Investigating the Effect of Different Donanemab Dosing Regimens on ARIA-E and Amyloid Lowering in Adults With Early Symptomatic Alzheimer's Disease
Phase: PHASE3
Conditions: Alzheimer's Disease, Dementia, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Neurodegenerative Diseases, Neurocognitive Disorders, Mental Disorders
Sponsor: Eli Lilly and Company

Protocol Amendment I5T-MC-AACQ (a) 
Investigating the Effect of Different Donanemab Dosing Regimens on ARIA-E and 
Amyloid Lowering in Adults with Early Symptomatic Alzheimer's Disease
NCT05738486 
Approval Date: 26-May-2023

CONFIDENTIAL 
I5T-MC-AACQ(a) 
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:
Investigating the Effect of Different Donanemab Dosing Regimens on ARIA-E and Amyloid 
Lowering in Adults with Early Symptomatic Alzheimer’s Disease 
Protocol Number: I5T-MC-AACQ 
Amendment Number: a 
Compound: LY3002813 
Brief Title: 
Exploration of Different Donanemab Dosing Regimens 
Study Phase: 3b 
Acronym: TRAILBLAZER-ALZ 6 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s): 
IND: 109157 
EU trial number: 2022-502268-18-00 
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below. 
Document ID: VV-CLIN-114998 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
2 
Medical Monitor Name and Contact Information will be provided separately. 
 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
3 
Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
28-Oct-2022 
Amendment [a] 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The main rationale for the amendment is to clarify the chosen dosing regimens for treatment 
arms 3 and 4 and other minor corrections/clarifications as stated below.   
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Updated visit frequency to 
every 2 weeks for the first 10 
visits (V2-V10) and every 4 
weeks thereafter 
Correction per SoA 
Addition of “<5 half-lives 
prior to randomization” to an 
exclusion criterion about 
passive anti-amyloid 
immunotherapy 
Clarification 
1.2. Schema 
Revised schema to align with 
every 2 weeks visit frequency 
for V2-V10, updated footnote 
a to align with visit frequency 
Correction 
1.3. Schedule of Activities 
Period II – Q2W visit 
frequency 
Alignment with Q2W visit frequency for 
V2-V10 
Period III - Clarify that V801 
is not needed if more than 
12 weeks have passed since 
last dose of IP at V25 or study 
discontinuation  
Clarification 
1.3.2. Period II – Treatment Visits 
2-15 
Orthostatic BP and pulse are 
measured at V2, V8, V12, 
V15, and unscheduled visits, 
sitting BP, pulse, and 
temperature will be measured 
at all visits 
Clarification 
MRI notes edited to align with 
Q2W visit frequency 
Alignment with Q2W visit frequency for 
V2-V10 
Removed footnote a to align 
with Q2W visit frequency 
Alignment with Q2W visit frequency for 
V2-V10 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
4 
Section # and Name 
Description of Change 
Brief Rationale 
1.3.3. Period II – Treatment Visits 
16-25 
Amyloid PET scan note 
regarding ED visit revised to 3 
months from last amyloid 
PET scan 
Correction 
4.1.1. Treatment Arms and 
Titration Regimen Outline 
Treatment arms 3 and 4 
established; removal of 
treatment arms 3 option 2 and 
4 option 2 and the language 
around this 
Clarification 
Removed “only if donanemab 
Q2W dosing regimen is 
chosen; otherwise these visits 
will be skipped” 
Alignment with visit/dosing frequency 
4.3. Justification for Dose 
Built-in dosing pauses 
updated to align with current 
dosing regimens 
Clarification 
5.2. Exclusion Criteria 
Addition of “<5 half-lives 
prior to randomization” to 
Exclusion Criterion 22 
Clarification 
6.3. Assignment to Study 
Intervention 
Clarified stratification 
regarding PET scan results 
and APOE genotype 
Clarification 
8.2.1. Physical/Neurological 
Examinations 
Addition of “neurological” to 
align with SoA 
Correction to align with SoA 
8.2.2. Vital Signs 
Clarified vital signs, including 
temperature, will be measured 
at all visits 
Clarification 
Clarified sitting BP is 
measured at all visits 
Clarification 
Clarified orthostatic BP and 
pulse to be measured supine 
and standing 
Clarification 
8.2.5. Suicidal Ideation and 
Behavior Risk Monitoring 
Corrected C-SSRS to be 
administered at V2 per the 
SoA 
Correction to align with SoA 
Clarified study partner may be 
present in person or on phone 
for all days C-SSRS is 
administered 
Clarification 
8.4. Pharmacokinetics 
Addition of PK sample 
collection regarding IP 
discontinuation 
Clarification 
9.3.1. General Considerations 
Alignment with objective 
tables for 76 weeks 
(corresponding visit V25) 
assessment 
Editorial 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
5 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Minor editorial changes 
Clarification/editorial 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
6 
Table of Contents  
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema  ...........................................................................................................................13 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
1.3.1. 
Period I - Screening ........................................................................................................15 
1.3.2. 
Period II - Treatment Visits 2-15 ....................................................................................18 
1.3.3. 
Period II - Treatment Visits 16-25, the Early Discontinuation 
Visit, and Period III Posttreatment Follow-Up Visit 801 ...............................................22 
2. 
Introduction ...................................................................................................................25 
2.1. 
Study Rationale ...............................................................................................................25 
2.2. 
Background .....................................................................................................................25 
2.3. 
Benefit/Risk Assessment ................................................................................................26 
2.3.1. 
Risk Assessment .............................................................................................................26 
2.3.2. 
Benefit Assessment .........................................................................................................27 
2.3.3. 
Overall Benefit-Risk Conclusion ....................................................................................28 
3. 
Objectives, Endpoints, and Estimands .......................................................................29 
4. 
Study Design ..................................................................................................................31 
4.1. 
Overall Design ................................................................................................................31 
4.1.1. 
Treatment Arms and Titration Regimen Outline  ...........................................................31 
4.1.2. 
Study Partners .................................................................................................................31 
4.2. 
Scientific Rationale for Study Design ............................................................................32 
4.3. 
Justification for Dose ......................................................................................................32 
4.4. 
End of Study Definition ..................................................................................................33 
5. 
Study Population ...........................................................................................................34 
5.1. 
Inclusion Criteria ............................................................................................................34 
5.2. 
Exclusion Criteria ...........................................................................................................35 
5.3. 
Lifestyle Considerations .................................................................................................37 
5.4. 
Screen Failures ................................................................................................................37 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................37 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................38 
6.1. 
Study Intervention(s) Administered................................................................................38 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................39 
6.3. 
Assignment to Study Intervention ..................................................................................39 
6.4. 
Blinding ..........................................................................................................................39 
6.5. 
Study Intervention Compliance ......................................................................................40 
6.6. 
Dose Modification ..........................................................................................................40 
6.7. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................40 
6.8. 
Treatment of Overdose ...................................................................................................40 
6.9. 
Prior and Concomitant Therapy ......................................................................................41 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................43 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
7 
7.1. 
Discontinuation of Study Intervention ............................................................................43 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................44 
7.1.2. 
Temporary Discontinuation ............................................................................................44 
7.1.3. 
Rechallenge in Cases of Systemic Hypersensitivity or Infusion-
related Reactions .............................................................................................................45 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................45 
7.3. 
Lost to Follow up ............................................................................................................46 
8. 
Study Assessments and Procedures.............................................................................47 
8.1. 
Efficacy Assessments .....................................................................................................47 
8.1.1. 
Amyloid PET Scan .........................................................................................................47 
8.1.2. 
Screening Mini Mental State Examination .....................................................................48 
8.2. 
Safety Assessments .........................................................................................................49 
8.2.1. 
Physical/Neurological Examinations ..............................................................................49 
8.2.2. 
Vital Signs .......................................................................................................................49 
8.2.3. 
Electrocardiograms .........................................................................................................49 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................50 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................50 
8.2.6. 
Hepatic Monitoring .........................................................................................................51 
8.2.7. 
Magnetic Resonance Imaging .........................................................................................54 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................56 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................57 
8.3.2. 
Pregnancy ........................................................................................................................58 
8.3.3. 
Adverse Events of Special Interest .................................................................................59 
8.4. 
Pharmacokinetics ............................................................................................................60 
8.5. 
Pharmacodynamics .........................................................................................................61 
8.6. 
Genetics ..........................................................................................................................61 
8.7. 
Biomarkers ......................................................................................................................61 
8.8. 
Immunogenicity Assessments.........................................................................................61 
8.9. 
Health Economics ...........................................................................................................61 
9. 
Statistical Considerations .............................................................................................62 
9.1. 
Statistical Hypotheses .....................................................................................................62 
9.1.1. 
Multiplicity Adjustment ..................................................................................................62 
9.2. 
Analyses Sets ..................................................................................................................63 
9.3. 
Statistical Analyses .........................................................................................................63 
9.3.1. 
General Considerations ...................................................................................................63 
9.3.2. 
Primary Endpoint Analysis .............................................................................................64 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................64 
9.3.4. 
Tertiary/Exploratory Endpoints Analysis .......................................................................64 
9.3.5. 
Safety Analyses ...............................................................................................................65 
9.3.6. 
Pharmacokinetic Analyses ..............................................................................................65 
9.3.7. 
Evaluation of Immunogenicity .......................................................................................65 
9.3.8. 
Handling of Missing Data ...............................................................................................66 
9.3.9. 
Treatment Group Comparability .....................................................................................66 
9.4. 
Interim Analysis  .............................................................................................................67 
9.5. 
Sample Size Determination ............................................................................................67 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
8 
10.
Supporting Documentation and Operational Considerations ..................................69
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................69
10.1.1.
Regulatory and Ethical Considerations ...........................................................................69
10.1.2.
Financial Disclosure........................................................................................................69
10.1.3.
Informed Consent Process ..............................................................................................70
10.1.4.
Data Protection................................................................................................................70
10.1.5.
Committees Structure......................................................................................................70
10.1.6.
Dissemination of Clinical Study Data.............................................................................71
10.1.7.
Data Quality Assurance ..................................................................................................71
10.1.8.
Source Documents ..........................................................................................................73
10.1.9.
Study and Site Start and Closure ....................................................................................73
10.1.10. Publication Policy ...........................................................................................................74
10.1.11. Investigator Information .................................................................................................74
10.1.12. Sample Retention ............................................................................................................74
10.2.
Appendix 2: Clinical Laboratory Tests ...........................................................................75
10.2.1.
Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................78
10.3.
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................79
10.3.1.
Definition of AE .............................................................................................................79
10.3.2.
Definition of SAE ...........................................................................................................80
10.3.3.
Definition of Product Complaints ...................................................................................81
10.3.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................81
10.3.5.
Reporting of SAEs ..........................................................................................................83
10.3.6.
Regulatory Reporting Requirements ...............................................................................83
10.4.
Appendix 4: Contraceptive and Barrier Guidance ..........................................................84
10.4.1.
Definitions.......................................................................................................................84
10.4.2.
Contraception Guidance..................................................................................................85
10.5.
Appendix 5: Genetics......................................................................................................86
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................87
10.7.
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................89
10.8.
Appendix 8: Abbreviations and Definitions ...................................................................93
11.
References ......................................................................................................................97
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
9 
1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: 
Investigating the Effect of Different Donanemab Dosing Regimens on ARIA-E and Amyloid 
Lowering in Adults with Early Symptomatic Alzheimer’s Disease 
Brief Title: 
Exploration of Different Donanemab Dosing Regimens 
Regulatory Agency Identifier Numbers: 
IND: 109157 
EU trial number: 2022-502268-18-00 
Rationale: 
This study will investigate different donanemab dosing regimens and their effect on the 
frequency and severity of ARIA-E in adults with early symptomatic Alzheimer’s disease (AD) 
and explore patient characteristics that might predict risk of ARIA. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
 
To assess the effect of alternative 
donanemab dosing regimens versus the 
standard donanemab dosing regimen on 
ARIA-E frequency 
Proportion of participants with any occurrence 
of ARIA-E by Week 24 
Secondary 
 
To assess the effect of alternative 
donanemab dosing regimens versus 
standard donanemab dosing regimen on 
ARIA-E frequency 
Proportion of participants with any 
occurrence of ARIA-E by Week 52 
To assess the effect of alternative 
donanemab dosing regimens versus 
standard donanemab dosing regimen on 
brain amyloid deposition 
Change from baseline in brain amyloid 
plaque deposition as measured by amyloid 
PET scan through 
 Week 24 
 Week 52 
 Week 76  
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
10 
To evaluate the effect of alternative 
donanemab dosing regimens on ARIA 
events  
 Proportion of participants with any 
occurrence of ARIA-H by 
o Week 24 
o Week 52 
 ARIA-E and ARIA-H by severity 
To assess peripheral PK and presence of 
anti-donanemab antibodies 
 Serum PK of donanemab 
 ADAs against donanemab, including TE-
ADAs and neutralizing antibodies 
Abbreviations: Aß = amyloid-beta peptide; ADA = antidrug antibody; ARIA = amyloid-related imaging 
abnormalities; PK = pharmacokinetic. 
 
Estimand 
The primary clinical question of interest is: 
What is the reduction in the frequency of ARIA-E events at Week 24 in participants with 
early symptomatic AD treated with an alternative donanemab dosing regimen compared 
to the standard donanemab dosing regimen, regardless of discontinuation or interruption 
of donanemab dosing for any reason and regardless of change in background AD 
medication? 
Overall Design 
This is a multicenter, randomized, double-blind, Phase 3b study in adults with early symptomatic 
AD. Early symptomatic AD refers to the combination of 2 stages, mild cognitive impairment and 
mild AD dementia. 
The study duration will be up to approximately 91 weeks and includes a 
 screening period 
 double-blind treatment period, and 
 posttreatment follow-up. 
The visit frequency is every 2 weeks for Visits 2-10 and every 4 weeks thereafter.  
The treatment duration will be up to approximately 72 weeks. 
If a participant meets amyloid plaque reduction criteria at Visit 12 (Week 24) or Visit 19 (Week 
52), they will no longer receive treatment, and the study-site personnel may conduct Visits 13, 
14, 16, 17, 18, 20, 21, 23, and 24 by telephone. 
Brief Summary: 
This study is intended to assess 
 alternate donanemab dosing regimens that could potentially reduce the risk of ARIA-E 
frequency, severity, symptoms 
 baseline and treatment response characteristics, including magnetic resonance imaging 
(MRI) and blood-based biomarkers, that might predict risk of ARIA-E, and 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
11 

amyloid lowering of alternate dosing regimens.
Magnetic resonance imaging of the brain will be used to check for evidence of ARIA-H or 
ARIA-E, and other clinically relevant safety findings. 
Amyloid positron emission tomography (PET) scans provide a quantitative assessment of 
amyloid plaque deposition in the brain and can serve as a biomarker of clearance of amyloid 
deposits. 
Part of the study eligibility criteria is determined by amyloid PET scans. Additional amyloid 
PET scans will be performed during the study. 
Study partners 
Each participant must have a study partner. 
A second study partner may serve as backup. The study partners are required to accompany the 
participant for signing consent. Certain study visits require that a study partner is available by 
telephone if not accompanying the participant at the visit. 
If a study partner must withdraw from study participation, a replacement may be allowed at the 
investigator’s discretion. 
Study Population: 
In general, an individual may take part in this study if they 

Are 60 to 85 years of age, at the time of signing the informed consent.

Have gradual and progressive change in memory function for ≥6 months from time of
signing the informed consent.

Have a Mini Mental State Examination (MMSE) score of 20 to 28 at Visit 1. The MMSE
is a brief instrument used to assess cognitive function.

Have an amyloid PET scan result that shows the presence of amyloid pathology.
In general, an individual may not take part in this study if they 

Have significant neurological disease affecting the central nervous system other than AD,
that may affect cognition or ability to complete the study, including but not limited to,
other dementias, serious infection of the brain, Parkinson’s disease, multiple concussions,
or epilepsy or recurrent seizures, except febrile childhood seizures.

Have a condition that in the investigator’s opinion could interfere with the analyses of
this study, or a current serious or unstable illness.

Have a life expectancy of less than 24 months.

Are not able to complete the MRI imaging procedures due to issues, such as
claustrophobia, or have metal implants or a cardiac pacemaker.

Are not able to complete the PET procedure or have sensitivity to the amyloid PET tracer
used in the procedure.

Have previously received donanemab or treatment before with passive anti-amyloid
immunotherapy <5 half-lives prior to randomization.
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
12 
Number of Participants: 
Approximately 800 participants will be randomly assigned to 1 of 4 treatment arms in a 1:1:1:1 
ratio. 
Intervention Groups and Duration: 
There will be 4 treatment arms in this study. 
All participants will receive a dosing regimen that includes donanemab, but at different dose 
levels and frequency of dosing. Placebo is given at specific visits to preserve the blind for the 
different dosing regimens. All dosing is administered by intravenous infusion. 
After Week 16, all participants are targeted to receive the maximum donanemab dose of 
1400 mg monthly until they meet the dose stopping criteria or until the end of the study. 
Ethical Considerations of Benefit/Risk: 
A potential key benefit for participation in this study is the delay in cognitive and functional 
decline associated with AD. 
The potential risks associated with participation in this study are the occurrence of ARIA and 
infusion-related reactions. These risks are observed with beta amyloid plaque-targeted therapies, 
including donanemab. 
Given the seriousness and limited treatments for AD, donanemab provides a clinically 
meaningful treatment alternative. Considering the measures taken to minimize risk to 
participants, the potential benefit-risk balance for this study is acceptable for testing different 
dosing regimens that may reduce the risk of ARIA. 
Data Monitoring Committee: Yes 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
13 
1.2. 
Schema  
 
 
a The visit frequency is every 2 weeks for Visits 2-10, and every 4 weeks thereafter. 
Note: If a participant meets amyloid plaque reduction criteria defined by the Sponsor, as measured by amyloid PET scan, at Visit 12 (Week 24) or Visit 19 
(Week 52), the participant will discontinue study intervention and stay in the study for the remaining study visits. 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
14 
1.3. 
Schedule of Activities (SoA)  
Three tables describe the SoA. 
Table 1 (Section 1.3.1) describes Period I Screening. 
Table 2 (Section 1.3.2) describes Period II Treatment Visits 2-15. 
Table 3 (Section 1.3.3) describes Period II Treatment Visits 16-25, the Early Discontinuation Visit, and Period III Posttreatment 
Follow-Up Visit 801. 
Period I – Screening 
Visit 1 procedures may be conducted over more than 1 day if all activities are completed within the allowable visit tolerance. 
Screening should not extend past 49 days. Sponsor may strictly control toward end of study enrollment. If the PET or MRI results are 
delayed due to technical or logistical circumstances, it is not considered a protocol deviation. 
Period II – Treatment 
The visit frequency is every 2 weeks for Visits 2-10, and every 4 weeks thereafter. See Section 4.1.1 for more treatment arm 
information. 
Early discontinuation 
If a participant discontinues the study before Visit 25, perform ED assessments. After the ED Visit, the participant proceeds to Period 
III to complete the follow-up visit, if possible. 
Period III – Follow-up 
Visit 801 occurs at least 12 weeks after the last dose of IP. V801 is not needed if more than 12 weeks have passed since last dose of IP 
at V25 or study discontinuation.  
Telephone visits 
If a participant meets amyloid plaque reduction criteria at Visit 12 or Visit 19 and discontinues study intervention, the study-site 
personnel may conduct Visits 13, 14, 16-18, 20, 21, 23, and 24 by telephone. See Sections 4.1.1 and 7.1 for details. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
15 
1.3.1. 
Period I - Screening  
I5T-MC-AACQ 
Period I 
Screening 
Notes 
Visit Number 
Visit 1 
 
Day Relative to Randomization 
-49 to -1 
 
Tolerance Interval for Visit (Days) 
≤49 before Visit 
2 
  
Entry and administrative 
procedures 
  
  
Informed Consent - Participant 
X 
The participant informed consent form must be signed before any protocol-specific tests or 
procedures are performed.  
Informed Consent - Study Partner 
X 
The study partner informed consent form must be signed before any protocol-specific tests or 
procedures are performed. 
Inclusion/exclusion review 
X 
Review inclusion and exclusion criteria as information becomes available. 
Demographics 
X 
Includes year of birth, sex, ethnicity (where permissible), and race. 
Preexisting conditions and medical 
history  
X 
Collect all ongoing conditions and medical history. 
Substance use  
(alcohol, caffeine, tobacco use, and 
nicotine replacement) 
X 
 
Concomitant medications 
X 
 
Adverse events (AEs) 
X 
Any events that occur after signing the informed consent are considered AEs as defined in 
Section 10.3. 
Safety assessments 
 
  
Height 
X 
 
Weight 
X 
 
Vital signs 
X 
Measure vital signs after the participant has been sitting at least 5 min, and before obtaining a 
local ECG tracing, or collection of blood samples for laboratory testing. 
Collect temperature with sitting vitals. 
Physical/neurological examination 
X 
See the Manual of Operations for details.  
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
16 
I5T-MC-AACQ 
Period I 
Screening 
Notes 
Visit Number 
Visit 1 
 
Day Relative to Randomization 
-49 to -1 
 
Tolerance Interval for Visit (Days) 
≤49 before Visit 
2 
  
ECG 12-lead (single, local) 
X 
Collect ECG before blood sample collection.  
Unscheduled ECGs may be performed at the discretion of investigator. 
Patient-reported outcomes (paper) 
 
 
MMSE 
X 
Participants must meet MMSE criteria before any other screening procedures are performed. See 
Section 5.5 for rescreening criteria.  
Administer the MMSE prior to medical procedures that could be stressful to the participant, for 
example before a blood draw. 
Laboratory tests and sample 
collections 
 
Blood draws for screening should be collected at the same time.   
Hematology 
X 
 
Clinical Chemistry 
X 
 
Urinalysis 
X 
 
Apolipoprotein E (ApoE) 
X 
Results will not be provided to the investigators. 
Plasma pTau 
X 
Results will not be provided to the investigators. 
Stored samples 
 
Collect only where available and allowed per local regulations. 
Genetics Sample 
X 
 
Exploratory Biomarker Samples 
X 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
17 
I5T-MC-AACQ 
Period I 
Screening 
Notes 
Visit Number 
Visit 1 
Day Relative to Randomization 
-49 to -1
Tolerance Interval for Visit (Days) 
≤49 before Visit 
2 
Screening PET scans and MRI 
Amyloid PET 
X 
The participant should meet all other eligibility criteria before the amyloid PET scan and MRI. If 
imaging results are received after the screening window, the participant remains eligible 
contingent on meeting the other eligibility criteria. If the investigator feels it is necessary, they 
may repeat the screening labs. 
A historical amyloid PET scan may be submitted for eligibility if performed within 12 months of 
Visit 2, randomization. The acceptance of a historical scan is at the discretion of the Sponsor. 
See Section 8.2.7 for MRI details. 
MRI of brain 
X 
Randomization and dosing 
Register visit with IWRS 
X 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
18 
1.3.2. 
Period II - Treatment Visits 2-15  
I5T-MC-AACQ 
Period II Treatment 
Notes 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week Relative to 
Randomization  
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
36 
 
Tolerance Interval for Visit 
(Days) 
0 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
  
Administrative 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion review 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Confirm participant meets all Visit 1 
eligibility criteria before proceeding to 
Visit 2 procedures. 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Any event(s) that occur after signing 
the informed consent are considered 
AEs as defined in Section 10.3. 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
  
  
  
  
  
X 
  
 
  
X 
  
 
X 
  
Vital signs and temperature 
X 
 X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sitting BP, pulse, and temperature will 
be measured at all visits. 
In addition, orthostatic BP and pulse 
will be measured at V2, V8, V12, V15, 
and unscheduled visits. 
 
See Section 8.2.2. 
Note: Measure BP and pulse for 
suspected hypersensitivity events when 
able to do so.  
Do not collect if visit is conducted by 
telephone. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
19 
I5T-MC-AACQ 
Period II Treatment 
Notes 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Week Relative to 
Randomization 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
36 
Tolerance Interval for Visit 
(Days) 
0 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Administrative 
Physical/neurological 
examination  
X 
X 
X 
X 
See the Manual of Operations for 
details. Note any clinically significant 
changes from baseline on the AE CRF. 
Clinician-administered 
Assessments (Paper) 
C-SSRS screening/baseline
X 
AE collection should occur prior to the 
collection of the C-SSRS. 
C-SSRS since last assessed
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests and sample 
collections 
Collect samples before dosing, unless 
indicated below. See Section 10.2 for 
details of testing included in panels. 
Hematology 
X 
X 
X 
X 
Clinical Chemistry 
X 
X 
X 
X 
High-sensitivity C-Reactive 
Protein 
X 
X 
X 
X 
X 
X 
Neurofilament Light chain 
X 
X 
X 
X 
X 
X 
Collect only where available and 
allowed per local regulations. 
Glial fibrillary acidic protein 
X 
X 
X 
X 
X 
X 
sTREM2 
X 
X 
X 
X 
X 
X 
Amyloid-Beta 40 and 42 
X 
X 
X 
X 
X 
X 
Plasma pTau 
X 
X 
X 
X 
X 
X 
Pharmacokinetic Samples 
(Predose) 
X 
X 
X 
X 
Sample may be collected from the IV 
site prior to the infusion. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
20 
I5T-MC-AACQ 
Period II Treatment 
Notes 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
Week Relative to 
Randomization  
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
36 
 
Tolerance Interval for Visit 
(Days) 
0 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
  
Administrative 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pharmacokinetic Samples 
(Postdose) 
X 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
Collect within 30 min after the end of 
infusion.  
Collect from different arm than one 
used for the infusion. 
Immunogenicity Samples 
X 
  
X 
  
X 
  
X 
  
  
  
X 
  
  
 
Collect before the infusion when 
applicable and possible. 
Stored Samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Biomarker 
Samples 
X 
  
X 
  
X 
  
 X 
  
  
  
X 
  
  
X 
Collect before the infusion where 
allowed per local regulations.  
Other Safety Measures 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
MRI of brain 
 
  
 X 
  
  
  
X 
  
  
  
X 
  
  
  
Visit 4: Perform and review MRI 
before the Visit 4 dose and at least 21 
days after the first infusion. 
Visit 8: Perform and review MRI 
before the Visit 8 dose.  
If dosing was missed in visits before 
Visit 8: perform and review an 
additional MRI before seventh dose . 
See Section 8.2.7.1 for MRI sequence 
details for each visit. 
Unscheduled MRIs may be performed 
at the discretion of investigator.  
Additional Efficacy Measures 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Amyloid PET scan 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
21 
I5T-MC-AACQ 
Period II Treatment 
Notes 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Week Relative to 
Randomization 
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
28 
32 
36 
Tolerance Interval for Visit 
(Days) 
0 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Administrative 
Randomization and Dosing 
Randomization using IWRS 
X 
Register visit with IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study intervention 
using IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer study intervention 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
The participant must be observed for a 
minimum of 30 min following the end 
of each infusion.  
Visits 2 to 10: Dosing intervals must 
be more than 7 days apart. 
Visits 10 to 15: Dosing intervals must 
be greater than or equal to 21 days 
apart. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
22 
1.3.3. 
Period II - Treatment Visits 16-25, the Early Discontinuation Visit, and Period III Posttreatment Follow-Up 
Visit 801  
I5T-MC-AACQ 
Period II Treatment 
 
Period 
III 
Notes 
Visit Number 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
ED 
801 
Week Relative to 
Randomization 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
 
84 
 
Tolerance Interval for 
Visit (Days)  
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
±14 
  
Administrative 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse events (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. 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
 
 
 
X 
 
 
X 
 
 
X 
X 
 
  
Vital signs and 
temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 8.2.2. 
For unscheduled visits, measure orthostatic 
BP and pulse. 
Do not collect if visit is conducted by 
telephone. 
Physical/neurological 
examination  
 
 
 
X 
 
 
X 
 
 
X 
X 
 
See the Manual of Operations for details.  
Note any clinically significant changes from 
baseline on the AE CRF. 
Clinician-Administered 
Assessments (Paper) 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS since last 
assessed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE collection should occur prior to the 
collection of the C-SSRS. 
Laboratory Tests and 
Sample Collections 
 
 
 
 
 
 
 
 
 
 
 
 
Collect samples before dosing, unless 
indicated below. See Section 10.2 for 
details of testing included in panels. 
Hematology 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
  
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
23 
I5T-MC-AACQ 
Period II Treatment 
 
Period 
III 
Notes 
Visit Number 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
ED 
801 
Week Relative to 
Randomization 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
 
84 
 
Tolerance Interval for 
Visit (Days)  
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
±14 
  
Clinical Chemistry 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
High-sensitivity  
C-Reactive Protein 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Neurofilament light 
chain 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Collect only where available and allowed 
per local regulations. 
Glial fibrillary acidic 
protein 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
sTREM2 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Amyloid-Beta 40 and 42  
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Plasma pTau 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Pharmacokinetic 
Samples (Predose) 
 
 
 
X 
 
 
 
 
 
 
 
 
May be collected from the IV site before the 
infusion. 
Pharmacokinetic 
Samples (Postdose) 
 
 
 
X 
 
 
 
 
 
 
 
 
Collect within 30 min of infusion 
completion. Collect from different arm than 
one used for the infusion. 
Pharmacokinetic 
Samples (Random) 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Do not collect if the last infusion was 
>6 months prior to the scheduled visit. 
Immunogenicity Samples 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Collect before infusion when applicable and 
possible. 
Stored Samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Biomarker 
Samples 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Collect before infusion unless not allowed 
or possible due to local regulation. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
24 
I5T-MC-AACQ 
Period II Treatment 
Period 
III 
Notes 
Visit Number 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
ED 
801 
Week Relative to 
Randomization 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
84 
Tolerance Interval for 
Visit (Days)  
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
Other Safety Measures 
MRI of the brain 
X 
X 
See Section 8.2.7.1 for MRI sequence 
details for each visit. 
Unscheduled MRIs may be performed at the 
discretion of investigator.  
ED Visit: Conduct only if ED occurs more 
than 6 wk from the previous MRI. 
Additional Efficacy 
Measures 
Amyloid PET scan 
X 
X 
X 
ED Visit: Conduct only if ED occurs after 3 
or more months from the last amyloid PET 
scan. 
Randomization and 
Dosing 
Register visit with IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study 
intervention using IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer study 
intervention 
X 
X 
X 
X 
X 
X 
X 
X 
X 
The participant must be observed for a 
minimum of 30 min following the end of 
each infusion.  
Dosing intervals must be more than 21 days 
apart. 
Abbreviations: AE CRF = AE case report form; BP = blood pressure; C-SSRS = Columbia-Suicide Severity Rating Scale; ED = early discontinuation; 
IWRS = interactive web-response system; IV = intravenous; MMSE = Mini Mental State Examination; MRI = magnetic resonance imaging; PET = positron 
emission tomography; Q2W = every 2 weeks; sTREM2 = soluble triggering receptor expressed on myeloid cells 2. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
25 
2. 
Introduction  
LY3002813 (donanemab) is a humanized immunoglobulin G1 antibody directed at the 
pyroglutamate formation of the third amino acid (N3pG) of amyloid-beta (Aβ) epitope that is 
present only in brain amyloid plaques. It is being developed as a treatment to slow the 
progression of AD. 
The donanemab clinical development program for the proposed indication currently comprises 
 almost 400 participants in 3 completed studies - Studies AACC, AACD, and AACG, and 
 approximately 3000 participants in ongoing studies.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of donanemab is 
provided in the IB. 
2.1. 
Study Rationale  
This study will investigate different donanemab dosing regimens and their effect on the 
frequency and severity of ARIA-E in adults with early symptomatic AD and explore patient 
characteristics that might predict risk of ARIA. 
2.2. 
Background  
ARIA  
ARIA-E and ARIA-H are considered a class effect with antibody therapies directed at amyloid, 
and APOE ε4 carriers (heterozygotes or homozygotes) have a greater risk for ARIA-E and 
ARIA-H than noncarriers.  
Patients with ARIA are usually asymptomatic. However, ARIA may be serious or life-
threatening and could lead to permanent disability or death. When asymptomatic, ARIA may be 
detected by routine brain MRI. When symptoms are present in association with imaging 
abnormalities, symptoms include, but are not limited to 
 headache 
 vomiting 
 dizziness 
 tremor 
 confusion 
 visual or speech disturbances, or 
 alteration of consciousness. 
See the IB, Section 6.1 for more details.  
ARIA events in clinical studies with donanemab 
Amyloid-related imaging abnormalities were observed in completed Phase 1 studies, AACD and 
AACC, Phase 2 Study AACG, and in the ongoing Phase 3 study, AACI. 
The ARIA events from the Phase 2 completed study are summarized below. Further details can 
be found in Sections 5.2.1.1.4.2, 5.2.1.2.4.2, and 5.2.1.3 of the IB. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
26 
Phase 2 Study AACG ARIA events 
Study AACG was a Phase 2, double-blind, placebo-controlled study in participants with early 
symptomatic AD with intermediate brain tau burden. In Study AACG, ARIA (-E, -H, or both) 
was observed in a higher percentage of participants treated with donanemab, compared to 
participants treated with placebo. A majority of ARIA-E and ARIA-H events were first observed 
within 12 weeks of treatment initiation, with most events observed by 24 weeks.  
ARIA-E occurred in 26.7% of participants treated with donanemab, with 6.1% of cases being 
symptomatic. Symptoms associated with ARIA-E included, but were not limited to, worsening 
of headache, altered mental status, confusion, and difficulty expressing themselves.  Serious 
symptomatic ARIA-E requiring hospitalization occurred in 1.5% of participants treated with 
donanemab.  
Donanemab dosing regimen 
The standard donanemab dosing regimen used in the clinical studies to date is described in 
Section 4.1.1. This study will evaluate different dosing regimens compared to the standard 
donanemab dosing regimen for the potential to reduce ARIA. In addition, it will measure 
amyloid removal and explore novel imaging and blood biomarkers that may be related to or 
predict ARIA (See Section 4.1.1). 
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. 
2.3.1. 
Risk Assessment
Potential risks for this study 
ARIA 
Amyloid-related imaging abnormalities have been observed with beta amyloid plaque-targeted 
therapies, including donanemab. ARIA can be detected by brain MRI. ARIA is usually 
asymptomatic with these therapies, though serious events can occur. 
Infusion-related reactions and hypersensitivity 
Infusion-related reactions, including anaphylaxis and other immediate hypersensitivity reactions, 
were associated with donanemab infusion. These reactions may occur with the first or 
subsequent infusions of donanemab and typically occur during infusion or within 30 minutes 
postinfusion. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
27 
Procedural risks 
MRI 
MRI scans will be performed as routine safety monitoring during the study. AEs with MRI 
procedures are rare. However, the procedure involves a strong, magnetic pulsed gradient field 
which presents risks for participants with metal implants or other accessory medical devices, 
such as pacemakers, stents, cochlear implants. Participants with such devices should not have an 
MRI procedure performed unless it has been confirmed that conditions are appropriate for safe 
use. 
The confined space of the MRI testing environment may cause some participants to experience 
claustrophobia, and some participants may find remaining still to be difficult for the duration of 
the imaging process. 
PET scans 
PET scans will be performed during the study. A PET scan uses a radioactive tracer. Multiple 
PET scans increase exposure to radiation, and at high levels, radiation has been shown to 
increase the risk of malignancy. As with MRI, the confined space of the PET testing 
environment may cause some participants to experience anxiety or claustrophobia. 
See Section 8.1.1 for additional details, including expected radiation exposure. 
More detailed information about the known and expected benefits and risks of the ß-amyloid 
tracers can be found in the  

United States Package Insert for florbetapir F18 Injection (AmyvidTM package insert,
2012)

Summary of Product Characteristics for florbetapir F18 (Amyvid SmPC, 2021)

United States Package Insert for florbetaben (NeuraceqTM package insert, 2014), and

Summary of Product Characteristics for florbetaben (Neuraceq SmPC, 2021).
Management of risks for this study 
ARIA 
To reduce the risk of serious ARIA, participants with evidence of ARIA-E, >4 cerebral 
microhemorrhages, >1 area of cortical superficial siderosis, any macrohemorrhage, or severe 
white matter disease in screening MRI are excluded. Management of ARIA risk is covered in 
Section 8.3.3.1, which describes temporary or permanent study intervention discontinuation and 
MRI scanning guidance. 
Infusion-related reactions and hypersensitivity 
Most IRRs occur during the infusion or within 30 minutes. Participants will be monitored for at 
least 30 minutes after each infusion. Additional management of hypersensitivity is covered in 
Sections 7.1 and 8.3.3.2. 
2.3.2. 
Benefit Assessment 
Delay in cognitive and functional decline is a key potential benefit for donanemab, demonstrated 
by rapid and deep clearance of amyloid (Shcherbinin, et al. 2022), a surrogate endpoint likely to 
predict clinical benefit. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
28 
In Study AACG, donanemab was statistically significantly better than placebo in slowing disease 
progression as measured by the iADRS. The effect size at endpoint was 0.29, resulting in a 32% 
slowing of decline (Mintun, et al. 2021). 
2.3.3. 
Overall Benefit-Risk Conclusion  
Overall, given the seriousness and limited disease-modifying treatments for AD, donanemab 
provides a clinically meaningful treatment alternative. The risks of donanemab, appropriately 
managed with the proposed approaches, are outweighed by the demonstrated effect on a 
surrogate biomarker likely predictive of a clinical benefit in those with AD. 
Considering the measures taken to minimize risk to participants, the potential benefit-risk 
balance for this study is acceptable for testing different dosing regimens that may reduce the risk 
of ARIA. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
29 
3.
Objectives, Endpoints, and Estimands
Objectives 
Endpoints 
Primary 
To assess the effect of alternative 
donanemab dosing regimens versus the 
standard donanemab dosing regimen on 
ARIA-E frequency 
Proportion of participants with any occurrence 
of ARIA-E by Week 24 
Secondary 
To assess the effect of alternative 
donanemab dosing regimens versus 
standard donanemab dosing regimen on 
ARIA-E frequency 
Proportion of participants with any 
occurrence of ARIA-E by Week 52 
To assess the effect of alternative 
donanemab dosing regimens versus 
standard donanemab dosing regimen on 
brain amyloid deposition 
Change from baseline in brain amyloid 
plaque deposition as measured by amyloid 
PET scan through 

Week 24

Week 52

Week 76
To evaluate the effect of alternative 
donanemab dosing regimens on ARIA 
events 

Proportion of participants with any
occurrence of ARIA-H by
o
Week 24
o
Week 52

ARIA-E and ARIA-H by severity
To assess peripheral PK and presence of 
anti-donanemab antibodies 

Serum PK of donanemab

ADAs against donanemab, including TE-
ADAs and neutralizing antibodies
Tertiary/Exploratory 
To explore characteristics that predict risk 
of ARIA-E and ARIA-H 

Association between exploratory MRI
imaging sequences and the occurrence
and severity of ARIA events

Association between blood-based
biomarkers and the frequency and
severity of ARIA events
o
NfL
o
pTau
o
Aß levels (40 and 42)
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
30 
Objectives 
Endpoints 
o
GFAP
o
sTREM2, and
o
hsCRP.
To evaluate the effect of alternative 
donanemab dosing regimens on IRR 

IRR events frequency and severity
Abbreviations: Aß = amyloid-beta peptide; ADA = antidrug antibody; ARIA = amyloid-related imaging 
abnormalities; hsCRP = high-sensitivity C-reactive protein; GFAP = glial fibrillary acidic protein; IRR = 
infusion-related reactions; NfL = neurofilament light chain; PK = pharmacokinetic; pTau = phosphorylated tau; 
sTREM2 = soluble triggering receptor expressed on myeloid cells 2. 
Primary estimand/coprimary estimand 
The primary clinical question of interest is: 
What is the reduction in the frequency of ARIA-E events at Week 24 in participants with 
early symptomatic AD treated with an alternative donanemab dosing regimen compared 
to the standard donanemab dosing regimen, regardless of discontinuation or interruption 
of donanemab dosing for any reason and regardless of change in background AD 
medication? 
The estimand is described by the following attributes: 

Population - Participants with early symptomatic AD

Endpoint - Occurrence of ARIA-E by Week 24

Treatment condition - 4 randomized treatment arms of donanemab with varying dosing
schemes

Population-level summary - The relative reduction in proportion of participants with
ARIA-E events in the alternative donanemab regimen compared to the standard
donanemab regimen

Intercurrent events - “Discontinuation or interruption of donanemab dosing for any
reason” and “change in background AD medication.” No other intercurrent events are
considered

Estimand strategy - Treatment policy. Data will be collected and analyzed regardless of
postrandomization events in the first 24 weeks of the trial. This strategy will be
implemented by a Bayesian logistic regression model

Rationale for estimand - The study primary objective is to evaluate the effect of
alternative donanemab dosing regimens versus the standard donanemab dosing regimen
on ARIA-E rate
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
31 
4. 
Study Design  
4.1. 
Overall Design  
This is a multicenter, randomized, double-blind, Phase 3b study in adults with early symptomatic 
AD. 
This study includes a 
 screening period 
 double-blind treatment period, and 
 posttreatment follow-up. 
See the SoA for visit schedule, procedural and assessment details (Section 1.3). 
4.1.1. 
Treatment Arms and Titration Regimen Outline  
All participants will receive a dosing regimen that includes donanemab, but at different dose 
levels and frequency of dosing. Placebo is given at specific visits to preserve the blind for the 
different dosing regimens. 
This table describes the planned dosing regimens for the first 16 weeks. After Week 16, all 
participants are targeted to receive 1400 mg monthly of donanemab until they meet the dose 
stopping criteria or until the end of the study. 
Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Study Week 
0 
2 
4 
6 
8 
10 
12 
14 
16 
Treatment Arm  
Dose (mg) 
1 standard regimen 
700 
PBO 
700 
PBO 
700 
PBO 
1400 
PBO 
1400 
2 
700 
PBO 
PBO 
PBO 
1400 
PBO 
1400 
PBO 
1400 
3 
350 
PBO 
700 
PBO 
1050 
PBO 
1400 
PBO 
1400 
4 
350 
350 
350 
350 
350 
350 
700 
700 
1400 
Abbreviations: PBO = placebo. 
Telephone visits 
If a participant meets amyloid plaque reduction criteria at Visit 12 (Week 24) or Visit 19 (Week 
52), and discontinues study intervention (Section 7.1), the study-site personnel may conduct 
Visits 13, 14, 16, 17, 18, 20, 21, 23, and 24 by telephone. 
4.1.2. 
Study Partners  
Each participant must have a study partner as described in Section 5.1. 
A second study partner may serve as backup. The study partners are required to accompany the 
participant for signing consent. Visits requiring the collection of AEs and concomitant 
medications must have a study partner available by telephone if not accompanying the 
participant at a visit. 
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 they accompany the participant. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
32 
4.2. 
Scientific Rationale for Study Design 
Study AACQ is a multicenter, randomized, double-blind study of donanemab in participants with 
early symptomatic AD, where early symptomatic AD refers to the combination of 2 stages, mild 
cognitive impairment and mild AD dementia. This study is intended to assess 

alternate donanemab dosing regimens that could potentially reduce the risk of ARIA-E
frequency, severity, symptoms

baseline and treatment response characteristics, including MRI and blood-based
biomarkers, that might predict risk of ARIA-E, and

amyloid lowering of alternate dosing regimens.
Characterizing the frequency, severity, onset, and resolution of ARIA events, in relation to 
dosing, is an important overall goal in understanding the benefit/risk of using amyloid lowering 
treatments for patients with early symptomatic AD. 
In Study AACQ, all participants will receive donanemab, but at different dose levels and 
frequency of dosing (See Section 4.1.1.). Placebo is given at specific visits to preserve the blind 
for the different dosing regimens. 
Study AACQ allows all participants to continue or change their symptomatic AD standard of 
care concomitant medications during the study. 
Physical and neurological examinations, MRI assessments, and assessments of SIB are included 
to facilitate a comprehensive safety evaluation, in addition to AE reporting, safety measures such 
as laboratory assessments, immunogenicity testing, vital signs, and weight monitoring. 
Collection of race and ethnicity data 
In this study, collection of demographic information includes race and ethnicity. The scientific 
rationale is based on the need to assess variable response in safety and/or efficacy based on race 
or ethnicity. This question can be answered only if all the relevant data are collected. 
4.3. 
Justification for Dose 
The standard donanemab dosing regimen has a titration schedule of 700 mg IV Q4W for the first 
3 doses and then 1400 mg IV Q4W. This study will investigate alternative dosing regimens that 
may potentially reduce the frequency and/or severity of ARIA-E. 
The doses and frequency were selected based on human safety, efficacy, PK, and PD data from 
Phase 1-3 studies. 
The goal is to investigate at least 3 additional dose regimens in addition to the standard 
donanemab regimen. The dosing regimen options are detailed in Section 4.1.1. These dosing 
regimens include either built-in dosing pause of 8 weeks between infusions, or administering a 
lower dose more frequently (Q2W), resulting in a lower maximum concentration but with the 
same monthly exposure compared to the standard donanemab regimen. All of the dosing 
regimens are anticipated to result in robust plaque clearance. 
It is hypothesized that 8-week dosing interval will allow time for potential asymptomatic ARIA 
to resolve and may decrease the risk of ARIA exacerbation (Salloway et al. 2022). 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
33 
Administering a lower dose, compared with the standard donanemab regimen, will result in a 
lower maximum concentration (Cmax). It is hypothesized that a lower Cmax and a slower increase 
in serum concentration may reduce ARIA risk (Hayato et al. 2020; Salloway et al. 2022). 
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 or 
last scheduled procedure shown in the SoA for the last participant in the study globally. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study, including the last scheduled procedure shown in the SoA. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
34 
5.
Study Population
Participant eligibility for enrollment in the study is based on the criteria listed in this section. The 
inclusion and exclusion criteria used to determine eligibility should only apply at screening or 
other specified visits, and not continuously throughout the study. 
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. Are 60 to 85 years of age inclusive, at the time of signing the informed consent.
Type of participant and disease characteristics 
2. Have gradual and progressive change in memory function reported by the participant or
informant for ≥6 months from time of signing the informed consent.
3. Have an MMSE score of 20 to 28 (inclusive) at Visit 1.
4. Have an amyloid PET scan result from central read, consistent with the presence of
amyloid pathology. A historical amyloid PET scan may be submitted for consideration
for eligibility if performed ≤12 months of Visit 2, randomization. The acceptance of a
historical scan is at the discretion of the Sponsor.
Sex and contraceptive/barrier requirements 
5.
Women not of childbearing potential and males may participate in this study.
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. For the contraception 
requirements of this protocol, see Appendix 10.4. 
Informed consent 
6. 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.
Other inclusion criteria 
7. Have a study partner who will provide written informed consent to participate, is in
frequent contact with the participant, and will accompany the participant to study visits
or be available by telephone at designated times. See Section 4.1.2 for details on study
partners.
8. Are reliable and willing to make themselves available for the duration of the study and
are able and willing to follow study procedures.
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
35 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
9. Have significant neurological disease affecting the central nervous system other than
AD, that may affect cognition or ability to complete the study, including but not limited
to, other dementias, serious infection of the brain, Parkinson’s disease, multiple
concussions, or epilepsy or recurrent seizures, except febrile childhood seizures.
10. Have a condition that in the investigator’s opinion could interfere with the analyses of
this study, or a current serious or unstable illness, including
o
cardiovascular
o
hepatic
o
renal
o
gastroenterologic
o
respiratory
o
endocrinologic
o
neurologic other than AD
o
psychiatric
o
immunologic, or
o
hematologic.
11. Have a life expectancy of less than 24 months.
12. Have a presence or history of malignant neoplasms within the past 5 years prior to
Visit 1.
Exceptions:
o
non-metastatic basal- or squamous-cell skin cancer
o
Stage 0 non-invasive carcinoma of the cervix
o
Stage 0 non-invasive prostate cancer, or
o
other cancers with low risk of recurrence or spread.
13. Are in the investigator’s opinion, actively suicidal and deemed a significant risk for
suicide.
14. Have a diagnosis of alcohol or drug use disorder, except tobacco use disorder, within 2
years of Visit 1.
15. Have a history of clinically significant multiple or severe drug allergies, significant
atopy, or severe posttreatment hypersensitivity.
Imaging, vital signs, electrocardiograms, laboratory tests, and physical examination 
16. Have a screening MRI that shows evidence of significant abnormality suggesting
another potential etiology for progressive dementia or a clinically significant finding that
may impact the participant’s ability to safely participate in the study.
17. Have any contraindications for MRI, including claustrophobia or the presence of
contraindicated metal (ferromagnetic) implants or a cardiac pacemaker.
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
36 
18. At Visit 1, have a centrally read MRI demonstrating the presence of 
o ARIA-E 
o >4 cerebral microhemorrhages 
o >1 area of cortical superficial siderosis 
o any macrohemorrhage, or 
o severe white matter disease. 
19. Have a contraindication to the PET procedure or sensitivity to the amyloid PET tracer. 
20. Have 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. 
21. Have laboratory values, in relation to the reference range, of 
ALT ≥2.5X ULN 
AST ≥2.5X ULN 
ALP ≥2.0X ULN, or 
TBL >1.5X ULN, except for participants diagnosed with Gilbert’s syndrome. 
Prior/concomitant therapy 
22. Have had prior treatment with a passive anti-amyloid immunotherapy <5 half-lives prior 
to randomization. 
23. Have received active immunization against Aβ in any other study. 
24. Have previously received donanemab. 
Prior/concurrent clinical study experience 
25. Are currently enrolled in any other interventional clinical study involving an 
investigational product or any other type of medical research judged not to be 
scientifically or medically compatible with this study. 
26. Have participated in a clinical study involving an investigational study intervention and 
have received an intervention within the last 30 days of Visit 1. 
27. Have previously completed or withdrawn from this study. This does not apply to 
participants who are allowed to rescreen before randomization in this study. 
Other exclusion criteria 
28. Are investigator site personnel directly affiliated with this study or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted. 
29. Are Lilly employees or are employees of third-party organizations involved in the study 
that require exclusion of their employees, or have study partners who are Lilly 
employees or are employees of third-party organizations that require exclusion of their 
employees. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
37 
5.3. 
Lifestyle Considerations  
Blood donation 
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. 
Alcohol consumption 
Participants should avoid excessive use of alcohol from the screening visit until the study ends. 
Excessive alcohol consumption is defined for men as consuming an average of more than 
3 drinks per day or more than 21 drinks per week. For women, excessive use of alcohol is 
defined as consuming an average of more than 2 drinks per day or more than 14 drinks per week. 
5.4. 
Screen Failures  
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 CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Individuals who screen fail for an MMSE >28 may be rescreened once after 24 weeks if the 
investigator feels there has been further cognitive decline. If an individual is rescreened, a new 
participant number is assigned, and the individual must sign a new ICF. 
Individuals who screen fail due to non-eligible imaging results, may not be rescreened. 
Other reasons for screen failure will require Sponsor approval for rescreen. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant  
This section is not applicable for this study. All entry criteria must be met within the specified visit 
intervals in the SoA. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
38 
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 or used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
This table lists the interventions used in this clinical study. 
Intervention 
Name 
Donanemab 
Placebo 
Florbetapir 
Florbetaben 
Dosage Level(s) 
350 mg 
700 mg 
1050 mg 
1400 mg 
Not applicable 
See Section 8.1.1 
See Section 8.1.1 
Route of 
Administration 
IV infusion  
IV infusion  
IV infusion 
IV infusion 
Authorized as 
defined by EU 
Clinical Trial 
Regulation  
Not authorized in the 
EU 
Authorized and not 
used according to 
EU authorization  
Authorized as 
Amyvid® and not 
used according to 
EU authorization 
Not authorized in 
EUa 
Authorized and not 
used according to 
EU authorization 
a Florbetapir solution for injection is manufactured in the EU per an MA as well as per an IMPD. There are different 
drug product-manufacturing sites in the EU MA compared to the IMPD. The manufacture of florbetapir solution 
for injection according to both an MA and an IMPD enables a more robust and larger area of supply for clinical 
trial sites throughout Europe.  
Florbetapir and florbetaben are amyloid PET tracers being used as AxMPs to aid in the 
assessment of study eligibility, endpoints, and dose stopping criteria. 
Donanemab administration 
Intervention is administered by IV infusion over a minimum of 30 minutes. Other detailed 
preparation and administration instructions for infusion information may be found in the 
Pharmacy Preparation Instructions. 
Safety supplies when dosing 
Resuscitation equipment and rescue medications must be available wherever intervention is 
administered. 
Packaging and labeling 
Study interventions will be supplied by the Sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
39 
6.2. 
Preparation, Handling, Storage, and Accountability  
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. 
Only participants enrolled in the study may receive study intervention. Only authorized study 
personnel may supply, prepare, or administer study intervention. 
All study 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. 
The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance, that is, receipt, reconciliation, and final 
disposition records. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
6.3. 
Assignment to Study Intervention  
Randomization 
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Before the study is initiated, the login information and directions for the IWRS will be provided 
to each site. 
Participants will be randomly assigned to 1 of 4 treatment groups in a 1:1:1:1 ratio. 
Participants will be stratified at baseline by amyloid PET scan results (≥24.1 and <54 centiloids; 
≥54 and <79 centiloids; ≥79 and <107 centiloids; ≥107 centiloids) and APOE genotype 
(heterozygous carrier, homozygous carrier, and noncarrier). 
6.4. 
Blinding  
This is a double-blind study. Blinding will be maintained throughout the conduct of the study, as 
described in the separate Blinding and Unblinding Plan. 
To maintain this blind, an otherwise uninvolved party, such as an unblinded pharmacist or other 
unblinded qualified individual, will be responsible for the preparation and dispensation of all 
study intervention according to the Pharmacy Preparation Instructions. 
The Sponsor may be unblinded to treatment assignments prior to the completion of the study if 
interim analyses that include safety analyses, futility, early efficacy, and sample size re-
estimation are conducted. If performed, operational details and a quantitative framework to 
provide information for these decisions will be prespecified and documented in a separate 
analysis plan. 
Sites, participants, and study partners will remain blinded to treatment assignment throughout the 
duration of the study. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
40 
Emergency unblinding 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participants’ 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. 
If a participant’s intervention assignment is unblinded, the Sponsor must be notified immediately 
within 24 hours of this occurrence. The date and reason that the blind was broken must be 
recorded. 
Discontinuation from the study in case of unblinding 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from the 
Sponsor for the participant to continue in the study. 
6.5. 
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. 
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, except if an infusion reaction occurs that prevents rechallenge. If 
less than 75% of the infusion solution is given, this must be recorded as an incomplete infusion 
on the CRF. 
Missed infusions should be recorded on the CRF. If at any time it is discovered that the 
participant has not completed proper dosing during the titration phase, the Sponsor should be 
contacted prior to the subsequent infusions to discuss the possibility of completing a proper 
titration phase, if needed. 
6.6. 
Dose Modification 
Dose reductions are not allowed in this study. 
If a participant develops ARIA during the titration period, the investigator may decide not to 
increase the dose as described in the Manual of Operations. 
6.7. 
Continued Access to Study Intervention after the End of the Study 
This section is not applicable for this study. 
6.8. 
Treatment of Overdose 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
41 
 contact the medical monitor immediately 
 evaluate the participant to determine, in consultation with the medical 
monitor, whether study intervention should be interrupted 
 closely monitor the participant for any AE or SAE and laboratory 
abnormalities, and 
 obtain a plasma sample for analysis of study intervention if requested by the 
medical monitor. 
6.9. 
Prior and Concomitant Therapy  
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 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 
 dosage information, including dose and frequency. 
Contact the medical monitor if there are any questions regarding concomitant or prior therapy. 
Medications for Alzheimer’s disease 
Permitted treatments 
Permitted treatments during the study include 
 use of approved or standard-of-care symptomatic treatments for AD 
 initiation, change, or discontinuation of symptomatic treatments, when medically 
indicated, and 
 nonmedication treatments for AD, such as behavioral management. 
Prohibited treatments 
These therapies are not allowed during the study: 
 Passive anti-amyloid immunotherapies, such as 
o gantenerumab 
o lecanemab, or 
o aducanumab. 
 Immunoglobulin G therapy, also known as gamma globulin or intravenous 
immunoglobulin. 
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. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
42 
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. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
43 
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  
When necessary, a participant may be permanently discontinued from study intervention. If 
study intervention is permanently discontinued, the participant should remain in the study for 
safety evaluations and biomarker collection, as shown in the SoA. 
A participant may be permanently discontinued from study intervention if 
 the participant or participant’s designee requests to discontinue the study intervention 
 the participant requires an excluded treatment 
 the participant answered “yes” to Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the C-SSRS 
 the participant answered “yes” to any of the suicide-related behaviors on the Suicidal 
Behavior portion of the C-SSRS 
A psychiatrist or appropriately trained professional may assist in the decision to 
discontinue the participant 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons or for severe noncompliance to the study 
protocol, and 
 ARIA (See Sections 7.1.2 and 8.3.3.1 for details). 
Additional guidance 
Systemic hypersensitivity reactions 
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from study 
intervention. See Section 7.1.3 for information on rechallenge in the case of systemic 
hypersensitivity reactions. 
Amyloid plaque reduction 
If a participant meets amyloid plaque reduction criteria defined by the Sponsor, measured by 
amyloid PET scan, at Visit 12 (Week 24) or Visit 19 (Week 52), the participant will discontinue 
study intervention and stay in the study for the remaining study visits. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
44 
7.1.1. 
Liver Chemistry Stopping Criteria  
Interrupting study intervention based on elevated liver tests 
The study intervention should be interrupted and close hepatic monitoring initiated (see Section 
8.2.6), if 1 or more of the conditions in this table occur. 
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 wk 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/Dl, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL >2x ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/Dl, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA 2009 and other consensus guidelines, with minor modifications. 
Abbreviations: INR = international normalized ratio; ULN = upper limit of normal. 
Resuming study intervention after elevated liver tests 
Resumption of the study intervention can be considered only in consultation with the 
Lilly-designated medical monitor and only if the liver test results return to baseline and if a 
self-limited, non-drug etiology is identified. Otherwise, the study intervention should be 
permanently discontinued. 
7.1.2. 
Temporary Discontinuation  
Temporary discontinuation from study intervention is allowed due to 
 hospitalization 
 personal or exceptional circumstances (See Section 10.7)  
 certain incidences of ARIA, or  
 evaluation of an AE. 
If temporary discontinuation is due to an AE, the investigator should report the event to the 
medical monitor. 
If temporary discontinuation of study intervention occurs, the investigator or designee 
determines if and when the study intervention may be restarted. See the Manual of Operations 
for temporary discontinuation guidance. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
45 
Temporary discontinuation of intervention due to ARIA 
The investigator may temporarily discontinue intervention if the participant develops treatment-
emergent ARIA-H or ARIA-E to an extent deemed clinically significant by the investigator. 
Reinitiating intervention can be considered after resolution of ARIA-E and stabilization of 
ARIA-H-imaging findings and the resolution of any associated symptoms. Both the decision to 
stop and restart intervention may be discussed with the Sponsor-designated medical monitor. 
See the Manual of Operations for temporary discontinuation guidance. 
See Section 6.6 for dose modification considerations. 
See Section 8.3.3.1 for details on adverse event reporting for ARIA-E and ARIA-H. 
7.1.3. 
Rechallenge in Cases of Systemic Hypersensitivity or Infusion-related Reactions  
Dosing rechallenge is contraindicated in participants that have experienced a suspected or 
possible anaphylactic reaction, a reaction involving 2 or more organ systems, for example, 
mucocutaneous, respiratory, cardiovascular, or gastrointestinal systems, that occurs very close to 
a prior dose (Sampson et al. 2006). 
For systemic hypersensitivity reactions or IRRs, which are not suspicious for anaphylaxis, after 
review of the data, and at the investigator’s discretion, the participant may be rechallenged. 
If rechallenge is planned, the participant may be premedicated for subsequent doses at the 
investigator discretion and according to local practice guidelines. Any premedication given will 
be documented as a concomitant therapy. 
Prior to initiating premedication or rechallenging, the investigator may consult with the Sponsor. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study 
 at any time at the participant’s own request for any reason or without 
providing any reason 
 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 enrolled in any other clinical study involving an investigational product, or 
enrolled in any other type of medical research judged not to be scientifically 
or medically compatible with this study 
 if the participant, for any reason, requires treatment with a therapeutic agent 
that is prohibited by the protocol and has been demonstrated to be effective 
for treatment of the study indication. In this case, discontinuation from the 
study occurs prior to introduction of the new agent 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
46 
 if the participant requires a ferromagnetic implant or insertion of a cardiac 
pacemaker that is not MRI compatible. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and follow-up, as shown in the SoA. If the participant has not 
already discontinued the study intervention, the participant will be permanently discontinued 
from the study intervention at the time of the decision to discontinue the study. 
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, the participant 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 they repeatedly fail 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 randomly assigned, 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. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
47 
8. 
Study Assessments and Procedures  
Study procedures and their timing are summarized in the SoA (Section 1.3). 
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. 
Amyloid PET Scan  
Amyloid PET scans provide a quantitative assessment of amyloid plaque deposition in the brain 
and can serve as a biomarker of clearance of amyloid deposits. 
Part of the study eligibility criteria is determined by amyloid PET scans. Additional amyloid 
PET scans will be performed as indicated in the SoA (Section 1.3). 
Personnel blinded to treatment allocation will assess the change in amyloid burden using the PET 
scan. 
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 procedures 
Specific imaging acquisition protocols designed to ensure consistency across sites will be 
provided in a PET Imaging Manual. 
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. 
PET scan safety 
The primary risk related to PET scans is radiation exposure. Details on the amount of exposure 
estimated to occur on each imaging occasion will be provided in the ICF. 
Only 1 of the ß-amyloid tracers, either florbetapir F18 or florbetaben F18, will be used at a given 
amyloid PET scan visit. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
48 
The table below shows the effective radiation dose from the PET scans. 
 
Effective 
Dose (mSv) 
per Scana 
Number of 
Scans in First 
Year 
Effective Dose 
(mSv) for 
Scans in First 
Year 
Number of 
Scans in 
Second Year 
Effective Dose 
(mSv) for 
Scans in 
Second Year 
Sum of 
Effective 
Dose (mSv) 
for Years 1 
and 2 
Florbetapir 
F18 Scan 
(10 mCi IV) 
7.43 
2 
14.86 
2 
14.86 
29.72 
Florbetaben 
F18 Scan 
(8.1 mCi 
IV) 
6.2 
2 
12.4 
2 
12.4 
24.8 
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. 
Number of scans allowed 
In the event a repeat scan is required, for example, the scan is not analyzable, 1 additional scan 
may be received in 1 year. 
In the event of an ED scan, up to 1 additional scan may be received in 1 year. 
The maximum number of scans per year is 3. 
8.1.2. 
Screening Mini Mental State Examination  
The MMSE is a brief instrument used to assess cognitive function in participants (Folstein et al. 
1975). The MMSE will be used for screening in this study. See Section 5.1. 
The instrument measures orientation, memory, and attention and 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. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
49 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical/Neurological Examinations  
A complete physical examination will include, at a minimum, assessments of these systems: 
 cardiovascular 
 respiratory 
 gastrointestinal, and 
 neurological. 
Height and weight will also be measured and recorded at screening and then just weight 
thereafter. 
The investigator may conduct a complete physical/neurological examination at any time a 
participant presents with physical complaints and is considered necessary. See details in the 
Manual of Operations. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2. 
Vital Signs  
Vital signs, including temperature, will be measured at all visits. Vital sign measurements 
include blood pressure, pulse, and temperature. 
For each participant, conduct vital signs measurements according to the SoA (Section 1.3). 
Measure vital signs before 
 obtaining an ECG tracing 
 collection of blood samples for laboratory testing, or 
 the start of infusion. 
 if possible, during an IRR or suspected hypersensitivity once participant is stabilized. 
Sitting blood pressure and pulse will be measured after 5 minutes in the sitting position at all 
visits. In addition, orthostatic blood pressure and pulse will be measured supine and standing at 
designated visits, as detailed in the SoA (Section 1.3).  
For orthostatic blood pressure monitoring, participants should be supine for at least 5 minutes 
and then stand for at least 3 minutes prior to taking the respective measurements. If the 
participant feels unable to stand, only supine vital signs will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. 
8.2.3. 
Electrocardiograms  
For each participant, collect a single 12-lead digital ECG according to the SoA. Record the ECG 
before collecting any blood. Participants must be supine for approximately 5 to 10 minutes 
before ECG collection and remain supine, but awake, during ECG collection. 
If deemed clinical necessary, ECGs may be obtained at additional times. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
50 
ECGs will be interpreted by the investigator or qualified designee at the study 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 the study entry criteria and for immediate participant 
management, if any clinically relevant findings are identified. 
8.2.4. 
Clinical Safety Laboratory Tests  
See Section 10.2 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 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 or 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 Section 10.2, 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, for example, SAE or AE or dose 
modification, then report the information as an AE. 
8.2.5. 
Suicidal Ideation and Behavior Risk Monitoring  
Participants 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. 
Families and caregivers of participants should be alerted about the need to monitor participants 
for the emergence of unusual changes in behavior, as well as the emergence of SIB and to report 
such symptoms immediately to the study investigator. 
Baseline assessment of SIB and intervention emergent SIB will be monitored during the study 
using the C-SSRS. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
51 
C-SSRS 
The 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 National Institute of 
Mental Health trial group for the purpose of being counterpart to the Columbia Classification 
Algorithm of Suicide Assessment categorization of suicidal events. 
The C-SSRS “Baseline” version will be used at Visit 2.  C-SSRS “Since Last Assessed” (Full 
version) scale will be administered at the subsequent visits as indicated in the SoA. C-SSRS must 
be administered by the clinician or appropriately trained study-site staff. 
One study partner is requested to be present (in person or on the phone) on all days the C-SSRS 
is administered. 
Timing of collection and AE monitoring 
Nonleading AE collection should occur prior to the collection of the C-SSRS. 
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. 
8.2.6. 
Hepatic Monitoring  
Close hepatic monitoring 
Initiating laboratory and clinical monitoring for abnormal liver laboratory test results 
Laboratory tests, including ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, 
and creatine kinase, should be repeated within 48 to 72 hours to confirm the abnormality and to 
determine if it is increasing or decreasing, if 1 or more of the conditions in this table occur. 
If a participant with baseline results of...  
Develops the following elevations… 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for participants with Gilbert’s 
syndrome) 
What to do if the abnormal condition persists or worsens 
If the abnormality persists or worsens, the investigator, in consultation with the Lilly-designated 
medical monitor, should initiate clinical and laboratory monitoring, and evaluation for possible 
causes of abnormal liver tests. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including 
 symptoms 
 recent illnesses, for example, heart failure, systemic infection, hypotension, or seizures 
 recent travel 
 history of concomitant medications, including over-the-counter, herbal, and dietary 
supplements, and 
 history of alcohol drinking and other substance abuse. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
52 
Frequency of monitoring 
Initially, monitoring of symptoms and hepatic biochemical tests should be done 1 to 3 times 
weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. 
Monitoring of ALT, AST, ALP, and TBL should continue until levels normalize or return to 
approximate baseline levels. 
Comprehensive hepatic evaluation 
When to perform a comprehensive evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of the conditions in this table 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 or 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 or 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 or symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
What a comprehensive evaluation should include 
At a minimum, this evaluation should include 
 physical examination and a thorough medical history, as outlined above 
 tests for 
o prothrombin time, INR 
o viral hepatitis A, B, C, or E, and 
o 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 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
53 
 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 
Collect additional hepatic safety data in hepatic safety CRFs if a study participant develops a 
hepatic event considered to be an SAE or discontinues study intervention due to a hepatic event 
or meets 1 of the conditions described in this table. 
If a participant with baseline results 
of...  
Develops the following elevations… 
ALT <1.5x ULN 
ALT to ≥5x ULN on 2 or more consecutive blood tests 
ALT ≥1.5x ULN 
ALT ≥3x baseline on 2 or more consecutive blood tests 
TBL <1.5x ULN 
TBL ≥2x ULN, except for participants with Gilbert’s syndrome 
TBL ≥1.5x ULN 
TBL ≥2x baseline  
ALP <1.5x ULN 
ALP ≥2x ULN on 2 or more consecutive blood tests 
ALP ≥1.5x ULN 
ALP to ≥2x baseline on 2 or more consecutive blood tests 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
54 
8.2.7. 
Magnetic Resonance Imaging  
Magnetic resonance imaging of the brain will be performed according to the SoA and as 
clinically indicated. The investigator may perform unscheduled MRIs if necessary. 
This technology will be used to check for evidence of ARIA-H or ARIA-E, and other clinically 
relevant safety findings. 
MRI sequence details for the study are in Section 8.2.7.1. 
MRI scan reviews 
The local review 
The standard MRI sequences will be reviewed by the investigator or qualified designee for 
immediate participant management. 
The exploratory MRI sequences should not be reviewed locally and will not impact participant 
management. 
The central review 
All MRI standard and exploratory sequences should be sent to centralized MRI vendor. 
The safety central review will only be based on the standard MRI sequences. 
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 or safety will be reported back to the 
investigator. 
Determination of MRI eligibility criteria 
Any clinically significant findings noted by the initial review by the investigator at screening that 
result in a diagnosis should be recorded as a preexisting condition or AE. 
The centralized MRI vendor will determine final MRI eligibility at screening and will report the 
MRI results to the investigator as “does” or “does not” meet MRI eligibility criteria. 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
55 
8.2.7.1. 
MRI Sequence Details for the Study  
The standard sequences will be used to determine participant eligibility, care and safety. 
The exploratory sequences will be used for exploratory analyses only and will not be used for 
participant management. 
This table provides MRI sequences and their timing throughout the study. 
Sequences 
Study Visits 
 
Screening/Before 
first infusiona 
Visit 4 
Week 4 
Visit 8 
Week 
12 
Visit 12 
Week 
24 
Visit 19 
Week 
52 
ED 
UV 
Standard 
 
 
 
 
 
 
 
  2D FLAIR 
X 
X 
X 
X 
X 
X 
X 
  2D T2 
X 
X 
X 
X 
X 
X 
X 
  GRE 
X 
X 
X 
X 
X 
X 
X 
  DWI 
X 
X 
X 
X 
X 
X 
X 
  3D T1 
X 
X 
X 
X 
X 
X 
X 
Exploratory 
 
 
 
 
 
 
 
  3D FLAIR 
X 
X 
X 
X 
X 
X 
X 
  3D T2 
X 
X 
X 
X 
X 
X 
X 
  DTIb 
X 
X 
X 
X 
X 
X 
X 
  SWIb 
X 
X 
X 
X 
X 
X 
X 
  Task-Fmrib 
X 
 
 
 
 
 
 
Abbreviations: DTI = diffusion tensor imaging; DWI = diffusion-weighted imaging; ED = early discontinuation 
visit; FLAIR = fluid-attenuated inversion recovery; Fmri = functional magnetic resonance imaging; 
GRE = gradient echo; SWI = susceptibility weighted imaging; UV = unscheduled visit. 
a Performed either with screening MRI or another time prior to first infusion at Visit 2. 
b Perform when or where available. 
Note: standard sequences denoted by bold text and shaded cells. 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
56 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Section 10.3: 
 AEs 
 SAEs, and 
 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 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention. 
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 or contacts. All SAEs and AEs of special interest as defined in Section 8.3.3 
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 Section 10.3. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
57 
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 
Backup 
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 
to study 
procedures or 
after receiving 
PET tracer 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hr 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 hr of 
awareness 
SAE CRF  
SAE paper 
form 
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 partners 
of male 
participants 
After the 
start of study 
intervention 
90 days after 
the last dose 
Within 24 hr  
(see Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
58 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Backup 
Method of 
Reporting 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hr of 
awareness 
Product Complaint 
Form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
Product Complaint 
Form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed Product 
Complaint 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 
Product Complaint 
Form 
 
a SAEs should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
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. 
After learning of a pregnancy in the female partner of a study participant, the investigator will 
 obtain a consent to release information from the pregnant female partner directly, 
and 
 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 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
59 
pregnancy will be reported regardless of gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
8.3.3. 
Adverse Events of Special Interest  
Specific safety topics of interest for this study include, but are not limited to 
 ARIA, and 
 hypersensitivity, immediate and non-immediate, including IRRs and anaphylaxis. 
The topics listed above, as well as other topics that may be subsequently determined by the Sponsor, 
will be subject to enhanced surveillance activities. 
8.3.3.1. 
Amyloid-Related Imaging Abnormalities (ARIA)  
While most cases of ARIA are asymptomatic, serious and life-threatening cases have been 
reported. Available data suggest serious cases are most likely to occur early in dosing, after the 
first, second, or third infusion of standard donanemab dosing. 
Symptoms possibly associated with ARIA 
Symptoms present in association with these imaging abnormalities may include, but are not 
limited to, headache, vomiting, unsteadiness, dizziness, tremor, confusion, visual disturbances, 
speech disturbances, worsening cognitive function, alteration of consciousness, and seizures 
(Ostrowitzki et al. 2012; Sperling et al. 2012; VandeVrede et al. 2020; Mintun et al. 2021; 
Swanson et al. 2021). 
Guidance for when a participant develops symptoms suggestive of ARIA 
If a participant simultaneously develops more than 1 of the symptoms suggestive of ARIA-E, 
then perform an unscheduled MRI. A single symptom suggestive of ARIA-E of sufficient 
severity may also warrant an unscheduled MRI. 
See Section 8.2.7 for additional instructions when conducting MRIs. 
MRI sequences for detecting ARIA 
If symptoms are reported, and ARIA-E is suspected, then the abnormality is best detected by 
FLAIR sequences on MRI. 
If symptoms are reported, and ARIA-H is suspected, then the abnormality is best detected with 
the T2 gradient-recalled echo on MRI. 
Guidance if ARIA is present 
If ARIA is present, repeat MRIs are recommended every 4 to 6 weeks until resolution of ARIA-
E or stabilization of ARIA-H. 
For asymptomatic or mild symptoms, the participant can be observed; for moderate symptoms 
associated with ARIA-E, the use of oral or IV steroids can be considered. In the case of severe 
symptoms associated with ARIA-E, it is recommended to hospitalize the participant for close 
observation and consider the use of IV steroids such as high-dose dexamethasone or a similar 
agent. See Manual of Operations and Section 7.1.2 for more guidance. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
60 
ARIA-E reporting 
If ARIA-E is present on MRI, the investigator will complete the CRF regarding the presence or 
absence of symptoms related to the ARIA-E and report the ARIA-E as an adverse event in the 
Adverse Events CRF. 
Temporary and permanent discontinuation of intervention guidance 
See Section 7.1.2 and the Manual of Operations for temporary and permanent discontinuation of 
intervention guidance. 
8.3.3.2. 
Hypersensitivity Reactions  
Hypersensitivity 
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. 
If such a reaction occurs, additional data should be provided to the Sponsor in the designated 
CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, sites should measure blood pressure, 
temperature and pulse, when able to do so, and collect additional blood samples as described in 
Section 10.2.1. Laboratory results are provided to the Sponsor via the central laboratory. 
8.4. 
Pharmacokinetics  
Serum samples will be collected for measurement of serum concentrations of study intervention 
as specified in the SoA. If IP infusion is permanently discontinued but the participant remains in 
the study, 1 PK sample should be collected at the soonest scheduled visit regardless if PK sample 
collection is on the SoA at that visit. Dosing dates and times should be collected. Subsequent PK 
sample collection should follow the protocol SoA unless the scheduled visit exceeds 6 months 
since discontinuation of infusions. No additional PK sample collection is required once the 
participant exceeds 6 months since discontinuation of infusions. 
The timing of sampling may be altered during the course of the study based on newly available 
data, for example, to obtain data closer to the time of peak plasma concentrations, to ensure 
appropriate monitoring. 
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. 
Bioanalytical samples remaining after the bioanalyses may be used for exploratory analyses, 
such as metabolism, protein binding, or bioanalytical method development or validation work. 
See Section 10.1.12 for details about sample retention and custody. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
61 
8.5. 
Pharmacodynamics  
The amyloid PET scan pharmacodynamic evaluations are described in Section 8.1.1. 
8.6. 
Genetics  
A blood sample for DNA isolation will be collected from participants. 
See Section 10.5 for information regarding genetic research and Section 10.1.12 for details about 
sample retention and custody. 
Apolipoprotein E genotyping 
An additional mandatory blood sample for APOE genotyping will be collected 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. 
8.7. 
Biomarkers  
Samples for biomarker research will be collected at the times specified in the SoA (Section 1.3), 
where local regulations allow. Sample test type is specified in Section 10.2. 
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 donanemab or research 
methods, 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, venous blood samples will be collected to determine 
antibody production against donanemab. Antibodies may be further characterized 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 9.3.7. 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 parameters are not evaluated in this study. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
62 
9. 
Statistical Considerations  
The SAP will be finalized prior to the first unblinding, and it will include a 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 objective of Study AACQ is to assess the effect of alternative donanemab dosing 
regimens compared to the standard donanemab dosing regimen on reducing the proportion of 
participants with occurrence of any ARIA-E event by 24 weeks. 
The primary analysis will be performed when all participants in the Safety Analysis Set (See 
Section 9.2) have had an opportunity to complete the Week 24 visit.  
The primary analysis will be a Bayesian logistic regression model for the primary endpoint of 
ARIA-E rate by Week 24. Note that throughout the document the term “ARIA-E rate” refers to 
the proportion of participants with any ARIA-E occurrence by a specific time point, and the 
same applies for the definition of ARIA-H rate. 
A mixture prior specification will be used to enable a formal dynamic use of historical data from 
other donanemab clinical studies for the ARIA-E rate by Week 24 in the standard dosing 
regimen. The Bayesian approach will compare the primary outcome, ARIA-E rate by Week 24, 
across the alternative donanemab dosing regimens. A Bayesian CSF will be established of the 
following form: 
Probability of at least X% relative reduction in ARIA-E rate by Week 24 with at least one 
of the alternative donanemab regimens compared to standard donanemab 
regimen > probability threshold. 
The Bayesian approach will be used to calculate the posterior probability of at least X% 
reduction in ARIA-E rates by Week 24 in each alternative donanemab regimen with respect to 
the standard regimen. If the posterior probability for at least 1 alternative regimen exceeds the 
prespecified probability threshold, the study will have met its primary endpoint. 
The exact CSF will be prespecified in the study SAP prior to the first unblinding of the primary 
endpoint. The margin of X% relative reduction in ARIA-E rate for the alternative regimens will 
be determined based on the clinical judgment. The probability threshold will be set to have a 
desired confidence level for the relative benefit of the alternative regimens, or to achieve the 
desired operating characteristics under a range of plausible scenarios of truth for the treatment 
effect. These scenarios include the null scenario where the alternative regimens would have 
similar ARIA-E frequency as the standard regimen. 
9.1.1. 
Multiplicity Adjustment  
Unless otherwise specified in the study SAP, no adjustments for multiplicity will be performed. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
63 
9.2. 
Analyses Sets  
Participant Analysis Set / 
Population 
Description 
Entered 
All participants who sign the ICF. 
Enrolled/intent-to-treat 
All participants randomly assigned to study treatment, regardless 
of whether they take any doses of study treatment, or if they took 
the correct treatment. Participants will be analyzed according to the 
treatment group to which they were assigned. 
Safety analysis set  
All participants randomly assigned to study treatment and who take 
at least 1 dose of study treatment. Participants will be analyzed 
according to the treatment group to which they were assigned.  
9.3. 
Statistical Analyses  
9.3.1. 
General Considerations  
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 
All analyses related to safety, including analyses for the primary endpoint, will be based on the 
Safety Analysis Set. 
The analysis for the secondary objective related to amyloid plaque deposition will be based on 
the Safety Analysis Set unless otherwise specified in the SAP. 
To allow for evaluation of the primary and secondary hypotheses at 24, 52, and 76 weeks, the 
assessments of corresponding primary and secondary objectives are expected to occur after all 
participants in the Safety Analysis Set have had the opportunity to complete visits 12, 19, and 25, 
respectively, including PET and MRI assessments. Data collected during the immunogenicity 
and safety follow-up period will be summarized and analyzed separately. 
For analyses using historical data, the sources of historical data and analysis considerations will 
be described in the SAP.  
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 non-missing observation collected prior to the first administration of study 
medications. 
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 CSR. Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Any adjustments 
to the planned analyses will be described in the final CSR. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
64 
 
9.3.2. 
Primary Endpoint Analysis  
Unless otherwise specified in the SAP, the primary endpoint will be based on the ARIA-E events 
as diagnosed by the scheduled or unscheduled MRIs up to and including Visit 12. 
The primary analysis will use a Bayesian logistic regression model to estimate and compare the 
relative reduction in ARIA-E rates by Week 24 for the alternative donanemab regimens versus 
the standard donanemab regimen. The logistic regression model will include the fixed effects for 
treatment, ApoE e4 status, and baseline amyloid level. The treatment effects will be presented in 
terms of the estimated odds ratios and relative reduction in ARIA-E rates by Week 24 for the 
alternative regimens relative to the standard regimen. The Bayesian CSF for the primary analysis 
will be defined in the SAP, and the 95% credible intervals will be provided for the key 
parameters of interest. 
The primary analysis model will have the ability to leverage information on the ARIA-E rate of 
the standard donanemab regimen by Week 24 through the construction of an informative prior 
using historical data. A mixture prior specification will be used to dynamically incorporate 
information based on the similarity in the ARIA-E rates of the standard regimen by Week 24 
compared to the historical data. The details of the analysis model along with the prior 
information and the details about the sources of historical data will be outlined in the SAP. 
A secondary analysis using the Bayesian logistic regression model for the primary endpoint will 
be fit using data from Study AACQ only, that is, in the absence of using historical data on the 
ARIA-E rate by Week 24. 
9.3.3. 
Secondary Endpoints Analysis  
Descriptive statistics will be presented for all primary and secondary ARIA-related endpoints. 
Bayesian modeling as described above for the primary endpoint will be performed for the 
secondary endpoint of ARIA-E frequency at 52 weeks. Further modeling may be performed on 
the other ARIA-related endpoints, such as ARIA-H, and will be described in the SAP. 
The frequency and severity of ARIA-E and of ARIA-H events will be summarized by 
symptomatic and asymptomatic events. 
Time to first occurrence of ARIA-E or other ARIA-related events, such as symptomatic ARIA-
E, may be analyzed and compared across the donanemab dosing regimens using a log-rank test 
for survival data. Participants who do not experience the event by the end of the study or drop 
out prior to the end of the study will be censored at their latest available time point. A Cox 
proportional-hazards model may also be used to analyze the data on time to event of first ARIA-
related incidence. Details of these analyses along with the endpoints will be provided in the SAP. 
To assess the effect of each alternative donanemab dosing regimen versus standard donanemab 
dosing regimen on brain amyloid deposition, a test of non-inferiority will be performed on the 
mean absolute change from baseline in brain amyloid plaque, from the amyloid PET scan, at 
Weeks 24, 52, and 76. Further details on defining margins for non-inferiority analyses will be 
described in the SAP. 
9.3.4. 
Tertiary/Exploratory Endpoints Analysis  
The analyses of tertiary endpoints will be specified in the SAP. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
65 
9.3.5. 
Safety Analyses  
An overview of AEs, including the number and percentage of participants who died, experienced 
SAEs, and discontinuations from study treatment due to an AE and TEAE, will be provided for 
all 4 dosing regimens. TEAE in the Safety Analysis Set will be defined as events that first 
occurred or worsened on or after the day of first infusion. 
Laboratory measurements will be analyzed using continuous data (change from baseline) and 
categorical or ordinal data (proportion of treatment-emergent abnormalities). If there are multiple 
records of laboratory measurements at baseline or postbaseline visit, the last record will be used. 
Vital sign measurements and weight will be analyzed using continuous data (change from 
baseline) and categorical data (proportion of potentially clinically significant changes). Vital sign 
measurements include systolic and diastolic blood pressure and pulse, orthostatic diastolic and 
orthostatic systolic blood pressures and orthostatic pulse, and temperature. 
Hypersensitivity and IRR will be analyzed by: 
 Potential immediate – defined as TEAEs occurring on the date of infusions, or for 
which a hypersensitivity follow-up form indicates the event occurred within 24 hours of 
study intervention administration, and 
 Potential non-immediate – defined as TEAEs that are not immediate but occur prior to 
the administration of a subsequent infusion. 
The number and percentage of participants who experienced a TEAE of hypersensitivity or IRR 
will be reported across the 4 treatment groups. 
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). 
9.3.6. 
Pharmacokinetic Analyses  
Compartmental modeling of donanemab PK data using nonlinear, mixed-effects modeling or 
other appropriate software may be explored, and population estimates for clearance and central 
volume of distribution may be reported. Depending on the model selected, other PK parameters 
may also be reported. 
Exploratory graphical analyses of the effect of dose level or demographic factors on PK 
parameters may be conducted. If appropriate, data from other studies of donanemab may be used 
in this analysis. 
The PK/PD relationships between serum donanemab concentration, ARIA incidence rate, or PD 
markers activity may be explored graphically. The relationship between the presence of 
antibodies to donanemab and PK, PD, safety, and/or efficacy may be assessed graphically. 
Additional modeling may be performed based on the results of the graphical analyses. 
Analyses will be detailed in a separate population PK/PD Analysis Plan. 
9.3.7. 
Evaluation of Immunogenicity  
The frequency and percentage of participants with preexisting ADA and with treatment-
emergent ADA to donanemab may be tabulated. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
66 
Treatment-emergent ADAs are defined as participants 
 with a titer 2-fold (1 dilution) greater than the minimum required dilution if no ADAs 
were detected at baseline (treatment-induced ADA) or 
 with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA). 
For the treatment-emergent ADA-positive participants, the distribution of maximum titers will be 
described. The frequency of neutralizing antibodies to donanemab may be tabulated in treatment-
emergent ADA-positive participants. 
The relationship between the presence of antibodies and the PK parameters and PD response, 
including safety and efficacy to donanemab, may be assessed. Additional details may be 
provided in the SAP. 
9.3.8. 
Handling of Missing Data  
For some secondary and exploratory endpoints, participants will be included in the analysis only 
if baseline and at least 1 postbaseline measurement are available; details will be given in the 
SAP. If data are missing, sensitivity analyses for endpoints or other imputation-based techniques 
for handling missing data may be considered and will be detailed in the SAP. 
9.3.9. 
Treatment Group Comparability  
9.3.9.1. 
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. 
9.3.9.2. 
Participant Characteristics  
These characteristics will be recorded: 
 participant’s age 
 sex 
 race 
 height 
 body weight 
 body mass index (weight (kg)/[height (m)]2) 
 APOE ε4 genotype 
 MMSE, and 
 having 1 or more first degree relatives with AD at baseline. 
Baseline characteristics will be summarized by treatment group and the overall population. 
Summaries will include descriptive statistics for continuous and categorical measures. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
67 
For categorical data, Fisher’s exact test or Pearson’s chi-square test will be used for treatment 
group comparisons. 
For continuous data, analysis of variance, with independent factors for treatment and 
investigator, will be used. 
9.3.9.3. 
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). 
Prior and concomitant medications will be listed. 
A summary of concomitant medications will be presented as frequencies and percentages for 
each treatment group. Medications will be coded using the World Health Organization drug 
dictionary. 
9.3.9.4. 
Treatment Compliance  
Summary statistics for treatment compliance will be provided for the 
 total number of complete infusions received 
 duration of complete infusion, and 
 volume of complete infusion by treatment group. 
Frequencies and percentages of reasons why infusion was stopped will also be presented. 
9.4. 
Interim Analysis  
Interim analyses may be conducted for Study AACQ. Potential interim analyses include safety 
analyses, futility, early efficacy, and sample size re-estimation. If performed, operational details 
and a quantitative framework to provide information for these decisions will be prespecified and 
documented in a separate analysis plan. 
9.5. 
Sample Size Determination  
Approximately 800 participants will be randomly assigned to 1 of 4 treatment arms in a 1:1:1:1 
ratio. This sample size will provide over 80% power to demonstrate that there is more than 80% 
probability that at least one of the alternative regimens will reduce the ARIA-E rate by at least 
20% compared to the standard regimen by 24 weeks. 
The study power was calculated based on an assumed relative benefit of 40% reduction in 
ARIA-E rate by Week 24 in each of the alternative donanemab regimens compared to the 
standard regimen. In power calculation, the true ARIA-E rate by Week 24 in the standard 
donanemab regimen is assumed to be 18.5% and informative prior is elicited from  the observed 
rate in historical data. 
In the null scenario where all of the dosing regimens have the same true ARIA-E rate of 18.5% 
by Week 24, the probability that the CSF is met (i.e., the false positive rate) is controlled at 5% 
one-sided, or equivalently 10% two-sided. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
68 
The power and false-positive rate of the study were determined by simulation using R 4.1.2. 
Multiple virtual clinical studies were simulated under both null and alternative scenarios, and the 
Bayesian logistic model was fit in each dataset to obtain the operating characteristics. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
69 
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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 Applicable ICH GCP Guidelines, and 
 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 Code of Federal Regulations, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
 Reporting to the Sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity 
● 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 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
70 
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 potential participant or the potential participant’s legally 
authorized representative, and answer all questions regarding the study. 
Potential 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 Code of Federal Regulations 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. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection  
Participants will be assigned a unique identifier by the Sponsor. Any participant records, 
datasets, or tissue samples that are transferred to the Sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable will not be 
transferred. 
The participant must be informed that 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  
10.1.5.1. Data Monitoring Committee  
An independent, external DMC will be responsible for reviewing unblinded data during the 
study. 
The committee will include, at a minimum, a physician with appropriate expertise and a 
statistician. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
71 
Access to the unblinded data will be limited to the DMC and the external Statistical Analysis 
Center statisticians who are providing the analysis of the data. These statisticians will be 
independent from the study team. The study team will not have access to the unblinded data. 
Only the DMC is authorized to evaluate unblinded interim analyses. 
Details about the membership, purpose, responsibilities, and operation will be included in the 
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. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, study not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The Sponsor provides access to all individual participant data collected during the study, after 
anonymization, with the exception of pharmacokinetic or genetic data. 
Data are available to 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, CSR, and blank or annotated case report 
forms, 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 review and confirm that data entries are accurate and complete throughout 
the duration of the study, by physically or electronically signing the CRF, as instructed by the 
Sponsor. All completed CRFs must be signed prior to archival. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source documents. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
72 
Quality tolerance limits will be predefined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These predefined parameters will be 
monitored during the study and important excursions from the quality tolerance limits, and 
remedial actions taken will be summarized in the CSR. 
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. 
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, for example, 
contract research organizations. 
The Sponsor or designee will perform monitoring to confirm that data transcribed 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 clinical trial agreement 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 electronic data capture 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 electronic data capture 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, clinical outcome assessment data (participant-focused outcome instrument) will be 
collected by authorized study personnel, via a paper source document, and will be transcribed by 
the authorized study personnel into the electronic data capture system. 
Data collected via the Sponsor-provided data capture system will be stored at a third party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. Prior to decommissioning, the investigator will receive or access an 
archival copy of pertinent data for retention. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
73 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the Sponsor data 
warehouse. 
Data from complaint forms submitted to the Sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.8. 
Source Documents  
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on 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. 
Study or site termination 
The Sponsor or Sponsor’s 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, and 
● total number of participants included earlier than expected. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
74 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy  
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 study. 
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 
donanemab or after donanemab becomes commercially available for AD. 
Sample Type 
Custodian 
Retention Period after Last Participant 
Visita 
Exploratory biomarkers  
Sponsor or Designee  
15 years  
Pharmacokinetic  
Sponsor or Designee  
1 year 
Immunogenicity  
Sponsor or Designee  
15 years  
a Retention periods may differ locally. 
 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
75 
10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in the table below will be performed by the Lilly-designated laboratory or by 
the local laboratory. 
Local laboratory results are only required if the central laboratory results are not available in 
time for either study intervention administration 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, 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. 
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
76 
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 
  
  Absolute count of: 
 
  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 (TBL) 
  
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  
  
Urinalysis 
Assayed by Lilly-designated laboratory. 
Specific gravity 
  
pH 
 
Protein 
 
Glucose 
 
Ketones 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
77 
Clinical Laboratory Tests 
Comments 
Blood 
 
Urine leukocyte esterase 
 
Chemistry 
 
High-sensitivity C-reactive protein (hsCRP) 
 
PK Samples – donanemab concentration 
Assayed by Lilly-designated laboratory. Results will not be 
provided to the investigators. 
Biomarkers 
Additional Testing 
Assayed by Lilly-designated laboratory. Results will not be 
provided to the investigators. 
Neurofilament light chain 
 
Glial fibrillary acidic protein 
 
sTREM2 
 
Apolipoprotein E (ApoE) 
Plasma pTau 
 
Amyloid-Beta 40 and 42 
 
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) 
  
  Whole Blood (PAXgene RNA) 
 
Immunogenicity Samples 
Assayed by Lilly-designated laboratory. Results will not be 
provided to the investigators.  
  Anti-donanemab antibodies  
  
  Anti-donanemab antibodies neutralization 
  
Abbreviations: EDTA = ethylenediaminetetraacetic acid; pTau = phosphorylated tau. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
78 
10.2.1. 
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity 
Event  
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The Sponsor will use the laboratory test results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed in the table below if a systemic hypersensitivity event is suspected. 
The timing should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up predose samples at the next regularly scheduled laboratory sample collection, 
ideally prior to the next dose after the event, to assess post-event return-to-baseline values. 
Timing 
Laboratory Testa 
Collect from 30 min to 4 hr after the start of 
the event. 
● 
Note: The optimal collection time is 
from 1 to 2 hr after the start of event. 
Total tryptase 
Complements (C3, C3a, and C5a)  
Cytokine panel (IL-6, IL‐1β, IL‐10, or any cytokine panel that 
includes these 3 cytokines) 
Collect only if not already collected on the 
same day as the event. 
● 
Note: If collecting, collect up to 12 hr 
after the start of the event. 
Donanemab antidrug antibodies (ADA) 
Donanemab concentration 
Abbreviation: IL = interleukin. 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be provided 
to the study site. If samples are not collected or are collected outside the specified time period, this will not be 
considered a protocol deviation. 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
79 
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 unfavorable 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, and 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 preexisting 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. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. 
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. 
 The disease or disorder being studied or expected progression, signs, or symptoms of the 
disease or 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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
80 
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more 
of the criteria listed: 
 Results in death 
 Is life threatening 
o 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. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
o 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. 
o Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an AE. 
 Results in persistent disability or incapacity 
o The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
o 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. 
 Is a congenital anomaly or birth defect 
o Abnormal pregnancy outcomes, for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy, are considered SAEs. 
 Other situations 
o 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. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
81 
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 PC 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 PCs: 
o deficiencies in labeling information, and 
o use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 PCs related to study interventions used in clinical trials are collected 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 they have a 
PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it should 
be reported as both a PC 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. 
 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 Product Complaint 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 PC 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 Product Complaint 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 or symptoms) will be documented as the AE/SAE. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
82 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 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 adverse event 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 an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe. 
An event is defined as “serious” when it meets at least 1 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. 
 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 in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that they have 
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 an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
83 
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 postmortem 
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) to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on an SAE paper form (see next section) or 
to the Sponsor by telephone. 
 Contacts for SAE reporting can be found on the SAE paper form. 
SAE reporting via paper form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the Sponsor. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found on the SAE paper form. 
10.3.6. 
Regulatory Reporting Requirements  
SAE regulatory reporting 
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward 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. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
84 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Word/Phrase 
Definition 
Women of 
childbearing 
potential 
(WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP.  
Women not of 
childbearing 
potential 
(WNOCBP) 
Females are considered WNOCBP if they 
 have a congenital anomaly, such as Müllerian agenesis 
 are infertile due to surgical sterilization, or 
 are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral 
salpingo-oophorectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal 
state 
The postmenopausal state is defined as a woman 
 at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or 
 aged at least 40 years and up to 55 years with an intact uterus, not 
on hormone therapya, 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 
 55 years or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea, or 
 aged at least 55 years with a diagnosis of menopause prior to 
starting hormone replacement therapy.  
a Women should not be taking medications during amenorrhea, such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that could induce transient amenorrhea. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
85 
10.4.2. 
Contraception Guidance  
For male participants 
 Males may participate in this study. 
 No male contraception is required except in compliance with specific local government 
study requirements. 
For female participants 
 Women of childbearing potential are excluded from the study. 
 Women not of childbearing potential may participate in this study. 
This table provides examples of highly effective, effective, and unacceptable methods of 
contraception. 
Methods 
Examples 
Highly effective 
contraception  
(less than 1% failure rate) 
 
female sterilization 
 
combination oral contraceptive pill 
 
progestin-only contraceptive pill (mini-pill) 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by hysterosalpingogram) 
 
combined contraceptive vaginal ring, or 
 
intrauterine devices 
Effective contraception 
 
male or female condoms with spermicide 
 
diaphragms with spermicide or cervical sponges 
 
barrier method with use of a spermicide 
o 
condom with spermicide 
o 
diaphragm with spermicide, or 
o 
female condom with spermicide 
Ineffective forms of 
contraception whether used 
alone or in any 
combination 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, temperature method, cervical 
mucus, or symptothermal) 
 
withdrawal 
 
postcoital douche, or 
 
lactational amenorrhea 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
86 
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 or assays, including diagnostic 
tests related to donanemab or other amyloid targeting interventions and AD. 
Genetic research may consist of the analysis of 1 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 CSR 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 AD diagnosis, 
progression, treatment, and monitoring continues but no longer than 15 years or 
other period as per local requirements. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
87 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic evaluation testing 
See Section 8.2.6 for guidance on appropriate test selection. 
The Lilly-designated central laboratory should complete the analysis of all selected testing 
except for testing listed in the investigator-designated local laboratory table. The central 
laboratory will report results if a validated test or calculation is available. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
Hepatitis A virus (HAV) testing 
   Hemoglobin 
    HAV total antibody 
   Hematocrit 
    HAV IgM antibody 
   Erythrocytes (RBCs - red blood cells) 
Hepatitis B virus (HBV) testing 
   Leukocytes (WBCs - white blood cells) 
    Hepatitis B surface antigen (HbsAg) 
   Differential: 
    Hepatitis B surface antibody (anti-HBs) 
       Neutrophils, segmented 
    Hepatitis B core total antibody (anti-HBc) 
       Lymphocytes 
    Hepatitis B core IgM antibody 
       Monocytes 
    HBV DNAa 
       Basophils 
Hepatitis C virus (HCV) testing 
       Eosinophils 
    HCV antibody 
   Platelets 
    HCV RNAa 
   Cell morphology (RBC and WBC) 
Hepatitis D virus (HDV) testing 
Hepatic Clinical Chemistry Panel 
    HDV antibody 
   Total bilirubin 
Hepatitis E virus (HEV) testing 
   Direct bilirubin 
    HEV IgG antibody 
   Alkaline phosphatase (ALP) 
    HEV IgM antibody 
   Alanine aminotransferase (ALT) 
    HEV RNAa 
   Aspartate aminotransferase (AST) 
Anti-nuclear antibody (ANA) 
   Gamma-glutamyl transferase (GGT) 
Anti-smooth muscle antibody (ASMA)b 
   Creatine kinase (CK) 
Anti-actin antibodyc 
Hepatic Coagulation Panel 
Immunoglobulin IgA (quantitative) 
   Prothrombin time, INR (PT-INR) 
Immunoglobulin IgG (quantitative) 
Urine Chemistry 
Immunoglobulin IgM (quantitative) 
   Drug screen 
Epstein-Barr virus (EBV) testing 
Haptoglobin 
    EBV antibody 
a Reflex or confirmation dependent on regulatory requirements, testing availability, or both. 
b Not required if anti-actin antibody is tested. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
88 
Tests assayed ONLY by investigator-designated local laboratory  
Acetaminophen 
Cytomegalovirus (CMV) testing: 
Acetaminophen protein adducts 
    CMV antibody 
Alkaline phosphatase isoenzymes 
    CMV DNAa 
Ceruloplasmin 
Herpes simplex virus (HSV) testing: 
Copper 
    HSV (Type 1 and 2) antibody 
Ethyl alcohol (EtOH) 
    HSV (Type 1 and 2) DNAa 
Phosphatidylethanol (Peth) 
Liver kidney microsomal type 1 (LKM-1) antibody 
Urine Chemistry 
Microbiology 
   Ethyl glucuronide (EtG) 
Culture 
Epstein-Barr virus (EBV) testing 
    Blood 
   EBV DNAa 
    Urine 
a Reflex or confirmation dependent on regulatory requirements, testing availability, or both. 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
89 
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the Sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the Sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies, and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required, for example, upon implementation and suspension of changes. All 
approvals and notifications must be retained in the study records. 
If the Sponsor grants written approval for changes in study conduct, the Sponsor will also 
provide additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study. 
Informed consent 
Additional consent from the participant and study partner(s) will be obtained for the below items, 
as required by ERB’s and local regulations. 
Additional consent from the participant and study partner(s) will be obtained, if required, for 
 participation in remote visits, as defined in Section “Remote Visits” 
 a change in the method of study intervention administration 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
90 
The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, 
but are not limited to 
 AE collection 
 concomitant medication review, or 
 administration of the C-SSRS. 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider 
at locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the Sponsor. Procedures 
performed at such visits include, but are not limited to 
 AE collection 
 concomitant medication review 
 administration of study intervention 
 blood sample collection, and 
 safety assessments. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the Sponsor to determine appropriate actions. These actions may 
include working with the Sponsor to determine how study intervention that is typically 
administered on site will be administered to the participant; for example, during a mobile 
healthcare visit or at an alternate location such as an infusion center. 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
91 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site, the investigator, 
Sponsor, or both should ensure oversight of the shipping process to ensure 
accountability and product quality (that is, storage conditions maintained and intact 
packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
If study intervention will be administered to the participant during a mobile healthcare visit 
or at an alternate location, these additional requirements must be met: 
 Only authorized study personnel may supply, prepare, or administer study 
intervention. 
 The main protocol safety requirements related to study intervention administration 
must be followed, for example 
o postinfusion observations 
o infusion duration 
o storage 
o preparation and handling of study intervention, and 
o resuscitation equipment. 
 Mobile healthcare personnel will be licensed healthcare providers with advanced life 
support training to manage emergency situations, for example, Advanced 
Cardiovascular Life Support certification. 
Screening period guidance 
To ensure safety of study participants, the site should follow the rules described in the protocol. 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual Schedule of Activities. To maximize the possibility that these visits 
can be conducted as on-site visits, the windows for visits may be adjusted, upon further guidance 
from the Sponsor. This minimizes missing data and preserves the intended conduct of the study. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing or shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
92 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
93 
10.8. 
Appendix 8: Abbreviations and Definitions  
Term 
Definition 
abuse 
use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AD 
Alzheimer’s disease 
ADA 
antidrug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARIA-E 
amyloid-related imaging abnormalities that show cerebral edema 
ARIA-H 
amyloid-related imaging abnormalities that show cerebral microhemorrhages 
AST 
aspartate aminotransferase 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labeling of the medicinal product, 
which is used as an investigational medicinal product 
authorized AxMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, 
which is used as an auxiliary medicinal product 
AxMP 
auxiliary medicinal product. See also NIMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment. AxMP does not include investigational medicinal product (IMP) or 
concomitant medications. Concomitant medications are medications unrelated to the 
clinical trial and not relevant for the design of the clinical trial 
blinding/masking 
A single-blind study is one in which the investigator and/or the investigator’s staff are 
aware of the treatment but the participant is not, or vice versa, or when the Sponsor is 
aware of the treatment but the investigator and/the investigator’s staff and the 
participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or Sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CIOMS 
Council for International Organizations of Medical Sciences 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
94 
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 
CONSORT 
Consolidated Standards of Reporting Trials 
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 study participant 
CSF 
critical success factor 
CSR 
clinical study report 
CT 
computerized tomography 
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 harm, or for futility. 
The composition of the committee is dependent upon the scientific skills and 
knowledge required for monitoring the particular study. 
ECG 
Electrocardiogram 
ED 
early discontinuation 
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. 
GCP 
good clinical practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical study. 
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. 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
95 
Interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the complete reporting database for the primary outcome is 
created/locked. 
Investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, 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. See also “IMP.” 
IRB 
Institutional Review Boards 
IRR 
Infusion-related reactions 
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 assigned 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 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold 1 or more of 
the 5 “rights” of medication use: the right participant, the right drug, the right dose, 
right route, at the right time. 
In addition to the core 5 rights, the following may also represent medication errors: 
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication’s labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both 
Misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MMSE 
Mini Mental State Examination 
MRI 
magnetic resonance imaging 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
96 
NIMP 
Non-investigational Medicinal Product See AxMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment. 
Participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical study, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PET 
positron emission tomography 
PK/PD 
pharmacokinetics/pharmacodynamics 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
screen 
the act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study 
SIB 
suicidal ideation and behavior 
sTREM2 
soluble triggering receptor expressed on myeloid cells 2 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment 
ULN 
upper limit of normal 
 
 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
97 
11. 
References  
AmyvidTM [package insert]. Indianapolis, IN: Eli Lilly and Company; 2012. 
Amyvid [Summary of Product Characteristics]. Utrecht, The Netherlands: Eli Lilly Nederland 
B.V.; 2021. 
[CUIMC] Columbia University Irving Medical Center. Columbia-Suicide Severity Rating Scale 
(C-SSRS). The Columbia Lighthouse Project website. 2016. Accessed December 18, 2020. 
https://www.cssrs.columbia.edu 
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. 
http://doi.org/10.1016/0022-3956(75)90026-6 
Hayato S, Reyderman L, Zhang Y, et al. OC14: BAN2401 and ARIA-E in early Alzheimer’s 
disease: pharmacokinetic / pharmacodynamic time-to-event analysis from the phase 2 study in 
early Alzheimer’s disease. J Prev Alzheimers Dis. 2020;7(Suppl 1): 2-54. 
https://doi.org/10.14283/jpad.2020.54 
Mintun MA, Lo AC, Evans CD, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 
2021;384(18):1691-1704. https://doi.org/10.1056/NEJMoa2100708 
NeuraceqTM [package insert]. Matran, Switzerland: Piramal Imaging; 2014. 
Neuraceq [Summary of Product Characteristics]. Berlin, Germany: Life Radiopharma Berlin 
GmbH; 2021. 
Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with 
Alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69(2):198-207. 
https://doi.org/10.1001/archneurol.2011.1538 
Salloway S, Chalkias S, Barkhof F, et al. Amyloid-related imaging abnormalities in 2 phase 3 
studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 
2022;79(1):13-21. https://doi.org/10.1001/jamaneurol.2021.4161 
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report—Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol. 2006;117(2):391-7. https://doi.org/ 10.1016/j.jaci.2005.12.1303. 
Shcherbinin S, Evans C, Lu M, et al. Association of Amyloid Reduction After Donanemab 
Treatment With Tau pathology and Clinical Outcomes The TRAILBLAZER-ALZ 
Randomized Clinical Trial. JAMA Neurol. Published September 12, 2022. 
https://doi.org/10.1001/jamaneurol.2022.2793 
Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in patients 
with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 
2012;11(3):241-249. https://doi.org/10.1016/S1474-4422(12)70015-7 
Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept 
clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. 
Alzheimers Res Ther. 2021;13(1):80. https://doi.org/10.1186/s13195-021-00813-8 
Approved on 26 May 2023 GMT

CONFIDENTIAL 
I5T-MC-AACQ(a) 
98 
VandeVrede L, Gibbs DM, Koestler M, et al. Symptomatic amyloid-related imaging 
abnormalities in an APOE ε4/ε4 patient treated with aducanumab. Alzheimer's Dement (Amst). 
2020;12(1):e12101. https://doi.org/10.1002/dad2.12101 
Approved on 26 May 2023 GMT

Si g nat ure Pa ge f or V V- C LI N- 1 1 4 9 9 8 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 1 1 4 9 9 8 v 1. 0
A p pr o val
Direct or
2 6- Ma y- 2 0 2 3 1 5: 1 7: 2 8 G M T + 0 0 0 0
A p pr o val
2 6- Ma y- 2 0 2 3 1 8: 2 1: 1 7 G M T + 0 0 0 0
A p pr o ve d o n 2 6 Ma y 2 0 2 3 G M T
P P D
P P D