid-related imaging abnormalities; C-
SSRS = Columbia Suicide-Severity Rating Scale; PET = positron emission tomography; SAP = Statistical 
Analysis Plan. 
NOTE: Other pre-specified, non-gated endpoints not listed will be detailed in the SAP. 
Estimands 
Estimands are described in the SAP. 
 

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Protocol number I5T-MC-AACN(b) 
28 
4. 
Study Design 
4.1. 
Overall Design 
Study AACN is a multicenter, randomized, open-label, head-to-head, Phase 3 study of 
donanemab compared to aducanumab in participants with early symptomatic AD. 
Participants who meet entry criteria will be randomized in a 1:1 ratio to 1 of the following 
treatment groups: 
 donanemab:  700 mg IV Q4W for first 3 doses and then 1400 mg IV Q4W 
 aducanumab:  refer to PI/routine clinical practice 
The maximum total duration of study participation for each participant, including screening and 
the post-treatment follow-up periods, is up to 127 weeks: 
 Lead-In:  any time prior to complete screening 
 Complete Screening:  up to 7 weeks 
 Open-label study period:  76 weeks 
 Follow-Up:  up to 44 weeks 
The maximum duration of treatment is 72 weeks. 
Scheduled Reduction of Donanemab 
Participants randomized to donanemab whose amyloid plaque reduction as measured by 
florbetapir F18 PET scans at Visit 8 (Week 24) or Visit 15 (Week 52) meets criteria will stop 
donanemab infusions but continue all other assessments for the remaining duration of the open-
label period and short-term follow-up period. These dose reduction rules are defined by the 
sponsor. 
Participants randomized to aducanumab will continue monthly infusions throughout the open-
label period, regardless of amyloid plaque reduction on florbetapir F18 PET scans.  
Change in amyloid burden (as assessed with florbetapir F18 PET by personnel blinded to 
treatment allocation) will be compared in donanemab and aducanumab-treated participants. 
Participant randomization will be stratified by amyloid burden and ApoE ε4 status 
(noncarrier/heterozygous/homozygous). 
4.2. 
Scientific Rationale for Study Design 
Study AACN is a Phase 3, open-label, head-to-head study to evaluate the superiority of 
donanemab to aducanumab in reaching amyloid plaque clearance in participants with early 
symptomatic AD. 
Amyloid plaque is a known hallmark pathology of AD, and is hypothesized to contribute to the 
cognitive and functional decline in people with AD. Therefore, it is hypothesized that the 
removal of amyloid by donanemab may slow clinical progression. 
The study includes a screening visit, which can last up to 49 days, at which participants are 
required to have florbetapir F18 PET imaging results in order to be randomized to donanemab or 
aducanumab. The duration of the open-label treatment period of the study is 76 weeks and 

CONFIDENTIAL 
Protocol number I5T-MC-AACN(b) 
29 
includes up to 72 weeks of treatment with primary endpoint measure at 6 months, to assess the 
superiority of donanemab versus aducanumab in reaching amyloid plaque clearance. 
In addition to AE reporting, safety measures such as laboratory assessments, MRI assessments 
(ARIA and emergent radiological findings), serious hypersensitivity reactions, and assessments 
of suicidal ideation and behavior are included to facilitate a comprehensive safety evaluation. 
4.3. 
Justification for Dose 
Decreased participant burden with a Q4W dosing schedule compared with a Q2W dosing 
schedule and comparable safety (see IB), 1400 mg Q4W dosing was selected as the highest dose 
regimen for robust amyloid plaque lowering. Safety data from Study AACG 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 ARIA-E, ARIA-H and hypersensitivity 
reactions, and the overall frequency, severity, and seriousness of AEs at this dose level. 
A titration schedule of 700 mg IV Q4W for the first 3 doses and then 1400 mg IV Q4W was 
chosen to decrease the risk of ARIA-E. 
Participants randomized to the aducanumab arm will receive approved-label dosing for 
aducanumab. 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit or the last scheduled procedure shown in the SoA. 
 

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Protocol number I5T-MC-AACN(b) 
30 
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: 
Age 
1. Participant must be 50 to 85 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Gradual and progressive change in memory function reported by the participant or 
informant for ≥6 months. 
3. Meet florbetapir F18 PET scan criteria.  
4. A Clinical Dementia Rating (CDR)-Global Score of 0.5 or 1. 
5. An MMSE score between 20 and 30 (inclusive). 
6. Must consent to apolipoprotein E (ApoE) genotyping. 
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 on all days the C-SSRS is administered and must be present at screening for the 
completion of the CDR. Other visits 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 
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. 
Sex and Contraceptive/Barrier Requirements 
10.  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. 

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Protocol number I5T-MC-AACN(b) 
31 
b. Female participants. 
a. Women not of childbearing potential (defined in Appendix 4, Section 10.4) 
may participate. 
Informed Consent 
11. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
12. 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, 
history of transient ischemic attack or stroke, or epilepsy or recurrent seizures (except 
febrile childhood seizures). 
13. Current serious or unstable medical illnesses including cardiovascular, hepatic, renal, 
gastroenterologic, respiratory, endocrinologic, psychiatric (including actively suicidal or 
deemed at risk of suicide, or current alcohol or substance abuse), immunologic, 
infectious, 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 approximately 
≤24 months. 
14. History of clinically significant multiple or severe drug allergies, or severe posttreatment 
hypersensitivity reactions (including but not limited to erythema multiforme major, linear 
immunoglobulin A dermatosis, toxic epidermal necrolysis, and/or exfoliative dermatitis). 
15.  History of bleeding disorder or use of medications with platelet anti-aggregant or anti-
coagulant properties (unless aspirin at ≤325 mg daily). 
Imaging, Electrocardiograms, Laboratory Tests, and Physical Examination  
16. Have any clinically important abnormality at screening, as determined by the 
investigator, on physical or neurological examination, ECG, MRI, or clinical laboratory 
test results that could be detrimental to the participant, compromise study integrity, or 
show evidence of other etiologies for dementia. 
17. Have any contraindications for MRI, including claustrophobia or the presence of 
contraindicated metal (ferromagnetic) implants/cardiac pacemaker. 
18. 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. 
19. Contraindications to having a PET scan. 
20. Sensitivity to florbetapir F18 or flortaucipir F18. 
21. Poor venous access. 

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Protocol number I5T-MC-AACN(b) 
32 
22. 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. 
23. ALT ≥2.5X ULN of the performing laboratory, AST ≥2.5X ULN, TBL ≥1.5X ULN, or 
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’s 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 
24. Have known allergies to donanemab or aducanumab, related compounds, or any 
components of the formulation. 
25. Have had prior or current treatment with donanemab or aducanumab. 
Prior/Concurrent Clinical Study Experience 
26. Prior or current participation in any active or passive immunotherapy study targeting Aβ, 
unless documentation of receipt of placebo. 
27. Are currently enrolled in any other interventional clinical trial involving a study 
intervention or any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
28. Have participated, within the last 30 days, in any clinical trial involving a study 
intervention. Participation in observational studies may be permitted upon review of the 
observational study protocol and approval by the sponsor. 
Other Exclusions 
29. Are study personnel directly involved with the execution of this study, and/or their 
immediate families. Immediate family is defined as a spouse, parent, child, or sibling, 
whether biological or legally adopted. 
30. Are Lilly employees or are employees of TPOs directly involved in the 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 study intervention. 
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. 

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Protocol number I5T-MC-AACN(b) 
33 
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 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 SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.   
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant 
Not applicable. 

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Protocol number I5T-MC-AACN(b) 
34 
6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
Intervention Name 
donanemab 
aducanumab 
Dosage Level(s) 
700 mg IV Q4W for 
first 3 doses and 
then 1400 mg IV 
Q4Wa 
refer to PI/routine 
clinical practice 
Route of 
Administration 
IV infusion 
IV infusion 
Use 
experimental 
active-comparator 
Abbreviations: IV = intravenous; PET = positron emission tomography; PI = package insert; Q4W = once every 4 
weeks. 
a Participants randomized to donanemab whose amyloid plaque reduction as measured by florbetapir F18 PET scans 
at Visit 8 (Week 24) or Visit 15 (Week 52) meets criteria will stop donanemab infusions but continue all other 
assessments for the remaining duration of the open-label period and short-term follow-up period. These dose 
reduction rules are defined by the sponsor. 
Donanemab 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 
manual. 
Donanemab is to be administered once Q4W. Donanemab must not be administered at a dosing 
interval of <21 days at any time in the study. 
See Section 8.3.3.1 for infusion-related reactions. 
For aducanumab, it is expected that the investigator review appropriate product label/institutional 
guidelines for confirmation dosing (i.e., need for pre-medication, dose, schedule, toxicity 
management and dose modifications). 
Resuscitation equipment and rescue medications must be available wherever study intervention 
is administered. 
6.2. 
Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 

CONFIDENTIAL 
Protocol number I5T-MC-AACN(b) 
35 
intervention 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 are responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and 
final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study in which participants will be randomized in a 1:1 ratio to 
donanemab:aducanumab. 
For between-group comparability, participant randomization will be stratified by amyloid burden 
and ApoE ε4 status (noncarrier/heterozygous/homozygous). Any further stratification variables 
will be stated in the SAP. Assignment to treatment groups will be determined by a computer-
generated random sequence using an IWRS. Randomization into 1 stratum may be discontinued 
or overenrolled at the discretion of the sponsor to manage between-group comparability. 
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Before the study is initiated, the log in information & directions for the IWRS will be provided to 
each site. 
In order to maintain the scientific integrity of this trial, access to certain aspects of the study data 
will be strictly controlled prior to the potential interim analysis and testing of the primary and 
key secondary objectives. Access to the EDC system will be limited to those who require this 
information for their role and all access will be documented. 
For the primary efficacy analysis database, that is, the database to which study statisticians (Lilly 
and/or its designee) have access, measurements from post-baseline florbetapir F18 PET scans 
will be scrambled or masked to preclude the ability to conduct the primary efficacy analysis. 
Scrambled or masked florbetapir F18 PET measurements will be used in the reporting database 
until the interim analysis or the 6-month database lock, and the same procedures will also be 
utilized for the testing of the objectives associated with 12- and 18-month outcomes. 
In the event of an interim efficacy analysis assigned to the DMC, only the designated SAC, 
which is independent of the sponsor, will perform analyses on unblinded data, that is, the 
primary efficacy analysis database with correct treatment assignments. 
Further details are included in the study blinding plan. 
6.4. 
Study Intervention Compliance 
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of study intervention 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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Protocol number I5T-MC-AACN(b) 
36 
Any infusion at which 75% 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 (for 
example, due to technical complications), every effort should be made to complete the infusion 
within 24 hours of preparation. 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. 
Dose Modification 
Dose modification of donanemab is not permitted in this study except for participants whose 
amyloid plaque reduction meets criteria, as described in Section 4.1, and some instances of 
ARIA; if ARIA occurs during the titration period (that is, before the fourth infusion of 
donanemab), dose modification can be considered at the discretion of the investigator or 
designee as described in the Manual of Operations. If an ARIA-E and/or symptomatic ARIA-H 
event occurs, additional data should be provided to the sponsor in the ARIA Related Events 
CRF.  
Investigators should consult the aducanumab appropriate product label/institutional guidelines 
toxicity management and dose modifications. 
6.6. 
Continued Access to Study Intervention after the End of the Study 
Not applicable. 
6.7. 
Treatment of Overdose 
In the event of an overdose, the investigator or treating physician should: 
1. Contact the medical monitor immediately. 
2. Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted or whether the dose should be reduced. 
3. Closely monitor the participant for any AE/SAE. 
4. Obtain a plasma sample for analysis of study intervention 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. 
6.8. 
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 along with 
 reason for use 
 dates of administration including start and end dates, and 

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Protocol number I5T-MC-AACN(b) 
37 
 dosage information including dose and frequency. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1. 
Medications for Alzheimer’s Disease 
Use of approved or standard of care symptomatic treatments for AD is permitted during the 
study. When medically indicated, initiation, increase, or discontinuation of symptomatic 
treatments for AD is permitted. 
Disease-modifying prescription medications are not allowed at any time during the study. 
Nonmedication treatments for AD, such as behavioral management, are permitted. 
6.8.2. 
Medications for Infusion Reactions 
If an infusion reaction occurs, medications managing the reaction may be administered at the 
discretion of the investigator or designee, 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 or designee. 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. 
6.8.3. 
Excluded Medications 
IgG therapy (also known as gamma globulin or IVIG) is not allowed during the study. Use of 
medications with platelet anti-aggregant or anti-coagulant properties (unless aspirin at ≤325 mg 
daily) are not allowed during the study. 

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Protocol number I5T-MC-AACN(b) 
38 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant should remain in 
the study to be evaluated for safety and biomarker collection. See the SoA for data to be 
collected at the time of discontinuation of study intervention and follow-up and for any further 
evaluations that need to be completed. 
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study 
 by request of the participant or participant’s designee (for example, legal guardian) 
 based on a specific AE profile, the Medical Monitor, or the study sponsor 
physician/scientist, in discussions with the Principal Investigator 
 incorrect enrollment 
 severe noncompliance to the study protocol in the judgment of the investigator 
 systemic hypersensitivity reaction suspicious for an anaphylactic reaction or angioedema 
 participant requires an excluded therapeutic agent 
 based on investigator clinical judgment 
 participants answered ‘yes’ to Question 4 or 5 on the ‘Suicidal Ideation’ portion of the 
C-SSRS, or 
 participants answered ‘yes’ to any of the suicide-related behaviors on the Suicidal 
Behavior portion of the C-SSRS. 
o a psychiatrist or appropriately trained professional may assist in the decision to 
discontinue the participant for C-SSRS responses. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Participants who are discontinued from study intervention due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via the CRF. 
Discontinuation of the study intervention 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 INR >1.5   
 ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
 ALP >3X ULN  

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Protocol number I5T-MC-AACN(b) 
39 
 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%)  
7.1.2. 
QTc Stopping Criteria 
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. 
7.1.3. 
Amyloid-Related Imaging Abnormalities (ARIA) 
The development of ARIA-E and/or ARIA-H (microhemorrhages and/or cSS) are expected 
events and occur more commonly on treatment with donanemab and aducanumab. 
While most cases of ARIA-E are asymptomatic, serious cases have been reported. Available data 
for donanemab suggest serious cases are most likely to occur early in dosing, after the first, 
second, or third infusion. For aducanumab, enhanced clinical vigilance for ARIA is 
recommended during the first 8 doses of treatment, particularly during titration. 
ARIA-E 
For asymptomatic mild-to-moderate ARIA-E, study intervention may be continued and 
participants may be monitored with unscheduled MRIs at the investigator’s discretion. 
If a participant develops ARIA-E to an extent deemed clinically significant by the investigator or 
designee, such as symptomatic ARIA-E or severe ARIA-E on imaging, then the investigator or 
designee may consider withholding study intervention (see Manual of Operations for temporary 
discontinuation guidance). The participant should be monitored for improvement by MRI(s) 
(fluid attenuation inversion recovery and T2* gradient-recall echo). Symptoms should be 
monitored in participants with symptomatic ARIA-E. Upon resolution of ARIA-E on imaging 
and resolution of associated symptoms, reinitiating study intervention can be considered by the 
investigator or designee. If resolution is not observed, participants should be permanently 
discontinued from study intervention, but continue other study activities (see Manual of 
Operations for permanent discontinuation guidance). 
If ARIA-E occurs during the titration period, dose modifications may be considered (see Manual 
of Operations). 
In the event of a finding of ARIA-E on MRI, the investigator is to complete the ARIA Related 
Events CRF regarding the presence or absence of symptoms related to the ARIA-E, and ARIA-E 
should be reported as an AE in the AE CRF. Information regarding symptoms attributed to the 
ARIA-E event should be entered in the ARIA Related Events CRF and should not be reported as 
AEs. 
ARIA-H 
See Manual of Operations for temporary and permanent discontinuation guidance. For new or 
increased number or severity of asymptomatic ARIA-H, in some circumstances, study 
intervention may be temporarily discontinued and participants monitored for related symptoms 

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Protocol number I5T-MC-AACN(b) 
40 
and with unscheduled MRIs at the investigator’s discretion. In the case of symptomatic ARIA-H, 
the investigator or designee should monitor for changes in symptoms and may consider 
withholding study intervention. Upon stabilization of ARIA-H and resolution of associated 
symptoms, reinitiating study intervention can be considered. If stabilization of imaging findings 
and resolution of associated symptoms is not observed, participants should be permanently 
discontinued from study intervention, but continue other study activities. 
In the event of symptomatic ARIA-H, the investigator is to complete the ARIA Related Events 
CRF regarding the symptoms related to the ARIA-H, and ARIA-H should be reported as an AE 
in the AE CRF. Information regarding symptoms attributed to the ARIA-H event should be 
entered in the ARIA Related Events CRF and should not be reported as AEs. 
7.1.4. 
Temporary Discontinuation 
Temporary discontinuation from study intervention treatment is allowed secondary to 
hospitalization, personal or exceptional circumstances, or to evaluate the study intervention 
impact on an uncertain AE.  
Study intervention may be restarted 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 the participant’s own request 
● at the request of the participant’s designee (for example, parents or legal 
guardian) 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study, or 
● if the participant, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent. 
Discontinuation is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation 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 from both the study intervention and the study at 
that time. 

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Protocol number I5T-MC-AACN(b) 
41 
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. 
7.3. 
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 or designee 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 investigational product. 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. 

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Protocol number I5T-MC-AACN(b) 
42 
8. 
Study Assessments and Procedures 
● Study procedures and their timing are summarized in the SoA. 
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● 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 
8.1.1. 
Biomarker Efficacy Measures 
Florbetapir F18 PET scan 
Change in amyloid burden (as assessed with florbetapir F18 PET by personnel blinded to 
treatment allocation) will be compared in donanemab and aducanumab-treated participants. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Vital Signs 
For each participant, vital signs measurements should be conducted according to the SoA 
(Section 1.3) and following the study-specific recommendations included in Manual of 
Operations for the study. 
8.2.2. 
Electrocardiograms 
For each participant, single 12-lead digital ECGs will be collected during the screening period, 
according to the SoA (Section 1.3) using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and QTc intervals. Refer to Section 7.1.2 for QTc withdrawal 
criteria and any additional QTc readings that may be necessary. 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. 
Electrocardiograms will 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 participant meets entry criteria at the relevant 
visit(s) and for immediate participant management, should any clinically relevant findings be 
identified. 

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Protocol number I5T-MC-AACN(b) 
43 
After enrollment, if a clinically significant increase in the 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 collection and any alert reports. 
8.2.3. 
Clinical Safety Laboratory Tests 
● See Appendix 2 for the list of clinical laboratory tests to be performed and 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 as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. 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 study intervention after the last dose of study intervention should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
○ 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. 
○ All protocol-required laboratory assessments, as defined in Appendix 2, must 
be conducted in accordance with the SoA, standard collection requirements, 
and laboratory manual. 
● 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 
(e.g., SAE or AE or dose modification), then report the information as an AE. 
8.2.4. 
Suicidal Ideation and Behavior Risk Monitoring 
Participants being treated with study intervention should be monitored appropriately and 
observed closely for SIB 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. Participants who experience signs of SIB should undergo a risk assessment. All 
factors contributing to SIB should be evaluated and consideration should be given to 
discontinuation of the study intervention. 

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Protocol number I5T-MC-AACN(b) 
44 
Baseline assessment of SIB and intervention-emergent SIB will be monitored during Study 
AACN using the C-SSRS. 
C-SSRS 
C-SSRS is a scale that captures the occurrence, severity, and frequency of SIB during the 
assessment period via a questionnaire. The scale was developed by the NIMH trial group for the 
purpose of being counterpart to the C-CASA categorization of suicidal events. 
8.2.5. 
Magnetic Resonance Imaging 
MRI 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. 
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. MRI scans are read locally and 
will be sent for analysis to a centralized MRI vendor (blinded to treatment allocation) 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 investigator as “does” or “does 
not” meet MRI eligibility criteria. 
Specific analyses of the scans, including assessments of ARIA-H and ARIA-E, 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 the 
investigator. 
8.2.6. 
Hepatic Safety Monitoring 
Close hepatic monitoring 
Laboratory tests (Appendix 6, Section 10.6), including ALT, AST, ALP, TBL, D. Bil, GGT, and 
CK, should be repeated within 48 to 72 hours to confirm the abnormality and to determine if it is 
increasing or decreasing, if one 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 

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Protocol number I5T-MC-AACN(b) 
45 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for participants 
with Gilbert’s syndrome) 
 
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, 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 lab 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 
one 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/symptomsa, 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/symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with Gilbert’s 
syndrome) 
 a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, and/or 
eosinophilia >5%. 

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46 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or CT scan). 
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-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 
blood 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. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN) 
 In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline on 2 
or more consecutive tests 
2. Elevated TBL to ≥ 2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
 In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
 In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline on 2 
or more consecutive blood tests 
4. Hepatic event considered to be a SAE 
5. Discontinuation of study drug due to a hepatic event  
Note: the interval between the two consecutive blood tests should be at least 2 days. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3: 
 AEs 
 SAEs 
 PCs 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 

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Protocol number I5T-MC-AACN(b) 
47 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or study (see Section 6.8.3). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial 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 8.3.4) 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). For PCs, the investigator is responsible for ensuring 
that follow-up includes any supplemental investigations as indicated to elucidate the nature 
and/or causality. Further information on follow-up procedures is provided in Appendix 10.3. 
8.3.1. 
Timing and Mechanism for Collecting Events 
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
with study 
procedures or 
occurring after 
receiving PET 
tracer 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE CRF  
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE CRF  
SAE paper 
form 

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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
SAEa – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
90 days after 
the last dose 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form  
N/A 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
Abbreviations: AE = adverse event; CRF = case reporting form; ICF = informed consent form; N/A = not 
applicable; PC = product complaint; PET = positron emission tomography; SAE = serious adverse event. 
a SAEs after study participation should not be reported unless the investigator deems them to be possibly related to 
study treatment or study participation. 

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8.3.2. 
Pregnancy 
Collection of pregnancy information 
Male participants with partners who become pregnant 
a. The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant 
is in this study. This applies only to male participants who receive study 
intervention. 
b. After learning of a pregnancy in the female partner of a study participant, the 
investigator will 
a. obtain a consent to release information from the pregnant female 
partner directly, and 
b. within 24 hours after obtaining this consent will record pregnancy 
information on the appropriate form and submit it to the sponsor. 
The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female participants who become pregnant 
a. The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial 
information will be recorded on the appropriate form and submitted to the 
sponsor within 24 hours of learning of a participant's pregnancy.  
b. The participant will be followed to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the sponsor. Generally, 
follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date. Any termination of pregnancy will be reported, 
regardless of gestational age, fetal status (presence or absence of anomalies) 
or indication for the procedure. 
c. While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will 
be reported as an AE or SAE.  
d. A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE 
and will be reported as such.  

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e. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as 
described in protocol Section 8.3.1. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may 
learn of an SAE through spontaneous reporting. 
f. Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention. If the participant is discontinued from the 
study, follow the standard discontinuation process and continue directly to the 
follow-up phase. The follow-up on the pregnancy outcome should continue 
independent of intervention or study discontinuation. 
8.3.3. 
Hypersensitivity Including Infusion-Related Reactions  
8.3.3.1. 
Management of Infusion-Related Reactions  
If a systemic hypersensitivity reaction occurs, additional data describing each sign or symptom 
should be provided to the sponsor in the Hypersensitivity, Anaphylactic, and Infusion-Related 
Reactions CRF. Participants who experience a systemic hypersensitivity, should have vital signs 
collected. 
Locations where study participants are receiving study intervention should have appropriately 
trained medical staff and appropriate resuscitation equipment and rescue measures. 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 2 or more organ systems (for example, 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 10.2.1. Tryptase and 
when applicable urine N-methylhistamine should be repeated in approximately 4 weeks (and 
prior to the next infusion, if applicable) to obtain post-event baseline. Laboratory results are 
provided to the sponsor via the central laboratory and are not needed for clinical management of 
the participant.  
8.3.3.2. 
Dosing Rechallenge and Premedication for Infusions 
Donanemab 
Premedication for dosing is not planned. Dosing rechallenge is contraindicated in participants 
that have experienced a suspected or possible anaphylactic reaction (for example, reaction 
involving 2 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, at the 
investigator’s discretion, the participant may continue to receive study intervention. The 
participant may be premedicated for subsequent doses at investigator’s discretion and according 
to local practice guidelines. Any premedication given will be documented as a concomitant 
therapy (Section 6.8). 
Aducanumab 

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Investigators should consult the product label and follow local practice. 
8.3.4. 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 
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 SAP. 
8.4. 
Pharmacokinetics 
a. Serum samples will be collected for measurement of serum concentrations of study 
intervention as specified in the SoA. 
b. The timing of sampling may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak plasma concentrations) to 
ensure appropriate monitoring. 
c. Instructions for the collection and handling of biological samples will be provided by 
the sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
d. Bioanalytical samples collected to measure study intervention will be retained for a 
maximum of 1 year following last participant 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. 
8.5. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics 
8.6.1. 
Apolipoprotein E Genotyping 
ApoE genotyping is a mandatory part of this study. Blood sampling for ApoE genotyping will be 
performed as shown in the SoA. Neither participants nor investigators will receive the genotype 
results unless there is a country-specific law or regulation that requires notification of the results. 
8.6.2. 
Whole Blood Samples for Pharmacogenetic Research 
A blood sample for DNA isolation will be collected from participants.  
See Appendix 5, Section 10.5 for information regarding genetic research and Appendix 1, 
Section 10.1.12 for details about sample retention and custody. 

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8.7. 
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 proteins, lipids, and other 
cellular elements. 
Serum and plasma, 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 study 
intervention, pathways associated with AD, mechanism of action of study intervention, 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 per Section 10.1.12. 
8.8. 
Immunogenicity Assessments 
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine antibody production against donanemab. Antibodies may be further characterized 
and/or evaluated for their ability to neutralize the activity of donanemab. To interpret the results 
of immunogenicity, a venous blood sample will be collected 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. 
Treatment-emergent ADAs are defined in Section 9.3.6.2. 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. 
Samples will be retained per Section 10.1.12. 
8.9. 
Health Economics 
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 

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9. 
Statistical Considerations 
The SAP will be finalized prior to first participant visit, and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints, including primary and key 
secondary endpoints. 
9.1. 
Statistical Hypotheses 
The primary objectives of this study are to demonstrate that donanemab is superior to 
aducanumab in achieving complete brain amyloid plaque clearance at 6 months in the overall  
population and the intermediate tau subpopulation. These two objectives will be considered as 
co-primary, with the 6-month test occurring when all participants have had a chance to receive 
their 6-month amyloid PET scan. 
The parameters of interest for the primary analyses (for both ITT and the intermediate tau 
subpopulation) are: 
 pdona,6m: the probability that a participant will achieve complete brain amyloid clearance 
at 6 months under the donanemab treatment regimen. 
 padu, 6m: the probability that a participant will achieve complete brain amyloid clearance at 
6 months under the aducanumab treatment regimen. 
Odds ratio:  OR6m = [(pdona,6m)/(1- pdona,6m)]/[(padu,6m)/(1- padu,6m)] 
                       
The null and alternative (1-sided) hypotheses to be tested are: 
 H0: OR6m = 1 
 HA: OR6m > 1 
The odds ratio for the overall population and for the intermediate tau subpopulation will be 
estimated using logistic regression models as described in Section 9.3. The analyses of the two 
primary end points and the key secondary endpoints will be controlled to be under a 2-sided 
Type 1 error rate of 5%, or equivalently, a 1-sided rate of 2.5%. The details regarding the testing 
scheme for these analyses will be described in the SAP.  
9.2. 
Analyses Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Full analysis set / ITT 
analysis set 
All randomized participants with baseline and at least one post-
baseline amyloid PET scan. Participants will be included in the 
analyses according to the planned intervention. 
Intermediate tau set 
All randomized participants with baseline and at least one post-
baseline amyloid PET scan and a baseline flortaucipir F18 PET 
scan meeting the intermediate tau criteria.  

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Participant Analysis Set 
Description 
Safety analysis set 
All participants who are exposed to study intervention. 
Participants will be analyzed according to the intervention they 
actually received. 
The full analysis and intermediate tau sets are used to analyze endpoints related to the amyloid 
plaque objectives and the safety analysis set is used to analyze the endpoints and assessments 
related to safety. 
9.3. 
Statistical Analyses 
9.3.1. General Considerations 
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 
Unless otherwise noted, 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. 
A suitable approach such as Bretz’s graphical approach may be utilized to provide strong control 
of the study wise Type I error rate for the primary and key secondary hypotheses at an alpha 
level of 0.05 (Bretz et al. 2009; Bretz et al. 2011). Details on the graphical approach and testing 
strategy will be specified in the SAP prior to the first participant visit. 
All amyloid plaque analyses will follow the ITT principle unless otherwise specified. An ITT 
analysis is an analysis of data by the groups to which participants are assigned by random 
allocation, even if the participant 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, participants 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. 
To allow for sequential testing, database locks and the testing of corresponding primary and key 
secondary objectives are expected to occur after all randomized participants have had a chance to 
complete the scheduled 24-week PET scan, the scheduled 52-week PET scan, and the scheduled 
76-week PET scan. Data collected during the immunogenicity and safety follow-up period will 
be summarized and analyzed separately. 
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 SAP and the clinical study report. Additional exploratory analyses of the data will be 
conducted as deemed appropriate. 
The SAP will be finalized prior to first participant visit and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a summary 

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of the planned statistical analyses of the most important endpoints including primary and key 
secondary endpoints.  
9.3.1.1. 
Handling of Missing Data for Efficacy Endpoints 
For most efficacy endpoints, participants will be included in the analysis only if baseline and at 
least one post-baseline measurement are available. For most endpoints analyzed after the 6 
month database lock, participants will be included only if both baseline and post-baseline 
measurements are available. For analyses on endpoints at 12 or 18 months, only participants with 
baseline and at least one post-baseline measurements will be included and will be analyzed 
within the framework of the repeated measures models as detailed in the analyses. Sensitivity 
analyses for endpoints including last observation carried forward or other imputation-based 
techniques for handling missing data may be considered and will be detailed in the SAP. 
9.3.2. 
Treatment Group Comparability 
9.3.2.1. 
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. 
When a participant discontinues from the study, the reason(s) will be collected and will be 
summarized by treatment group for all randomized participants. The percentage of participants 
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. 
9.3.2.2. 
Participant Characteristics 
The participant’s age, sex, race, height, body weight, body mass index (weight (kg)/[height 
(m)]2), ApoE ε4 genotype, MMSE, CDR-global score, and having 1 or more first degree 
relatives with AD at baseline will be recorded. 
Baseline characteristics will be summarized by treatment group and the overall population.  
Summaries will include descriptive statistics for continuous and categorical measures. Fisher’s 
exact test or Pearson’s chi-square test will be used for treatment group comparisons of 
categorical data. For continuous data, analysis of variance, with independent factors for 
treatment and investigator, will be used. 
9.3.2.3. 
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. 
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. 

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Summary tables will also be provided for concomitant anticholinergics that affect cognitive 
function and acetyl-cholinesterase-inhibitor/memantine medications. 
Medications will be coded using the World Health Organization drug dictionary. 
9.3.2.4. 
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. 
9.3.3. 
Primary Analyses 
Proportion of Participants with Amyloid Plaque Clearance at 6 months 
The primary objective of this study is to test the hypothesis that participants treated with 
donanemab will have a significantly greater proportion of participants who reach amyloid plaque 
clearance compared to participants treated with aducanumab at the 6-month timepoint in both the 
ITT population and the intermediate tau subpopulation. 
As the 6-month timepoint is the first scheduled opportunity to collect a post-baseline florbetapir 
F18 PET scan, the comparison of donanemab to aducanumab in complete brain amyloid 
clearance at 6 months will be performed using logistic regression. The logistic regression model 
will include fixed effect for treatment, ApoE ε4 genotype, and baseline amyloid level. The test 
for this endpoint will be based on the contrast for the main effect of treatment from this logistic 
regression model. Treatment effects will be presented using odds ratios and 95% confidence 
intervals. This analysis will be conducted on the full ITT population and the intermediate tau 
subpopulation. 
9.3.4. 
Secondary Analyses 
The mean change from baseline in amyloid plaque levels at months 6, 12, and 18, and the time to 
amyloid plaque clearance are the four key secondary endpoints. It is expected that these 
endpoints will be analyzed sequentially as data for them are available. That is, for any efficacy 
analyses for 6-month/12-month/18-months endpoints, data will be available at baseline and for 
all timepoints up to and including the time point in question.  
9.3.4.1. 
Mean Change from Baseline in Amyloid Plaque 
Consequently, mean change from baseline in amyloid plaque levels at Month 6 will be analyzed 
using an analysis of covariance method with the treatment group as fixed effect variable of 
interest, and APOE e4 genotype, and baseline amyloid levels as the covariates. For the analysis 
of mean change from baseline at 12 and 18 months, a separate mixed model repeated measures 
(MMRM) analysis with data up to that specific time point will be used. This model will include 
the fixed effects of treatment, time, and treatment by time interaction, and APOE e4 genotype, 
and baseline amyloid level as covariates. Correlation among repeated measures on the same 
subject will be accounted for by enforcing an unstructured variance covariance matrix among the 
residuals. If the unstructured covariance structure matrix results in a lack of convergence, the 
following structures will be used in sequence until convergence is reached: heterogeneous 

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Toeplitz covariance structure, heterogeneous autoregressive covariance structure, heterogeneous 
compound symmetry covariance structure, and compound symmetry covariance structure. The 
Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. 
9.3.4.2. 
Time to Amyloid Plaque Clearance 
Time to amyloid plaque clearance between the two treatment groups will be analyzed and 
compared using a log-rank test for survival data. Time to amyloid plaque clearance is defined as 
the earliest time (6/12/18 months) at which the participant reaches plaque levels below a certain 
pre-defined threshold. Subjects who do not have their plaque cleared by the end of the study 
period or those who drop out prior to the end of the study without achieving amyloid plaque 
clearance will be censored at their last available time point. Kaplan-Meier estimates of percent of 
patients reaching amyloid plaque clearance and p-value from the log-rank test will be used to 
determine the superiority of donanemab vs aducanumab in lowering time to plaque clearance. 
Additionally, time to plaque clearance may also be analyzed using a Cox proportional-hazards 
model. More details on these analyses will be provided in the SAP as appropriate. 
9.3.4.3. 
Proportion of Participants with Amyloid Plaque Clearance 
The 12-month and 18-month comparison of proportion of participants with amyloid plaque 
clearance for donanemab versus aducanumab will include repeated post-baseline amyloid plaque 
clearance status (Yes/No) measurements and will be analyzed using separate generalized linear 
mixed model (PROC GLIMMIX) as pseudo-likelihood-based mixed effects repeated measures 
analysis assuming binomial distribution with a logit link. These models will be analyzed using 
data for outcomes up to and including the time point in question. The GLIMMIX model will 
include fixed effects for treatment, month, treatment-by-month interaction, APOE e4 genotype, 
and baseline amyloid level as covariates. An unstructured variance-covariance matrix will be 
used to model the correlation among repeated measures on the same individual. If model 
convergence is not reached, as planned for the MMRM analyses, lesser restrictive variance-
covariance structures will be employed until model convergence is attained. 
9.3.4.4. 
Other Outcomes 
Analyses of other secondary outcomes such as mean percent change in amyloid levels from 
baseline at 6, 12, and 18 months, non-inferiority of donanemab at 6 months versus aducanumab 
at 12 and 18 months with respect to mean change from baseline in amyloid levels, superiority of 
donanemab at 6 months vs aducanumab at 12 months, will be done using the appropriate models 
for continuous and binary outcomes for repeated or non-repeated data as specified above. 
Treatment effects will be estimated using least squares mean differences or odds ratios along 
with 95% confidence intervals using appropriate contrasts for the treatment main effect or the 
treatment by time interaction effects from statistical models described above. Further details on 
analyses for other secondary or exploratory outcomes including defining margins for non-
inferiority analyses will be described in the SAP. 
9.3.5. 
Other Safety Analyses 
All safety analyses will be made on the safety population. Refer to the SAP for additional details. 

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9.3.6. 
Other Analyses 
9.3.6.1. 
Pharmacokinetics Analyses 
Data from this study may be combined with data from other studies to better characterize the PK 
of donanemab, as well as to explore the relationship between exposure and efficacy and/or safety 
outcomes. In this case, a separate PK analysis plan will be developed, and the results of these 
analyses will be described in a separate PK report. 
9.3.6.2. 
Evaluation of Immunogenicity 
The frequency and percentage of participants with preexisting ADA and with TE-ADA to 
donanemab may be tabulated. 
Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA) or 
those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA). 
The frequency of neutralizing antibodies may also be tabulated in TE ADA+ participants. 
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to donanemab may be assessed. 
9.3.6.3. 
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 (CUIMC 
2016). 
9.4. 
Interim Analysis  
An interim analysis may occur for an early efficacy assessment of the primary objective. The 
timing of the interim analysis may occur when a sufficient number of participants (for example, 
approximately 75-125) have had a chance to receive their 6-month amyloid PET scan. 
Regardless of the result of the interim analysis, the study will continue in order to assess the 12- 
and 18-month objectives. 
If the interim analysis is deemed not necessary to be conducted by the sponsor, the primary 
efficacy analysis will be conducted when all participants have had a chance to receive their 6-
month amyloid PET scan. The SAP and blinding plan will describe the potential to conduct an 
interim analysis in greater detail as well as the testing scheme and alpha spending function to 
control the Type-I error should the interim be performed. If the interim analysis is conducted, the 
analysis will be executed through an external DMC. 
9.5. 
Sample Size Determination 
Approximately 200 participants will be enrolled and randomized in a 1:1 ratio to the 2 treatment 
regimens (donanemab and aducanumab). It is expected that approximately 180 participants will 
complete 6-month florbetapir F18 PET scans (approximately 90 per treatment regimen).  It is 

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further anticipated that approximately 50% of participants randomized will belong to the 
intermediate tau subpopulation. 
This sample size will provide at least 98% power to demonstrate that donanemab is superior to 
aducanumab in achieving complete amyloid brain plaque clearance individually at 6 months in 
the overall population and the intermediate tau subpopulation. Power estimates were obtained 
using specific contrasts for the 6-month time point of treatment by time interaction effect within 
the framework of generalized linear mixed effect model assuming a logit link. 
The assumptions for this power calculation are that 35.7%, 50.1%, and 54.6% of donanemab 
treated participants reach complete brain amyloid clearance at 6 months, 12 months, and 18 
months, respectively. The corresponding complete brain amyloid clearance percentages for 
aducanumab treated participants are assumed to be 3.0%, 22.8%, and 27.8%, respectively. The 
simulation for the power calculation and sample size determination was carried out in SAS 
Enterprise Guide Version 7.15 and all sample size estimates were obtained assuming a 2-sided 
significance level of 0.05. 

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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: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and CIOMS International Ethical Guidelines 
○ Applicable ICH GCP Guidelines 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (for example, 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. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ 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 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ 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 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators 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 

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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 the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participant or the participant’s 
legally authorized representative and answer all questions regarding the study. 
● Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representatives will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, privacy and data protection requirements, where applicable, and 
the IRB/IEC or study center. 
● 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 is kept on file. 
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 the participant’s 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 their 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. 
● The sponsor has processes in place to ensure data protection, information security 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
10.1.5. 
Committees Structure 
A DMC consisting of members external to Lilly will be established. The purpose of the 
establishment of the DMC is for the potential to conduct an early efficacy analysis for Study 
AACN. If the interim analysis is not deemed necessary to be conducted by the sponsor, the DMC 
will not be convened to review study data. The DMC will consist of a minimum of 3 members, 

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Protocol number I5T-MC-AACN(b) 
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including a physician with expertise in AD and a statistician. No member of the DMC will 
influence study sites. A 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 
study. Further details of the DMC will be described in a DMC charter. 
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, SAP, 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.vivli.org. 
10.1.7. 
Data Quality Assurance 
● All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (for example, 
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. 
● QTLs will be pre-defined to identify systematic issues that can impact participant 
safety and/or reliability of study results. These pre-defined parameters will be 
monitored during the study and important excursions from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
● Monitoring details describing strategy (for example, 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. 

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● The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
● 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 the time period outlined in the CTA 
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, 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 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 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) and other data will be 
collected by the participant/caregiver/authorized study personnel, via a paper source document 
and will be transcribed by the authorized study personnel into the EDC system. 
Data collected via the sponsor-provided data capture system(s) will be stored (at third parties). 
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 or access 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/electronic transfers will be provided to the 
investigator for review 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. 

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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 or entered in the CRF and 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. 
● Definition of what constitutes source data can be found in Section 10.1.7. 
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
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 signed ICF and will be the study start date. 
Study or Site Termination 
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: 
For study termination: 
 Discontinuation of further study intervention development 
For site termination: 
 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 (evaluated after a reasonable amount of time) of 
participants by the investigator 
 Total number of participants included earlier than expected. 
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. 

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10.1.10. 
Publication Policy 
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information 
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
10.1.12. 
Sample Retention 
Sample retention 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 the 
study intervention. 
Sample Type 
Custodian 
Retention Period 
After Last Participant 
Visita 
Biomarkers 
Sponsor or Designee 
15 years 
PK 
Sponsor or Designee 
1 year  
Genetics 
Sponsor or Designee 
15 years 
Immunogenicity (ADA) 
Sponsor or Designee 
15 years 
Abbreviations:  ADA = anti-drug antibody; PK = pharmacokinetic. 
a Max potential retention unless local requirements differ. 
  
 
 

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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). 
 Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be recorded. 
 In circumstances where the sponsor approves local laboratory testing in lieu of 
central laboratory testing (in the table below), the local laboratory must be 
qualified in accordance with applicable local regulations. 
 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 required by local regulations. 
 Investigators must document their review of the laboratory safety results. 
Clinical Laboratory Tests 
Comments 
Hematology 
Assayed by Lilly-designated laboratory 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs - Red Blood Cells) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Leukocytes (WBCs - White Blood Cells)  
  
Differential 
  
   Neutrophils, segmented 
   Lymphocytes 
  
   Monocytes 
  
   Eosinophils 
  
   Basophils 
  
Platelets 
  
Cell morphology (RBCs and WBCs) 
  
  
  
Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
Total bilirubin 
  

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Clinical Laboratory Tests 
Comments 
Direct bilirubin 
  
Alkaline phosphatase (ALP) 
  
Alanine aminotransferase (ALT) 
  
Aspartate aminotransferase (AST) 
  
Gamma-glutamyl transferase (GGT) 
  
Blood urea nitrogen (BUN) 
  
Creatinine  
  
Creatine kinase (CK) 
  
Uric acid 
  
Albumin 
  
Calcium 
  
Glucose 
  
Cholesterol  
  
  
  
PK Samples – donanemab and aducanumab 
concentration 
Assayed by Lilly-designated laboratory.   
Results will not be provided to the investigative sites. 
 
 
Biomarkers 
Additional Testing 
Assayed by Lilly-designated laboratory. 
 
Apolipoprotein E (ApoE) 
Results will not be provided to the investigators. 
 
 
Genetics Sample 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigators. 
  
  
Exploratory Biomarker Storage Samples 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigators. 
   Serum 
  
   Plasma (EDTA) 
  
 
 
Immunogenicity (ADA) Samples 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigators. 
   Anti-donanemab antibodies  
  
   Anti-donanemab antibodies neutralization  
  
 
 
 
10.2.1. 
Clinical Laboratory Tests for Hypersensitivity Events  
 Laboratory assessments should be performed if the participant experiences 
generalized urticaria or if anaphylaxis or angioedema is suspected. 

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 Collect sample after the participant has been stabilized, and within 1 to 2 hours of 
the event; however, samples may be obtained as late as 12 hours after the event as 
analytes can remain altered for an extended period of time. Record the time at 
which the sample was collected. 
 Sample should be repeated in approximately 4 weeks (and prior to the next 
infusion, if applicable) to obtain post-event baseline. 
The table below summarizes the laboratory parameters that will be evaluated. These laboratory 
tests are bundled in the hypersensitivity laboratory testing kit. 
Hypersensitivity Tests 
Notes 
Selected test may be obtained in the event of anaphylaxis or systemic 
allergic/hypersensitivity reactions. 
   donanemab  ADAs 
(immunogenicity/ADA) 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigators. 
   donanemab  concentrations 
(PK) 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigators. 
   Tryptase 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigators. 
Note:  
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. 
If a tryptase sample is obtained more than 2 hours after the event (that is, 
within 2 to 12 hours), or is not obtained because more than 12 hours have 
lapsed since the event, obtain urine sample for N-methylhistamine testing. Note 
that for tryptase serum samples obtained within 2 to 12 hours of the event, 
urine N-methylhistamine testing is performed in addition to tryptase testing. 
Collect the first void urine sample following the event. Tryptase and when 
applicable urine N-methylhistamine should be repeated in approximately 4 
weeks (and prior to the next infusion, if applicable) to obtain post-event 
baseline. 
   N-methylhistamine 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigators. 
   Drug-specific IgE 
Will be performed if a validated assay is available. 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigators. 
   Basophil activation test 
Will be performed if a validated assay is available. 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigators. 
Note: The basophil activation test is an in vitro cell-based assay that only 
requires a serum sample. It is a surrogate assay for drug-specific IgE but is not 
specific for IgE. 

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Abbreviations: ADA = antidrug antibody; IgE = immunoglobulin E; IL = interleukin; PK = pharmacokinetic.
   Complement (C3, C3a, and 
C5a) 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigators. 
   Cytokine panel (IL‐6, IL‐
1β, and IL‐10) 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigators. 

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Protocol number I5T-MC-AACN(b) 
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10.3. 
Appendix 3: Adverse Events and Serious 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 administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention 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 study 
intervention 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 or 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 AE or SAE if they fulfill the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 

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 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. 
 Medical or surgical procedure (for example, 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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
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 hospital or 
emergency ward (usually involving at least an overnight stay) 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 pre-existing 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 (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 

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e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator 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. 
Definition of Product Complaints 
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints 
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 

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 The investigator will then record all relevant AE/SAE/PC information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and PC 
information is reported on the PC Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the PC Form for PCs. 
 There may be instances when copies of medical records for certain cases are requested 
by 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 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: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with a 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. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship 

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 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. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, in their 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 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 Sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send a 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 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 Sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5. 
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 SAE paper form (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. 

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 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 SAE paper form (see next 
section) or to the medical monitor by telephone. 
 Contacts for SAE reporting can be found in site training material. 
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the medical monitor. 
 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 in site training material. 
10.3.6. 
Regulatory Reporting Requirements 
SAE Regulatory Reporting 
● 
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention 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 a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, 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 then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements. 
 
 

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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions
Word/Phrase 
Definition 
WOCBP 
Females are considered a WOCBP if 
 
they have had at least one cycle of menses, or 
 
they have Tanner 4 breast development. 
 
Any amount of spotting should be considered menarche.  If Tanner Staging of 
breasts is performed as part of study procedures, please refer to the Reproductive, 
Pregnancy and Pediatrics Safety Committee Safety Guidance for Children in 
Clinical Trial regarding Tanner staging. 
Women not of 
child bearing 
potential 
Females are considered women not of child bearing potential if 
 
they have a congenital anomaly such as Mullerian agenesis,  
 
they are infertile due to surgical sterilization, or  
 
they are post-menopausal. 
 
Examples of surgical sterilization include:  hysterectomy, bilateral oophorectomy, 
tubal ligation. 
Post-menopausal 
state 
The post-menopausal state should be defined as: 
1. A woman at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or  
2. A woman at least 40 years of age and up to 55 years old with an intact 
uterus, not on hormone therapy*, who has had cessation of menses for at 
least 12 consecutive months without an alternative medical cause, AND  
With a follicle-stimulating hormone >40 mIU/mL; or  
3. A woman 55 or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea, or 
4. A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy 
 
* Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
selective estrogen receptor modulators (SERMs), or chemotherapy that could 
induce transient amenorrhea. 
Reproductive 
Toxicology 
Studies 
Embryo-fetal studies are toxicity studies in pregnant animals designed to identify 
abnormalities in the development of fetuses, which could indicate potential for 
teratogenicity in humans.  The relevant dosing period is during organogenesis. 
 
10.4.2. 
Contraception Guidance 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
 
 
 

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10.5. 
Appendix 5: Genetics 
Use/Analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to donanemab or AD and related 
diseases. They may also be used to develop tests/assays including diagnostic tests 
related to donanemab or other amyloid targeting interventions and AD. Genetic 
research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome (as appropriate). 
● DNA samples will be analyzed for pharmacogenetic research. 
● The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to donanemab or study interventions of this class 
to understand study disease or related conditions. 
● The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
● The samples will be retained while research on donanemab or other amyloid 
targeting interventions continues but no longer than 15 years or other period as 
per local requirements. 
 
 

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Protocol number I5T-MC-AACN(b) 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
10.6.1. 
Hepatic Evaluation Testing 
See Section 8.2.6 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed, in addition to central testing, when necessary for evaluation and 
immediate participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 

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Protocol number I5T-MC-AACN(b) 
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    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA)a 
    HBV DNAd 
Anti-actin antibodyb 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNAd 
    EBV DNAd 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNAd 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNAd 
    HSV (Type 1 and 2) DNAd 
Microbiologyc 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
 
    Blood 
 
    Urine 
 
a Not required if anti-actin antibody is tested. 
b Not required if anti-smooth muscle antibody is tested. 
c Assayed ONLY by investigator-designated local laboratory; no central testing available. 
d Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
 
 

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Protocol number I5T-MC-AACN(b) 
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10.7. 
Appendix 7: Flortaucipir F18 PET Imaging 
Flortaucipir F18 PET scan will be performed after eligibility is established (Section 1.3). 
No results will be provided to site investigators, participants, and study partners for the 
flortaucipir F18 scans. 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 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. 
The table below shows the effective radiation dose of the Study AACN’s PET scans. 
 
Effective 
Dose (mSv) 
per Scana 
Number of 
Scans in First 
Yearb 
Effective Dose 
(mSv) for 
Scans in First 
Year 
Number of 
Scans in 
Second 
Yearb 
Effective Dose 
(mSv) for 
Scans in 
Second Year 
Sum of 
Effective 
Dose (mSv) 
for Years 1 
and 2 
Flortaucipir 
F18 Scan 
(10 mCi IV) 
9.10 
1 
9.10 
0 
0 
9.10 
Florbetapir 
F18 Scan 
(10 mCi IV) 
7.43 
2 
14.86 
2 
14.86 
29.72 
Totals 
 
3 
23.96 
2 
14.86 
38.82 

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Abbreviations:  CT = computerized tomography; ED = early discontinuation; IV = intravenous infusion; 
PET = positron emission tomography. 
a 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. 
b In the event of an ED scan, up to 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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Protocol number I5T-MC-AACN(b) 
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10.8. 
Appendix 8:  Florbetapir F18 PET Imaging 
Florbetapir F18 PET scans will be performed as part of the study eligibility criteria to determine 
participant eligibility for participation in Study AACN. Additional florbetapir F18 PET scans 
will be performed as indicated in the SoA (Section 1.3). 
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 in Appendix 7 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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Protocol number I5T-MC-AACN(b) 
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10.9. 
Appendix 9:  CDR and MMSE 
10.9.1. 
CDR 
The CDR-SB (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 semistructured 
and in-depth interview with both the affected individual and their study partner. The study 
partner and participant must be interviewed separately. This scale demonstrates acceptable 
psychometric characteristics (Coley et al. 2011; Cedarbaum 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). 
10.9.2. 
MMSE 
The MMSE is a brief instrument used to assess cognitive function in patients (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. 
 
 

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Protocol number I5T-MC-AACN(b) 
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10.10. Appendix 10: Abbreviations and Definitions 
Term 
Definition 
Aβ 
Amyloid beta 
AChEI 
acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
ApoE 
Apolipoprotein E 
ARIA 
Amyloid-related imaging abnormalities 
AST 
aspartate aminotransferase 
C-CASA 
Columbia Classification Algorithm of Suicide Assessment 
CDR 
Clinical Dementia Rating 
CDR-SB 
CDR-Sum of Boxes 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine kinase 
COA 
clinical outcome assessment 
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, good clinical practice (GCP), and applicable regulatory 
requirements. 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
cSS 
cortical superficial siderosis 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 

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Protocol number I5T-MC-AACN(b) 
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CTA 
Clinical Trial Agreement 
D. Bil 
direct bilirubin 
DNA 
deoxyribonucleic acid 
DMC 
data monitoring committee. A data monitoring committee, or data monitoring board 
(DMB) is a group of independent scientists who are appointed to monitor the safety and 
scientific integrity of a human research intervention, and to make recommendations to 
the sponsor regarding the stopping of a study for efficacy, or for harms, or for futility. 
The composition of the committee is dependent upon the scientific skills and 
knowledge required for monitoring the particular study. 
ECG 
Electrocardiogram 
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 informed consent form directly 
or through their legally acceptable representatives. 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GGT 
Gamma-glutamyl transferase 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
informed consent 
A process by which a participant voluntarily confirms their 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 informed consent form. 
INR 
international normalized ratio 
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. 

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Protocol number I5T-MC-AACN(b) 
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IVIG 
intravenous immunoglobulin 
IRB 
Institutional Review Board 
ITT 
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a 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 
IWRS 
interactive web-response system 
MCI 
Mild cognitive impairment 
MMSE 
Mini-Mental State Examination 
MRI 
Magnetic resonance imaging 
NIMH 
National Institute of Mental Health 
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 
PC 
product complaint 
PD 
pharmacodynamics 
PET 
positron emission tomography 
PI 
package insert 
PK 
pharmacokinetics 
PT-INR 
Prothrombin time – INR 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
Quality tolerance limit 
SAC 
Statistical Analysis Center 
SAE 
serious adverse event 
SAP 
statistical analysis plan 

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Protocol number I5T-MC-AACN(b) 
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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.  
SIB 
Suicidal ideation and behavior 
SoA 
Schedule of activities 
TBL 
Total bilirubin level 
TE 
Treatment-emergent 
TPOs 
Third-party organizations 
ULN 
Upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
WOCBP 
Women of childbearing potential 
 
 

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Protocol number I5T-MC-AACN(b) 
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10.11. 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment a: (11-Oct-2021) 
 
Overall Rationale for the Amendment: 
This amendment allows for better characterization of the incidence and severity of ARIA at an 
earlier time point. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3. Schedule of 
Activities 
Modified “Weeks relative to 
randomization first infusion”. 
Clarification. Visits should be scheduled 
in relation to the first IP infusion. 
  
Changed V3 interval tolerance 
from “±7” days to “7 to +10” 
days. 
To provide additional time to perform and 
review MRI prior to infusion. 
 
Added line to collect weight 
for aducanumab participants. 
Aducanumab uses weight-based dosing. 
Weight is not recorded in the CRF. 
 
Added MRI at V3. Added text 
to the Comments 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. 
6.5. Dose 
Modification 
Modified description of 
ARIA events in relation to 
dose modification and 
providing data for the ARIA 
Related Events CRF. 
Clarification. 
6.8.1. Medications 
for Alzheimer’s 
Disease 
Added “When medically 
indicated, initiation, increase, 
or discontinuation of 
symptomatic treatments for 
AD is permitted.” 
Clarification. 
7.1.3. Amyloid-
Related Imaging 
Abnormalities 
(ARIA) 
Added note “While most 
cases of ARIA-E are 
asymptomatic, serious cases 
have been reported. Available 
data suggest serious cases are 
most likely to occur early in 
To provide additional information. 

CONFIDENTIAL 
Protocol number I5T-MC-AACN(b) 
89 
Section # and 
Name 
Description of Change 
Brief Rationale 
dosing, after the first, second, 
or third infusion.” 
 
Added cross-references to the 
Manual of Operations 
regarding information about 
temporary and permanent 
discontinuation guidance. 
To provide further guidance. 
 
Modified text regarding 
considerations related to 
reinitiating study 
intervention.. 
Recommendation of DMC. 
 
Added instructions to 
complete the ARIA Related 
Events CRF in the event of 
symptomatic ARIA-H. 
To provide instructions. 
8.2.5. Magnetic 
Resonance 
Imaging 
Added text to allow 
performance of unscheduled 
MRIs. 
Clarification. 
 
 
 

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Protocol number I5T-MC-AACN(b) 
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11. 
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