Clinical trial NCT05567159
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2022-10-04; Completion date: 2023-07-14
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to assess how fast donanemab (LY3002813) gets into the blood stream and how long it takes the body to remove it when administered as single dose in healthy participants. The study will also evaluate the safety and tolerability of donanemab. The study will last up to approximately 22 weeks.

Detailed description:

Arms: arm 1: Participants received a 350 milligrams (mg) intravenous (IV) infusion of donanemab every two weeks for six treatment periods (1 to 6), each lasting two weeks. Treatments were administered on the first day of each period, i.e., days 1, 15, 29, 43, 57, and 71.
Interventions: intervention 1: Donanemab
Intervention descriptions: intervention 1: Administered IV.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Protocol: I5T-MC-AACP(a) 
 
 
A Phase 1, Open-Label Study to Characterize the 
Pharmacokinetics of Donanemab Following Intravenous 
Doses in Healthy Participants 
 
 
NCT05567159 
 
 
Approval Date: 12 Dec 2022 


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I5T-MC-AACP(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 Phase 1, Open-Label Study to Characterize the Pharmacokinetics of Donanemab Following 
Intravenous Doses in Healthy Participants  
Protocol Number: I5T-MC-AACP 
Amendment Number: a  
Compound: LY3002813 
Brief Title:  
A Study to Characterize the Pharmacokinetics of Donanemab Following Intravenous Doses in 
Healthy Participants 
Study Phase: Phase 1 
Acronym: AACP 
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 Electronically Signed and Approved by Lilly on date provided below.  
Document ID: VV-CLIN-076261 
 
 
 
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I5T-MC-AACP(a) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
31-Aug-2022 
Amendment (a)  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The protocol was amended to increase the number of participants who may enroll in the study to 
ensure the required number of subjects complete the study and to make minor procedural 
updates.  
Minor changes were needed for consistency within the protocol and between the protocol and 
informed consent form (ICF). 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Updated number of participants who may 
be enrolled. 
 
 
Added “IV” when discussing study design 
and summary. 
Approximately 40 participants may be 
enrolled to ensure the required number of 
subjects complete the study. 
 
To be more specific regarding type of 
administration. 
Section 1.3 Schedule 
of Activities 
Added a note that height is measured at 
screening only. 
There is no need for height to be 
measured at other timepoints. 
Section 4.1 Overall 
Design 
Updated number of participants who may 
be enrolled. 
 
Added “IV” when discussing study design 
and summary. 
Approximately 40 participants may be 
enrolled. 
 
To be more specific regarding type of 
administration. 
Section 4.3 
Justification for Dose 
Added “IV” for the dose selected for this 
study. 
To be more specific regarding type of 
administration. 
Section 5.3 Lifestyle 
Considerations 
Changed when participants should abstain 
from alcohol from “until after collection of 
the final PK sample” to “until leaving the 
CRU”. 
To align with alcohol restrictions set out 
in Exclusion Criteria 30 and in the ICF. 
Section 8 Study 
Assessments and 
Procedures 
Removed “in the CRF” from the line 
regarding recording of actual time. 
Actual times need to be recorded, but not 
in the CRF. 
Section 9.5 Sample 
Size Determination 
Updated number of participants who may 
be enrolled. 
Approximately 40 participants may be 
enrolled. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.7 
Appendix 7 
Removed sentence stating that “This is 
documented as a screen failure in the 
CRF”. 
EMP does not capture screen failures in 
the CRF. 
Abbreviations: CRF = case report form; CRU = clinical research unit; EMP = Exploratory Medicine and 
Pharmacology; ICF = informed consent form; IV = intravenous; PK = pharmacokinetics.  
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I5T-MC-AACP(a) 
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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 ............................................................................................19 
4. 
Study Design ..................................................................................................................20 
4.1. 
Overall Design ................................................................................................................20 
4.2. 
Scientific Rationale for Study Design ............................................................................20 
4.3. 
Justification for Dose ......................................................................................................21 
4.4. 
End of Study Definition ..................................................................................................21 
5. 
Study Population ...........................................................................................................22 
5.1. 
Inclusion Criteria ............................................................................................................22 
5.2. 
Exclusion Criteria ...........................................................................................................23 
5.3. 
Lifestyle Considerations .................................................................................................25 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................25 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................25 
5.3.3. 
Activity ...........................................................................................................................25 
5.4. 
Screen Failures ................................................................................................................25 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................25 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................26 
6.1. 
Study Intervention(s) Administered................................................................................26 
6.1.1. 
Administration Details ....................................................................................................26 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................27 
6.3. 
Assignment to Study Intervention ..................................................................................27 
6.4. 
Blinding ..........................................................................................................................27 
6.5. 
Study Intervention Compliance ......................................................................................28 
6.6. 
Dose Modification ..........................................................................................................28 
6.7. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................28 
6.8. 
Treatment of Overdose ...................................................................................................28 
6.9. 
Prior and Concomitant Therapy ......................................................................................28 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................30 
7.1. 
Discontinuation of Study Intervention ............................................................................30 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................30 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................32 
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7.3. 
Lost to Follow up ............................................................................................................33 
8. 
Study Assessments and Procedures.............................................................................34 
8.1. 
Efficacy Assessments .....................................................................................................34 
8.2. 
Safety Assessments .........................................................................................................34 
8.2.1. 
Physical Examinations ....................................................................................................34 
8.2.2. 
Vital Signs .......................................................................................................................35 
8.2.3. 
Electrocardiograms .........................................................................................................35 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................35 
8.2.5. 
Pregnancy Testing ...........................................................................................................36 
8.2.6. 
Neurological Examination ..............................................................................................36 
8.2.7. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................37 
8.2.8. 
Safety Monitoring ...........................................................................................................37 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................41 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................42 
8.3.2. 
Pregnancy ........................................................................................................................44 
8.4. 
Pharmacokinetics ............................................................................................................45 
8.5. 
Pharmacodynamics .........................................................................................................45 
8.6. 
Genetics ..........................................................................................................................45 
8.7. 
Biomarkers ......................................................................................................................45 
8.8. 
Immunogenicity Assessments.........................................................................................45 
8.9. 
Health Economics ...........................................................................................................46 
9. 
Statistical Considerations .............................................................................................47 
9.1. 
Statistical Hypotheses .....................................................................................................47 
9.1.1. 
Multiplicity Adjustment ..................................................................................................47 
9.2. 
Analyses Sets ..................................................................................................................47 
9.2.1. 
Study Participant Disposition .........................................................................................47 
9.2.2. 
Study Participant Characteristics ....................................................................................47 
9.3. 
Statistical Analyses .........................................................................................................47 
9.3.1. 
General Considerations ...................................................................................................47 
9.3.2. 
Primary Endpoint Analyses: Pharmacokinetic Analyses ................................................48 
9.3.3. 
Secondary Endpoint(s) Analyses ....................................................................................48 
9.3.4. 
Exploratory Analyses ......................................................................................................48 
9.3.5. 
Safety Analyses ...............................................................................................................49 
9.3.6. 
Immunogenicity Assessments .........................................................................................49 
9.3.7. 
Other Analyses ................................................................................................................49 
9.4. 
Interim Analysis ..............................................................................................................49 
9.5. 
Sample Size Determination ............................................................................................50 
10. 
Supporting Documentation and Operational Considerations ..................................51 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................51 
10.1.1. Regulatory and Ethical Considerations ...........................................................................51 
10.1.2. Financial Disclosure........................................................................................................52 
10.1.3. Informed Consent Process ..............................................................................................52 
10.1.4. Data Protection................................................................................................................52 
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I5T-MC-AACP(a) 
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10.1.5. Committees Structure......................................................................................................52 
10.1.6. Dissemination of Clinical Study Data.............................................................................53 
10.1.7. Data Quality Assurance ..................................................................................................53 
10.1.8. Source Documents ..........................................................................................................54 
10.1.9. Study and Site Start and Closure ....................................................................................55 
10.1.10. Publication Policy ...........................................................................................................55 
10.1.11. Investigator Information .................................................................................................56 
10.1.12. Long-Term Sample Retention.........................................................................................56 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................57 
10.2.1. Blood Sampling Summary ..............................................................................................59 
10.2.2. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................59 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................61 
10.3.1. Definition of AE .............................................................................................................61 
10.3.2. Definition of SAE ...........................................................................................................62 
10.3.3. Definition of Product Complaints ...................................................................................63 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................63 
10.3.5. Reporting of SAEs ..........................................................................................................66 
10.3.6. Regulatory Reporting Requirements ...............................................................................66 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................67 
10.4.1. Definitions.......................................................................................................................67 
10.4.2. Contraception Guidance..................................................................................................67 
10.5. 
Appendix 5: Genetics......................................................................................................69 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................70 
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................72 
10.8. 
Appendix 8: Abbreviations and Definitions ...................................................................75 
11. 
References ......................................................................................................................78 
 
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I5T-MC-AACP(a) 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title:  
A Phase 1, Open-Label Study to Characterize the Pharmacokinetics of Donanemab Following 
Intravenous Doses in Healthy Participants  
Brief Title:  
A Study to Characterize the Pharmacokinetics of Donanemab Following Intravenous Doses in 
Healthy Participants 
Regulatory Agency Identifier Number: 
IND: 109157 
Rationale:   
Study I5T-MC-AACP (AACP) will investigate the pharmacokinetics (PK) and safety of 
intravenous (IV) administration of donanemab in healthy participants every 2 weeks (Q2W) for 
10 weeks at a 350 mg dose to support dosing regimens in future studies. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
 To characterize the PK profile of 
donanemab following administration 
of 350 mg IV doses in healthy 
participants 
 AUC 0-4Weeks 
 Cmax,ss, and  
 AUCt,ss  
Secondary 
 
 To investigate the safety and 
tolerability of donanemab following 
administration of 350 mg IV doses in 
healthy participants 
 Incidence of treatment-emergent 
adverse events and serious adverse 
events 
Abbreviations: AUC,ss = area under the concentration versus time curve during a dosing interval at steady state; 
AUC0-4Weeks = area under the concentration versus time curve 0 to 4 weeks; Cmax,ss = maximum observed drug 
concentration during a dosing interval at steady state; IV = intravenous; PK = pharmacokinetic. 
Overall Design:  
This is a Phase 1, open-label study to evaluate the PK, safety, and tolerability of 350 mg 
donanemab administered as a single IV dose Q2W for 10 weeks in healthy participants. 
Approximately 40 participants may be enrolled so that approximately 25 participants complete 
the study. Participants will receive a single 350 mg dose of donanemab IV Q2W for 10 weeks. 
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I5T-MC-AACP(a) 
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After each dose administration, participants will remain in the clinical research unit (CRU) for 
up to 5 days. Participants will return to the CRU for regular outpatient visits until the next dose 
of donanemab. After the last dose of donanemab, participants will return for outpatient visits up 
to 12 weeks after the last dose.  
Brief Summary: 
The purpose of this study is to measure the PK of 350 mg donanemab IV administered Q2W for 
10 weeks in healthy participants.   
Study details include: 
 The study duration will be up to 22 weeks. 
 The treatment duration will be up to 10 weeks. 
 The visit frequency will be Q2W. 
Study Population: 
Healthy participants will be enrolled in this study. 
Number of Participants: 
Approximately 40 participants will be enrolled to donanemab so that approximately 
25 participants complete the study.  
Intervention Groups and Duration: 
Screening period: 28 days prior to enrollment into the study. 
Treatment periods: On Day -1 prior to dosing of each of the 6 treatment periods, participants will 
be admitted to the CRU. On Day 1 of each treatment period, participants will be dosed with a 
single IV dose (350 mg) of donanemab Q2W for 10 weeks. After each dose administration, 
participants will remain in the CRU for up to 5 days.  
Follow-up period: Up to 12 weeks after the last dose of donanemab. 
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. 
In this study (Study AACP), 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. 
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-AACP(a) 
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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-AACP(a) 
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1.2. 
Schema  
 
Abbreviation: CRU = clinical research unit. 
 
 
 
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I5T-MC-AACP(a) 
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1.3. 
Schedule of Activities (SoA)  
Assessment Period 
Screening 
Treatment Periods 1-6 
Follow-up 
(Treatment Period 6) 
ED 
Notes 
Study Day   
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
37 
96 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Admission to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
X 
X 
X 
X 
 
 
 
 
Discharge from CRU 
can be at a minimum of 
2 days postdose and up 
to 5 days postdose at 
the discretion of the 
investigator. 
Outpatient visit 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Donanemab administration 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical history, 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight, height, BMI 
X 
 
 
 
 
 
 
 
 
X 
X 
Height measured at 
screening only. 
Physical examination, medical 
assessment 
X 
X 
X 
X 
 
 
Xa 
 
 
X 
X 
a If discharge from 
CRU is on Days 2, 3, or 
4, physical examination 
will be taken at the 
earlier CRU discharge 
visit.  
Full physical exam at 
screening and Day -1 
and symptom-directed 
medical assessment at 
other time points and as 
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I5T-MC-AACP(a) 
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Assessment Period 
Screening 
Treatment Periods 1-6 
Follow-up 
(Treatment Period 6) 
ED 
Notes 
Study Day   
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
37 
96 
 
 
deemed necessary by 
investigator. 
Neurological examination 
X 
X 
 
24 hr 
 
 
Xb 
 
X 
X 
X 
b If discharge from 
CRU is on Days 2, 3, or 
4, neurological 
examination will be 
taken at the earlier CRU 
discharge visit. 
C-SSRS 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
Vital signs (supine): blood 
pressure, pulse rate, 
temperature  
X 
X 
Predose, 
6 hr 
24 hr 
X 
X 
X 
 
X 
X 
X 
Temperature should 
only be measured at 
screening and predose 
on Day 1. 
12-lead ECG 
X 
 
Predose 
 
 
 
 
 
 
X 
X 
Single 12-lead ECG. 
Time points may be 
added, if clinically 
indicated.  
AE and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory tests  
X 
X 
 
24 hr 
 
 
 
 
 
X 
X 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, and HIV 
Ethanol and urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
Ethanol test (urine or 
breath) may be repeated 
at other time points at 
the discretion of the 
investigator. 
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I5T-MC-AACP(a) 
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Assessment Period 
Screening 
Treatment Periods 1-6 
Follow-up 
(Treatment Period 6) 
ED 
Notes 
Study Day   
-28 to -2 
-1 
1 
2 
3 
4 
5 
8 
37 
96 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
X 
X 
Females only. Serum 
pregnancy test at 
screening. Urine 
pregnancy test at all 
other time points. 
Serum FSH 
X 
 
 
 
 
 
 
 
 
 
 
For postmenopausal 
females only. 
PK sample 
 
X 
Predose, 
End of 
infusion 
24 hr 
48 hr 72 hr 96 hr 
X 
X 
X 
X 
PK sample and 
immunogenicity sample 
should be taken at the 
same time on Day -1. 
Immunogenicity 
 
Xc 
 
 
 
 
 
 
X 
X 
X 
c Immunogenicity 
sample taken on Day -1 
of Treatment Periods 1, 
2, 3 and 6. 
Pharmacogenetics – 
apolipoprotein E genotype ε4 
 
X 
 
 
 
 
 
 
 
 
 
Day -1 of Treatment 
Period 1 only. 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; BMI = body mass index; CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity 
Rating Scale; ECG = electrocardiogram; ED = early discontinuation; FSH = follicle stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; hr = hour; PK = pharmacokinetics. 
Note: Site should schedule activities as appropriate. In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures: ECG, vital signs, PK samples, ADA. 
 
 
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I5T-MC-AACP(a) 
15 
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-AACP (AACP) will investigate the pharmacokinetics (PK) and safety of 
intravenous (IV) administration of donanemab in healthy participants every 2 weeks (Q2W) for 
10 weeks at a 350-mg dose to support dosing regimens in future studies. 
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. 
As of 05 January 2021, donanemab has been administered in 3 completed clinical studies (see 
below). A total of 243 participants have received at least 1 dose of donanemab. Of those 
243 participants, donanemab has been administered to 6 healthy participants and in 237 study 
participants with MCI due to AD; mild to moderate AD or with early symptomatic AD and 
intermediate cerebral tau burden. 
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 
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I5T-MC-AACP(a) 
16 
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 40 mg/kg were administered. In both studies, rapid and 
sustained reduction in cerebral amyloid plaques were observed with donanemab doses 
10 mg/kg.  
One Phase 2 study (Study I5T-MC-AACG [AACG]) has been conducted in participants with 
early symptomatic AD and intermediate (low to medium) cerebral tau burden. In Study AACG, 
700 mg of donanemab IV once every 4 weeks (Q4W) for first 3 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 high proportion of patients receiving donanemab have TE-ADA (92.2%; additional detail 
available in the IB). While patients experiencing hypersensitivity events were more likely to 
show high titer TE-ADA, a high titer was not predictive of adverse events (AEs). 
Currently, Phase 3 Study I5T-MC-AACI in early symptomatic AD, Phase 2 
Study I5T-MC-AACH in symptomatic AD, and Phase 3 Study I5T-MC-AACM in cognitively 
unimpaired participants with evidence of AD pathology are ongoing. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of donanemab is 
provided in the IB. 
2.3. 
Benefit/Risk Assessment  
The following are the risks and discomforts associated with donanemab: 
 ARIA 
 TE-ADAs 
 IRR and, 
 hypersensitivity. 
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I5T-MC-AACP(a) 
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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% to 1%. Incidences of ARIA-H occur 
spontaneously at rates of 10% to 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 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 AACP), 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 (eg, swelling of the lips and/or tongue) 
 hypotension, and 
 anaphylactic reaction. 
See IB Section 6.2.2.7 for more information regarding frequency of hypersensitivity reactions. 
There were no hypersensitivity reactions in healthy participants in Study AACC. 
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.  
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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 study. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of donanemab may be found in the IB. 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
 To characterize the PK profile of 
donanemab following administration 
of 350 mg IV doses in healthy 
participants 
 
AUC 0-4Weeks  
 
Cmax,ss, and  
 
AUC,ss  
Secondary 
 
 To investigate the safety and 
tolerability of donanemab following 
administration of 350 mg IV doses in 
healthy participants 
 Incidence of treatment-emergent 
adverse events and serious adverse 
events 
Exploratory 
 
 To assess the effect of TE-ADAs on 
the PK of 350 mg IV donanemab  
 
 
 
 To characterize immunogenicity of 
donanemab following administration 
of 350 mg IV doses in healthy 
participants 
 Model parameters for the 
exposure-response relationship 
between donanemab serum 
concentrations and ADA titer  
 
 Incidence of TE-ADA 
Abbreviations: ADA = anti-drug antibody; AUC,ss = area under the concentration versus time curve during a 
dosing interval at steady state; AUC 0-4Weeks = area under the concentration versus time curve 0 to 4 weeks; 
Cmax,ss = maximum observed drug concentration during a dosing interval at steady state; IV = intravenous; 
PK = pharmacokinetic; TE-ADA = treatment-emergent anti-drug antibodies. 
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4. 
Study Design  
4.1. 
Overall Design  
This is a Phase 1, open-label study to evaluate the PK, safety, and tolerability of 350 mg 
donanemab administered as a single IV dose Q2W for 10 weeks in healthy participants. 
Approximately 40 participants may be enrolled so that approximately 25 participants complete 
the study. Participants will receive a single 350 mg dose of IV donanemab Q2W for 10 weeks. 
After each dose administration, participants will remain in the clinical research unit (CRU) for 
up to 5 days. Participants will return to the CRU for regular outpatient visits until the next dose 
of donanemab. These visits will occur on Days 3, 4, 5, and 8 (unless the participant is still 
admitted to the CRU, in which activities for those days will be performed during the inpatient 
stay). After the last dose of donanemab, participants will return for outpatient visits up to 
12 weeks after the last dose.  
Screening may occur up to 28 days prior to enrollment into the study. 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. Eligible participants will be 
admitted to the CRU on Day -1 prior to dosing in each of the 6 treatment periods. On Day 1 of 
each treatment period, participants will be dosed with an IV dose of donanemab and remain in 
the CRU until discharge on Day 2, although participants may remain inpatient up to Day 5 of 
each treatment period at the discretion of the investigator. After dosing with 350 mg donanemab, 
participants will return to the CRU approximately 2 weeks later to be admitted at Day -1 of the 
subsequent period.  
Safety and tolerability will be assessed through electrocardiograms (ECGs), clinical laboratory 
tests, vital sign measurements, recording of AEs, physical examination, and neurological 
examination. Additionally, immunogenicity will be assessed. 
After discharge from the CRU after the final treatment period, participants will return for further 
outpatient assessments (safety, PK, and immunogenicity) until 12 weeks after the final dose. 
4.2. 
Scientific Rationale for Study Design  
Blinding 
The study will be open label as the primary outcome is PK. Therefore, placebo treatment is not 
required. Although safety and tolerability is a secondary objective, the safety profile of 
donanemab is well understood and at higher doses than that administered in this study. 
Pharmacokinetic sampling 
Pharmacokinetic sampling time points have been selected to allow evaluation of PK sufficient to 
fulfill the study objectives. 
Study Population 
Healthy participants have been selected for this study as it has been demonstrated previously that 
the PK profile of donanemab is comparable between healthy participants and AD patients. In 
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addition, there are no patient-centric outcomes in this study so a healthy participant population is 
considered appropriate.  
4.3. 
Justification for Dose  
Donanemab 350 mg IV Q2W was selected for this study because this dose is within the dose 
range previously evaluated in Phase 1 and Phase 2 studies. A 350 mg dose of donanemab 
administered as a single IV dose is within the dose range previously evaluated in Phase 1 studies 
(Studies AACC and AACD). In Study AACC, doses of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 
and 10 mg/kg (equivalent to approximately 7 mg, 21 mg, 70 mg, 210 mg, and 700 mg, 
respectively) of donanemab were assessed. Doses at or below 3 mg/kg (210 mg) had lower than 
dose proportional exposure (with half-life ~ 4.7 days) whereas exposure following the single 
doses of donanemab between 10 mg/kg (700 mg) and 40 mg/kg (2800 mg) were shown to be 
dose proportional (with half-life of 11 days) in Study AACD.  
Observed exposure following a 350-mg dose of donanemab from this study will assess whether 
this exposure falls within linear or nonlinear exposure range compared with a 700- to 2800-mg 
dose range. 
In participants with MCI due to AD or mild to moderate AD, including Japanese and 
non-Japanese, the following doses were generally well tolerated: 
 up to 40 mg/kg, that is approximately 2800 mg as a single dose, and 
 up to 20 mg/kg, that is approximately 1400 mg as multiple doses administered Q4W. 
4.4. 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit. 
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5. 
Study Population  
Eligibility of participants for enrollment in the study will be based on the results of screening 
medical history, physical examination, vital signs, clinical laboratory tests, and ECG. The nature 
of any conditions present at the time of the physical examination and any preexisting conditions 
will be documented.  
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only unless otherwise specified, and not continuously throughout the trial. 
Screening may occur up to 28 days prior to enrollment. Participants who are not enrolled within 
28 days of screening may undergo an additional medical assessment and/or clinical 
measurements to confirm their eligibility. 
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, vital signs, and cardiac 
monitoring 
Weight 
3. Body mass index (BMI) within the range of 19.0 to 32.0 kg/m2 (inclusive). 
Sex and Contraceptive/Barrier Requirements 
4. Male or female 
Women of childbearing potential will be excluded from the study.  
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. For the contraception 
requirements of this protocol, see Appendix 10.4. 
Informed Consent 
5. 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. 
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Other Inclusions 
6. Clinical laboratory test results within normal reference range for the population or 
investigator site, or results with acceptable deviations that are judged to be not clinically 
significant by the investigator. 
7. Venous access sufficient to allow IV drug delivery and blood sampling as per the 
protocol. 
8. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures and research unit policies. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
9. Have a history of intracranial hemorrhage, cerebrovascular aneurysm or arteriovenous 
malformation, carotid, carotid artery occlusion, stroke or epilepsy or family history of 
dementia or Down’s syndrome. 
10. Have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, immunological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; or constituting 
a risk when taking the study medication; or of interfering with the interpretation of data. 
11. Have allergies to either humanized monoclonal antibodies, diphenhydramine, 
epinephrine, or methylprednisolone. 
12. Have had gamma globulin therapy within the last 6 months. 
13. Have a history within the past 5 years of a primary or recurrent malignant disease. 
14. Have a history of clinically significant multiple or severe drug allergies or severe 
posttreatment hypersensitivity reactions (including but not limited to erythema 
multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, 
exfoliative dermatitis). 
15. Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at 
significant risk for suicide. 
16. Have answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or have answered “yes” 
to any of the suicide-related behaviors on the “suicidal behavior” portion of the C-SSRS, 
and the ideation or behavior occurred within the past month. 
17. Have a history or presence of psychiatric disorders considered to be clinically significant 
in the opinion of the investigator. 
18. Have evidence of human immunodeficiency virus (HIV) infection and/or positive HIV 
antibodies. 
19. Have spontaneously cleared hepatitis C virus (HCV) infection, defined as a positive HCV 
antibody test and a negative HCV RNA test. Participants with no history of HCV 
antibody (anti-HCV) treatment, may be eligible for inclusion in the study, provided they 
have no detectable HCV RNA at screening for this study.   
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20. Have a current infection with hepatitis B virus (HBV), that is, positive for hepatitis B 
surface antigen, polymerase chain reaction (PCR) positive for HBV DNA or both. 
21. Are lactating. 
Prior/Concomitant Therapy 
22. Have used over-the-counter or prescription medications, including herbal medication, 
within 7 days prior to dosing. 
Prior/Concurrent Clinical Study Experience 
23. Are currently enrolled in, have completed or discontinued dosing within the last 30 days 
or 5 half-lives of investigational product from a clinical trial involving an investigational 
product; or are concurrently enrolled in any other type of medical research. 
24. Have previously completed or withdrawn from this study or any other study investigating 
donanemab. 
Diagnostic Assessments 
25. Have screening clinical laboratory test results with unacceptable deviations that are 
judged to be clinically significant by the investigator. 
26. Have an abnormality in the 12-lead ECG, abnormal blood pressure, and pulse rate 
considered clinically significant by the investigator. 
Other Exclusions 
27. Are investigator site personnel directly affiliated with the study, or are immediate family 
of investigator site personnel directly affiliated with the study. Immediate family is 
defined as a spouse, parent, child, or sibling, whether biological or legally adopted. 
28. Are Lilly employees or employees of third-party organizations involved with the study. 
29. Known history of alcohol or drug abuse (as defined by the Diagnostic and Statistical 
Manual, fifth Edition, Text Revision) within 2 years prior to enrolling or a positive result 
regarding use of illicit drugs on the drug screening test. 
30. Have an average weekly alcohol intake that exceeds 21 units for males and 14 units for 
females per week, or are unwilling to stop alcohol consumption [from 24 hours prior to 
dosing until leaving the CRU] (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 
1.5 oz or 45 mL of distilled spirits). 
31. Have donated blood of more than 400 mL within the last 3 months, or any blood donation 
(including apheresis) within the last 1 month, or total volume of blood donation within 
12 months is 1200 mL at screening. 
32. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study. 
33. Are pregnant or intend to become pregnant or to breastfeed during the study. 
34. Smoke more than 10 cigarettes per day or are unable to abide by investigative site 
smoking restrictions. 
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5.3. 
Lifestyle Considerations  
5.3.1. 
Meals and Dietary Restrictions  
 Standard meals will be provided at all times while participants are resident at the CRU, as 
per the CRU’s policy.  
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco  
 During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 24 hours 
before the start of dosing until after collection of the final PK and/or pharmacodynamic 
sample. 
 During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of dosing until leaving the CRU. 
 Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical 
unit.  
5.3.3. 
Activity  
Participants will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities during studies 
(eg, watching television, reading). 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently enrolled in the study.  
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. If applicable, participants may be re-tested at the discretion of the investigator (eg, 
abnormal laboratory result) before being deemed a screen failure.   
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  
This table lists the interventions used in this clinical study. 
Intervention Name 
Donanemab 
Dosage Level(s) 
350 mg Q2W 
Route of Administration 
IV infusion 
Abbreviations: IV = intravenous; Q2W = every 2 weeks. 
Packaging and labeling 
Study interventions will be supplied by the sponsor in accordance with current Good 
Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements.  
6.1.1. 
Administration Details  
Donanemab will be administered as slow IV infusion over at least 30 minutes. Resuscitation 
equipment, emergency drugs, and appropriately trained staff must be available during the 
infusion and for at least 4 hours after participants have completed their infusion. 
6.1.1.1. 
Management of Infusion Reactions  
There is a risk of infusion reaction with any biological agent; therefore, all participants should be 
monitored closely. Symptoms and signs that may occur as part of an infusion reaction include, 
but are not limited to:   
 fever 
 chills 
 nausea 
 headache 
 bronchospasm 
 hypotension 
 angioedema 
 throat irritation 
 rash 
 pruritus 
 myalgia, and  
 dizziness.   
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In the event that a significant infusion reaction occurs, the following guidance should be 
followed:  
 The investigational product infusion should be slowed (eg, reduce infusion rate by 50% 
[eg, an infusion rate of 12 mL/h becomes 6 mL/h or slower]) or stopped, depending on 
the symptoms/signs present:  
o if slowed, the infusion should be completed at the slower rate, as tolerated  
o if determined by the investigator that the infusion should no longer continue, no 
further attempts to dose the participant should be made  
 Supportive care should be employed in accordance with the symptoms/signs  
If a participant’s infusion reaction is sufficiently severe to discontinue the infusion, subsequent 
infusions may be administered with premedication at the discretion of the investigator following 
agreement with the Lilly clinical research physician (CRP) or clinical pharmacologist.  
If a participant’s infusion rate is reduced due to an infusion reaction, subsequent infusions may 
be administered at the discretion of the investigator following agreement with the Lilly CRP or 
clinical pharmacologist. If further infusions are administered, the infusion rate must not exceed 
the slowest rate used to complete the infusion on the occasion the infusion reaction occurred. 
Premedication may be administered at the discretion of the investigator. 
If it is determined the participant should not receive further doses of investigational product, the 
participant should complete AE and other follow-up procedures per Section 1.3 of this protocol. 
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 Pharmacy Manual. 
6.3. 
Assignment to Study Intervention  
This is an open-label study with only 1 treatment.  
6.4. 
Blinding  
Not applicable as this is an open-label study with only 1 treatment. 
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6.5. 
Study Intervention Compliance  
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of donanemab and study participant identification will be confirmed prior to 
the time of dosing. The date and time of each dose administered will be recorded in the source 
documents and in the case report form (CRF). 
6.6. 
Dose Modification  
Dose adjustments are not permitted in this study. 
6.7. 
Continued Access to Study Intervention after the End of the Study  
Not applicable. 
6.8. 
Treatment of 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, and 
 obtain a plasma sample for PK analysis if requested by the medical monitor 
(determined on a case-by-case basis).  
6.9. 
Prior and Concomitant Therapy  
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) or other specific categories of interest that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
 reason for use 
 dates of administration including start and end dates, and 
 dosage information including dose and frequency 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 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 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. 
Acetaminophen, at doses of 3 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. Any 
additional medication used during the course of the study must be documented. 
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COVID-19 Considerations 
Government guidance for Health Facilities should be followed when conducting visits.  
The use of a severe acute respiratory syndrome coronavirus 2 of the genus Betacoronavirus 
(SARS-CoV-2) vaccine in participants treated with donanemab has not been studied by Lilly. 
However, given the risk posed by coronavirus disease 2019 (COVID-19) in the midst of this 
pandemic, decisions regarding the use of any vaccination, including approved/authorized for use 
vaccines, in participants treated with donanemab should be made at the discretion of the treating 
physician using their best clinical judgment and after careful consideration of risk benefit factors 
for the participant. If you have any questions regarding the type of vaccine that can be used for 
your clinical study participants, please contact your Centers for Disease Control and Prevention 
(CDC) or medical monitor for further instructions. Please have information on the vaccine(s) 
available in your country, prior to contacting your medical monitor.  
Please consult the vaccine product label for further information regarding associated risks and 
precautions, and guidance from your local regulatory agency. Hypersensitivity events have been 
reported in association with certain vaccines, in close temporal relation to the application. Taking 
this into consideration, it is recommended that study drug not be administered sooner than 5 days 
before or after a vaccination.  
As with all other concomitant medications, please ensure you record applicable information 
regarding an individual’s receipt of vaccination(s) in the participant’s source documents, and 
then follow the CRF instructions for concomitant medications for appropriate capture of vaccine 
administration in the CRFs. Please record each administration date of the vaccine (each time) as 
a concomitant medication in the CRF. If the participant is vaccinated outside of your facility, 
please request and record information such as manufacturer and dose date, when available. Any 
possible related AEs from the vaccination should be reported according to the Lilly Adverse 
Event/Serious Adverse Event reporting guidance and to the appropriate manufacture, according 
to local practice. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Participants discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 1.3 of this protocol. 
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  
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study and follow procedures for remaining study visits, as 
shown in the SoA. A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study, 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons 
 if the investigator determines that a systemic hypersensitivity reaction has occurred 
related to study intervention administration, the participant may be permanently 
discontinued from the study intervention, and the sponsor’s designated medical monitor 
should be notified. If the investigator is uncertain about whether a systemic 
hypersensitivity reaction has occurred and whether discontinuation of study intervention 
is warranted, the investigator may consult the sponsor. 
In addition, study drug may be discontinued if participants 
 answered “yes” to Question 4 or Question 5 on the “Suicidal Ideation” portion of the 
C-SSRS, or 
 answered “yes” to any of the suicide-related behaviors on the Suicidal Behavior portion 
of the C-SSRS. 
A psychiatrist or appropriately trained professional may assist in the decision to discontinue the 
participant. 
7.1.1. 
Liver Chemistry Stopping Criteria  
Discontinuation of the study intervention for abnormal liver tests should be considered by the 
investigator when a participant meets 1 of the following conditions after consultation with the 
Lilly designated medical monitor:  
 ALT (alanine aminotransferase ) or AST (aspartate aminotransferase) >5× for healthy 
participants upper limit of normal (ULN) 
 ALT or AST >3× ULN for healthy participants sustained for more than 2 weeks or  
 ALT or AST >3× ULN and total bilirubin level (TBL) >2× ULN or international 
normalized ratio (INR) >1.5 or  
 ALT or AST >3× ULN the appearance of fatigue, nausea, vomiting, right upper-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
 alkaline phosphatase (ALP) >3× ULN  
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 ALP >2.5× ULN and TBL >2× ULN  
 ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).  
Participants who discontinue from study intervention due to the abnormal liver tests will undergo 
monitoring as described in Appendix 10.6.  
Interrupting study drug based on liver test elevations in participants with normal or 
near-normal baseline liver tests 
In study participants with normal or near normal baseline liver tests (ALT, AST, ALP <1.5× 
ULN), the study drug should be interrupted and close hepatic monitoring initiated (see 
Section 8.2.8.1) if one or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >5× ULN 
 
ALT or AST >3× ULN and either TBL >2× ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2× ULN. 
ALT or AST >3× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3×ULN, when the source of increased ALP is the liver 
 
ALP >2.5× ULN and TBL >2× ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2× ULN. 
ALP >2.5× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal.  
Source: [FDA] United States Food and Drug Administration. Drug-induced liver injury: premarketing clinical 
evaluation: guidance for industry. July 2009. Accessed August 26, 2022. 
https://www.fda.gov/media/116737/download 
 
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Interrupting study drug based on elevated liver tests in participants with abnormal 
baseline liver tests 
In study participants with abnormal baseline liver tests (ALT, AST, ALP ≥1.5× ULN), the study 
drug should be interrupted if one or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >3× baseline 
 
ALT or AST >2× baseline and either TBL >2× ULN or INR 
>1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2× ULN. 
ALT or AST >2× baseline with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%) 
 
ALP >2.5× baseline, when the source of increased ALP is the 
liver 
 
ALP >2× baseline and TBL >2× ULN  
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2× ULN. 
ALP >2× baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal.  
Source: [FDA] United States Food and Drug Administration. Drug-induced liver injury: premarketing clinical 
evaluation: guidance for industry. July 2009. Accessed August 26, 2022. 
https://www.fda.gov/media/116737/download 
Resuming study drug after elevated liver tests 
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if the liver test results return to baseline and if a self-limited nondrug 
etiology is identified. Otherwise, the study drug should be discontinued. 
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 (eg, parents or legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
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 if enrolled in any other clinical study involving an investigational product, or enrolled in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
 if the participant, for any reason, requires treatment with a therapeutic agent that is 
prohibited by the protocol and has been demonstrated to be effective for treatment of the 
study indication. In this case, discontinuation from the study occurs prior to introduction 
of the new agent. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit, as shown in the SoA. If the participant has not already 
discontinued the study intervention, the participant will be permanently discontinued from the 
study intervention at the time of the decision to discontinue the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records.  
7.3. 
Lost to Follow up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.  
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get investigational product. Public sources may be searched for vital status 
information. If vital status is determined to be deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information.  
 
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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 collection 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. 
 Appendix 10.2 lists the laboratory tests that will be performed for this study. 
 Appendix 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  
Not applicable. 
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 and 
weight will also be measured and recorded. 
 Symptom-directed physical assessment may be conducted at other visits as 
mentioned in SoA and as clinically indicated. Symptom-directed physical 
examinations may also be conducted at other visits, as determined by the 
investigator, if a participant presents with complaints.  
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 Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.2. 
Vital Signs  
 For each participant, vital signs measurements should be conducted according to 
the SoA (Section 1.3). 
 Additional vital signs may be measured during the study if warranted. 
 Blood pressure and pulse rate should be measured after at least 5 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 5 minutes and stand for at least 
3 minutes. If the participant feels unable to stand, only the supine vital signs will 
be recorded.  
 Body temperature should be measured as indicated in the SoA, 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, and corrected QT interval (QTc).  
 For each participant, ECGs should be collected according to the SoA 
(Section 1.3). 
 Any clinically significant findings from ECGs that result in a diagnosis and that 
occur after the participant receives the first dose of the investigational product, 
should be reported to Lilly, or its designee, as an AE via the eCRF. 
 Electrocardiograms 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. All ECGs recorded should be stored at the investigational site. 
 Electrocardiograms will be interpreted by a qualified physician (the investigator 
or qualified designee) as soon after the time of ECG collection as possible, and 
ideally while the participant is still present, to determine whether the participant 
meets entry criteria at the relevant visit(s) and for immediate participant 
management, should any clinically relevant findings be identified. 
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. 
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 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 
(Section 10.2), must be conducted in accordance with the SoA, standard 
collection requirements, and laboratory manual. 
 If laboratory values from non-protocol specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the investigator 
(eg, SAE or AE or dose modification), then report the information as an AE.  
8.2.5. 
Pregnancy Testing  
Pregnancy testing will be performed as specified in the SoA. 
8.2.6. 
Neurological Examination  
A neurological examination will be performed by the investigator (or designee) at the time points 
specified in the SoA. 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. 
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The table below presents the scoring of the neurological examination findings. 
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 
 
 
 
 
8.2.7. 
Suicidal Ideation and Behavior Risk Monitoring  
C-SSRS 
Columbia-Suicide Severity Rating Scale is a scale that captures the occurrence, severity, and 
frequency of suicidal ideation and behavior during the assessment period via a questionnaire. 
The scale was developed by the National Institute of Mental Health trial group for the purpose of 
being counterpart to the Columbia Classification Algorithm of Suicide Assessment 
categorization of suicidal events. The C-SSRS will be performed by the investigator (or 
designee) at the time points specified in the SoA. 
Donanemab is considered to be a central nervous system-active drug. Participants being treated 
with donanemab should be monitored appropriately and observed closely for suicidal ideation 
and behavior (SIB) or any other unusual changes in behavior, especially at the beginning and end 
of the course of intervention, or at the time of dose changes, either increases or decreases. 
Participants who experience signs of SIB should undergo a risk assessment. All factors 
contributing to SIB should be evaluated and consideration should be given to discontinuation of 
the study intervention.  
In the clinical trials with donanemab to date, there has been no association between donanemab 
treatment and suicidal ideation. 
When informed consent or assent has been given, families and caregivers of participants being 
treated with donanemab should be alerted about the need to monitor participants for the 
emergence of unusual changes in behavior, as well as the emergence of suicidal ideation and 
behavior and to report such symptoms immediately to the study investigator. 
Baseline assessment of suicidal ideation and intervention emergent suicidal ideation and 
behavior will be monitored during Study AACP using the C-SSRS. 
8.2.8. 
Safety Monitoring  
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study. 
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Lilly will review SAEs within time frames mandated by company procedures. The Lilly clinical 
pharmacologist or CRP will periodically review  
 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. 
8.2.8.1. 
Hepatic Safety  
Close hepatic monitoring 
Laboratory tests (Appendix 6 [Section 10.6]), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine if it is increasing or decreasing, if 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 
TBL ≥1.5× ULN 
TBL ≥1.5× 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. 
 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (eg, heart 
failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, and history of alcohol 
drinking and other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
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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 
(PT-INR); tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal 
imaging study (eg, 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 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy.   
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Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
 Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5× ULN) 
o In participants with baseline ALT ≥1.5× ULN, the threshold is ALT ≥3× baseline 
on 2 or more consecutive tests 
 Elevated TBL to ≥ 2x ULN (if baseline TBL <1.5× ULN) (except for cases of known 
Gilbert’s syndrome) 
o In participants with baseline TBL ≥1.5× ULN, the threshold should be TBL ≥2× 
baseline 
 Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5× ULN) 
o In participants with baseline ALP ≥1.5× ULN, the threshold is ALP ≥2× baseline 
on 2 or more consecutive blood tests 
 Hepatic event considered to be an SAE 
 Discontinuation of study drug due to a hepatic event  
Note: the interval between the two consecutive blood tests should be at least 2 days. 
8.2.8.2. 
Hypersensitivity Reactions Including Infusion Related Reactions  
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
Hypersensitivity, Anaphylactic, and Infusion Related Reactions CRFs. 
Locations where study participants are receiving investigational product should have 
appropriately trained medical staff and appropriate medical equipment and rescue medications 
available. It is recommended that participants who experience a systemic hypersensitivity 
reaction be treated per the local standard of care.  
If a participant experiences a systemic hypersensitivity reaction or infusion related reaction either 
involving two or more organ systems (eg, mucocutaneous, respiratory, cardiovascular, or 
gastrointestinal systems), or that is severe, additional blood and urine samples should be 
collected as close to the event as possible, as described in Appendix 2 (Section 10.2.2). Tryptase 
and when applicable urine N-methylhistamine should be repeated in approximately 4 weeks to 
obtain postevent baseline. Laboratory results are provided to the sponsor via the central 
laboratory. 
8.2.8.3. 
Dosing Rechallenge and Premedication for Infusions  
Premedication for dosing is not planned. Dosing rechallenge is contraindicated in participants 
that have experienced a suspected or possible anaphylactic reaction (eg, reaction involving 2 or 
more organ systems [eg, mucocutaneous, respiratory, cardiovascular, or gastrointestinal systems] 
occurring in close proximity to dosing), in a prior dose (Sampson et al. 2006). For infusion 
related reactions which are not suspicious for anaphylaxis, after review of the data, and at the 
investigator’s discretion, the participant may be rechallenged. If rechallenge is planned, the 
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participant may be premedicated for subsequent doses at the investigator discretion and 
according to local practice guidelines. Prior to initiating premedication, the investigator may 
consult with the sponsor. Any premedication given will be documented as a concomitant 
therapy. 
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, and 
 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 
product complaints, 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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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 informed 
consent form 
(ICF)  
participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
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 
SAEa – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
60 days 
following the 
after final 
dose 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
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 
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; ICF = informed consent form; N/A = not applicable; PC = product complaints; 
SAE = serious adverse event. 
a Serious adverse events should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
 
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. 
8.3.1.1. 
Adverse Event Monitoring with a Systematic Questionnaire  
Nonleading AE collection should occur prior to the collection of the C-SSRS. 
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. 
If an AE is serious or leads to discontinuation, it needs to be included on the AE form and the 
process for reporting SAEs is followed. 
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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 donanemab. 
 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. 
Female participants who become pregnant 
 The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
 The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of gestational age, fetal status (presence or absence 
of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE.  
 A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring 
at ≥20 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
 Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in protocol 
Section 8.3.1. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
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 Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. If the participant is discontinued from the study, follow the 
standard discontinuation process and continue directly to the follow-up phase. The 
follow-up on the pregnancy outcome should continue independent of intervention or 
study discontinuation. 
Prior to continuation of study intervention following pregnancy, the following must occur: 
 The sponsor and the relevant Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) give written approval. 
 The participant gives signed informed consent. 
 The investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and the participant’s offspring. 
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 (Section 1.3).  
 A maximum of 3 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 
(eg, 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. 
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics  
A blood sample for DNA isolation will be collected from participants.  
See Appendix 5 (Section 10.5) for Information regarding genetic research and Appendix 1 
(Section 10.1.11) for details about sample retention and custody.  
8.7. 
Biomarkers  
Biomarkers are not evaluated in this study. 
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.  
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Immunogenicity will be assessed by a validated assay designed to detect anti-drug antibodies 
(ADAs) in the presence of donanemab at a laboratory approved by the sponsor.  
Treatment-emergent ADAs are defined in Section 9.3.6. 
Samples will be retained for a maximum of 15 years after the last participant visit, if local 
regulations allow, at a facility selected by the sponsor. The duration allows the sponsor to 
respond to future regulatory requests related to donanemab. Any samples remaining after 
15 years will be destroyed. 
8.9. 
Health Economics  
Health economics 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 first participant first visit, and it will include 
a more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses  
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 
Pharmacokinetic 
All enrolled participants who received at least 1 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. 
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 
9.2.1. 
Study Participant Disposition  
A detailed description of participant disposition will be provided at the end of the study. 
9.2.2. 
Study Participant Characteristics  
Demographic and baseline characteristics will be summarized. 
9.3. 
Statistical Analyses  
9.3.1. General Considerations  
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 
Pharmacokinetic analyses will be conducted on data from all participants who receive at least 
1 dose of the investigational product and have evaluable PK data. 
Safety analyses will be conducted for all enrolled participants who received study intervention, 
whether or not they completed all protocol requirements.  
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Summary statistics, data tabulations, and data graphs will be provided as deemed appropriate. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. Study 
results may be pooled with the results of other studies for safety, immunogenicity, and 
population PK analysis purposes to avoid issues with post-hoc analyses and incomplete 
disclosures of analyses. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the statistical analysis plan, where 
appropriate. Adjustments to the planned analyses are described in the final clinical study report.  
9.3.2. 
Primary Endpoint Analyses: Pharmacokinetic Analyses  
9.3.2.1. 
Pharmacokinetic Parameter Estimation  
Pharmacokinetic parameter estimates for donanemab will be calculated by standard 
noncompartmental methods of analysis.  
The primary parameters for analysis will be maximum drug concentration (Cmax,ss) and area 
under the concentration versus time curve 0 to 4 weeks (AUC 0-4Weeks) and during a dosing 
interval at steady state (AUC,ss) following multiple dosing of donanemab. Other 
noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of 
distribution may be reported. 
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. 
Exposure (AUC 0-4Weeks) will be calculated. Other noncompartmental parameters may be 
reported, as appropriate. 
Exploratory graphical analyses relating donanemab serum exposure and immunogenicity may be 
conducted. 
9.3.3. 
Secondary Endpoint(s) Analyses  
The incidence of TEAEs and SAEs to investigate the safety and tolerability of donanemab 
following IV administration of donanemab in healthy participants Q2W for 10 weeks at a 
350 mg dose will be listed and/or summarized.  
9.3.4. 
Exploratory Analyses  
The number of TEAEs will be reported. The frequency and percentage of participants with 
preexisting ADAs and with TE-ADAs to donanemab will be tabulated. The relationship between 
the presence of TE-ADAs and serum donanemab concentration may be assessed.  
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9.3.5. 
Safety Analyses  
9.3.5.1. 
Clinical Evaluation of Safety  
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.  
The incidence of AEs will be presented by severity and by association with investigational 
product as perceived by the investigator. Adverse events reported to occur prior to study entry 
will be distinguished from those reported as new or increased in severity during the study. Each 
AE will be classified by the most suitable term from the medical regulatory dictionary. 
9.3.5.2. 
Statistical Evaluation of Safety  
All study intervention and protocol procedure AEs and SAEs will be listed, and if the frequency 
of events allows, safety data will be summarized using descriptive methodology. The incidence 
of symptoms will be presented by severity and by association with the study intervention as 
perceived by the investigator. Symptoms reported to have occurred 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 AEs and SAEs will be reported.  
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters. The safety parameters will be listed and summarized using standard descriptive 
statistics. Additional analysis will be performed if warranted upon review of the data. 
9.3.6. 
Immunogenicity Assessments  
Treatment-emergent ADAs are defined as those with either 
 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, when 
available. 
The relationship between the presence of antibodies and the PK parameters and 
pharmacodynamic response including safety and efficacy to donanemab may be assessed. 
9.3.7. 
Other Analyses  
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide. 
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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Access to safety, PK, and immunogenicity data may occur on an ongoing basis throughout the 
study. The purpose of these reviews is to inform the design of subsequent studies. 
9.5. 
Sample Size Determination  
Approximately 40 participants may be enrolled so that approximately 25 participants complete 
the study. The sample sizes described are customary for Phase 1 studies evaluating safety, PK, 
and immunogenicity and is not powered on the basis of statistical hypothesis testing. 
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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 IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
● The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility and 
adherence to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations 
○ Reporting to the sponsor or designee significant issues related to participant safety, 
participant rights, or data integrity 
● Investigator sites are compensated for participation in the study as detailed in the clinical 
trial agreement. 
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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 complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
 The investigator or 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 trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by 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 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. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor 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 review, 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. 
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 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. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the time period outlined in the Clinical Trial 
Agreement (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 systems 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. 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. 
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 Data reported on or entered in the CRF and are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available. 
 Definition of what constitutes source data can be found in Section 10.1.7. 
10.1.9. 
Study and Site Start and Closure  
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
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. 
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10.1.11. 
Investigator Information  
Not applicable. 
10.1.12. 
Long-Term 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.   
Sample Type 
Custodian 
Retention Period After Last 
Patient Visit* 
Long-term storage samples 
Sponsor or Designee 
15 years 
Pharmacokinetic 
Sponsor or Designee 
2 years  
Genetics 
Sponsor or Designee 
15 years 
Immunogenicity 
Sponsor or Designee 
15 years 
 
 
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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.  
 
 
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Safety Laboratory Tests 
Hematology 
Clinical Chemistry 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Mean cell volume  
Chloride  
Mean cell hemoglobin  
Glucose (random) 
Mean cell hemoglobin concentration  
Blood urea nitrogen (BUN) or ureac 
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) 
Urinalysisa 
Gamma-glutamyl transferase (GGT)  
Specific gravity 
pH 
 
Protein 
Glucose 
 
Ketones 
Ethanol testingd 
Bilirubin 
Urine drug screend 
Urobilinogen 
Hepatitis B surface antigenb 
Blood 
Hepatitis C antibodyb,e 
Nitrite 
HIVe 
Microscopic examination of sedimentb 
Pregnancy testf 
 
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.  
a Performed by dipstick. Microscopic examination to be performed if dipstick is abnormal for blood, protein, or 
nitrates. 
b Performed at screening only. 
c Either BUN or urea will be tested, whichever is feasible. 
d Urine drug screen and ethanol (urine or breath) level performed at screening and at admission to the clinical 
research unit. 
e Participants with a positive hepatitis C antibody test result can have a confirmatory hepatitis C RNA test. 
f 
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. 
 
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10.2.1. 
Blood Sampling Summary  
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study. 
Protocol I5T-MC-AACP Sampling Summary 
 
Purpose 
Blood Volume per 
Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa 
45 
1 
45 
Clinical laboratory testsa 
12.5 
13 
162.5 
Pharmacokinetics  
4 
50 
200 
Immunogenicity 
10 
6 
60 
Pharmacogenetics 
10 
1 
10 
Total 
 
 
477.5 
Total for clinical purposes [rounded up to nearest 10 mL] 
480 
a Additional samples may be drawn if needed for safety purposes. 
 
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 tests 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 predose samples at the next regularly scheduled laboratory sample collection 
(ideally prior to the next dose after the event) to assess post-event return-to-baseline values. 
 
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Timing 
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. 
Total tryptase 
complements (C3, C3a, and C5a)  
cytokine panel (IL-6, IL‐1β, IL‐10 or any cytokine 
panel that includes these 3 cytokines)  
Collect only if not already collected on the same day as 
the event. 
● 
Note: If collecting, collect up to 12 hours after 
the start of the event. 
donanemab (LY3002813) ADA 
donanemab (LY3002813) concentration 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
a All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting  
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 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. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
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 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
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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. 
 The investigator will also consult the IB, in their assessment. 
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 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. 
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10.3.5. 
Reporting of SAEs  
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see 
next section) in order to report the event within 24 hours.  
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a SAE paper form (see next 
section) or to the medical monitor/SAE coordinator by telephone. 
 Contacts for SAE reporting can be found in the SAE Report. 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form 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 CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in the 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. 
● 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, 
Institutional Review Boards (IRB)/Independent Ethics Committees (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  
 
Definition 
Women of childbearing 
potential (WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP. 
Any amount of spotting should be considered menarche. 
Women not of childbearing 
potential (WNOCBP) 
Females are considered WNOCBP if they 
 
have a congenital anomaly such as Müllerian agenesis  
 
are infertile due to surgical sterilization, or  
 
are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral 
salpingo-oophorectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal state 
The postmenopausal state is defined as a woman: 
 
at any age at least 6 weeks postsurgical bilateral oophorectomy with 
or without hysterectomy, confirmed by operative note; or  
 
aged at least 40 years and up to 55 years with an intact uterus, not on 
hormone therapya, who has had cessation of menses for at least 
12 consecutive months without an alternative medical cause, AND 
with a follicle-stimulating hormone >40 mIU/mL; or  
 
55 years or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea, or 
 
aged at least 55 years with a diagnosis of menopause prior to starting 
hormone replacement therapy. 
a Women should not be taking medications during amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor modulators, or chemotherapy that 
could induce transient amenorrhea. 
 
Females 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative urine result 
within 24 hours prior to treatment exposure. See the protocol Schedule of Activities 
for subsequent pregnancy testing requirements. 
Contraception 
Abstinence or 2 effective forms of contraception where at least 1 form is highly 
effective, maintained for at least 5 half-lives plus 30 days 
 
10.4.2. 
Contraception Guidance  
For male participants: 
 Males may participate in this study. 
 No male contraception is required except in compliance with specific local government 
study requirements. 
For female participants: 
 Women of childbearing potential are excluded from the study. 
 Women not of childbearing potential may participate in this study. 
See Appendix 4, Section 10.4.1 for definitions. 
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Examples of highly effective, effective, and unacceptable methods of contraception can be found 
below. 
Methods 
Examples 
Highly effective 
contraception (less than 1% 
failure rate) 
 
female sterilization 
 
combination oral contraceptive pill 
 
progestin-only contraceptive pill (mini-pill) 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
Effective contraception 
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical sponges 
 
barrier method with use of a spermicide 
o 
condom with spermicide 
o 
diaphragm with spermicide, or 
o 
female condom with spermicide 
Ineffective forms of 
contraception whether used 
alone or in any 
combination 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, temperature method, cervical 
mucus, or symptothermal) 
 
withdrawal 
 
postcoital douche, or 
 
lactational amenorrhea 
 
 
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10.5. 
Appendix 5: Genetics  
Use/Analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to donanemab and related 
diseases. They may also be used to develop tests/assays including diagnostic tests 
related to donanemab and/or interventions of this drug class. Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of 
genetic markers throughout the genome or analysis of the entire genome (as 
appropriate). 
● DNA samples will be analyzed for apolipoprotein E genotype ε4. Additional 
analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 
● The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to donanemab or study interventions of this class 
to understand study disease or related conditions. 
● The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
● The samples will be retained while research on donanemab or study interventions 
of this class or indication continues but no longer than 15 years or other period as 
per local requirements. 
 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic Evaluation Testing 
See Section 8.2.8.1 for guidance on appropriate test selection. 
Testing by an investigator-designated local laboratory should be performed for all testing defined 
by this guidance. 
The local laboratory must be qualified in accordance with applicable local regulations. 
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 
   Acetaminophen 
       Eosinophils 
   Acetaminophen protein adducts 
   Platelets 
   Alkaline phosphatase isoenzymes 
   Cell morphology (RBC and WBC) 
   Ceruloplasmin 
Hepatic Coagulation Panel 
   Copper 
    Prothrombin time, INR (PT-INR) 
   Ethyl alcohol (EtOH) 
Hepatitis A virus (HAV) testing: 
   Haptoglobin 
    HAV total antibody 
   Immunoglobulin IgA (quantitative) 
    HAV IgM antibody 
   Immunoglobulin IgG (quantitative) 
Hepatitis B virus (HBV) testing: 
   Immunoglobulin IgM (quantitative) 
    Hepatitis B surface antigen (HbsAg) 
   Phosphatidylethanol (Peth) 
    Hepatitis B surface antibody (anti-HBs) 
Urine Chemistry 
    Hepatitis B core total antibody (anti-HBc) 
   Drug screen 
    Hepatitis B core IgM antibody 
   Ethyl glucuronide (EtG) 
    HBV DNA b 
Other Serology 
Hepatitis C virus (HCV) testing: 
   Anti-nuclear antibody (ANA) 
    HCV antibody 
   Anti-smooth muscle antibody (ASMA) a 
    HCV RNA b 
   Anti-actin antibody c 
Hepatitis D virus (HDV) testing: 
   Epstein-Barr virus (EBV) testing: 
    HDV antibody 
       EBV antibody 
Hepatitis E virus (HEV) testing: 
       EBV DNA b 
    HEV IgG antibody 
   Cytomegalovirus (CMV) testing: 
    HEV IgM antibody 
       CMV antibody 
    HEV RNA b 
       CMV DNA b 
Microbiology  
    Herpes simplex virus (HSV) testing: 
   Culture: 
       HSV (Type 1 and 2) antibody 
       Blood 
       HSV (Type 1 and 2) DNA b 
       Urine 
    Liver kidney microsomal type 1 (LKM-1) antibody 
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Abbreviations: Ig = immunoglobulin; INR = international normalized ratio; PT-INR = prothrombin 
time-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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10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits,” and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
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Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, 
but are not limited to, 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 visits implemented, the protocol requirements regarding the 
reporting of adverse events (AEs), serious adverse events (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 safety of study participants, laboratory values and other eligibility assessments taken 
at 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. The participant can reconsent and be rescreened as a 
new participant. The screening procedures per the usual Schedule of Activities should 
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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 Schedule of Activities. To maximize the possibility that these visits 
can be conducted as on-site visits, the windows for visits may be adjusted, upon further guidance 
from the sponsor. This minimizes missing data and preserves the intended conduct of the study. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing/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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10.8. 
Appendix 8: 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 
ARIA–edema/effusions 
ARIA-H 
ARIA–hemorrhage/hemosiderin deposition 
AST 
aspartate aminotransferase 
AUC 0-4Weeks 
area under the concentration versus time curve 0 to 4 weeks 
AUC0-∞ 
area under the concentration versus time curve from time 0 to infinity 
AUC0-tlast 
area under the concentration versus time curve from time 0 to last measured 
concentration 
AUC,ss 
area under the concentration versus time curve during a dosing interval at steady state 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
Cmax 
maximum observed drug concentration 
Cmax,ss 
maximum observed drug concentration during a dosing interval at steady state 
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. 
COVID-19 
coronavirus disease 2019 
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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. 
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 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
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. 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
iADRS 
integrated Alzheimer’s Disease Rating Scale 
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. 
INR 
international normalized ratio 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. See also “IMP.” 
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IRB 
Institutional Review Board 
IRR 
infusion-related reactions 
IV 
intravenous 
MCI 
mild cognitive impairment 
N3pG 
pyroglutamate formation of the third amino acid 
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 
PCR 
polymerase chain reaction 
PK 
pharmacokinetics 
PT-INR 
prothrombin time-international normalized ratio 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 of the genus Betacoronavirus 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SIB 
suicidal ideation and behavior 
SoA 
Schedule of Activities 
TBL 
total bilirubin level 
TE-ADA 
treatment-emergent anti-drug antibodies 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
ULN 
upper limit of normal 
 
 
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abnormalities in an APOE ε4/ε4 patient treated with aducanumab. Alzheimers Dement (Amst). 
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Approved on 12 Dec 2022 GMT


CONFIDENTIAL 
I5T-MC-AACP(a) 
79 
Wessels AM, Siemers ER, Yu P, et al. A combined measure of cognition and function for 
clinical trials: the integrated Alzheimer’s Disease Rating Scale (iADRS). J Prev Alzheimers 
Dis. 2015;2(4):227-241. https://doi.org/10.14283/jpad.2015.82 
Approved on 12 Dec 2022 GMT


Signature Page for VV-CLIN-076261 v1.0
Signature Page for VV-CLIN-076261 v1.0
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Approved on 12 Dec 2022 GMT
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan:  I5T-MC-AACP (v2) 
 
 
A Phase 1, Open-Label Study to Characterize the Pharmacokinetics of 
Donanemab Following Intravenous Doses in Healthy Participants 
 
 
NCT05567159 
 
 
Approval Date: 01-Mar-2023 


 
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STATISTICAL ANALYSIS PLAN 
A Phase 1, Open-Label Study to Characterize the Pharmacokinetics of Donanemab 
Following Intravenous Doses in Healthy Participants 
Statistical Analysis Plan Status: Final 
Statistical Analysis Plan Version: 2.0 
Statistical Analysis Plan Date: 28Feb2023 
Investigational Medicinal Product: LY3002813 (Donanemab) 
Protocol Reference: I5T-MC-AACP  
Labcorp Drug Development Study: 8503300 
Clinical Phase I 
 
 
 
 
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1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ................................................................................................... 2 
2. 
ABBREVIATIONS ............................................................................................................ 4 
3. 
INTRODUCTION .............................................................................................................. 6 
4. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 7 
5. 
STUDY DESIGN ............................................................................................................... 7 
6. 
BLINDING ......................................................................................................................... 8 
7. 
TREATMENT .................................................................................................................... 8 
8. 
SAMPLE SIZE JUSTIFICATION ..................................................................................... 9 
9. 
DEFINITION OF ANALYSIS POPULATIONS .............................................................. 9 
10. STATISTICAL METHODOLOGY ................................................................................... 9 
10.1 General ......................................................................................................................... 9 
10.2 Demographics and Participant Disposition ............................................................... 10 
10.3 Pharmacokinetic Assessment ..................................................................................... 10 
10.3.1 Pharmacokinetic Analysis ................................................................................ 10 
10.3.2 Pharmacokinetic Statistical Methodology ........................................................ 14 
10.4 Safety and Tolerability Assessments ......................................................................... 14 
10.4.1 Adverse events ................................................................................................. 14 
10.4.2 Concomitant medication ................................................................................... 14 
10.4.3 Clinical laboratory parameters ......................................................................... 15 
10.4.4 Vital signs ......................................................................................................... 15 
10.4.5 Electrocardiogram (ECG) ................................................................................. 15 
10.4.6 Hepatic Monitoring .......................................................................................... 15 
10.4.7 Immunogenicity Assessments .......................................................................... 15 
10.4.8 Neurological Examinations .............................................................................. 16 
10.4.9 Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 16 
10.4.10 Hypersensitivity reactions ................................................................................ 16 
10.4.11 Infusion Related Reactions ............................................................................... 16 
10.4.12 Other assessments ............................................................................................. 16 
10.4.13 Safety and Tolerability Statistical Methodology .............................................. 17 
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11. INTERIM ANALYSES .................................................................................................... 17 
12. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 17 
13. REFERENCES ................................................................................................................. 17 
14. DATA PRESENTATION ................................................................................................ 17 
14.1 Derived Parameters .................................................................................................... 17 
14.2 Missing Data .............................................................................................................. 17 
14.3 Insufficient Data for Presentation .............................................................................. 17 
15. APPENDICES .................................................................................................................. 18 
Appendix 1: Document History .......................................................................................... 18 
 
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Protocol Reference: I5T-MC-AACP 
2. ABBREVIATIONS  
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]). 
%AUC(tlast-∞) 
Fraction of AUC(0-∞) extrapolated 
AE 
Adverse event 
ADA 
Anti-drug antibody 
AUC 
Area under the concentration versus time curve 
AUC0-4weeks 
Area under the concentration vs time curve from time 0 to 4weeks 
AUC0-2weeks 
Area under the concentration vs time curve for first dosing interval 
AUCτ,ss 
Area under the concentration versus time curve during one dosing 
interval at steady state 
AUC(0-∞) 
Area under the concentration versus time curve from time zero to 
infinity 
AUC(0-tlast) 
Area under the concentration versus time curve from time zero to time 
t, where t is the last time point with a measurable concentration 
BQL 
Below the quantifiable lower limit of the assay 
CL 
Total body clearance of drug calculated after intravenous 
administration 
CL,ss 
Total body clearance of drug calculated at steady state after 
intravenous administration 
Clast 
Last quantifiable drug concentration 
Cmax 
Maximum observed drug concentration 
Cmax,ss 
Maximum observed drug concentration during a dosing interval at 
steady state 
Cmin,ss 
Minimum observed drug concentration during a dosing interval at 
steady state 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
CSSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficient of variation 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
ICH 
International Conference on Harmonisation 
IV 
Intravenous  
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IRR 
Infusion related reactions 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
Q2W 
Every 2 weeks 
RAAUC 
Accumulation ratio for AUCτ,ss at steady state / AUC0-2weeks 
RACmax 
Accumulation ratio for Cmax,ss at steady state / Cmax, day 1 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation  
SOP 
Standard Operating Procedure 
TBL 
Total bilirubin 
TE-ADA 
Treatment emergent antidrug antibodies 
TEAE 
Treatment emergent adverse event 
TFLs 
Tables, Figures, and Listings 
t1/2 
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis 
tmax 
Time of maximum observed drug concentration 
Vss 
Volume of distribution at steady state following  intravenous 
administration 
Vz 
Volume of distribution during the terminal phase 
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3. INTRODUCTION  
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
12 December 2022). 
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document. 
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. This SAP must 
be finalized prior to first participant visit. When the SAP and TFL shells are agreed upon and 
finalized, they will serve as the template for this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with 
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2. 
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4. STUDY OBJECTIVES AND ENDPOINTS  
Objectives 
Endpoints 
Primary 
 
 To characterize the PK profile of donanemab 
following administration of 350 mg 
intravenous (IV) doses in healthy 
participants 
 Area under the concentration versus 
time curve 0 to 4 weeks (AUC0-4 Weeks) 
 Maximum observed drug concentration 
during a dosing interval at steady state 
(Cmax, ss) and 
 Area under the concentration versus 
time curve during a dosing interval at 
steady state (AUC𝜏, ss) 
Secondary 
 
 To investigate the safety and tolerability of 
donanemab following administration of 
350 mg IV doses in healthy participants  
 Incidence of treatment-emergent 
adverse events (TEAE) and serious 
adverse events (SAE). 
Exploratory 
 
 To assess the effect of treatment-emergent 
anti-drug antibodies (TE-ADAs) on the PK 
of 350 mg IV donanemab 
 Model parameters for the 
exposure-response relationship 
between donanemab serum 
concentrations and anti-drug antibody 
(ADA) titer  
 To characterize immunogenicity of 
donanemab following administration of 
350 mg IV doses in healthy participants  
 Incidence of TE-ADA  
5. STUDY DESIGN  
This is a Phase 1, open-label study to evaluate the PK, safety, and tolerability of 350 mg 
donanemab administered as a single IV dose every 2 weeks (Q2W) for 10 weeks in healthy 
participants. Approximately 40 participants may be enrolled so that approximately 
25 participants complete the study. Participants will receive a single 350 mg dose of donanemab 
Q2W for 10 weeks. After each dose administration, participants will remain in the clinical 
research unit (CRU) for up to 5 days. Participants will return to the CRU for regular outpatient 
visits until the next dose of donanemab. These visits will occur on Days 3, 4, 5, and 8 (unless the 
participant is still admitted to the CRU, in which activities for those days will be performed 
during the inpatient stay). After the last dose of donanemab, participants will return for 
outpatient visits up to 12 weeks after the last dose. 
Screening may occur up to 28 days prior to enrollment into the study. Once the informed consent 
is signed by the participants, they will be assessed for eligibility and will undergo screening 
procedures. 
Participants who are not enrolled within 28 days of screening may undergo an additional medical 
assessment and/or clinical measurements to confirm their eligibility. Eligible participants will be 
admitted to the CRU on Day -1 prior to dosing in each of the 6 treatment periods. On Day 1 of 
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each treatment period, participants will be dosed with an IV dose of donanemab and remain in 
the CRU until discharge on Day 2, although participants may remain inpatient up to Day 5 of 
each treatment period at the discretion of the investigator. After dosing with 350 mg donanemab, 
participants will return to the CRU approximately 2 weeks later to be admitted at Day -1 of the 
subsequent period. 
Safety and tolerability will be assessed through electrocardiograms (ECGs), clinical laboratory 
tests, vital sign measurements, recording of adverse events (AEs), physical examination, and 
neurological examination. Additionally, immunogenicity will be assessed. 
After discharge from the CRU after the final treatment period, participants will return for further 
outpatient assessments (safety, PK, and immunogenicity) until 12 weeks after the final dose. 
Study Schema
 
Abbreviations: CRU = Clinical research unit 
Figure 1: Illustration of Study Design for Protocol I5T-MC-AACP 
6. BLINDING  
This is a non-randomized, open-label study. 
7. TREATMENT  
The following shows the study treatment abbreviation that will be used in the TFLs. 
Study Treatment Name 
Treatment order in TFL 
350 mg donanemab Q2W 
1 
Abbreviations: Q2W = every 2 weeks 
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8. SAMPLE SIZE JUSTIFICATION  
Approximately 40 participants may be enrolled so that approximately 25 participants complete 
the study. The sample sizes described are customary for Phase 1 studies evaluating safety, PK, 
and immunogenicity and is not powered on the basis of statistical hypothesis testing. 
9. DEFINITION OF ANALYSIS POPULATIONS  
The “Entered” population will consist of all participants who sign the informed consent form. 
The “Enrolled” population will consist of all enrolled participants. 
The “Safety” population will consist of all participants randomly assigned to study intervention 
and who take at least 1 dose of study donanemab. Participants will be analyzed according to the 
amount of intervention they actually received. 
The “Pharmacokinetic” population will consist of all enrolled participants who received at least 
1 full dose of donanemab and have baseline and at least one post-baseline evaluable PK sample. 
Participants will be analyzed according to the amount of intervention they actually received. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations. 
10. 
STATISTICAL METHODOLOGY  
10.1 
General  
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
minimum, maximum and number of observations; for log-normal data (e.g. the PK parameters: 
area under the concentration versus time curve [AUCs] and maximum observed drug 
concentration [Cmax]) the geometric mean and geometric coefficient of variation (CV%) will also 
be presented. For categorical data, frequency count and percentages will be presented. Data 
listings will be provided for all participants up to the point of withdrawal, with any participants 
excluded from the relevant population highlighted. Summary statistics and statistical analyses 
will generally only be performed for participants included in the relevant analysis population. 
For the calculation of summary statistics and statistical analysis, unrounded data will be used.  
For change from baseline summary statistics, each individual change from baseline will be 
calculated by subtracting the individual participant’s baseline value from the value at that time 
point. The individual participants’ change from baseline values will be used to calculate the 
summary statistics (arithmetic mean, arithmetic SD, median, minimum, maximum and number 
of observations) using a SAS procedure such as Proc Univariate. 
Data analysis will be performed using SAS® Version 9.4 or greater. 
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10.2 
Demographics and Participant Disposition  
Participant disposition will be summarized and listed. The demographic variables age, sex, race, 
ethnicity, country of enrolment, site ID, body weight, height and body mass index will be 
summarized and listed. All other demographic variables will be listed only. 
10.3 
Pharmacokinetic Assessment  
10.3.1 Pharmacokinetic Analysis  
Noncompartmental methods applied with a validated software program (WinNonlin Phoenix 
v8.3.5 or higher) to the serum concentrations of LY3002813 (donanemab), will be used to 
determine the following PK parameters, when possible:   
 
Serum Pharmacokinetic Parameters of LY3002813 (Donanemab): 
Parameter 
Units 
Definition 
AUC0-4weeks 
ug*h/m
L 
area under the concentration versus time curve from time 0 to 
4weeks (Month 1, 2 and 3)a 
AUC0-2weeks 
ug*h/m
L 
area under the concentration versus time curve for first dosing 
interval (Treatment Period 1 to 6) 
AUCτ,ss 
 
ug*h/mL 
area under the concentration versus time curve during one dosing 
interval at steady state (Treatment Period 6) 
AUC(0-tlast) 
ug*h/mL 
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration 
(Treatment Periods 1 to 6) 
AUC (0-∞) 
ug*h/mL 
area under the concentration versus time curve from zero to infinity 
(only after 1st dose and after last dose on Day 71) 
%AUC(tlast-)  
Percentage of AUC(0-∞) extrapolated 
Cmax,ss 
ug/mL 
maximum observed drug concentration during a dosing interval at 
steady state (Treatment Period 6) 
Cmax 
ug/mL 
maximum observed drug concentration (Treatment Periods 1 to 5) 
Cmin 
ug/mL 
minimum observed drug concentration during a dosing interval at 
steady state (Treatment Period 1 to 5) 
Cmin,ss 
ug/mL 
minimum observed drug concentration during a dosing interval at 
steady state (Treatment Period 6) 
t1/2 
days 
half-life associated with the terminal rate constant (λz) in non-
compartmental analysis (Treatment Period 6) 
tmax 
days 
time to maximum observed drug concentration (Treatment Period 1 
to 5) 
tmax,ss 
days 
time to maximum observed drug concentration at steady state 
(Treatment Period 6) 
CL,ss 
L/h 
total body clearance of drug calculated at steady state after 
intravenous administration (Treatment Period 6) 
 
 
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Vss 
L 
volume of distribution at steady state following intravenous 
administration (Treatment Period 6) 
RAAUC 
 
accumulation ratio for AUCτ,ss at steady state / AUC0-2weeksb 
RACmax 
 
accumulation ratio for Cmax,ss at steady state / Cmax, day 1b 
a Parameter will be calculated as the sum of AUC0-2weeks for treatment periods 1 and 2 (Month 1), periods 3 and 4 
(Month 2) and periods 5 and 6 (Month 3). 
b AUCτ,ss and Cmax,ss based on Period 6; AUC0-2weeks and Cmax values based on Period 1 
Additional PK parameters may be calculated, as appropriate.  
The software and version used for the final analyses will be specified in the CSR. Any 
exceptions or special handling of data will be clearly documented within the final CSR. 
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool 
effective at the time of PK analysis will be followed. 
General PK Parameter Rules 
 Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation. 
 Cmax will be reported from observed values.  
 AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification, with at least 
one of these concentrations following Cmax. AUC(0-) values where the percentage of 
the total area extrapolated is more than 20% will be flagged. Any AUC(0-) value 
excluded from summary statistics will be noted in the footnote of the summary table. 
 Half-life (t1/2) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each participant will be defined by visual inspection and generally will be the 
first point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t1/2 is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t1/2 value excluded from summary statistics will be documented in the footnote of the 
summary table.  
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 A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve. 
 The parameters based on predicted Clast will be reported. 
Individual PK Parameter Rules 
 Only quantifiable concentrations will be used to calculate PK Parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL). Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met:  
o The compound is non-endogenous. 
o The samples are from the initial dose period for a participant or from a subsequent 
dose period following a suitable wash-out period. 
o The time points occur before the first quantifiable concentration. 
 All other BQL concentrations that do not meet the above criteria will be set to missing.  
 Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug. 
For multiple-dosing data, when pre-dose concentrations are missing, the value to be substituted 
will be Cmin for the dosing interval. 
Individual Concentration vs. Time Profiles 
 Individual concentrations will be plotted utilizing actual sampling times. 
 The terminal point selections will be indicated on a semi-logarithmic plot. 
Average Concentration vs. Time Profiles 
 The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.  
 The average concentration profiles will be graphed using arithmetic average 
concentrations. 
 The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations. 
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 Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles. 
 Concentrations excluded from the mean calculation will be documented in the final study 
report. 
 A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report. 
Treatment of Outliers during Pharmacokinetic Analysis 
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis. 
Data within an Individual Profile 
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met: 
 For PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples. 
 For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable. 
 For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.  
Data between Individual Profiles 
1. If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation: 
a. Transform all values in the calculation to the logarithmic domain. 
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset. 
c. Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values. 
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d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not 
an outlier and will be retained in the dataset. 
e. If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis. 
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 1 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values. 
Reporting of Excluded Values 
Individual values excluded as outliers will be documented in the final CSR. Approval of the final 
CSR will connote approval of the exclusion.  
10.3.2 Pharmacokinetic Statistical Methodology  
No formal statistical analysis is planned for this study. The PK parameters will be listed and 
summarized by study week using standard descriptive statistics. Insert stats methodology here. 
10.4 
Safety and Tolerability Assessments  
10.4.1 Adverse events  
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as a condition that starts before the 
participant has provided written informed consent and is ongoing at consent. A non-treatment 
emergent AE is defined as an AE which starts after informed consent but prior to dosing. A 
TEAE is defined as an AE which occurs post-dose or which is present prior to dosing and 
becomes more severe post-dose.  
All AEs will be listed. TEAEs will be summarized by severity and relationship to the study drug. 
The frequency (the number of AEs, the number of participants experiencing an AE and the 
percentage of participants experiencing an AE) of treatment-emergent AEs will be summarized 
by Medical Dictionary for Regulatory Activities (MedDRA) (version is documented in the Data 
Management Plan [DMP]) system organ class and preferred term. The summary and frequency 
AE tables will be presented for all causalities and those considered related to the study drug by 
the investigator. Any SAEs and product complaints will be listed. AEs by week of onset will be 
presented. 
Discontinuations due to AEs will be listed. 
10.4.2 Concomitant medication  
Concomitant medication will be coded using the World Health Organization drug dictionary 
(version is documented in the DMP). Concomitant medication will be listed. 
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10.4.3 Clinical laboratory parameters  
All clinical chemistry and hematology data will be summarized by time point, and listed. 
Urinalysis data will be listed. Additionally, clinical chemistry, hematology and urinalysis data 
outside the reference ranges will be listed and flagged on individual participant data listings. 
10.4.4 Vital signs  
Vital signs data collected during the treatment periods will be summarized by time point together 
with changes from baseline, where baseline is defined as the Day 1 pre-dose assessment in each 
treatment period. Figures of mean vital signs and mean changes from baseline profiles will be 
presented by treatment.  
Values for individual participants will be listed. 
10.4.5 Electrocardiogram (ECG)  
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE. 
10.4.6 Hepatic Monitoring  
If a participant experiences elevated laboratory parameters, as detailed in Section 8.2.8.1 of the 
protocol, additional tests will be performed to confirm the abnormality. Additional safety data 
may be collected if required, as defined in the protocol. Where applicable, the following will be 
presented. 
The participants’ liver disease history and associated person liver disease history data will be 
listed. Use of acetaminophen during the study, which has potential for hepatotoxicity, will be 
listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography scan, and biopsy assessments will be listed, if performed. 
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized and listed. Alcohol and recreational drug use data will also be listed. 
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual participant data listings. 
10.4.7 Immunogenicity Assessments  
Immunogenicity data will be listed and frequency tables will be presented if analysed. The 
frequency and percentage of participants with pre-existing ADA and with TE ADAs will be 
presented. TE ADAs are those that are boosted or induced by exposure to study drug, with a 
4-fold increase in titer compared to baseline if ADAs were detected at baseline or a titer 2-fold 
greater than the minimum required dilution (1:5 if no ADAs were detected at baseline, where 
baseline is defined as sample taken on Day -1 in Treatment Period 1. 
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Protocol Reference: I5T-MC-AACP 
The frequency and percentage of participants with neutralizing antibodies, if measured, may also 
be tabulated for participants with TE ADA.  
To assess the relationship between the PK parameters and ADA, a box plot of CL,ss versus TE 
ADA status (TE ADA+ versus TE ADA-) will be presented. Scatter plots will be presented for 
the observed Ctrough (y - axis) vs ADA titer (Day 15, 29, 43, 57, 71) also boxplot of individual 
CLss vs ADA titer. Additional analyses may be conducted, if appropriate. 
10.4.8 Neurological Examinations  
The below table presents the scoring of the neurological examination findings. 
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 
 
 
 
The frequency of neurological survey data will be summarized by time point, and listed. For 
tremor, nystagmus and reflexes, only data from the nonspecific location assessment will be 
summarized. The overall neurological assessment will also be summarized by timepoint. 
10.4.9 Columbia Suicide Severity Rating Scale (C-SSRS)  
Data from the C-SSRS questionnaire will be listed. 
10.4.10 Hypersensitivity reactions  
For all drug hypersensitivity and anaphylactic reactions, additional follow-up data will be 
collected to assess the participant’s medical history, alternative causes, and symptoms. The 
relationship between hypersensitivity reactions and TE-ADAs as well as PK parameters may be 
explored.  
These data will be listed. 
10.4.11 Infusion Related Reactions  
Infusion related reactions data will be summarized and listed. The relationship between IRRs and 
TE-ADAs as well as PK parameters may be explored. 
10.4.12 Other assessments  
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
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Statistical Analysis Plan  
 
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Labcorp Drug Development Study: 8503300  
Protocol Reference: I5T-MC-AACP 
10.4.13 Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned. 
11. 
INTERIM ANALYSES  
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. 
Access to safety, PK, and immunogenicity data may occur on an ongoing basis throughout the 
study. The purpose of these reviews is to inform the design of subsequent studies. 
12. 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES  
There were no changes from the protocol specified statistical analyses. 
13. 
REFERENCES  
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
14. 
DATA PRESENTATION  
14.1 
Derived Parameters  
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. Number of 
observations and percentage values should be reported as whole numbers. Median values should 
be treated as an observed parameter and reported to the same number of decimal places as 
minimum and maximum values. 
14.2 
Missing Data  
Missing data will not be displayed in listings. 
14.3 
Insufficient Data for Presentation  
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.” 
 
 
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Statistical Analysis Plan  
 
CONFIDENTIAL 
Labcorp Drug Development Study: 8503300  
Protocol Reference: I5T-MC-AACP 
15. 
APPENDICES  
Appendix 1: Document History  
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
Final Version 2.0 
28FEB2023 
1) Updated number of subjects in study design and 
sample size section as per protocol amendment 
2) 10.3.1 Updated the PK Parameters definition 
3) Enrolled population definition included for more 
clarity in TFL’s 
NA = not applicable 
Approved on 01 Mar 2023 GMT


Signature Page for VV-CLIN-082328 v1.0
Signature Page for VV-CLIN-082328 v1.0
Approval
Statistician
28-Feb-2023 16:45:54 GMT+0000
Approval
Project Leader
28-Feb-2023 17:00:30 GMT+0000
Approval
Statistician
28-Feb-2023 17:03:57 GMT+0000
Approval
PKPDPMx
01-Mar-2023 10:57:51 GMT+0000
Approved on 01 Mar 2023 GMT
PPD
PPD
PPD
PPD