A Parallel-group Treatment, Phase 1, Participant- and Investigator-Blind, Randomized Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Intravenous Dose of Donanemab Compared With Placebo in Healthy Chinese Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol I5T-MC-AACK(a) 
A Parallel-group Treatment, Phase 1, Participant- and Investigator-Blind, Randomized, 3 Arm 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Intravenous Dose of 
Donanemab Compared with Placebo in Healthy Chinese Participants 
NCT05533411 
Approval Date: 17-Jun-2022 

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I5T-MC-AACK(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: A Parallel-group Treatment, Phase 1, Participant- and Investigator-Blind, 
Randomized, 3 Arm Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Single Intravenous Dose of Donanemab Compared with 
Placebo in Healthy Chinese Participants 
Protocol Number: I5T-MC-AACK 
Amendment Number: AACK(a) 
Compound: Donanemab (LY3002813) 
Brief Title: A Parallel-group Treatment Phase 1 Study of Single Intravenous Dose of 
Donanemab in Healthy Chinese Participants 
Study Phase: 1 
Acronym: AACK 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Eli Lilly and Company, Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Number 
IND: 109157 
Approval Date: Protocol Amendment (a) Electronically Signed and Approved by Lilly on date 
provided below. 
 
Document ID: VV-CLIN-062541 
 
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I5T-MC-AACK(a) 
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Medical Monitor Name and Contact Information will be provided separately 
 
 
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I5T-MC-AACK(a) 
3 
Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
11-Jan-2022 
Amendment [a]  
Overall Rationale for the Amendment: 
The protocol is being amended to 
 update the clinical laboratory tests to allow flexibility for testing of blood urea nitrogen or 
urea 
 improve clarity on contraception and barrier guidance, and 
 to accommodate changes as per updated protocol template. 
A high-level description of the change(s), with a brief rationale, is outlined in the table below. 
Minor or editorial changes have not been mentioned in the table. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Specified 
 regulatory agency identifier number 
 study population, and 
 ethical considerations of benefit/risk. 
Changes were included as per 
updated protocol template. 
5.1 Inclusion 
Criteria 
 Updated language regarding 
contraceptive requirements for male 
participants. 
 Updated examples of surgical 
sterilization for definition of 
WNOCBP. 
 No contraception is 
required by male 
participants participating 
in this study. 
 Changes were included as 
per updated definitions for 
WNOCBP. 
8.2.6.2 Hepatic 
Safety 
Updated the abnormalities that may occur 
upon close hepatic monitoring or 
comprehensive hepatic evaluation. 
Updated the elevations that 
may occur if a participant had 
baseline results more than 
1.5× ULN. 
8.3.1 Timing and 
Mechanism for 
Collecting 
Events 
Updated collection stop timing for 
pregnancy events. 
The overall study period was 
more than 56-60 days, which 
is at least 5 terminal half-lives 
after the last dose of study 
drug. 
10.1 Appendix 1: 
10.1.1 
Updated the responsibilities of the study 
investigator. 
Changes were included as per 
updated protocol template. 
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I5T-MC-AACK(a) 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Regulatory and 
Ethical 
Considerations 
10.2 Appendix 2: 
Clinical 
Laboratory Tests 
 Deleted bicarbonate testing. 
 Added urea. 
 Added footnote for BUN or urea 
testing. 
Tests were included or 
removed depending on 
feasibility of testing. The 
footnote was added to allow 
flexibility for testing of BUN 
or urea. 
10.4 Appendix 4: 
Contraceptive 
and Barrier 
Guidance 
 
The following have been updated: 
 Section 10.4.1 Definitions 
o Examples of surgical sterilization 
for definition of WNOCBP.  
 Section 10.4.2 Contraception 
Guidance 
o Male and female participation in 
this trial. 
o Table for contraception guidance 
for men has been deleted. 
o examples of highly effective 
methods of contraception for 
females, and 
o ineffective forms of contraception. 
 Changes were included as 
per updated definitions for 
contraceptive and barrier 
guidance. 
 No contraception is 
required by male 
participants participating 
in this study. 
 
10.5 Appendix 5: 
Liver Safety: 
Suggested 
Actions and 
Follow-up 
Assessments 
Updated hepatic evaluation testing panel. 
Changes were included as per 
updated liver safety 
assessments. 
10.7 Appendix 7: 
Abbreviations 
and Definitions 
Updated list of abbreviations and 
definitions, where applicable.  
Only abbreviations and 
definitions used in this 
document have been retained. 
Abbreviations: BUN = blood urea nitrogen; IP = investigational product; ULN = upper limit of normal; WNOCBP = 
women not of childbearing potential. 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................11 
1.3. 
Schedule of Activities (SoA) ..........................................................................................12 
2. 
Introduction ...................................................................................................................15 
2.1. 
Study Rationale ...............................................................................................................15 
2.2. 
Background .....................................................................................................................15 
2.3. 
Benefit/Risk Assessment ................................................................................................16 
3. 
Objectives and Endpoints ............................................................................................18 
4. 
Study Design ..................................................................................................................19 
4.1. 
Overall Design ................................................................................................................19 
4.1.1. 
Screening Period .............................................................................................................19 
4.1.2. 
Inpatient Period ...............................................................................................................19 
4.1.3. 
Follow-up Period ............................................................................................................19 
4.2. 
Scientific Rationale for Study Design ............................................................................19 
4.3. 
Justification for Dose ......................................................................................................20 
4.4. 
End of Study Definition ..................................................................................................20 
5. 
Study Population ...........................................................................................................21 
5.1. 
Inclusion Criteria ............................................................................................................21 
5.2. 
Exclusion Criteria ...........................................................................................................22 
5.3. 
Lifestyle Considerations .................................................................................................23 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................24 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................24 
5.3.3. 
Activity ...........................................................................................................................24 
5.4. 
Screen Failures ................................................................................................................24 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................24 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................25 
6.1. 
Study Intervention(s) Administered................................................................................25 
6.1.1. 
Administration Details ....................................................................................................25 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................26 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................27 
6.4. 
Study Intervention Compliance ......................................................................................28 
6.5. 
Dose Modification ..........................................................................................................28 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................28 
6.7. 
Treatment of Overdose ...................................................................................................28 
6.8. 
Concomitant Therapy .....................................................................................................28 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................30 
7.1. 
Discontinuation of Study Intervention ............................................................................30 
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7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................30 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................30 
7.3. 
Lost to Follow-up............................................................................................................31 
8. 
Study Assessments and Procedures.............................................................................32 
8.1. 
Efficacy Assessments .....................................................................................................32 
8.2. 
Safety Assessments .........................................................................................................32 
8.2.1. 
Physical Examinations ....................................................................................................32 
8.2.2. 
Vital Signs .......................................................................................................................33 
8.2.3. 
Electrocardiograms .........................................................................................................33 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................34 
8.2.5. 
Pregnancy Testing ...........................................................................................................34 
8.2.6. 
Safety Monitoring ...........................................................................................................35 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................37 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................38 
8.3.2. 
Pregnancy ........................................................................................................................39 
8.4. 
Pharmacokinetics ............................................................................................................39 
8.4.1. 
Bioanalysis ......................................................................................................................40 
8.5. 
Pharmacodynamics .........................................................................................................40 
8.6. 
Genetics ..........................................................................................................................40 
8.7. 
Biomarkers ......................................................................................................................40 
8.8. 
Immunogenicity Assessments.........................................................................................41 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................41 
9. 
Statistical Considerations .............................................................................................42 
9.1. 
Statistical Hypotheses .....................................................................................................42 
9.1.1. 
Multiplicity Adjustment ..................................................................................................42 
9.2. 
Analyses Sets ..................................................................................................................42 
9.3. 
Statistical Analyses .........................................................................................................42 
9.3.1. 
General Considerations ...................................................................................................42 
9.3.2. 
Primary Endpoint Analysis .............................................................................................43 
9.3.3. 
Secondary Endpoint Analysis .........................................................................................43 
9.3.4. 
Exploratory Endpoint Analysis .......................................................................................43 
9.4. 
Interim Analysis ..............................................................................................................43 
9.5. 
Sample Size Determination ............................................................................................44 
10. 
Supporting Documentation and Operational Considerations ..................................45 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................45 
10.1.1. Regulatory and Ethical Considerations ...........................................................................45 
10.1.2. Financial Disclosure........................................................................................................46 
10.1.3. Informed Consent Process ..............................................................................................46 
10.1.4. Data Protection................................................................................................................46 
10.1.5. Committees Structure......................................................................................................46 
10.1.6. Dissemination of Clinical Study Data.............................................................................47 
10.1.7. Data Quality Assurance ..................................................................................................47 
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I5T-MC-AACK(a) 
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10.1.8. Source Documents ..........................................................................................................48 
10.1.9. Study and Site Start and Closure ....................................................................................49 
10.1.10. Publication Policy ...........................................................................................................49 
10.1.11. Investigator Information .................................................................................................49 
10.1.12. Sample Retention ............................................................................................................49 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................50 
10.2.1. Blood Sampling Summary ..............................................................................................52 
10.2.2. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................52 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................54 
10.3.1. Definition of AE .............................................................................................................54 
10.3.2. Definition of SAE ...........................................................................................................55 
10.3.3. Definition of Product Complaints ...................................................................................56 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................56 
10.3.5. Reporting of SAEs ..........................................................................................................58 
10.3.6. Regulatory Reporting Requirements ...............................................................................58 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................60 
10.4.1. Definitions.......................................................................................................................60 
10.4.2. Contraception Guidance..................................................................................................61 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................62 
10.6. 
Appendix 6: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................64 
10.7. 
Appendix 7: Abbreviations and Definitions ...................................................................67 
11. 
References ......................................................................................................................70 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
A Parallel-group Treatment, Phase 1, Participant- and Investigator-Blind, Randomized, 3 Arm 
Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Intravenous Dose of 
donanemab Compared with Placebo in Healthy Chinese Participants 
Brief Title:  
A Parallel-group Treatment Phase 1 Study of Single Intravenous Dose of donanemab in Healthy 
Chinese Participants 
Regulatory Agency Identifier Number:  
IND: 109157 
Rationale: 
Study I5T-MC-AACK will investigate the safety, tolerability, and pharmacokinetics (PK) of 
single dose intravenous (IV) administration of donanemab in healthy Chinese participants. 
 
 
 
Objectives, and Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
To investigate the safety and tolerability of 
donanemab versus placebo following single 
dose IV administration in healthy Chinese 
participants 
 
Incidence of treatment-emergent adverse 
events and serious adverse events 
Secondary 
 
To characterize the pharmacokinetic profile of 
donanemab following single dose IV 
administration in healthy Chinese participants 
 
Cmax, and AUC0-∞ 
Abbreviations: AUC0-∞ = area under the concentration versus time curve from time 0 to infinite time; 
Cmax = maximum observed drug concentration; IV = intravenous. 
Overall design 
This is a parallel treatment, Phase 1, participant- and investigator-blind, placebo-controlled, 
randomized study to evaluate the safety, tolerability, and PK of a single IV dose of donanemab in 
healthy Chinese participants. This study will be conducted in China. Up to 36 participants may 
be enrolled so that approximately 30 participants complete the study. 
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I5T-MC-AACK(a) 
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The study will include 3 cohorts, each with 12 participants randomized in a 5 (donanemab): 1 
(placebo) ratio. The planned doses are: 
 Cohort 1: 350 mg IV single dose, 
 Cohort 2: 700 mg IV single dose, and  
 Cohort 3: 1400 mg IV single dose.  
Brief summary: 
The purpose of this study is to investigate the safety, tolerability, and PK with donanemab 
compared with placebo in healthy Chinese participants. 
Study details include: 
● Study duration: approximately 85 days. 
● Treatment duration: single dose on Day 1. 
● Visit frequency: approximately weekly to once in 2 weeks. 
Study Population: 
Study AACK will be conducted in young healthy Chinese participants. 
Number of participants:  
Approximately 36 participants will be enrolled to study intervention.  
Intervention groups and duration: 
Screening period: 28 days prior to randomization, 
Inpatient period: Day -1 to Day 5; Single IV dose of donanemab (350 mg, 700 mg, or 1400 mg) 
or placebo on Day 1, and  
Follow-up period: 12 weeks ± 7 days after completion of dosing or until early discontinuation. 
Ethical Considerations of Benefit/Risk: 
The following are the risks and discomforts associated with donanemab: 
 amyloid-related imaging abnormalities (ARIA) 
 treatment-emergent anti-drug antibodies (TE-ADAs), and 
 infusion-related reactions (IRRs) and hypersensitivity. 
o 
In Study AACK, amyloid-related imaging abnormality–edema/effusions (ARIA-E) and 
amyloid-related imaging abnormality–hemorrhage/hemosiderin deposition (ARIA-H) events 
are not expected given the young healthy population being enrolled. These participants are 
expected to not have amyloid deposits in their brain and thus the risk of ARIA-E and ARIA-H 
is considered low. 
o 
TE-ADAs have been observed after a single dose of donanemab across all dose levels 
assessed, including the single cohort of healthy participants in Study I5T-MC-AACC (AACC). 
Therefore, TE-ADAs will be carefully monitored in this study. 
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I5T-MC-AACK(a) 
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o 
IRRs have been observed in Studies AACC, I5T-MC-AACD, and I5T-MC-AACG. All 
biological agents carry the risk of systemic allergic and hypersensitivity reactions and patients 
should be monitored for the occurrence of these reactions. 
Data Monitoring Committee: No 
 
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I5T-MC-AACK(a) 
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1.2. 
Schema 
 
Abbreviations: IV = intravenous; LY = LY3009813; N = number of participants; PBO = placebo. 
 
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I5T-MC-AACK(a) 
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1.3. 
Schedule of Activities (SoA) 
Study Schedule Protocol I5T-MC-AACK 
 
Procedure 
Screening 
Inpatient period 
Follow-up 
Comments 
Study Day (D)  
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
±1d 
15 
±1d 
22 
±1d 
29 
±1d 
43 
±4d 
57 
±4d  
71 
±4d 
85/ED
±7d 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admit to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Outpatient visit 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Donanemab/placebo 
administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history，
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, height, BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical exam at screening and 
symptom-directed physical 
assessment at other timepoints and 
as deemed necessary by investigator 
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Procedure 
Screening 
Inpatient period 
Follow-up 
Comments 
Study Day (D)  
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
±1d 
15 
±1d 
22 
±1d 
29 
±1d 
43 
±4d 
57 
±4d  
71 
±4d 
85/ED
±7d 
 
Neurological exam 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Vital signs (supine): 
blood pressure, pulse 
rate, temperature 
(hour)a 
X 
X 
0, 6 
24 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Time points may be added if 
warranted and agreed upon between 
Lilly and the investigator. 
12-lead ECG (hour)a 
X 
 
0, 6 
24 
 
 
X 
 
 
 
X 
 
 
 
X 
Single ECG 
AE and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical lab tests 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
Includes hematology, clinical 
chemistry, urinalysis 
Serologyb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen, 
Hepatitis C antibody, HIV antibody 
Ethanol and urine 
drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For postmenopausal females only 
Pharmacokinetic 
sampling (hours)d  
 
 
P, 
end 
of 
infus
-ion, 
3 
24 
48 
72 
96 
X 
X 
X 
X 
X 
X 
 
X 
Sampling times are relative to the 
time of study treatment 
administration (0 min). 
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I5T-MC-AACK(a) 
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Procedure 
Screening 
Inpatient period 
Follow-up 
Comments 
Study Day (D)  
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
±1d 
15 
±1d 
22 
±1d 
29 
±1d 
43 
±4d 
57 
±4d  
71 
±4d 
85/ED
±7d 
 
Immunogenicity 
samplingd 
 
 
P 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Pharmacogenetic 
samplee – 
apolipoprotein E 
genotype ε4  
 
 
P 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BMI = body mass index; CRU = clinical research unit; D = day; ECG = electrocardiogram; ED = early discontinuation; FSH 
= follicle stimulating hormone; I/E = inclusion/exclusion criteria; P = predose. 
a 
Times with respect to start of dosing. ECGs, blood pressure, and pulse rate after 5 minutes supine. Zero-hour collection within 2 hours before dosing. Time 
allowances (minutes): 6 hour (±30), 24 hour (±90). 
b These tests may be waived if performed within 6 months prior to screening, and if test results are available for “review” for Hepatitis B, C and HIV 
c 
Females only. Serum pregnancy test at screening and urine pregnancy test at other timepoints as indicated or when performed at investigator’s discretion 
d 
Assayed by Lilly-designated laboratory.  
e 
Pharmacogenetic sampling for apolipoprotein E genotype ε4 carrier status will be collected as allowed by local regulations. 
 
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I5T-MC-AACK(a) 
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2. 
Introduction 
LY3002813 (donanemab) is a humanized immunoglobulin (Ig) 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 Alzheimer’s disease (AD). 
2.1. 
Study Rationale 
Study I5T-MC-AACK (AACK) will investigate the safety, tolerability, and pharmacokinetics 
(PK) of single dose intravenous (IV) administration of donanemab in healthy Chinese 
participants.
 
 
2.2. 
Background 
Alzheimer’s disease is an age-related neurodegenerative disorder characterized by a progressive 
decline in cognitive function and a decline in ability to perform activities of daily living. It can 
ultimately lead to death due to complications of the disease. Strong genetic and biochemical 
evidence highlights a central role of the amyloid pathway in the pathogenesis of AD (Hardy and 
Selkoe, 2002).  
Pathologic hallmarks of AD identified at autopsy include the presence of neuritic Aβ plaques, 
neurofibrillary tangles (Hyman et al. 2012), and neuronal loss in brain regions important for 
cognition, such as the hippocampus and temporal cortex (Selkoe, 1991). Pathological data 
obtained from patients with AD demonstrate that extensive plaque deposition exists in the patient 
population well before the first memory complaint (Morris and Price, 2001; Jack et al. 2010).  
Immunotherapy is an increasingly promising therapeutic approach that is focused on using 
antibodies to facilitate clearance of pathogenetic peptides, such as the Aβ peptide 
(Avgerinos et al. 2021). The mechanism of action of donanemab is considered to be targeting 
and removal of existing amyloid plaques. The clinical strategy for donanemab is based on the 
amyloid hypothesis of AD, which states that the production and deposition of A plaques is an 
early and necessary event in the pathogenesis of AD. Clinical support for this hypothesis comes 
from the demonstration that parenchymal Aβ levels are elevated before the diagnosis of AD. 
Furthermore, early in the disease, the presence of brain amyloid appears to increase the risk of 
conversion from mild cognitive impairment (MCI) to AD. It is implicit in this hypothesis that 
enhanced clearance of Aβ plaques will lead to amelioration of AD symptoms and slow 
progression of AD. 
Two Phase 1 studies (Study I5T-MC-AACC [AACC] and Study I5T-MC-AACD [AACD]) have 
been conducted in participants with MCI due to AD and mild to moderate AD. In Study AACC, 
single IV dose of donanemab from 0.1 mg/kg to 10 mg/kg was administered in single-ascending 
dose phase, and IV doses from 0.3 mg/kg to 10 mg/kg once per month for a total of 4 doses were 
administered in multiple-ascending dose phase. In addition, a single IV dose of 1 mg/kg 
donanemab was administered to a single cohort of healthy participants. In Study AACD, single 
and multiple doses from 10 mg/kg to 40mg/kg were administered. In both studies, rapid and 
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sustained reduction in cerebral amyloid plaques were observed with donanemab doses 
10 mg/kg.  
One Phase 2 study (Study I5T-MC-AACG [AACG]) has been conducted in participants with 
early symptomatic AD and intermediate (low to medium) cerebral tau burden. In Study AACG, 
700 mg of donanemab IV once every 4 weeks (Q4W) for first three doses followed by 1400 mg 
Q4W for up to 72 weeks was administered. Treatment with donanemab compared with placebo 
resulted in a significant slowing (32%; p = 0.04) of disease progression, as measured by the 
integrated Alzheimer’s Disease Rating Scale (iADRS; Wessels et al. 2015), as well as deep and 
rapid reduction in amyloid plaque level. 
Key safety findings from these completed studies included amyloid-related imaging 
abnormalities (ARIA), infusion-related reactions (IRR), and the presence of treatment emergent 
anti-drug antibodies (TE-ADAs). The most common treatment-emergent adverse events 
(TEAEs) observed were: 
 ARIA–edema/effusions (ARIA-E) 
 ARIA–hemorrhage/hemosiderin deposition (ARIA-H)  
 superficial siderosis of central nervous system 
 IRRs 
 fall 
 headache 
 dizziness 
 upper respiratory tract infections, and 
 urinary tract infection. 
 
A detailed description of the chemistry, pharmacology, efficacy, and safety of donanemab is 
provided in the investigator’s brochure (IB). 
2.3. 
Benefit/Risk Assessment 
The following are the risks and discomforts associated with donanemab: 
 ARIA, 
 TE-ADAs, and 
 IRR and hypersensitivity. 
Amyloid-related imaging abnormalities have been observed in patients with MCI or AD in 
completed Phase 1 studies, AACD and AACC, Phase 2 study AACG, and in the ongoing Phase 3 
studies. Events of ARIA may be serious, or life threatening and could lead to permanent 
disability or death. 
Incidences of ARIA-E occur spontaneously at rates of 0.1-1%. Incidences of ARIA-H occur 
spontaneously at rates of 10-20% (Ketter et al. 2017). Both spontaneously occur more frequently 
in apolipoprotein E genotype ε4 (ApoE4) carriers than noncarriers, and ARIA-E is a risk factor 
for the occurrence of ARIA-H. Both ARIA-E and ARIA-H occur more frequently with antibody 
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I5T-MC-AACK(a) 
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therapies directed at amyloid and are considered a class effect. Other anti-amyloid antibodies in 
clinical development have demonstrated a dose-dependent risk for ARIA-E. Most of these cases 
are asymptomatic and have been detected by routine brain magnetic resonance imaging. When 
symptoms are present in association with these imaging abnormalities, they have been reported 
to include 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). In most cases, these imaging abnormalities have not required treatment 
other than discontinuation of the investigational compound, typically resulting in resolution of 
imaging abnormalities. Infrequently, high-dose steroid therapy has been administered in the 
presence of prominent symptoms. 
In this study (Study AACK), ARIA-E and ARIA-H events are not expected given the young 
healthy population being enrolled. These participants are expected to not have amyloid deposits 
in their brain and thus the risk of ARIA-E and ARIA-H is considered low.  
Treatment emergent-ADAs and IRRs have been observed in studies, AACC, AACD, and 
AACG. 
All biological agents carry the risk of systemic allergic/hypersensitivity reactions and patients 
should be monitored for the occurrence of these reactions. Clinical manifestations of these 
reactions may include but are not limited to the following: 
 Skin rash, 
 Pruritus (itching), 
 Dyspnea, 
 Urticaria (hives), 
 Angioedema (for example, swelling of the lips and/or tongue), 
 Hypotension, and 
 Anaphylactic reaction. 
Treatment emergent-ADAs have been observed after a single dose of donanemab across all dose 
levels assessed and including the single cohort of healthy participants in the Study AACC. 
Therefore, TE-ADAs will be carefully monitored in this study.  
There is no anticipated therapeutic benefit for the healthy participants in this study. However, 
participants may benefit from the screening procedures (through detection of unknown health 
issues) even if they receive no therapeutic benefit from the trial. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of donanemab may be found in the IB. 
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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To investigate the safety and tolerability of 
donanemab versus placebo following single 
dose IV administration in healthy Chinese 
participants 
 
Incidence of treatment-emergent adverse 
events and serious adverse events 
Secondary 
 
To characterize the pharmacokinetic profile of 
donanemab following single dose IV 
administration in healthy Chinese participants 
 
Cmax, and AUC0-∞  
Exploratory 
 
 
To characterize immunogenicity of 
donanemab following single dose IV 
administration in healthy Chinese participants 
 
Incidence of TE-ADA 
Abbreviations: AUC0-∞ = area under the concentration versus time curve from time 0 to infinite time; Cmax = 
maximum observed drug concentration; IV = intravenous; TE-ADA = treatment-emergent anti-drug antibodies. 
 
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4. 
Study Design 
4.1. 
Overall Design 
This is a parallel treatment, Phase 1, participant- and investigator-blind, placebo-controlled, 
randomized study to evaluate the safety, tolerability, and PK of a single IV dose of donanemab in 
healthy Chinese participants. This study will be conducted in China. Up to 36 participants may 
be enrolled so that approximately 30 participants complete the study. 
The study will include 3 cohorts, each with 12 participants randomized in a 5 (donanemab): 1 
(placebo) ratio. The planned doses are: 
 Cohort 1: 350 mg IV single dose, 
 Cohort 2: 700 mg IV single dose, and  
 Cohort 3: 1400 mg IV single dose.  
4.1.1. 
Screening Period 
Screening may occur up to 28 days prior to randomization and dosing with study intervention. 
Once the informed consent is signed by the participants, they will be assessed for eligibility and 
will undergo screening procedures outlined in the Schedule of Activities (SoA; Section 1.3). 
Participants who are not enrolled within 28 days of screening may undergo an additional medical 
assessment and/or clinical measurements to confirm their eligibility. In such instances, the 
following screening tests and procedures may be repeated: vital signs and clinical laboratory 
tests. 
4.1.2. 
Inpatient Period  
Eligible participants will be admitted to the clinical research unit (CRU) on Day -1 prior to 
dosing with study intervention. On Day 1, participants will be dosed with single IV dose of 
donanemab or placebo. Participant will be discharged on Day 5 at the discretion of the 
investigator and after completion of all assessments as mentioned in SoA (Section 1.3). 
Participants will be monitored for safety and PK, and immunogenicity samples will be collected 
as mentioned in SoA (Section 1.3). 
4.1.3. 
Follow-up Period 
After discharge from CRU, participants will be required to visit the CRU on an outpatient basis 
at the timepoints indicated in SoA (Section 1.3). The follow-up period will be 12 weeks ± 7 days 
after completion of dosing or until early discontinuation. 
4.2. 
Scientific Rationale for Study Design 
 
 
  
 
 
 
 
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4.3. 
Justification for Dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 trial. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit or the last scheduled procedure shown in the SoA. 
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5. 
Study Population 
Eligibility of participants for study enrollment will be based on the results of a screening medical 
history, physical examination, vital signs, electrocardiogram (ECG), and safety laboratory tests. 
The nature of any conditions present at the time of physical examination and any preexisting 
conditions will be documented. 
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only, and not continuously throughout the trial. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 18 to 40 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
2. Participants who are overtly healthy as determined by medical evaluation, including 
medical history, physical examination, laboratory tests, and ECG. 
3. Are native Chinese participants. To qualify as a native Chinese, the participant, the 
participant’s biological parents, and all four of the participant’s biological grandparents 
must be of Chinese origin. 
4. Have clinical laboratory test results within the normal reference range for the population 
or investigative site or results with acceptable deviations that are judged to be not 
clinically significant by the investigator. 
5. Have venous access sufficient to allow for blood sampling and administration of 
investigational product for IV administration as per the protocol. 
6. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures. 
Weight 
7. Have a body mass index (BMI) of 18.0 and 28.0, kg/m2, inclusive. 
Sex and contraceptive/barrier requirements 
8.  Male and/or female 
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 4 (Section 10.4). 
a. Male participants: 
No male contraception is required except in compliance with specific local government 
study requirements . 
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b. Female participants:  
Women not of child-bearing potential may participate in the study. Females are 
considered women not of child-bearing potential if: 
 they have a congenital anomaly such as mullerian agenesis,  
 they are infertile due to surgical sterilization (examples of surgical sterilization include 
total hysterectomy, bilateral salpingo-oophorectomy, bilateral salpingectomy, or bilateral 
oophorectomy.), or  
 they are post-menopausal. 
Refer to Appendix 4 (Section 10.4) for other definitions. 
Informed Consent 
9. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1), 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
10. Are lactating.  
11. Are women of childbearing potential. 
12. Have known allergies to donanemab, related compounds or any components of the 
formulation or history of significant atopy. 
13. Have a clinically significant ECG abnormality as determined by the investigator. 
14. Have an abnormal blood pressure and/or pulse rate as determined by the investigator. 
15. Have significant previous or current history of comorbidities capable of significantly 
altering the absorption, metabolism, or elimination of drugs; of constituting a risk when 
taking the study intervention; or of interfering with the interpretation of data. 
16. Have history of intracranial hemorrhage, cerebrovascular aneurysm or arteriovenous 
malformation, or carotid artery occlusion, stroke or epilepsy. 
17. Have a history or presence of psychiatric disorders considered clinically significant in 
the opinion of the investigator that may compromise the safety of the participant or 
compliance to study procedures.  
18. Regularly use known drugs of abuse and/or show positive findings on drug screening. 
19. Show evidence of human immunodeficiency virus (HIV) infection and/or positive 
human HIV antibodies. 
20. Show evidence of hepatitis C and/or positive hepatitis C antibody. 
21. Show evidence of hepatitis B and/or hepatitis B surface antigen. 
22. Have donated blood of more than 400 mL within the previous 8 weeks of study 
screening. 
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23. Have had leukemia, lymphoma, or any malignancy within the past five years except for 
basal cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for three years. 
24. Have had breast cancer within the past 10 years. 
Prior/Concomitant Therapy 
25. Have used or intend to use over-the-counter or prescription medication (including herbal 
medications and traditional medications) within 14 days prior to dosing. Specific 
medications listed in Section 6.8, concomitant medications, may be allowed. 
26. Have had gamma globulin therapy within the last six months. 
27. Have received treatment with biologic agents (such as monoclonal antibodies, including 
marketed drugs) within three months or five half-lives (whichever is longer) prior to 
dosing. 
28. Have significant allergies to humanized monoclonal antibodies  
29. Have clinically significant multiple or severe drug allergies, or intolerance to topical 
corticosteroids, or severe post treatment hypersensitivity reactions (including, but not 
limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal 
necrolysis, or exfoliative dermatitis). 
Prior/Concurrent Clinical Study Experience 
30. Have participated, within the last 30 days, in a clinical study involving an investigational 
product; at least five half-lives or 30 days (whichever is longer) should have passed. 
31. Have previously completed or withdrawn from this study or any other study 
investigating donanemab. 
Other Exclusions 
32. Have an average weekly alcohol intake that exceeds 21 units per week (males ≤65 years 
old) and 14 units per week (females), or are unwilling to stop alcohol consumption from 
48 hours prior to admission, until the participant has been discharged from the CRU  
33. Smoke more than 10 cigarettes, or cigarette equivalent per day or are unable to abide by 
CRU smoking restrictions. 
34. Are unwilling to comply with the dietary restrictions required for this study. 
35. Are CRU personnel directly affiliated with this study and their immediate families. 
Immediate family is defined as a spouse, parent, child or sibling, whether biological or 
legally adopted. 
36. Are employees of Eli Lilly and Company (Lilly) or the CRU. 
37. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study. 
5.3. 
Lifestyle Considerations 
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study. 
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5.3.1. 
Meals and Dietary Restrictions 
Standard meals will be provided at all times while participants are resident at the CRU. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco 
 Participants should avoid caffeinated beverages while at the CRU, and for 12 hours prior 
to admission to the CRU. At other times during the outpatient period, participants are 
permitted to maintain their regular caffeine consumption. Decaffeinated beverages are 
permitted. 
 Alcohol consumption is not permitted while at the CRU, and for 48 hours prior to 
admission and outpatient visits until leaving the CRU. At other times, participants are 
permitted to have an average weekly alcohol intake not exceeding 21 units per week 
(males ≤65 years old) and 14 units per week (females). One unit is equal to:  
o 12 oz or 360 mL of beer,  
o 5 oz or 150 mL of wine, or  
o 1.5 oz or 45 mL of distilled spirits. 
 Participants who smoke will be advised to not smoke more than 10 cigarettes per day 
during the study. Participants will be asked to refrain from smoking for approximately 
one hour prior to each ECG and vital sign measurement, and to abide by the CRU 
smoking restrictions. 
5.3.3. 
Activity 
 Participants will be advised to maintain their regular levels of physical activity or 
exercise during the study but to refrain from vigorous exercise.  
 Strenuous activity should be avoided from 24 hours prior to admission until discharge 
from the CRU.  
 While certain study procedures are in progress at the CRU, participants may be required 
to remain recumbent or sitting. 
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention/enrolled in the study.  
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention of 
a Participant 
Not applicable. 
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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.  
6.1. 
Study Intervention(s) Administered 
 
 
 
 
  
 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
6.1.1. 
Administration Details 
 
 
 
6.1.1.1. 
Premedication for Infusions 
 
 
 
 
 
 
 
 
 
 
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6.1.1.2. 
Management of Infusion Reactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
6.2. 
Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized study personnel. 
3. The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual. 
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Note: In some cases, CRU may destroy the material if, during the CRU selection, the evaluator 
has verified and documented that the CRU has appropriate facilities and written procedures to 
dispose of clinical materials. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a participant- and investigator-blind study. The sponsor and site monitors are not blinded.  
On Day 1, participants will be assigned a unique number (randomization number) in ascending 
numerical order. The randomization number encodes the participant’s assignment to one of the 2 
arms of the study (randomization ratio 5:1), according to the randomization schedule generated 
prior to the study by the statistics department at sponsor/designee. Each participant will be 
dispensed a blinded study intervention, labeled with the participant’s unique randomization 
number, throughout the study. 
Investigators will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. To maintain this blind, an otherwise uninvolved third party will be 
responsible for the reconstitution and dispensation of all study interventions and will endeavor to 
ensure that there are no differences in time taken to dispense following randomization. 
In the event of a Quality Assurance audit, the auditors will be allowed access to unblinded study 
intervention records at the sites to verify that randomization or dispensing has been done 
accurately. 
To preserve the blinding of the study, a minimum number of Lilly personnel and staff at the 
CRU (namely, CRU pharmacy staff) will see the randomization table before the study is 
complete. Individuals involved in study drug preparation will not be involved in any of the 
clinical aspects of the study, including study drug administration and AE assessments.  
Blinding will be maintained throughout the conduct of the study as described in the blinding and 
unblinding plan section of the statistical analysis plan (SAP) or in a separate document. 
Emergency codes will be available to the investigator. A code, which reveals the study 
intervention for a specific study participant, may be opened during the study only if 
the participant’s well-being requires knowledge of the participant’s treatment assignment. 
If a participant’s study treatment assignment is unblinded, the participant must be discontinued 
from the study, unless the investigator obtains specific approval from a Lilly clinical 
pharmacologist or CRP for the study participant to continue in the study. If a participant is 
discontinued, safety assessments will be collected per protocol for the remainder of the inpatient 
period. See early discontinuation procedures provided in SoA (Section 1.3). During the study, 
emergency unblinding should occur only by accessing the study participant’s emergency code.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event. The 
participant’s safety must always be the first consideration in making such a determination. 
Where feasible and when timing of the emergent situation permits, the investigator should 
attempt to contact the Lilly medical monitor before unblinding a participant’s treatment 
assignment. If the investigator decides that unblinding is warranted, it is the responsibility of the 
investigator to promptly document the decision and rationale and notify Lilly as soon as 
possible.  
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Upon completion of the study, all codes must be returned to Lilly or its designee. 
6.4. 
Study Intervention Compliance 
Study intervention will be administered under medical supervision by designated CRU staff. The 
dose of study intervention and study participant identification will be confirmed prior to the time 
of dosing. The date and time of the dose administered will be recorded in the source documents 
and will be provided to the sponsor as requested. 
6.5. 
Dose Modification 
This is a parallel treatment, single dose study. Dose adjustments are not permitted in this study. 
6.6. 
Continued Access to Study Intervention after the End of the Study 
Not applicable. 
6.7. 
Treatment of Overdose 
For this study, any dose of study intervention greater than dose of study intervention assigned 
through randomization will be considered an overdose. 
In the event of an overdose, the investigator or treating physician should: 
 Contact the medical monitor immediately. 
 Closely monitor the participant for any AE/serious adverse event (SAE) and laboratory 
abnormalities. 
 Obtain a plasma sample for PK analysis if requested by the medical monitor (determined 
on a case-by-case basis). 
6.8. 
Concomitant Therapy 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 Reason for use. 
 Dates of administration including start and end dates. 
 Dosage information including dose and frequency for concomitant therapy of special 
interest. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 14 days or five half-lives (whichever is longer) before 
the start of study intervention until completion of the follow-up visit, unless, in the opinion of the 
investigator and sponsor, the medication will not interfere with the study. 
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Acetaminophen, at doses of  2 grams/day, is permitted for use in a 24-hour period at the 
discretion of the investigator. Other concomitant medication may be considered on a case-by-
case basis by the investigator in consultation with the medical monitor if required. 
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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 
(Section 10.1). 
7.1. 
Discontinuation of Study Intervention 
Not applicable since this is single dose study. 
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, 
 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, and 
 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. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and post-treatment 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 the destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants 
If the sponsor or investigator identifies a participant who did not meet enrolment criteria and was 
inadvertently enrolled, discussion must occur between the Lilly clinical pharmacologist or CRP 
and the investigator to determine if the participant may continue in the study. If both agree that it 
is medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist or CRP to allow the inadvertently enrolled participant to continue 
in the study. 
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7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designees 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.  
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8. 
Study Assessments and Procedures 
 Study procedures and their timing are summarized in the SoA.  
 Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
Section 1.3 lists the SoA, detailing the study procedures and their timing (including tolerance 
limits for timing).  
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits. Modifications may be made to the time points 
based upon emerging clinical information. The scheduled time points may be subject to minor 
alterations; however, the actual time must be correctly recorded in the case report form (CRF).  
Appendix 2 (Section 10.2) lists the clinical laboratory tests that will be performed for this study. 
Appendix 2 (Section 10.2.1) provides a summary of the maximum number and volume of 
invasive samples, for all sampling, during the study. 
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results. Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards. 
8.1. 
Efficacy Assessments 
Efficacy is not evaluated in the study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
 A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height, weight, 
and BMI will also be measured and recorded. 
 Symptom-directed physical assessment may be conducted at other visits as mentioned in 
SoA and as determined by the investigator. 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses.  
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8.2.1.1. 
Neurological Examination 
A directed neurological examination will be performed by the investigator (or designee) at the 
time points specified in the SoA (Section 1.3). If clinically significant abnormalities are noted at 
these time points, additional examinations should be performed as clinically necessary. The 
examiner should be familiar with the participant’s baseline examination. Elements of the 
examination may include inspection for tremors, extraocular movements, brachial and patellar 
deep tendon reflexes, finger-nose pointing, and Romberg sign. 
Table AACK.8.1 presents the scoring of the neurological examination findings.  
Table AACK.8.1. 
Scoring of Neurological Examinations Surveys 
Score 
0 
1 
2 
3 
4 
Tremor 
Absent 
Visible with limb 
extension and/or 
careful inspection 
Visible without 
limb extension 
Interferes with 
motor function 
 
Nystagmus 
Absent 
1 to 3 beats on 
lateral gaze 
>3 beats on 
lateral gaze 
Present on 
forward gaze 
 
Reflexes (brachial or patellar) 
Normal 
Trace 
Absent 
Increased 
Clonic 
Finger-nose 
Normal 
Abnormal 
 
 
 
Romberg sign 
Absent 
Present 
 
 
 
8.2.2. 
Vital Signs 
 For each participant, vital signs measurements should be conducted according to the 
Schedule of Activities (Section 1.3) and following the study-specific recommendations 
included in Manual of Operations for the study. 
 Additional vital signs may be measured during the study if warranted. 
 Blood pressure and pulse rate should be measured after at least five minutes supine. 
 Unscheduled orthostatic vital signs should be assessed if possible, during any AE of 
dizziness or posture-induced symptoms. If orthostatic measurements are required, 
participants should be supine for at least five minutes and stand for at least three minutes. 
If the participant feels unable to stand, only the supine vital signs will be recorded.  
8.2.2.1. 
Body Temperature 
Body temperature should be measured as indicated in Section 1.3, or any time that it is clinically 
indicated. 
8.2.3. 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT intervals.  
For each participant, a single 12-lead ECG will be collected according to the SoA (see 
Section 1.3). ECGs must be recorded before collecting any blood samples. Participants must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection. Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary by the investigator. All ECGs recorded should be stored at the CRU. 
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Electrocardiograms will be interpreted by the investigator or qualified designee at the CRU: 
 as soon as possible after the time of ECG collection, and  
 ideally while the participant is still present, to determine whether the participant meets 
entry criteria at the relevant visits and for immediate management, should any clinically 
relevant findings be identified. 
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/corrected QT interval from baseline), the investigator will determine if the participant can 
continue in the study. The investigator, or qualified designee, is responsible for determining if 
any change in participant management is needed and must document his or her review of the 
ECG printed at the time of collection. 
Any new clinically relevant finding should be reported as an AE. 
8.2.4. 
Clinical Safety Laboratory Tests 
 See Appendix 2 (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/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the 
sponsor notified. 
○ All protocol-required laboratory assessments, as defined in Appendix 2, must 
be conducted in accordance with the SoA, standard collection requirements, 
and laboratory manual. 
 If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the investigator (for example, SAE or AE or dose 
modification), then report the information as an AE.  
8.2.5. 
Pregnancy Testing  
Pregnancy testing will be carried out as mentioned in SoA. 
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8.2.6. 
Safety Monitoring 
The Lilly clinical pharmacologist or CRP will monitor safety data throughout the course of the 
study. 
Lilly will review SAEs within time frames mandated by company procedures. The Lilly clinical 
pharmacologist or CRP will periodically review the following data: 
 trends in safety data, 
 laboratory analytes, 
 AEs, including monitoring of incidence of any nature of any neurological symptoms, 
infusion related reaction, and allergic or hypersensitivity reactions, 
 ECGs, 
 neurological examinations, and 
 physical examinations 
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist. 
8.2.6.1. 
Hypersensitivity Reactions 
Many drugs, including oral 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, additional blood samples should be 
collected as described in Appendix 2 (Section 10.2.2). Laboratory results are provided to the 
sponsor via the central laboratory. 
8.2.6.2. 
Hepatic Safety 
Close hepatic monitoring 
Laboratory tests (Appendix 5 [Section 10.5]), including alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (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 one or more 
of these conditions occur: 
If a participant with baseline 
results of  
develops the following elevations: 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN 
ALP <1.5× ULN 
ALP ≥2× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for patients with Gilbert’s syndrome) 
 
 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
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TBL ≥1.5× ULN 
TBL ≥1.5× baseline (except for patients with Gilbert’s syndrome) 
Abbreviation: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include a physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking, and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
one to three times weekly, based on the participant’s clinical condition and hepatic biochemical 
tests. Subsequently, the frequency of monitoring may be lowered to once every one to two weeks 
if the participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 
If a participant with baseline 
results of  
develops the following elevations: 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN with hepatic signs/symptomsa, or  
ALT or AST ≥5× ULN 
ALP <1.5× ULN 
ALP ≥3× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for patients with Gilbert’s syndrome) 
 
 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline with hepatic signs/symptomsa, or 
ALT or AST ≥3× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥2× baseline (except for patients with Gilbert’s syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for Prothrombin time- international normalized ratio; 
tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging 
study (for example, ultrasound or computed tomography scan). 
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus 
cytomegalovirus Epstein-Barr virus acetaminophen levels, acetaminophen protein adducts, urine 
toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and blood 
phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
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hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet one or more of the following five conditions: 
1. Elevation of serum ALT to ≥5× ULN on two or more consecutive blood tests (if baseline 
ALT <1.5× ULN) 
 In participants with baseline ALT ≥1.5× ULN, the threshold is ALT ≥3× baseline 
on two or more consecutive tests. 
2. Elevated TBL to ≥ 2× ULN (if baseline TBL <1.5× ULN) (except for cases of known 
Gilbert’s syndrome) 
 In participants with baseline TBL ≥1.5× ULN, the threshold should be TBL ≥2× 
baseline 
3. Elevation of serum ALP to ≥2× ULN on two or more consecutive blood tests (if baseline 
ALP <1.5× ULN) 
 In participants with baseline ALP ≥1.5× ULN, the threshold is ALP ≥2× baseline 
on two or more consecutive blood tests 
4. Hepatic event considered to be a SAE 
5. Discontinuation of study drug due to a hepatic event  
Note: the interval between the two consecutive blood tests should be at least two days. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3 (Section 10.3): 
 AEs 
 SAEs 
 Product complaints (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 (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). For PCs, 
the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Appendix 3 (Section 10.3). 
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Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant.  
The investigator is responsible for the appropriate medical care of participants during the study.  
8.3.1. 
Timing and Mechanism for Collecting Events 
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection Start 
Collection Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for 
Reporting 
Back-up 
Method 
of 
Reporting 
Adverse Event 
AE 
signing of the ICF   participation in 
study has ended 
As soon as 
possible upon 
site awareness 
AE eCRF 
N/A 
Serious Adverse Event 
SAE and SAE updates – 
prior to start of study 
intervention and deemed 
reasonably possibly 
related to study 
procedures 
signing of the ICF 
start of intervention 
Within 24 
hours of 
awareness 
SAE paper 
form 
SAE 
paper 
form 
SAE# and SAE updates 
– after start of study 
intervention 
start of 
intervention 
participation in 
study has ended 
Within 24 
hours of 
awareness 
SAE paper 
form 
SAE 
paper 
form 
SAE* – after 
participant’s study 
participation has ended 
and the investigator 
becomes aware 
After participant’s 
study 
participation has 
ended 
N/A 
Promptly 
SAE paper 
form 
N/A 
Pregnancy 
Pregnancy in [female 
participants and female 
partners of male 
participants] 
After the start of 
study intervention 
participation in 
study has ended  
Within 24 
hours (see 
Section 8.3.2) 
Pregnancy 
paper form 
Pregnancy 
paper 
form 
Product Complaints 
PC associated with an 
SAE or might have led to 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 
hours of 
awareness 
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 
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Event 
Collection Start 
Collection Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for 
Reporting 
Back-up 
Method 
of 
Reporting 
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 
 
Abbreviations: AE = adverse event; eCRF = electronic case report form; ICF = informed consent form; N/A = not 
applicable; PC = product complaints; SAE = serious adverse event 
* Serious adverse events 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: 
o obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.  
The female partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of gestational age, fetal status (presence or absence of 
anomalies) or indication for the procedure. 
8.4. 
Pharmacokinetics 
Venous blood samples of approximately 4 mL will be collected for measurement of serum 
concentrations of donanemab as specified in the SoA. The actual date and time (24-hour clock 
time) of each sampling will be recorded. On the day of dosing, every attempt should be made to 
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collect samples at the specified time. However, failure to do so will not constitute a protocol 
violation. 
A maximum of three samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. The timing of sampling 
may be altered during the course of the study based on newly available data (e.g, to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate monitoring.  
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. 
Samples will be used to evaluate the PK of donanemab. Samples collected for analyses of 
donanemab serum concentration may also be used to evaluate safety aspects related to concerns 
arising during or after the study. 
Drug concentration information that would unblind the study will not be reported to CRU or 
blinded personnel until the study has been unblinded. 
8.4.1. 
Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of donanemab will be assayed using a validated enzyme-linked immunosorbent 
assay (ELISA) method. Analyses of samples collected from placebo-treated participants are not 
planned. 
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of one year following the last participant visit for the study. During this 
time, samples remaining after the bioanalyses may be used for exploratory studies or exploratory 
analyses such as bioanalytical assay validation or cross-validation exercises. 
8.5. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics 
A blood sample for deoxyribonucleic acid isolation will be collected from participants as per 
local regulations. Samples will be assessed for ApoE4 carrier status as allowed by local 
regulations. Previous studies have suggested that ApoE4 carriers may be at increased risk of 
ARIA-E. Assessment of ApoE4 carrier status may help better define the risk of ARIA-E in 
participants administered donanemab. 
Samples will be stored as per local regulations or ethics committee requirements. Samples will 
be immediately destroyed once donanemab is launched or there is no further request for testing 
the samples from Chinese authority. 
8.7. 
Biomarkers 
Biomarkers are not evaluated in this study. 
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8.8. 
Immunogenicity Assessments 
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine antibody production against donanemab. Antibodies may be further characterized 
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. Treatment-emergent ADAs are defined in Section 9.3.4.1. 
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of donanemab at a laboratory approved by the sponsor. Antidrug antibody samples will be stored 
as per local regulation or ethics committee requirements. Samples will be immediately destroyed 
once donanemab is launched or there is no further request on testing the samples from China 
authority. Samples may also be used for development and control of an immunogenicity assay. 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
 
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9. 
Statistical Considerations 
The statistical analysis plan will be finalized prior to unblinding, and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints, including 
primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses 
Not applicable.  
9.1.1. 
Multiplicity Adjustment 
Not applicable.  
9.2. 
Analyses Sets 
The following populations are defined: 
Population 
Description 
Entered 
All participants who sign the informed consent form 
Safety 
All participants randomly assigned to study intervention and who take at least 
1 dose of study intervention. Participants will be analyzed according to the 
intervention they actually received. 
Pharmacokinetic analysis 
All enrolled participants who received at least one full dose of donanemab and 
have baseline and at least one postbaseline evaluable pharmacokinetic sample. 
Participants will be analyzed according to the intervention they actually 
received. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
Pharmacokinetic analysis may be conducted on data from participants who receive at least one 
dose of the study intervention and have evaluable PK data. Safety analyses will be conducted for 
all enrolled participants who receive study intervention, whether or not they completed all 
protocol requirements.  
Summary statistics, data tabulations, and data graphs will be provided as deemed appropriate. 
Additional exploratory analyses of the data may be conducted as deemed appropriate. Details of 
analyses will be fully documented in the SAP. 
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. Adjustments to 
the planned analyses are described in the final clinical study report. 
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9.3.2. 
Primary Endpoint Analysis 
The primary endpoint is the incidence of TEAEs and SAEs events to investigate the safety and 
tolerability of donanemab versus placebo following IV administration of single dose in Chinese 
healthy participants.  
The statistical evaluation of safety will be listed and/or summarized by treatment group. 
All study intervention and protocol procedure AEs will be listed, and if the frequency of events 
allows, safety data will be summarized using descriptive methodology. 
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters. Safety parameters will be listed and summarized using standard descriptive 
statistics as appropriate.  
The incidence of symptoms for each treatment will be presented by severity and by association 
with the study intervention as perceived by the investigator. Symptoms reported to have occured 
prior to randomization will be distinguished from those reported as new or increased in severity 
during the study. Each symptom will be classified by the most suitable term from the Medical 
Dictionary for Regulatory Activities. 
The number of TEAEs and SAEs will be reported. 
9.3.3. 
Secondary Endpoint Analysis 
Noncompartmental analysis will be conducted, and PK parameter estimates of maximum 
observed drug concentration (Cmax), area under the concentration versus time curve from time 0 
to infinite time (AUC0-∞), area under the concentration versus time curve from time 0 to last 
measured concentration (AUC0-tlast), clearance and half-life will be reported for donanemab. 
Other noncompartmental parameters may be reported, as appropriate. 
Exploratory graphical analyses relating donanemab serum exposure and immunogenicity may be 
conducted.  
9.3.4. 
Exploratory Endpoint Analysis 
9.3.4.1. 
Evaluation of immunogenicity 
The frequency and percentage of participants with preexisting ADA and with TE-ADA to 
donanemab will be tabulated by treatment. Treatment emergent ADAs are defined as those with 
a titer 2-fold (1 dilution) greater than the minimum required dilution if no ADAs were detected at 
baseline (treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared 
to baseline if ADAs were detected at baseline (treatment-boosted ADA). 
The frequency of neutralizing antibodies may also be tabulated in TE-ADA+ participants by 
treatment. 
9.4. 
Interim Analysis  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.  
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9.5. 
Sample Size Determination 
Approximately 36 participants may be enrolled in three dosing cohorts. The sample sizes 
described are customary for Phase 1 studies evaluating safety and PK parameters and is not 
powered on the basis of statistical hypothesis testing. Each cohort will comprise approximately 
12 participants with a randomization ratio of 5:1 between donanemab and placebo. Participants 
who discontinue the study before completing may be replaced at the discretion of the sponsor 
and investigator. The replacement participant can complete the entire study period. 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
● This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines. 
○ Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines. 
○ Applicable laws and regulations. 
● The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (for example, advertisements) must be submitted to an Institutional Review 
Board (IRB)/Independent Ethics Committee (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 (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
o 
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 (CTA). 
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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 a complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
one year after completion of the study. 
10.1.3. 
Informed Consent Process 
 The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or the participant’s legally authorized 
representative and answer all questions regarding the study. 
 Participants must be informed that their participation is voluntary. Participants [or their 
legally authorized representatives will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
privacy and data protection requirements, where applicable, and the IRB/IEC or study 
center. 
 The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the ICF(s) must be provided to the participant [or the participant’s legally 
authorized representative] and is kept on file. 
10.1.4. 
Data Protection 
 Participants will be assigned a unique identifier by the sponsor. Any participant records, 
datasets or tissue samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
 The participant must be informed that the participant’s personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent.  
 The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 The sponsor has processes in place to ensure data protection, information security and 
data integrity. These processes include appropriate contingency plan(s) for appropriate 
and timely response in the event of a data security breach. 
10.1.5. 
Committees Structure 
Not applicable. 
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10.1.6. 
Dissemination of Clinical Study Data 
Communication of suspended or terminated dosing 
If a decision is taken to suspend or terminate dosing in the study due to safety findings, this 
decision will be communicated by Lilly to all investigators (e.g, through phone and/or email) as 
soon as possible. It will be a requirement that investigators respond upon receipt to confirm that 
they understand the communication and have taken the appropriate action prior to further dosing 
any participants with study intervention. Any investigator not responding will be followed up by 
Lilly personnel prior to any further planned dosing. If a dose is planned imminently, Lilly 
personnel will immediately, and continually, use all efforts to reach investigators until contact is 
made and instructions are verified. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis, taking into consideration the 
ability to anonymize the data and the nature of the data collected. 
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. Source data may include laboratory tests, medical 
records, and clinical notes. 
 The investigator must permit study-related monitoring, audits, IRB/IEC reviews, and 
regulatory agency inspections and provide direct access to source data documents. 
 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). 
 Study monitors will perform ongoing source data verification 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. 
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 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the time period outlined in the CTA unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
 In addition, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may be 
audited by Sponsor or its representatives, and/or regulatory agencies at any time. 
Investigators will be given notice before an audit occurs. 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture system(s) will be stored at third-party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s). Prior to decommissioning, the investigator will receive or access 
an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports 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 10.1.7. 
 
 
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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. 
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. 
 Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
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 if the results are deemed to be of significant medical 
importance. 
10.1.11. 
Investigator Information 
Not applicable. 
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 become(s) commercially available for AD. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
 The tests detailed in the table below will be performed by the local laboratory. 
 In circumstances where the sponsor approves local laboratory testing in lieu of central 
laboratory testing (in the table below), the local laboratory must be qualified in 
accordance with applicable local regulations. 
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
 Additional tests may be performed at any time during the study, as determined necessary 
by the investigator or required by local regulations. 
 Investigators must document their review of the laboratory safety results.  
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
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Clinical Laboratory Tests 
Hematology 
Clinical Chemistry 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
 
Mean cell volume  
Chloride  
Mean cell hemoglobin  
Glucose random 
Mean cell hemoglobin concentration  
Blood urea nitrogen (BUN) or ureaf 
Leukocytes (WBC)  
Platelets 
Creatinine  
Uric acid 
 
Total cholesterol 
Differential WBC [Absolute counts] of: 
Total protein 
Neutrophils 
Albumin  
Lymphocytes 
Total bilirubin  
Monocytes 
Alkaline phosphatase (ALP) 
Eosinophils 
Aspartate aminotransferase (AST) 
Basophils 
Alanine aminotransferase (ALT) 
 
Creatine kinase (CK) 
Urinalysis 
Gamma-glutamyl transferase (GGT)  
Specific gravity 
pH 
 
Protein 
Glucose 
 
Ketones 
Ethanol testinga 
Bilirubin 
Urine drug screena 
Urobilinogen 
Hepatitis B surface antigenb,d 
Blood 
Hepatitis C antibodyb,d 
Nitrite 
HIVd 
Microscopic examination of sedimentc 
Pregnancy teste 
 
FSH (postmenopausal females only)b  
Abbreviations: FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells. 
Note: Results of these assays will be validated by the local laboratory at the time of testing. Additional tests may be 
performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed. Some of the 
above parameters are calculated from measured values. Omission of calculated values will not be considered a 
protocol violation. 
a Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other 
times indicated in the Schedule of Activities 
b Performed at screening only 
c If clinically indicated, per the investigator’s discretion. 
d These tests may be waived if performed within 6 months prior to screening, and if test results are available for 
“review” for Hepatitis B, C and HIV. 
e 
In females only. Serum pregnancy test at screening and urine pregnancy test will be performed at other 
timepoints as indicated in SoA or at investigator’s discretion. 
f 
Either BUN or urea will be tested, whichever is feasible. 
 
 
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10.2.1. 
Blood Sampling Summary 
This table summarize the maximum number of venipunctures and blood volumes for all blood 
sampling (screening, safety laboratories, and bioanalytical assays) during the study. Fewer 
venipunctures and blood draws may occur, but this will not require a protocol amendment. 
 
Purpose 
Maximum Blood Volume 
per Sample (mL) 
Maximum Number 
of Blood Samples 
Maximum Total 
Volume (mL) 
Screening testsa 
26 
1 
26 
Clinical laboratory testsa 
8 
6 
48 
Pharmacokinetics samplingb 
4 
14 (+3) 
68 
Blood discard for cannula patencyc 
3 
15 
45 
Immunogenicity samplinga 
10 
5 
50 
Pharmacogenetics 
10 
1 
10 
Total 
 
 
247 
Total for clinical purposes (rounded to the nearest 10 mL) 
250 
a Additional samples may be drawn if needed for safety purposes. 
b A maximum of 3 blood samples per patient may be drawn at additional time points during the study, if warranted 
and agreed upon between both the investigator and sponsor. 
c Site may choose to use a cannula for blood collection as per site procedure. 
10.2.2. 
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 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 pre-dose 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 
Sample Type 
Laboratory Test a 
Collect from 30 minutes to 4 hours 
after the start of the event.  
● Note: The optimal collection 
time is from 1 to 2 hours after 
the start of event. 
Serum 
total tryptase 
Serum 
complements (C3, C3a, and C5a) 
Serum 
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 hours after the start of the 
event. 
Serum 
donanemab (LY3002813) anti-drug antibodies (ADA) 
Serum/plasma 
donanemab (LY3002813) concentration 
Abbreviations: IL = interleukin. 
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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. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product that does not necessarily have a causal relationship with the 
study intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 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/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
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 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
c. 
Results in death 
d. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
e. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
f. 
Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
g. Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
h. Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
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events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
10.3.3. 
Definition of Product Complaints 
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints 
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint 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/product complaint 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 
product complaint information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE. 
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 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 product complaints. 
 There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:  
 Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of 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 a SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.  
 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship/ 
 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. 
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 The investigator will also consult the IB in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to Sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5. 
Reporting of SAEs 
SAE Reporting via SAE Report 
 Facsimile transmission of the SAE Report is the preferred method to transmit this 
information to the medical monitor or the SAE coordinator. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE Report within the designated reporting time frames. 
 Contacts for SAE reporting can be found in SAE Report.  
10.3.6. 
Regulatory Reporting Requirements 
SAE Regulatory Reporting 
 Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
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● 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 a SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements. 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Word/Phrase 
Definition 
Women of child 
bearing potential 
Females are considered a woman of child bearing potential if: 
 
they have had at least one cycle of menses, or 
 
they have Tanner 4 breast development. 
 
Any amount of spotting should be considered menarche. If Tanner Staging of 
breasts is performed as part of study procedures, please refer to the Reproductive, 
Pregnancy and Pediatrics Safety Committee Safety Guidance for Children in 
Clinical Trial regarding Tanner staging. 
Women not of 
child bearing 
potential 
Females are considered women not of child bearing potential if: 
 
they have a congenital anomaly such as Mullerian agenesis,  
 
they are infertile due to surgical sterilization, or  
 
they are post-menopausal. 
 
Examples of surgical sterilization include total hysterectomy, bilateral salpingo-
oophorectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Post-menopausal 
state 
The post-menopausal state should be defined as: 
1. A woman at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or  
2. A woman at least 40 years of age and up to 55 years old with an intact 
uterus, not on hormone therapy*, who has had cessation of menses for at 
least 12 consecutive months without an alternative medical cause, AND  
With a follicle-stimulating hormone >40 mIU/mL; or  
3. A woman 55 or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea, or 
4. A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy 
 
* Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
selective estrogen receptor modulators, or chemotherapy that could induce 
transient amenorrhea. 
Reproductive 
toxicology 
studies 
Embryo-fetal studies are toxicity studies in pregnant animals designed to identify 
abnormalities in the development of fetuses that could indicate potential for 
teratogenicity in humans. The relevant dosing period is during organogenesis. 
 
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10.4.2. 
Contraception Guidance 
For male participants: 
Males may participate in this trial. 
No male contraception is required except in compliance with specific local government study 
requirements. 
For female participants: 
1. Women of childbearing potential (WOCBP) are excluded from the trial. 
2. Women not of childbearing potential (WNOCBP) may participate in this trial.  
See Appendix 4, Section 10.4.1 for definitions. 
 
Examples of highly effective, effective, and unacceptable methods of contraception can be found below: 
Methods 
Examples 
Highly effective contraception  
 
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 
Note: The barrier method must include use of a 
spermicide (i.e, condom with spermicide, diaphragm 
with spermicide, female condom with spermicide) to 
be considered effective. 
Ineffective forms of contraception 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of above 2, 
cervical mucus, symptothermal) 
 
withdrawal, 
 
post coital douche 
 
lactational amenorrhea 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
See Section 8.2.6.2 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must 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.  
Hepatic evaluation testing 
Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
Hepatic Clinical Chemistry Panel 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
  Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
  Lymphocytes 
Creatine kinase (CK) 
  Monocytes 
Other Chemistry 
  Basophils 
Alkaline phosphatase isoenzymes 
  Eosinophils 
Ceruloplasmin 
Platelets 
Ethyl alcohol (EtOH) 
Cell morphology (RBC and WBC) 
Haptoglobin 
Hepatic Coagulation Panel 
Immunoglobulin IgA (quantitative) 
Prothrombin time, International Normalized ratio 
(PT-INR) 
Immunoglobulin IgG (quantitative) 
Serology 
Immunoglobulin IgM (quantitative) 
Hepatitis A virus (HAV) testing: 
Urine Chemistry 
  HAV total antibody 
Drug screen 
  HAV IgM antibody 
Other Serology 
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Tests assayed by Lilly-designated central laboratory 
Hepatis B virus (HBV) testing: 
Anti-nuclear antibody (ANA) 
  Hepatitis B surface antigen (HBsAg) 
Anti-smooth muscle antibody (ASMA)a 
  Hepatitis B surface antibody (anti-HBs) 
Anti-actin antibodyc 
  Hepatitis B core total antibody (anti-HBc) 
Epstein-Barr virus (EBV) testing: 
  Hepatitis B core IgM antibody 
  EBV antibody 
  HBV DNAb 
  EBV DNAb 
Hepatis C virus (HCV) testing: 
Cytomegalovirus (CMV) testing: 
  HCV antibody 
  CMV antibody 
  HCV RNAb 
  CMV DNAb 
Hepatitis D virus (HDV) testing: 
Herpes simplex virus (HSV) testing: 
  HDV antibody 
  HSV (Type 1 and 2) antibody 
Hepatitis E virus (HEV) testing: 
  HSV (Type 1 and 2) DNAb 
  HEV IgG antibody 
Liver kidney microsomal type 1 (LKM-1) antibody 
  HEV IgM antibody 
 
  HEV RNAb 
 
Tests assayed ONLY by investigator-designated local laboratory 
Microbiology 
Other Chemistry 
Culture: 
Acetaminophen 
  Blood 
Acetaminophen protein adducts 
  Urine 
Copper 
Urine Chemistry 
Phosphatidylethanol (PEth) 
Ethyl glucuronide (EtG) 
 
Abbreviations: DNA = deoxyribonucleic acid; Ig = immunoglobulin; INR = international normalized ratio. 
a 
Not required if anti-actin antibody is tested. 
b 
Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c 
Not required if anti-smooth muscle antibody (ASMA) is tested. 
  
 
 
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10.6. 
Appendix 6: 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 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 GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits,” 
 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. 
The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of remote visits 
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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, AEs and concomitant medications.  
Other alternative locations: Participants may visit local hospital 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 safety 
monitoring (physical examination, vital signs, ECG, body temperature, neurological 
examinations), sample collections for clinical laboratory tests. 
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 visit implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints 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. 
Screening period guidance  
To ensure the safety of study participants, laboratory values and other eligibility assessments 
taken at the screening visit are valid for a maximum of 28 days. The following rules will be 
applied for active, nonrandomized participants whose participation in the study must be paused 
due to exceptional circumstances: 
 If screening is paused for less than 28 days from screening visit to randomization 
visit: the participant will proceed to the next study visit per the usual Schedule of 
Activities, provided that randomization visit must be conducted within 28 days from 
first screening visit.  
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 28 days from screening visit to randomization 
visit: The participant must be discontinued because of screening interruption due to 
an exceptional circumstance. This is documented as a screen failure in the CRF. The 
participant can reconsent and be rescreened as a new participant. The screening 
procedures per the usual SoA should be followed, starting at screening visit to ensure 
participant eligibility by randomization visit. 
Adjustments to visit windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
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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, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
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.  
 
 
 
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10.7. 
Appendix 7: Abbreviations and Definitions 
 
Term 
Definition 
Aβ 
amyloid beta 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AD 
Alzheimer’s disease 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
ApoE4 
apolipoprotein E genotype ε4 
ARIA 
amyloid-related imaging abnormalities 
ARIA-E 
amyloid-related imaging abnormality–edema/effusions 
ARIA-H 
amyloid-related imaging abnormality–hemorrhage/hemosiderin deposition 
AST 
aspartate aminotransferase 
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. 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
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CRP 
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
CRU 
clinical research unit 
ECG 
electrocardiogram 
EDC 
electronic data capture system 
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 
HIV 
Human immunodeficiency virus 
I5T-MC-AACC 
AACC 
I5T-MC-AACD 
AACD 
I5T-MC-AACG 
AACG 
I5T-MC-AACK 
AACK 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
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 trial. 
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. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
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investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IRB 
Institutional Review Board 
IRR 
infusion-related reactions 
IV 
intravenous 
Lilly 
Eli Lilly and Company 
MCI 
mild cognitive impairment 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK  
pharmacokinetics\ 
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.  
SoA 
Schedule of Activities 
TBL 
total bilirubin 
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. 
TE-ADA 
treatment-emergent anti-drug antibodies 
 
 
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11. 
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Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on 
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Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging–Alzheimer's Association 
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