Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early Symptomatic Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer Disease
Sponsor: Eli Lilly and Company

Protocol I9X-MC-MTAE(e)
Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early Symptomatic 
Alzheimer's Disease
NCT05063539
Approval Date: 01-Oct-2024

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
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 LY3372689, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
 
Note to Regulatory Authorities:  This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure.  Eli Lilly and Company requests consultation regarding release/redaction prior to any 
public release.  In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early 
Symptomatic Alzheimer’s Disease 
Protocol Number: I9X-MC-MTAE 
Amendment Number: e 
Compound: LY3372689 
Study Phase: 2 
Short Title: Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early 
Symptomatic Alzheimer’s Disease 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers: 
IND: 141582 
EudraCT: 2021-000170-29 
EU CT number: 2024-512295-36-00 
Approval Date: Protocol Amendment (e) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-007992 
 
 
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Protocol I9X-MC-MTAE(e) 
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Medical Monitor Name and Contact Information will be provided separately.  
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Protocol I9X-MC-MTAE(e) 
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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Amendment d 
18-Apr-2024 
Amendment c 
22-Mar-2024 
Amendment b 
02-Sep-2021 
Amendment a 
09-Jun-2021 
Original Protocol 
06-Jan-2021 
Amendment [e] 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the safety or the rights of the study participants. 
Overall Rationale for the Amendment: 
The main rationale for this amendment is the follow-up of safety findings and biomarker changes 
that emerged during the double-blind treatment period. The key changes include replacing the 
optional open-label extension (OLE) period with post-treatment safety follow-up period and 
removing the flortaucipir F18 PET imaging and MRI substudy. 
Minor editorial and formatting changes are not included in this table.  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
 Deleted objective and endpoint 
of the OLE period 
 Overall Design subsection: 
Deleted sentence regarding 
OLE consent and duration 
 Intervention Groups and 
Duration subsection: 
Revised study duration from 
“217” to “149” weeks 
Deleted OLE period and 
safety follow-up (V802) 
Added post-treatment safety 
follow-up period and 
corresponding duration 
To align with the changes made to the 
study design (replacing the OLE period 
with post-treatment safety follow-up 
period) 
1.2. Schema 
Deleted schema depicting OLE 
period and respective footnote 
1.3.4. Study Period 4- 
Post-treatment Safety 
Follow-up Period 
 Revised occurrence of OLE 
period to Post-treatment 
Safety Follow-up Period 
 Deleted V31 through V802 
(except V32) 
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Protocol I9X-MC-MTAE(e) 
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Section # and Name 
Description of Change 
Brief Rationale 
 Retained V32 as V803 
 Revised ECG comments to 
read as: “single ECG with 
central reads” 
 V802 (previously V30) 
changes: Added MRI imaging 
 V803 (previously V31) 
changes: Added CDR, 
ADAS-Cog13, ADCS-ADL, 
MMSE 
 Laboratory Tests and Sample 
Collections row: Added 
comment for testosterone, 
LH, FSH and Inhibin B that it 
will be collected only in men 
 Exploratory Biomarker 
Samples row: Added 
comments “Includes P-Tau” 
 Deleted footnotes that are no 
longer applicable and re-
arranged the sequence 
3. Objectives and 
Endpoints 
 Replaced the table for OLE 
period with objectives and 
endpoints for the post-
treatment safety follow-up 
period 
4.1. Overall Design 
 Revised study duration from 
“217” to “149” weeks 
 Deleted OLE period and safety 
follow-up (V802) 
 Added post-treatment safety 
follow-up period and 
corresponding duration 
 Deleted paragraph detailing 
specifics of the OLE period 
4.1.5. Post-treatment 
Safety Follow-up 
Period 
 Deleted paragraph on OLE 
period (V30-V37) and follow-
up (V802) 
 Added activities during the 
post-treatment safety follow-
up period 
4.2. Scientific 
Rationale for Study 
Design 
Deleted paragraph on rationale for 
the OLE study design 
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Protocol I9X-MC-MTAE(e) 
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Section # and Name 
Description of Change 
Brief Rationale 
4.3. Justification for 
Dose 
Deleted paragraph for the OLE 
dose selection 
5.2. Exclusion Criteria Deleted criterion 44, 45, and 46 
5.3. Post-Treatment 
Safety Follow-up 
Period (newly added 
section) 
Added exclusion criterion 47 
6. Study Intervention 
Deleted treatment regimen table 
for OLE period 
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
 Deleted sentence “The 
extension phase of this study 
is open-label” 
 Revised OLE period to Post-
treatment Safety Follow-up 
Period in the last paragraph 
6.5.1. Standard of 
Care for Alzheimer’s 
Disease 
Revised occurrence of OLE 
period to Post-treatment Safety 
Follow-up Period in the last 
paragraph and replaced the visits 
from “V30-V37” to “V802 and 
V803” 
6.6. Dose 
Modification 
Deleted last paragraph detailing 
dose modification during the OLE 
period 
6.7. Intervention after 
the End of the Study 
 Deleted statement that optional 
OLE will be offered to 
participants who complete the 
study through the double-
blind study periods 
 Added “study intervention will 
not be made available to 
participants after conclusion 
of the study” 
9.4.1. General 
Considerations 
 Revised occurrence of OLE 
period to Post-treatment 
Safety Follow-up Period 
 Updated paragraph to capture 
the study will include 2 SAPs 
(previously several separate 
SAPs), and a supplemental 
SAP to detail additional 
exploratory analyses related 
to biomarkers 
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Protocol I9X-MC-MTAE(e) 
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Section # and Name 
Description of Change 
Brief Rationale 
10.10. Appendix 10: 
Flortaucipir F18 PET 
Imaging and MRI 
Substudy 
Deleted substudy 
 
 
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Protocol I9X-MC-MTAE(e) 
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Table of Contents  
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................14 
1.3. 
Schedule of Activities (SoA) ..........................................................................................15 
1.3.1. 
Study Period 1-Screening ...............................................................................................15 
1.3.2. 
Study Period 2a-Treatment Period ..................................................................................18 
1.3.3. 
Study Period 2b-Treatment Period..................................................................................23 
1.3.4. 
Study Period 4-Post-treatment Safety Follow-up Period  ...............................................27 
2. 
Introduction ...................................................................................................................29 
2.1. 
Study Rationale ...............................................................................................................29 
2.2. 
Background .....................................................................................................................29 
2.2.1. 
Nonclinical Studies .........................................................................................................29 
2.2.2. 
Clinical Studies ...............................................................................................................30 
2.3. 
Benefit/Risk Assessment ................................................................................................31 
2.3.1. 
Benefit Assessment .........................................................................................................32 
2.3.2. 
Overall Benefit/Risk Conclusion ....................................................................................33 
3. 
Objectives and Endpoints ............................................................................................34 
4. 
Study Design ..................................................................................................................37 
4.1. 
Overall Design ................................................................................................................37 
4.1.1. 
Lead-In and Screening Period (V601 and V1) ...............................................................37 
4.1.2. 
Double-Blind Period 2a (V2-21) ....................................................................................38 
4.1.3. 
Double-Blind Period 2b (V22-29) ..................................................................................38 
4.1.4. 
Follow-up (V801) ...........................................................................................................39 
4.1.5. 
Post-Treatment Safety Follow-up Period (V802 and V803) ..........................................39 
4.2. 
Scientific Rationale for Study Design ............................................................................39 
4.3. 
Justification for Dose ......................................................................................................40 
4.4. 
End of Study Definition ..................................................................................................40 
5. 
Study Population ...........................................................................................................41 
5.1. 
Inclusion Criteria ............................................................................................................41 
5.2. 
Exclusion Criteria ...........................................................................................................43 
5.3. 
Post-Treatment Safety Follow-up Period .......................................................................45 
5.4. 
Lifestyle Considerations .................................................................................................45 
5.5. 
Screen Failures ................................................................................................................46 
6. 
Study Intervention ........................................................................................................47 
6.1. 
Study Intervention(s) Administered................................................................................47 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................48 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................48 
6.4. 
Study Intervention Compliance ......................................................................................49 
6.5. 
Concomitant Therapy .....................................................................................................49 
6.5.1. 
Standard of Care for Alzheimer’s Disease......................................................................50 
6.6. 
Dose Modification ..........................................................................................................50 
6.7. 
Intervention after the End of the Study ...........................................................................51 
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Protocol I9X-MC-MTAE(e) 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................52 
7.1. 
Discontinuation of Study Intervention ............................................................................52 
7.1.1. 
Temporary Discontinuation ............................................................................................53 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................53 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................54 
7.3. 
Lost to Follow-up............................................................................................................54 
8. 
Study Assessments and Procedures.............................................................................55 
8.1. 
Efficacy Assessments .....................................................................................................55 
8.1.1. 
Primary Efficacy Assessment .........................................................................................55 
8.1.2. 
Secondary Efficacy Assessments ....................................................................................56 
8.1.3. 
Exploratory Assessments ................................................................................................57 
8.2. 
Safety Assessments .........................................................................................................57 
8.2.1. 
Physical Examinations ....................................................................................................57 
8.2.2. 
Vital Signs .......................................................................................................................58 
8.2.3. 
Electrocardiograms .........................................................................................................59 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................59 
8.2.5. 
Magnetic Resonance Imaging .........................................................................................60 
8.2.6. 
Hepatic Safety Monitoring ..............................................................................................61 
8.2.7. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................62 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................62 
8.3.1. 
Timing Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................63 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................63 
8.3.3. 
Follow-Up of AEs and SAEs ..........................................................................................64 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................64 
8.3.5. 
Pregnancy ........................................................................................................................64 
8.3.6. 
Adverse Events of Special Interest .................................................................................64 
8.3.7. 
Complaint Handling ........................................................................................................65 
8.4. 
Treatment of Overdose ...................................................................................................65 
8.5. 
Pharmacokinetics ............................................................................................................65 
8.6. 
Pharmacodynamics .........................................................................................................66 
8.6.1. 
Imaging Measures ...........................................................................................................66 
8.6.2. 
Fluid Measures ................................................................................................................66 
8.7. 
Genetics ..........................................................................................................................67 
8.7.1. 
Apolipoprotein E Genotyping .........................................................................................67 
8.7.2. 
Whole Blood Samples for Pharmacogenetic Research ...................................................67 
8.8. 
Biomarkers ......................................................................................................................67 
8.8.1. 
Blood Sample Collection for Exploratory Biomarkers ...................................................68 
8.9. 
Immunogenicity Assessments.........................................................................................68 
8.10. 
Medical Resource Utilization and Health Economics ....................................................68 
9. 
Statistical Considerations .............................................................................................70 
9.1. 
Statistical Hypotheses .....................................................................................................70 
9.2. 
Sample Size Determination ............................................................................................70 
9.3. 
Populations for Analyses ................................................................................................71 
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9.4. 
Statistical Analyses .........................................................................................................71 
9.4.1. 
General Considerations ...................................................................................................71 
9.4.2. 
Primary Endpoint(s) ........................................................................................................72 
9.4.3. 
Secondary Endpoint(s) ....................................................................................................73 
9.4.4. 
Tertiary/Exploratory Endpoint(s)....................................................................................74 
9.4.5. 
Treatment Group Comparability .....................................................................................74 
9.4.6. 
Safety Analyses(s) ..........................................................................................................75 
9.4.7. 
Other Analyses ................................................................................................................75 
9.5. 
Interim Analyses .............................................................................................................75 
9.6. 
Data Monitoring Committee ...........................................................................................76 
10. 
Supporting Documentation and Operational Considerations ..................................77 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................77 
10.1.1. Regulatory and Ethical Considerations ...........................................................................77 
10.1.2. Financial Disclosure........................................................................................................77 
10.1.3. Informed Consent Process ..............................................................................................78 
10.1.4. Data Protection................................................................................................................78 
10.1.5. Committees Structure......................................................................................................79 
10.1.6. Dissemination of Clinical Study Data.............................................................................79 
10.1.7. Data Quality Assurance ..................................................................................................80 
10.1.8. Source Documents ..........................................................................................................81 
10.1.9. Study and Site Start and Closure ....................................................................................82 
10.1.10. Publication Policy ...........................................................................................................82 
10.1.11. Investigator Information .................................................................................................82 
10.1.12. Long-Term Sample Retention.........................................................................................82 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................84 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................86 
10.3.1. Definition of AE .............................................................................................................86 
10.3.2. Definition of SAE ...........................................................................................................87 
10.3.3. Definition of Product Complaints ...................................................................................88 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................88 
10.3.5. Reporting of SAEs ..........................................................................................................90 
10.3.6. Regulatory Reporting Requirements ...............................................................................91 
10.4. 
Appendix 4:  Liver Safety:  Suggested Actions and Follow-Up 
Assessments ....................................................................................................................92 
10.5. 
Appendix 5:  Flortaucipir F18 Tau PET Imaging ...........................................................94 
10.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................95 
10.7. 
Appendix 7: Genetics......................................................................................................96 
10.8. 
Appendix 8. Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................97 
10.9. 
Appendix 9: Abbreviations ...........................................................................................101 
10.10. 
Appendix 10: Protocol Amendment History ................................................................106 
11. 
References ....................................................................................................................116 
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Protocol I9X-MC-MTAE(e) 
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1. 
 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early 
Symptomatic Alzheimer’s Disease 
Short Title: Assessment of Safety, Tolerability, and Efficacy of LY3372689 in Early 
Symptomatic Alzheimer’s Disease 
Regulatory Agency Identifier Numbers: 
IND: 141582 
EudraCT: 2021-000170-29 
EU CT number: 2024-512295-36-00 
Rationale: 
LY3372689 is an orally available, potent inhibitor of O-linked N-acetyl glucosaminidase (OGA). 
This glycoside hydrolase is the enzyme that removes the single-sugar modification, O-linked β-
N-acetyl glucosamine (O-GlcNAc), from intracellular proteins including the microtubule 
associated protein tau. This modification is regulated by the action of 2 enzymes, O-GlcNAc 
transferase (OGT) and OGA.   
By inhibiting OGA, LY3372689 is hypothesized to delay the progression of tau aggregation-
related diseases by slowing the accumulation of hyperphosphorylated, insoluble tau filaments 
within cells of the central nervous system (CNS), resulting in reduced propagation of tau 
pathology and preserved neuronal function.  
Objectives and Endpoints: 
Primary Objective  
Endpointsa 
To assess the effect of LY3372689 vs. placebo 
on clinical progression in participants with 
early symptomatic AD with demonstrated 
presence of moderateb levels of tau pathology 
iADRS change from baseline through end time point 
(76-124 weeks) 
Key Secondary Objective 
Endpoints 
To assess the effect of LY3372689 vs. placebo 
on clinical progression in full study population 
(moderate + highc levels of tau pathology) with 
early symptomatic AD 
iADRS change from baseline through end time point 
(76-124 weeks)  
Other Secondary Objectives  
Endpoints 
To evaluate safety and tolerability of 
LY3372689 
Standard safety assessments 
 
Spontaneously reported AEs 
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Protocol I9X-MC-MTAE(e) 
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 
Clinical laboratory tests 
 
Vital sign and body weight measurements 
 
12-lead ECGs 
 
Physical and neurological examinations 
 
C-SSRS, and 
 
MRI (treatment-emergent radiological 
findings) 
To assess the effect of LY3372689 vs. placebo 
on clinical progression in full study population 
and moderate tau sub population with early 
symptomatic AD 
Change in cognition and function from baseline 
through end time point (76-124 weeks) as measured 
by: 
 
ADAS-Cog13 
 
ADCS-iADL 
 
CDR-SB, and 
 
MMSE 
To assess the effect of LY3372689 vs. placebo 
on brain region volumes 
Change in volumetric MRI measures from baseline 
through end time point (76 - 124 weeks) 
To assess the effect of LY3372689 vs. placebo 
on brain tau deposition 
Change in brain tau deposition from baseline through 
end time point (76-100 weeks) as measured by 
flortaucipir F18 PET scan 
To assess the PK of LY3372689 
Plasma concentrations of LY3372689 
Abbreviations: ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-iADL = 
Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living; AD = Alzheimer’s Disease; 
AE = Adverse Event; CDR-SB = Clinical Dementia Rating Scale- Sum of Boxes; C-SSRS = Columbia Suicide-
Severity Rating Scale; ECG = electrocardiograms; iADRS = integrated Alzheimer’s Disease Rating Scale; 
MMSE = Mini Mental State Examination; MRI = Magnetic Resonance Imaging; PET = Positron emission 
tomography; PK = Pharmacokinetics.  
a 
Based on common close design, participants final endpoint time will be between 76-124 weeks. 
b Moderate tau pathology is defined as those who meet tau PET inclusion criteria for evidence of tau pathology 
consistent with Alzheimer’s disease (Fleisher et al. 2020), but do not have widespread and high levels of cortical 
tau pathology.  
c  High levels of cortical tau pathology by flortaucipir F18 PET is defined by the top quartile of quantitative 
standardized uptake value ratios in a population of amyloid positive Alzheimer’s participants and cognitively 
normal older controls (Pontecorvo et al. 2019).
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Overall Design: 
Study I9X-MC-MTAE (MTAE) is a multicenter, randomized, double-blind, placebo-controlled, 
Phase 2 study of LY3372689 in participants with early symptomatic Alzheimer’s disease (AD). 
This study will utilize a 76-week common close design. Under the common close design, all 
enrolled participants will remain on double-blind randomized treatment and complete 
assessments until the last enrolled participant that has not discontinued from treatment has 
achieved 76 weeks of assigned treatment. The maximum duration of treatment is 124 weeks.  
Study Population: 
Eligible participants will have a gradual and progressive change in memory function with Mini 
Mental State Examination (MMSE) 22-30, Clinical Dementia Rating Scale (CDR) global score 
of 0.5 to 1.0, with a memory box score ≥0.5. Participants who meet plasma P-tau and flortaucipir 
F18 PET scan criteria will be eligible. Prior treatments with disease-modifying therapy or any 
commercially approved prescription medication for the treatment of AD, which meet study 
criteria are allowed. Participants who fail to complete the required psychometric tests, those with 
medical conditions, such as significant neurological disease affecting the CNS, cardiovascular, 
hepatic, renal, gastroenterological, respiratory, endocrinologic, neurologic, psychiatric, 
immunologic, hematologic disease, or cancer, may be excluded from participation in the study. 
Number of Participants: 
Approximately 110 participants will be randomly assigned per arm for a total of 330 randomized 
participants for study intervention. 
Intervention Groups and Duration: 
Participants who meet entry criteria will be randomized in a 1:1:1 (1 LY: 1 LY: 1 PBO) 
randomization to the following treatment groups:   
 LY3372689: low dose daily 
 LY3372689: high dose daily, and 
 Placebo. 
The maximum total duration of study participation for each participant, including screening and 
the post-treatment follow-up periods, is up to approximately 149 weeks:   
 Lead-In: complete any time prior to complete screening visit 
 Complete Screening: -63 days to -1 day prior to randomization 
 Double-Blind: 76 weeks or up to 124 weeks 
 Safety Follow-up (V801): approximately 4 weeks after completion of double-blind study 
period 2b, and 
 Post-treatment Safety Follow-up period: approximately 12 weeks and starts with 
Visit 802 
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Protocol I9X-MC-MTAE(e) 
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Ethical Considerations of Benefit/Risk: 
The available nonclinical and clinical data support the oral administration of LY3372689 to the 
intended study population according to the clinical investigation plan and also provide a 
sufficient margin of safety for the study design and doses. There are currently no disease-
modifying anti-tau treatments for AD. The potential benefits of LY3372689 showing disease-
modifying properties in participants with AD are considered to outweigh the potential risks. 
Data Monitoring Committee: Yes
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Protocol I9X-MC-MTAE(e) 
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1.2. 
Schema  
 
a 
Study I9X-MC-MTAE (MTAE) has a common close design in which all enrolled participants continue to study Period 2b until the last enrolled participant 
that has not discontinued from treatment reaches 76 weeks of treatment. The maximum study treatment period length will be 124 weeks. 
 
 
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1.3. 
  Schedule of Activities (SoA)  
1.3.1. 
Study Period 1-Screening  
Study Period 1- Screeninga                                  
 
LEAD-IN 
SCREENING 
COMPLETE 
SCREENING 
Comments 
Visit No.: 
601 
1 
 
Days Relative to 
Randomization 
Can be done 
any time prior 
to V1 
-63 to -1 
(≤63 before V2) 
 
Tolerance Interval for 
Visit (Days) 
Can be done 
any time 
≤63 before V2 
 
Entry and Administrative 
Abbreviated or full 
informed consent 
(participant and study 
partner) 
X 
 
The abbreviated informed consent grants consent only for procedures and assessments 
marked under V601. 
Study partner(s) is(are) not required to complete the abbreviated informed consent 
form. 
Full informed consent 
(participant and study 
partner) 
 
X 
Do not collect if full informed consent was collected at V601. 
Inclusion and exclusion 
criteria, review, and confirm 
 
X 
Confirm that the participant has met all V1 eligibility criteria before proceeding to V2 
procedures. 
Demographics 
X 
X 
Do not collect demographics at V1 if collected at V601. 
Preexisting conditions and 
medical history, including 
relevant surgical history 
 
X 
 
Prespecified medical history 
(indication and history of 
interest) 
 
X 
 
Substance use (alcohol, 
caffeine, and tobacco use)  
 
X 
 
Concomitant medications 
 
X 
 
AEs 
 
X 
 
 
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Study Period 1- Screeninga                                  
 
LEAD-IN 
SCREENING 
COMPLETE 
SCREENING 
Comments 
Visit No.: 
601 
1 
 
Days Relative to 
Randomization 
Can be done 
any time prior 
to V1 
-63 to -1 
(≤63 before V2) 
 
Tolerance Interval for 
Visit (Days) 
Can be done 
any time 
≤63 before V2 
 
Physical Evaluation 
Height  
 
X 
 
Weight 
 
X 
 
Vital signs 
 
X 
BP, pulse, and temperature (after 5 min in sitting position). 
Physical examination 
 
X 
12-lead ECG (central) 
 
X 
Triplicate ECG  
PET Scans and MRI 
Flortaucipir F18 PET 
scanb,c,d 
 
X 
A historical flortaucipir F18 PET scan may be submitted to be considered for eligibility if 
performed within 6 months of randomization. The acceptance of a historical scan is at the 
discretion of the sponsor.  
MRIb,d  
 
X 
Clinician-Administered Assessments (Electronic)e 
CDR 
 
X 
The CDR must always be administered to the study partner first and then to the 
participant. 
MMSE 
X 
X 
Do not perform MMSE at V1 if collected at V601, unless >3 months since V601. 
Laboratory Tests and Sample Collections 
Hematology 
 
X 
 
Clinical chemistry  
 
X 
 
Hepatitis B virus (HBV) 
Screening tests 
 
X 
Perform at screening in participants with a past history (suspected or confirmed) of 
Hepatitis B. 
Hepatitis C virus (HCV) 
Screening tests 
 
X 
Perform at screening in participants with a past history (suspected or confirmed) of 
Hepatitis C (resolved >6 months prior to enrollment). 
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Study Period 1- Screeninga                                  
 
LEAD-IN 
SCREENING 
COMPLETE 
SCREENING 
Comments 
Visit No.: 
601 
1 
 
Days Relative to 
Randomization 
Can be done 
any time prior 
to V1 
-63 to -1 
(≤63 before V2) 
 
Tolerance Interval for 
Visit (Days) 
Can be done 
any time 
≤63 before V2 
 
Plasma P-taud  
X 
X 
Do not collect plasma P-tau at V1 if collected at V601. Historical evidence of AD pathology 
may be accepted for eligibility at the discretion of the sponsor. A plasma sample should 
be collected for all participants, regardless of whether or not the site is approved to use 
P-tau testing as part of eligibility determination. 
Stored Samples 
Genetics sample 
 
X 
Collect unless not allowed or unfeasible due to local regulations. 
Exploratory biomarker 
samples  
X 
X 
Collect unless not allowed or unfeasible due to local regulations. Do not collect 
exploratory biomarker samples at V1 if collected at V601. 
Abbreviations: AD = Alzheimer’s Disease; AE = adverse event; BP = blood pressure; CDR = Clinical Dementia Rating Scale; C-SSRS = Columbia Suicide 
Severity Rating Scale; DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; MMSE = Mini Mental State Examination; MRI = magnetic 
resonance imaging; PET = positron emission tomography; V = Visit. 
a Visit 1 procedures may be conducted over more than 1 day as long as all activities are completed within the allowable visit tolerance.   
b The participant should meet all other eligibility criteria before the screening flortaucipir F18 PET scan and MRI.   
c If results are received after the 63-day screening period, the participant remains eligible contingent on meeting the other eligibility criteria. May require review 
and/or retest of screening safety labs if >63 days between V1 and V2. 
d If plasma P-tau testing is not available to the site for eligibility determination at the time of screening, the sample should still be collected and submitted. In 
such cases, the participant may proceed to screening flortaucipir F18 PET scan and MRI if all other screening requirements are met, with no requirement to 
document plasma P-tau eligibility results. Sites will be notified if this situation applies. This will not be considered a protocol deviation. 
e Administer prior to medical procedures that could be stressful to the participant (blood draws, etc.). These tests include the audio voice recording of the rater’s 
questions and the participant and study partner responses to assessment questions. 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
18 
 
1.3.2. 
Study Period 2a-Treatment Period  
Study Period 2a - Treatment period a 
 
Visit No.: 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
ET 
(Period 
2a) 
Comments 
Weeks Relative to 
Randomization  
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
 
 
Remote Visit 
Option 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Remote home visits are 
an option to on-site 
visit. 
Televisits 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
Visits are to be 
performed by phone.  
Tolerance 
interval for visit 
(Days) 
0 
±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Evaluation 
Weight 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
BP, pulse, and 
temperature (after 5 
min in sitting position). 
In addition, orthostatic 
BP and pulse will be 
measured at V2, V5, V8, 
V11, V15, V18, V21, ET, 
and unscheduled visits.  
Physical/neuro 
examination 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
19 
 
Study Period 2a - Treatment period a 
 
Visit No.: 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
ET 
(Period 
2a) 
Comments 
Weeks Relative to 
Randomization  
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
 
 
Remote Visit 
Option 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Remote home visits are 
an option to on-site 
visit. 
Televisits 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
Visits are to be 
performed by phone.  
Tolerance 
interval for visit 
(Days) 
0 
±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 
 
 
Symptom-directed 
physical 
examination 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
12-lead ECG 
(central) 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Single ECG 
PET Scans and MRI 
Flortaucipir F18 
PET scan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X b 
No more than one PET 
scan should be obtained 
in Period 2a. 
MRI  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Xc 
MRI not performed if 
<24 weeks since last 
MRI.  
Clinician-Administered Assessments (Electronic) d 
ADAS-Cog13 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X e 
ADCS-ADL 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Xe 
 
CDR 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Xe 
The CDR must always 
be administered to the 
study partner first and 
then to the participant. 
MMSE 
X f 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Xe 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
20 
 
Study Period 2a - Treatment period a 
 
Visit No.: 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
ET 
(Period 
2a) 
Comments 
Weeks Relative to 
Randomization  
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
 
 
Remote Visit 
Option 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Remote home visits are 
an option to on-site 
visit. 
Televisits 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
Visits are to be 
performed by phone.  
Tolerance 
interval for visit 
(Days) 
0 
±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 
 
 
DSST 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Xe 
Digital clock 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Xe 
Clinician-Administered Assessments (Paper) 
C-SSRS baseline 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS since last 
visit 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests and Sample Collectionsg 
Hematology 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Clinical chemistry  X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Urinalysis  
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Estrogen h 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
Testosteroneh 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xi 
LHh 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xi 
FSHh 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xi 
Inhibin Bh 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xi 
ApoE j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample 
X k 
Xl 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Xm 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
21 
 
Study Period 2a - Treatment period a 
 
Visit No.: 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
ET 
(Period 
2a) 
Comments 
Weeks Relative to 
Randomization  
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
 
 
Remote Visit 
Option 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Remote home visits are 
an option to on-site 
visit. 
Televisits 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
Visits are to be 
performed by phone.  
Tolerance 
interval for visit 
(Days) 
0 
±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 ±7 
 
 
Exploratory Endpoint and Stored Samples 
Exploratory 
biomarker 
samples j 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Randomization and Dosing 
Contact IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study 
drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Xn 
 
Drug to be dispensed at 
prior in-person visit for 
televisits 
Administer study 
drug at site 
 
Xo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant 
returns study 
drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Assess study drug 
compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
22 
 
Abbreviations:  ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities 
of Daily Living; AE = Adverse Event; ApoE = Apolipoprotein E; BP = blood pressure; ECG = electrocardiogram; CDR = Clinical Dementia Rating Scale; C-
SSRS = Columbia Suicide Severity Rating Scale; DSST = Digit Symbol Substitution Test; ET = Early Termination; FSH = Follicle Stimulating Hormone; IP 
= Investigational Product; IWRS = interactive web-response system; LH = Luteinizing Hormone; MMSE = Mini Mental State Examination; MRI = magnetic 
resonance imaging; PET = positron emission tomography; PK = pharmacokinetics; V = Visit 
a Procedures for some visits may take more than 1 day. For early terminations that occur before the last visit in treatment period, see the activities listed for ET in 
this table. 
b ET PET scan if on study drug for at least 12 weeks. Participants who discontinue treatment but remain in the study off IP should receive imaging as scheduled 
and should not receive an ET PET scan unless the ET visit coincides with Week 76.  
c ET MRI scan is only performed if it is at least 24 weeks since last MRI assessment.  
d Administer the ADAS-Cog13, ADCS-ADL, CDR, MMSE, DSST, and Digital Clock prior to medical procedures that could be stressful to the participant (blood 
draws, etc.). These tests include the audio voice recording of the rater’s questions and the participant and study partner responses to assessment questions. 
e For participants who permanently discontinued from IP but remain in the study, cognitive assessments should be performed only if they coincide with a 
protocol-defined study window where cognitive testing would have otherwise occurred during Period 2a as defined by the SoA.   
For participants who permanently discontinue from IP and the study, cognitive assessments should be performed only if >10 weeks since the last cognitive 
assessments. 
f MMSE not to be performed at V2 if done at V1 or within 3 months of V601. 
g Unscheduled lab tests may be performed at the discretion of the investigator. Collect labs prior to administration of IP, unless otherwise noted. Record the date 
and times of sample collection on the Lab Requisition Form. 
h Hormone panel to be collected in the morning. From Weeks 76 through 124 and V801, hormone panel would be collected only in men. 
i Collect if ET coincides with a protocol-defined study window where hormone panel collection would have otherwise occurred. 
j Collect unless not allowed or unfeasible due to local regulations. 
k At V2, take PK sample within 0.5-4 h after drug administration. 
l At V3, take the first PK sample prior to receiving drug at site, and second PK sample after receiving drug at site but prior to participant leaving the site.   
m Collect a PK sample at ET only if participant is discontinued due to an AE. At ET, the PK sample should be taken following clinician-administered 
assessments.   
n Dispensed at V21 if participant is continuing on to Period 2b. 
o All V2 baseline clinical assessments and testing should be performed prior to study drug administration at site. 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
23 
 
1.3.3. 
Study Period 2b-Treatment Period  
 
Study Period 2b  - Common Close (or Treatment Beyond Week 76) a 
Study Period 
3-Post-
treatment 
safety follow-
up period 
 
Visit No.: 
22 
23 
24 
25 
26 
27 
28 
29 
ET (Period 2b) 
b 
V801 
4 weeks±10 
days after 
participant’s 
last Study 
Period 2 visit 
Comments 
Weeks relative to 
Randomization 
82 
88 
94 
100 
106 
112 
118 
124 
 
Televisit 
X 
 
X 
 
X 
 
X 
 
 
Visits to be performed by 
phone.  
Tolerance interval for visit 
(days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Evaluation 
Weight 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital signs 
 
X 
 
X 
 
X 
 
X 
X 
X 
BP, pulse, and temperature 
(after 5 min in sitting position). 
In addition, orthostatic BP and 
pulse will be measured at V23, 
V25, V27, V29, and ET. 
Physical/neuro examination 
 
X 
 
X 
 
X 
 
X 
X 
X 
12-lead ECG (central) 
 
X 
 
X 
 
X 
 
X 
X 
X 
Single ECG. 
PET Scans and MRI 
Flortaucipir F18 PET scan 
 
 
 
X 
 
 
 
 
Xc 
 
No more than one PET scan 
should be obtained in Period 2b. 
MRI 
 
 
 
X 
 
 
 
X 
Xd 
 
MRI not performed if <24 weeks 
since last MRI assessment. 
Clinician-Administered Assessments (Electronic) e 
ADAS-Cog13 
 
X 
 
X 
 
X 
 
X 
Xf 
 
ADCS-ADL 
 
X 
 
X 
 
X 
 
X 
Xf 
 
 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
24 
 
 
Study Period 2b  - Common Close (or Treatment Beyond Week 76) a 
Study Period 
3-Post-
treatment 
safety follow-
up period 
 
Visit No.: 
22 
23 
24 
25 
26 
27 
28 
29 
ET (Period 2b) 
b 
V801 
4 weeks±10 
days after 
participant’s 
last Study 
Period 2 visit 
Comments 
Weeks relative to 
Randomization 
82 
88 
94 
100 
106 
112 
118 
124 
 
Televisit 
X 
 
X 
 
X 
 
X 
 
 
Visits to be performed by 
phone.  
Tolerance interval for visit 
(days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
 
CDR 
 
X 
 
X 
 
X 
 
X 
Xf 
 
The CDR must always be 
administered to the study 
partner first and then to the 
participant. 
MMSE 
 
X 
 
X 
 
X 
 
X 
Xf 
 
 
DSST 
 
X 
 
X 
 
X 
 
X 
Xf 
 
Digital Clock 
 
X 
 
X 
 
X 
 
X 
Xf 
 
Clinician-Administered Assessments (Paper) 
C-SSRS Since Last Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Tests and Sample Collectionsg 
Hematology 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Clinical chemistry  
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Urinalysis  
 
 
 
 
 
 
 
 
X 
X 
 
PK sample   
 
 
 
 
 
 
 
 
Xh 
 
Testosteronei 
 
X 
 
X 
 
X 
 
X 
X 
X 
Collected only in men 
LHi 
 
X 
 
X 
 
X 
 
X 
X 
X 
FSHi 
 
X 
 
X 
 
X 
 
X 
X 
X 
Inhibin Bi 
 
X 
 
X 
 
X 
 
X 
X 
X 
Exploratory Endpoint and Stored Samples 
Exploratory Biomarker 
Samplesj 
 
X 
 
X 
 
X 
 
X 
X 
 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
25 
 
 
Study Period 2b  - Common Close (or Treatment Beyond Week 76) a 
Study Period 
3-Post-
treatment 
safety follow-
up period 
 
Visit No.: 
22 
23 
24 
25 
26 
27 
28 
29 
ET (Period 2b) 
b 
V801 
4 weeks±10 
days after 
participant’s 
last Study 
Period 2 visit 
Comments 
Weeks relative to 
Randomization 
82 
88 
94 
100 
106 
112 
118 
124 
 
Televisit 
X 
 
X 
 
X 
 
X 
 
 
Visits to be performed by 
phone.  
Tolerance interval for visit 
(days) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
 
Randomization and Dosing 
Contact IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
 
X 
 
X 
 
 
 
 
Drug to be dispensed at prior 
in-person visit for televisits 
Participant returns study 
drug 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Assess study drug 
compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviations:  ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities 
of Daily Living; AE = Adverse Event; BP = blood pressure; CDR = Clinical Dementia Rating Scale; C-SSRS = Columbia Suicide Severity Rating Scale; 
DSST = Digit Symbol Substitution Test; ECG = electrocardiogram; ET = Early Termination; IP = Investigational Product; MMSE = Mini Mental State 
Examination; MRI = magnetic resonance imaging; PET = positron emission tomography; PK = pharmacokinetics; V = Visit. 
a All participants are to complete Period 2a and continue to period 2b/3 unless otherwise notified by sponsor. Procedures for some visits may take more than 1 
day. For early terminations that occur before the last visit in treatment period, see the activities listed for ET in this table. 
b For participants in Period 2b at the time of the common close (that is, when the last participant completes 76 weeks of treatment), the ET visit activities are to 
be conducted as the next and final Period 2b visit, the End-of-Study ET Visit. 
c ET PET scan only to be performed if ET occurs at Week 100 ± 7 days and Visit 25 PET scan did not occur. 
d  ET MRI scan is only performed if it is at least 24 weeks since last MRI assessment. 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
26 
 
e Administer the ADAS-Cog13, ADCS-ADL, CDR, MMSE, DSST, and Digital Clock prior to medical procedures that could be stressful to the participant (blood 
draws, etc.). These tests include the audio voice recording of the rater’s questions and the participant and study partner responses to assessment questions. 
f For participants who permanently discontinue from IP but remain in the study, cognitive assessments should be performed only if they coincide with a protocol-
defined study window where cognitive testing would have otherwise occurred during Period 2b as defined by the SoA.   
For participants who permanently discontinue from IP and the study, cognitive assessments should be performed only if >10 weeks since the last cognitive 
assessments.   
When the last enrolled participant that does not discontinue reaches week 76, all remaining participants will be in Period 2b and should complete an end-of-
study ET visit at that time.  At this visit, cognitive assessments should be performed only if they coincide with a protocol-defined study window where 
cognitive testing would have otherwise occurred as defined by the SoA or if it has been >10 weeks since the last assessment. 
g Unscheduled lab tests may be performed at the discretion of the investigator. Collect labs prior to administration of IP, unless otherwise noted. Record the date 
and times of sample collection on the Lab Requisition Form. 
h Collect a PK sample at ET only if participant discontinues treatment due to an AE. At ET, the PK sample should be taken following clinician-administered 
assessments.  
i  Hormone panel to be collected in the morning. From Weeks 76 through 124 and V801, hormone panel would be collected only in men. 
j Collect unless not allowed or unfeasible due to local regulations. 
 
 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
27 
 
1.3.4. 
Study Period 4-Post-treatment Safety Follow-up Period  
Note: All randomly assigned participants are eligible for participation. 
Visit No.: 
802 
803 
Comments 
Weeks  
0 
12 
Tolerance interval for visit (days) 
±7 
±7 
Informed consent (participant and study partner) 
X 
 
Reconsent must be completed prior to initiating Visit 
802 procedures. 
Concomitant medications 
X 
X 
 
AEs 
X 
X 
 
Physical Evaluation 
Weight 
X 
X 
Vital signs 
X 
X 
Physical/neuro examination 
X 
 
Symptom-directed physical examination 
 
X 
12-lead ECG (central) 
X 
X 
Single ECG with central reads. 
Imaging 
MRI 
X 
 
Clinician-Administered Assessments (Electronic)a 
CDR 
X 
X 
The CDR must always be administered to the study 
partner first and then to the participant. 
ADAS-Cog13 
X 
X 
ADCS-ADL 
X 
X 
 
MMSE 
X 
X 
 
Clinician-Administered Assessments (Paper) 
C-SSRS Since Last Visit 
X 
X 
 
Laboratory Tests and Sample Collectionsb 
Hematology 
X 
X 
 
Clinical chemistry  
X 
X 
 
Testosteronec 
X 
X 
Collected only in men. 
LHc 
X 
X 
FSHc 
X 
X 
Inhibin Bc 
X 
X 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
28 
 
Visit No.: 
802 
803 
Comments 
Weeks  
0 
12 
Tolerance interval for visit (days) 
±7 
±7 
Exploratory Endpoint and Stored Samples 
Exploratory Biomarker Samplesd 
X 
X 
Includes P-Tau. 
Abbreviations:  ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities 
of Daily Living; AE = adverse event; CDR = Clinical Dementia Rating Scale; ECG = electrocardiogram; ET = early termination; C-SSRS = Columbia 
Suicide Severity Rating Scale; ET = Early Termination; FSH = follicle stimulating hormone; IWRS = interactive web-response system; LH = luteinizing 
hormone; MMSE = mini mental state examination; OLE = open-label extension; PK = pharmacokinetics; V = Visit. 
a Administer the ADAS-Cog13, ADCS-ADL, CDR, and MMSE prior to medical procedures that could be stressful to the participant (for example, blood draws). 
These tests include the audio voice recording of the rater’s questions and the participant and study partner responses to assessment questions. 
b  Unscheduled laboratory tests may be performed at the discretion of the investigator. Collect labs prior to administration of IP, unless otherwise noted. Record 
the date and times of sample collection on the Lab Requisition Form. 
c   Hormone panel to be collected in the morning. 
d Collect unless not allowed or unfeasible due to local regulations. 
 
 
Approved on 22 Aug 2024 GMT
Approved on 01 Oct 2024 GMT

CONFIDENTIAL 
Protocol I9X-MC-MTAE(e) 
29 
 
2. 
Introduction  
2.1. 
Study Rationale  
AD is an age-related neurodegenerative disorder characterized by a progressive decline in 
cognitive function and ability to perform activities of daily living that ultimately leads to death 
due to complications of the disease. Pathologic hallmarks of AD identified at autopsy include the 
presence of neuritic amyloid-β plaques, tau neurofibrillary tangles (Hyman et al. 2012), and 
neuronal loss, particularly pronounced in brain regions important for cognition, such as the 
hippocampus and temporal cortex (Selkoe 1991). Extent and pattern of tau pathology closely 
tracks with cognitive symptoms in AD (Brier et al. 2016; Pontecorvo et al. 2019). The current 
Study MTAE aims to demonstrate that LY3372689 slows cognitive and functional decline, and 
to assess safety of chronic administration, in early symptomatic AD participants demonstrating 
evidence of tauopathy. For the purposes of this study, early symptomatic AD is defined as those 
with mild cognitive impairment due to AD or mild Alzheimer’s dementia, consistent with stages 
2 through 4 of the FDA draft guidance entitled “Early Alzheimer’s Disease: Developing Drugs 
for Treatment. Guidance for Industry” (February 2018; 
https://www.fda.gov/media/110903/download) and the NIA-AA Research Framework: Toward a 
biological definition of Alzheimer’s disease (Jack et al. 2018). 
2.2. 
Background  
OGA is a glycoside hydrolase enzyme that removes the single-sugar modification O-GlcNAc 
from intracellular proteins, such as microtubule-associated protein tau. OGA inhibitors increase 
tau O-GlcNAc levels by blocking the removal of this single-sugar from unbound tau protein. 
This inhibition has been shown to reduce the accumulation of hyperphosphorylated, insoluble 
tau, including neurofibrillary tangles, in animal models of tauopathy (Yuzwa et al. 2014; Graham 
et al. 2014; Hastings et al. 2017).  
LY3372689 is an orally available, potent inhibitor of OGA and is hypothesized to delay the 
progression of tau-related diseases by slowing the accumulation of hyperphosphorylated, 
insoluble tau filaments within cells of the CNS, resulting in reduced propagation of tau 
pathology and preserved neuronal function. Reduction of tau propagation is hypothesized to slow 
clinical progression of people diagnosed with early symptomatic AD.  
2.2.1. 
Nonclinical Studies  
Nonclinical studies demonstrate that LY3372689 engages the OGA enzyme target in vivo, 
inhibits OGA enzyme activity, and increases the levels of protein O-GlcNAc and tau O-GlcNAc 
levels in the brain of mice and rats after single and multiple doses. Treatment with another 
proprietary aminothiazole compound reduced pathologic tau in the forebrain of the P301S tau 
transgenic mouse model following chronic (3 months) dosing. 
In vitro metabolism studies suggest that
 
 Solubility and permeability data for 
LY3372689 are consistent with Biopharmaceutics Classification System Class 1-like 
compounds.  
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The toxicity of LY3372689 has been characterized in GLP nonclinical safety studies in Sprague-
Dawley rats and beagle dogs, including 9-month (dogs), 6-month (rats), 28-day, and 2-day 
repeat-dose general toxicology studies, as well as genetic toxicology and safety pharmacology 
studies. The 9-month and 6-month repeat-dose toxicity studies included 13-week reversibility 
periods. The 28-day repeat-dose toxicity studies included an 8-week reversibility period in dogs 
and a 13-week reversibility period in rats. The 2-day repeat-dose toxicity studies included a 14-
day reversibility period in both species. Developmental and reproductive toxicology (DART) 
studies were performed in rats and rabbits. 
2.2.2. 
Clinical Studies  
Overall LY3372689 has been evaluated in 4 Phase 1 studies. These studies included healthy 
participants from Studies MTAA, MTAB, MTAC, and MTAD. LY3372689 was administered as 
a single dose in Studies MTAA and MTAB and as repeat doses for 14 days in Studies MTAC 
and MTAD. The safety data indicate that LY3372689 was well tolerated. To date, 71 healthy 
participants received at least 1 dose of LY3372689. In these 4 studies, no deaths or SAEs were 
reported. One discontinuation due to an AE was reported, influenza type A in Study MTAC, and 
was not considered related to the study drug by the investigator.  
The SAD Study MTAA was a Phase 1, placebo-controlled, randomized study in 23 healthy male 
and female participants (15 males, 8 females; aged 22 to 63 years). Participants received 
LY3372689 (0.15 to 16 mg) and placebo in a crossover manner, over 3 study periods. Safety and 
PK data were collected for 7 days in each period. LY3372689 exposure based on AUC0-∞ and 
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Cmax increased in a generally dose-proportional manner from 0.6 to 16 mg. Safety data indicated 
that LY3372689 was well tolerated when administered as a single dose up to 16 mg.  
Study MTAB was a single-dose PET study utilizing [18F]LY3316612 PET tracer to assess 
enzyme occupancy (EO), and to establish the relationship between plasma LY3372689 
concentration and EO, after single oral doses of LY3372689. Sixteen healthy males were dosed 
0.25, 1, or 5 mg across 4 cohorts, with 4 participants within each cohort. The EO was assessed at 
2 and 24 h post-dose at all doses, as well as 30 h and 54 h post-dose at 1 mg only. In general, a 
dose- and concentration-dependent change in EO was observed. At 1 and 5 mg, near maximum 
EO (97% to 98%) was observed at 2 h post-dose. The EO at 5 mg declined slightly from 98% at 
2 h to 93% at 24 h post-dose. At 1 mg, the EO declined from 97% at 2 h, to 81% at 24 h, to 30% 
at 54 h post-dose. The EO at 0.25 mg was 26% at 2 h and 46% at 24 h. The PK profile of 
LY3372689 in this study was similar to what was observed in the prior single-dose SAD Study. 
Safety data indicated that LY3372689 was well tolerated up to 5 mg. 
Study MTAC was a Multiple Ascending Dose (MAD), placebo-controlled, randomized study in 
women of non-childbearing potential, vasectomized males, and 7 Japanese participants as a 
subgroup. LY3372689 was administered at doses of 1, 3, and 7 mg given QD for 14 days. 
Following repeat dosing, there was a small degree of accumulation of LY3372689 with a relative 
accumulation of 1.06-1.34 across the dose range. The impact of food was also tested which 
showed no effect on the extent of exposure but a 43% decrease in Cmax with a delay in tmax by 
5 h, compared to the fasted state. In terms of safety, there was no dose dependency in incidence 
or severity for treatment-emergent AEs. There were no clinically significant changes in ECGs, 
including no evidence of QTc, nor PR interval prolongation. There were also no clinically 
significant changes in vital signs, neurological examinations, or safety laboratory tests, including 
male hormones. 
Study MTAD was an open-label, nonrandomized, multiple-dose PET study, utilizing 
[18F]LY3316612 to assess OGA brain EO resulting from oral doses of LY3372689 administered 
QD for 14 days in a single cohort of 4 healthy participants. PET scans were conducted 
approximately 24 h after the first administration (on Day 1) and last administration (on Day 14) 
of 1 mg LY3372689 given QD for 14 days. Initial results show no change in enzyme occupancy 
from Day 1 to Day 15 of the study. These data provide confidence that brain OGA EO can be 
sustained with multiple dosing. Overall, no dose-dependent relationship in incidence or severity 
of treatment-related AEs was observed, and blood markers of inflammation or muscle injury 
were within normal limits. There were no clinically significant changes in vital signs, ECGs, 
neurological examinations, or safety laboratories, including male hormone panel and creatinine 
kinase. 
2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3372689 may be found in the IB. 
Potential Risks of Clinical Significance 
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Mitigation Strategy  
Summary/Rationale for Risk  
In summary, the available nonclinical and clinical safety data support administration of 
LY3372689 in the intended study population. The noted risk mitigation strategy allows for 
careful monitoring for potential AEs.   
2.3.1. Benefit Assessment  
There is a large unmet medical need for disease-modifying treatments for AD. Animal models 
suggest that OGA inhibition will reduce progression or spread of the aggregated forms of tau. In 
addition to the assessment of safety and tolerability of LY3372689, this study will also assess 
whether inhibition of OGA and potential reduction in aggregated tau can slow the progression of 
the disease as assessed by clinical measures and biomarkers of disease pathology and 
neurodegeneration relative to placebo treatment. 
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2.3.2. Overall Benefit/Risk Conclusion  
In conclusion, the available nonclinical and clinical data support the oral administration of 
LY3372689 to the intended study population according to the clinical investigation plan and also 
provide a sufficient margin of safety for the study design and doses. There are currently no 
disease-modifying anti-tau treatments for AD. The potential benefits of LY3372689 showing 
disease-modifying properties in participants with AD are considered to outweigh the potential 
risks. 
 
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3. 
Objectives and Endpoints  
Primary Objective  
Endpointsa 
To assess the effect of LY3372689 vs. placebo on 
clinical progression in participants with early 
symptomatic AD with demonstrated presence of 
moderateb levels of tau pathology 
iADRS change from baseline through end time 
point (76-124 weeks) 
Key Secondary Objective 
Endpoints 
To assess the effect of LY3372689 vs. placebo on 
clinical progression in full study population 
(moderate + highc levels of tau pathology) with 
early symptomatic AD 
iADRS change from baseline through end time 
point (76-124 weeks) 
Other Secondary Objectives  
Endpoints 
To evaluate safety and tolerability of LY3372689 
Standard safety assessments 
 
Spontaneously reported AEs 
 
Clinical laboratory tests 
 
Vital sign and body weight measurements 
 
12-lead ECGs 
 
Physical and neurological examinations 
 
C-SSRS, and 
 
MRI (treatment-emergent radiological 
findings) 
To assess the effect of LY3372689 vs. placebo on 
clinical progression in full study population and 
moderate tau sub population with early 
symptomatic AD 
Change in cognition and function from baseline 
through end time point (76-124 weeks) as 
measured by: 
 
ADAS-Cog13 
 
ADCS-iADL  
 
CDR-SB, and 
 
MMSE 
To assess the effect of LY3372689 vs. placebo on 
brain region volumes 
Change in volumetric MRI measures from 
baseline through end time point (76 - 124 weeks) 
To assess the effect of LY3372689 vs. placebo on 
brain tau deposition 
Change in brain tau deposition from baseline 
through end time point (76-100 weeks) as 
measured by flortaucipir F18 PET scan  
To assess the PK of LY3372689 
Plasma concentrations of LY3372689 
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Exploratory Objectives 
Endpoints 
To assess the effect of LY3372689 vs placebo on 
blood-based biomarkers 
Change from baseline through end time point (76-
124 weeks) on blood-based biomarkers of AD 
pathology and neurodegeneration 
To assess the effect of LY3372689 vs placebo on 
additional assessments of cognition 
Change from baseline through end time point (76-
124 weeks) as measured by: 
 
Digital Clock Drawing Test, and 
 
DSST 
To explore the relationship between tau burden 
and clinical outcomes 
Tau burden 
 
Blood-based biomarkers, and 
 
Flortaucipir F18 PET 
Clinical outcomes 
 
ADAS-Cog13 
 
ADCS-iADL  
 
CDR-SB 
 
iADRS, and 
 
MMSE 
To explore the relationship between blood-based 
biomarkers and imaging 
Blood-based biomarkers of AD pathology and 
neurodegeneration 
Imaging 
 
Flortaucipir F18 PET, and 
 
MRI 
To assess the efficacy of LY3372689 to prolong 
time to clinical progression 
CDR global score 
Abbreviations: ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-iADL = 
Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living; AD = Alzheimer’s Disease; AE = 
Adverse Event; CDR-SB = Clinical Dementia Rating Scale-Sum of Boxes; C-SSRS = Columbia Suicide-Severity 
Rating Scale; ECG = electrocardiograms; iADRS = integrated Alzheimer’s Disease Rating Scale; MMSE = Mini 
Mental State Examination; MRI = Magnetic Resonance Imaging; PET = Positron emission tomography; PK = 
Pharmacokinetics.  
a Based on common close design, participants final endpoint time will be between 76-124 weeks. 
b Moderate tau pathology is defined as those who meet tau PET inclusion criteria for evidence of tau pathology 
consistent with Alzheimer’s disease (Fleisher et al. 2020), but do not have widespread and high levels of cortical 
tau pathology.  
c High levels of cortical tau pathology by flortaucipir F18 PET is defined by the top quartile of quantitative 
standardized uptake value ratios in a population of amyloid positive Alzheimer’s participants and cognitively 
normal older controls (Pontecorvo et al. 2019). 
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Post-Treatment Safety Follow-up Period 
Objectives 
Endpoints 
To assess clinical effects after previous treatment 
with LY3372689 on clinical progression in 
participants with early symptomatic AD who 
participated in the double-blind treatment periods 
Change in cognitive and functional assessments:  
 
iADRS 
 
ADAS-Cog13 
 
ADCS-iADL 
 
CDR-SB, and 
 
MMSE 
To assess safety effects after previous treatment 
with LY3372689 
Standard safety assessments  
 
spontaneously reported AEs 
 
MRI (treatment-emergent radiological 
findings) 
 
clinical laboratory tests 
 
vital sign and body weight measurements 
 
12-lead ECGs 
 
physical and neurological examinations, 
and 
 
C-SSRS 
To assess effect after previous treatment with 
LY3372689 on brain region volumes 
Volumetric MRI measures 
To assess effect after previous treatment with 
LY3372689 on blood-based biomarkers 
Change from baseline through end time point on 
blood-based biomarkers of AD pathology and 
neurodegeneration 
Abbreviations: ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – Cognitive subscale; 
ADCS- iADL = Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living; AD = 
Alzheimer’s disease; AE = adverse event; CDR-SB = Clinical Dementia Rating Scale-Sum of Boxes; C-SSRS = 
Columbia Suicide-Severity Rating Scale; ECG = electrocardiogram; iADRS = integrated Alzheimer’s Disease 
Rating Scale; MMSE = mini mental state examination; MRI = Magnetic Resonance Imaging. 
 
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4. 
Study Design  
4.1. 
Overall Design  
Study MTAE is a multicenter, randomized, double-blind, placebo-controlled, Phase 2 study of 
LY3372689 in participants with early symptomatic AD. Participants who meet entry criteria will 
be randomized in a 1:1:1 (1 LY: 1 LY: 1 PBO) randomization of the following treatment groups:   
 LY3372689: low dose once daily 
 LY3372689: high dose once daily, and 
 Placebo. 
The maximum total duration of study participation for each participant, including screening and 
the post-treatment follow-up periods, is up to approximately 149 weeks:   
 Lead-In: complete any time prior to complete screening visit 
 Complete Screening:  -63 days to -1 day prior to randomization    
 Double-Blind: 76 weeks or up to 124 weeks 
 Safety Follow-up (V801): approximately 4 weeks after completion of double-blind study 
period 2b, and 
 Post-treatment Safety Follow-up Period: approximately 12 weeks and starts with Visit 
802 
This study will utilize a 76-week common close design. Under the common close design, all 
enrolled participants will remain on double-blind randomized treatment and complete 
assessments until the last enrolled participant that has not discontinued from treatment has 
achieved 76 weeks of assigned treatment. The maximum duration of treatment is 124 weeks.  
4.1.1. 
Lead-In and Screening Period (V601 and V1)  
At or before Visit 1, the study will be explained to the participant (and his or her legal 
representative, if applicable) and study partner. Informed consent must be obtained before any 
study procedures are conducted. The lead-in period (V601) is optional and may occur any time 
prior to Visit 1.  
The screening period spans the time between Visit 1 to Visit 2.  
For those who participate in V601, a preliminary screening informed consent or full study 
consent will be obtained to conduct lead-in screening to collect demographics data, administer 
the MMSE, and collect a blood sample for plasma phosphorylated tau (P-tau). The P-tau assay is 
an investigational device. Participants who do not meet the MMSE screening criteria are not to 
have any other screening procedures performed. For rescreening instructions, see Section 5.5. 
Participants who meet both MMSE and plasma P-tau screening criteria (where available) or have 
other evidence of AD pathology (approved by sponsor) may proceed to the remaining V1 
screening procedures once they have given signed or dated informed consent for the full study. 
Plasma P-tau testing may not be available at all locations for screening purposes. At these sites, a 
P-tau blood sample should still be collected and submitted. In such cases, only MMSE criteria 
must be met to proceed to V1. 
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For V1, once the full informed consent is signed, 63 days are allowed for completion of the 
remaining Visit 1 screening assessments and procedures, as described in the SoA (Section 1.3). 
For those who do not complete V601 prior to signing full study consent and proceed directly to 
V1, MMSE and CDR screening criteria will need to be met before proceeding to have blood 
samples collected for plasma P-tau, other lab testing, and performing other cognitive 
assessments. The MRI and flortaucipir F18 PET scans are to be performed only after the 
participant meets all other eligibility criteria in the complete screening visit (V1). For sites at 
which P-tau testing will not be available as a screening procedure, it will not be a protocol 
deviation to continue with flortaucipir F18 PET scanning without meeting the P-tau screening 
criterion. In such cases, P-tau results will not be required for randomization and enrollment if all 
other screening criteria are met. Although imaging may be the last screening procedures of the 
study, it is expected that the centrally read results will be available within the timeframe of 63 
days. However, it will not be a protocol deviation, should imaging screening results not be 
available until after 63 days. Participants whose screening imaging results are not available until 
after 63 days will remain eligible within Visit 1 until these results become available. 
Visit 1 is not considered complete until all required screening procedures have been completed, 
results have been reviewed by the investigator or qualified designee, and the investigator or 
qualified designee has confirmed that the participant is eligible to be randomized. Only then can 
the participant proceed to Visit 2.  
4.1.2. 
Double-Blind Period 2a (V2-21)  
The treatment period 2a is a double-blind treatment phase beginning at Visit 2 (randomization). 
At Visit 2, appointments should be made for all remaining visits and should be scheduled as 
close as possible to the target date, relative to Visit 2. Participants who meet entry criteria and 
proceed to Visit 2 will be enrolled and randomized to receive up to 124 weeks of treatment with 
LY3372689 low dose, LY3372689 high dose, or placebo. During this double-blind period, 
participants will take study drug tablets once daily as dispensed. Assessments and procedures 
will be performed as indicated in the SoA (Section 1.3). Procedures for some visits may take 
more than 1 day.  
All participants that continue assessments in the study will have a minimum of 76 weeks of study 
assessments. All participants except the last enrolled participant that has not discontinued from 
the study will continue to Study Period 2b. The last enrolled participant that has not discontinued 
from the study will have their last visit with final assessments occurring at week 76 (V21). Sites 
will be notified if a participant at their site is to have their study completion visit at week 76, 
otherwise all participants should continue to study Period 2b (V22-29). 
4.1.3. 
Double-Blind Period 2b (V22-29)  
All participants other than the last enrolled participant, who has a study completion visit at V21, 
will continue with assessments and procedures as indicated in the SoA for Study Period 2b. The 
final visit for participants in Study Period 2b will occur when the last enrolled participant that 
has not discontinued from the study completes their V21 study completion visit. At that time, all 
participants in study Period 2b will undergo a study completion visit (end-of-study ET visit) at 
their next scheduled visit (following the instructions for the Period 2b ET visit) as described in 
the SoA and Manual of Operations. Study sponsor will notify sites when the last enrolled 
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participant achieves study completion V21, to enable scheduling of end of study ET visits for 
Period 2b. End-of-study ET visits will follow assessments as indicated by the ET visit in Period 
2b (see SoA; Section 1.3). 
4.1.4. 
Follow-up (V801)  
Participants are to return to the site for safety follow-up visit (Visit 801) 4 weeks ±10 days after 
the last double-blind treatment visit has occurred. Assessments are to be performed as indicated 
in the SoA (Section 1.3). 
4.1.5. 
Post-Treatment Safety Follow-up Period (V802 and V803)  
Participants will be offered the opportunity to participate in the post-treatment safety follow-up 
period. Participants are to return to the site for post-treatment safety follow-up visit which lasts 
for approximately 12 weeks and starts at Visit 802. Assessments are to be performed as indicated 
in the SoA (Section 1.3.4). 
4.2. 
Scientific Rationale for Study Design  
Study MTAE is a multicenter, randomized, double-blind, placebo-controlled study of 
LY3372689 in participants with early symptomatic AD, MMSE 22-30, CDR-global score of 0.5-
1.0, with cerebral tau burden that is elevated, as measured by flortaucipir F18. For the purposes 
of this study, early symptomatic AD is defined as those with mild cognitive impairment due to 
AD or mild Alzheimer’s dementia, consistent with Stages 2 through 4 of the FDA draft guidance 
entitled “Early Alzheimer’s Disease: Developing Drugs for Treatment. Guidance for Industry” 
(February 2018; https://www.fda.gov/media/110903/download) and the NIA-AA Research 
Framework: Toward a biological definition of Alzheimer’s disease. (Jack et al. 2018). 
Study MTAE includes a placebo treatment arm and allows all participants to continue their AD 
standard-of-care concomitant medications. The use of a placebo comparator in Study MTAE is 
needed to determine the efficacy and safety of LY3372689 therapy. Inclusion of a placebo 
treatment arm is acceptable in Study MTAE because there are no available disease-modifying 
anti-tau treatments for AD; this approach is in agreement with the use of placebo described in the 
Declaration of Helsinki (WMA 2013).  
The study includes a screening visit, which can last up to 63 days from the time of signing the 
full ICF, at which participants are required to have plasma tau (where available) and flortaucipir 
F18 PET imaging results consistent with the presence of elevated tau pathology in order to be 
randomized to the double-blind period. A common close study design is used to maximize 
efficiency by increasing overall duration of treatment in the study population without increasing 
the overall length of the study. This is intended to result in increased likelihood of detecting 
LY3372689 effects on study endpoints while minimizing overall study length and number of 
enrolled participants.  
See Section 8.1 for descriptions of outcome measures. In addition to clinical outcomes, imaging 
biomarkers will also be measured to assess the direct effect of LY3372689 on brain atrophy and 
aggregated tau neurofibrillary tangle accumulation over time, which are a known hallmark 
pathologies of AD, and hypothesized to contribute to the cognitive and functional decline in 
people with AD. Tau pathology is theorized to be a mediator for clinical decline and therefore it 
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is hypothesized that the reduction of tau aggregation and further propagation may slow clinical 
decline. 
4.3. 
Justification for Dose  
Doses of 0.75 mg QD (low dose) and 3 mg QD (high dose) are being administered to assess a 
comparison of efficacy and safety compared to placebo in this study. The dose justification for 
the study rests on characteristics of the nonclinical safety and pharmacology profile, and 
pharmacokinetic (PK), pharmacodynamic (PD), and safety findings in healthy human volunteers. 
Specifically, OGA EO was assessed in the brain of healthy participants using a novel PET 
radiotracer [18F] LSN3316612 after single oral doses of LY3372689 ranging from 0.25 to 0.5 
mg, and after once daily dosing of 1 mg for 14 days. There was a dose- and concentration-
dependent change in OGA brain EO, which was maintained with multiple dosing up to 14 days. 
Based on PK/PD modeling, a dose of 0.75 mg is predicted to achieve at trough a median EO of 
84% with a 62% probability of achieving 80%, and 3 mg is predicted to achieve at trough a 
median EO of 95% with a 98% probability of achieving 80% EO. To note, brain EO of 80% was 
shown in preclinical animal models to reduce tau pathology and used as a benchmark to optimize 
doses for this clinical trial in AD participants. 
Overall, doses of 0.75 and 3 mg once daily were selected because both doses are predicted to 
achieve at trough an EO of >80%. The lower dose has the potential for improved safety profile 
relative to a higher dose based on nonclinical toxicology findings (Section 2.2.1), with the higher 
dose of 3 mg providing near maximum EO to fully interrogate the OGA inhibition mechanism of 
action and test the OGA hypothesis. Furthermore, 3 mg in this study is less than the top dose of 
16 mg in the single ascending dose study and 7 mg in the MAD study studies (Section 2.2.2), 
which in both studies did not demonstrate any dose-limiting AEs.  
If during study conduct the external DMC recommends dose reduction at the study arm level, the 
high-dose arm could be reduced to 1.5 mg (Section 6.6).  
4.4. 
End of Study Definition  
A participant is considered to have completed the study if he or she has completed all required 
phases of the study including the last visit or the last scheduled procedure shown in the SoA. 
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5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Early symptomatic AD participants, as defined in the inclusion criteria (Section 5.1), will be 
enrolled into Study MTAE. The inclusion criteria ensure that participants meet clinical criteria 
for having an AD clinical syndrome and have biomarker evidence consistent with the presence of 
AD pathology (Jack et al. 2018). With the use of  tau PET imaging, with or without plasma P-
Tau levels, as part of the eligibility criteria, enrolled participants will be highly likely to meet 
pathological criteria for AD, including the presence of both key pathologies, brain amyloid 
plaque and aggregated tau neurofibrillary tangles. (Fleisher et al. 2020; Palmqvist et al. 2020). 
This study population is hypothesized to represent those that will most benefit from the 
mechanism of action of LY3372689, which is believed to reduce further accumulation of 
pathological tau but not remove existing tau; further, a population at the earlier stages of tau 
pathology may benefit the most from LY3372689 treatment. It is also necessary to enroll a 
population that is likely to demonstrate clinical decline in the timeframe of Study MTAE. 
Elevated levels of tau pathology have been associated with increased risk for clinical progression 
(Pontecorvo et al. 2019). Therefore, the inclusion criteria for Study MTAE are selected to 
identify a study population with known tau pathology targeted by LY3372689, at levels 
consistent with risk of short-term clinical progression.   
5.1. 
Inclusion Criteria  
Participant Characteristics 
[1] Men or women (not of childbearing potential), 60 to 85 years of age. 
a. Female participants are considered women not of childbearing potential if 
 they have a congenital anomaly, such as Mullerian agenesis, or  
 they are infertile due to surgical sterilization (e.g., hysterectomy, or at least 6 
weeks post-surgical bilateral oophorectomy or tubal ligation), or  
 they are post-menopausal. 
b. The post-menopausal state is defined as 
i. a woman 55 or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea, or 
ii. a woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy. 
[2] Gradual and progressive change in memory function reported by the participant or informant 
for ≥6 months.  
[3] MMSE 22-30 (inclusive).  
[4] CDR global score of 0.5 to 1.0 (inclusive), with a memory box score ≥0.5.   
[5] Meet plasma P-tau criteria (where available for screening purposes). The acceptance of a 
historical evidence of positive AD pathology in the place of plasma P-tau is at the discretion 
of the sponsor.  
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[6] Meet flortaucipir F18 PET scan criteria. A historical flortaucipir F18 PET scan may be 
submitted to be considered for eligibility if performed within 6 months of randomization. The 
acceptance of a historical scan is at the discretion of the sponsor.  
[7] Have a study partner who will provide written informed consent to participate, is in frequent 
contact with the participant (defined as at least 10 h per week), and will accompany the 
participant to study visits or be available by telephone at designated times. 
A second study partner may serve as backup. The study partner(s) is(are) required to 
accompany the participant for signing consent. One study partner is requested to be present 
on all days the C-SSRS is administered and must be present on all days the cognitive and 
functional scales are administered. If a participant has a second study partner, it is preferred 
that 1 study partner be primarily responsible for the CDR and the ADCS-ADL assessments. 
Visits not requiring CDR must have a study partner available by telephone if not 
accompanying participant at a visit for the following assessments: 
 AEs and concomitant medications, and 
 relevant portions of the C-SSRS 
If a study partner must withdraw from study participation, a replacement may be allowed at the 
investigator’s discretion. The replacement will need to sign a separate informed consent on the 
first visit that he or she accompanies the participant.   
[8] Are reliable and willing to make themselves available for the duration of the study and are 
willing to follow study procedures. 
[9] Males who agree to use effective methods of contraception may participate in this 
trial. 
Contraception 
a. Male participants 
(i). 
should refrain from sperm donation for the duration of the study 
and until 92 days following the last dose of study drug. 
(ii). 
regardless of their fertility status, with nonpregnant female 
partners of childbearing potential, must agree to either remain 
abstinent (if this is their preferred and usual lifestyle) or use 
condoms with spermicide during intercourse for the duration of 
the study and for 92 days after study drug dosing. 
(iii). 
who are in exclusively same sex relationships (as their preferred 
and usual lifestyle) are not required to use contraception. 
 [10] If taking a commercially approved prescription medication for the treatment of AD, 
have received treatment with a stable dose for at least 1 month before screening 
(V1). If approved prescription medication for AD is a disease-modifying therapy 
(e.g., anti-amyloid or anti-tau), then have received treatment with a stable dose for 
at least 3 months prior to V2. If a participant has recently stopped an approved AD 
medication, he or she must have discontinued treatment at least 2 months or >5 
half-lives (whichever is longer) of the medication before randomization. 
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[11] Changes in concomitant medications that could potentially affect cognition and their 
dosing should be stable for at least 1 month before screening, and between screening 
and randomization (does not apply to medications discontinued due to exclusions or 
with limited duration of use, such as antibiotics). 
Informed Consent 
[12] Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria  
[13] Lack, in the investigator’s opinion, of adequate premorbid literacy, adequate vision, 
or adequate hearing to complete the required psychometric tests. 
[14] Significant neurological disease affecting the CNS, other than AD, that may affect 
cognition or ability to complete the study, including but not limited to, other 
dementias, serious infection of the brain, Parkinson’s disease, multiple concussions, 
or epilepsy or recurrent seizures (except febrile childhood seizures). 
[15] Current serious or unstable illnesses including cardiovascular, hepatic, renal, 
gastroenterological, respiratory, endocrinologic (including unstable diabetes), 
neurologic (other than AD), psychiatric, immunologic, or hematologic disease and 
other conditions that, in the investigator’s opinion, could interfere with the analyses 
in this study; or has a life expectancy of <24 months. 
[16] History of cancer within the last 5 years, with the exception of nonmetastatic basal 
and/or squamous cell carcinoma of the skin, in situ cervical cancer, nonprogressive 
prostate cancer, or other cancers with low risk of recurrence or spread. 
[17] Participants with any current primary psychiatric diagnosis other than AD if, in the 
judgment of the investigator, the psychiatric disorder or symptom is likely to 
confound interpretation of drug effect, affect cognitive assessment, or affect the 
participant’s ability to complete the study. Participants with a history of 
schizophrenia or other chronic psychosis are excluded. 
[18] Are clinically judged by the investigator to be at serious risk for suicide as assessed 
by medical history, or examination.  
[19] History of alcohol or drug abuse disorder (except tobacco use disorder) within 2 
years before the screening visit. 
[20] Known positive serologic findings for human immunodeficiency virus antibodies. 
Local laws and regulations may apply to whether testing is required. 
[21] Participants with a past history (suspected or confirmed) of Hepatitis B should have 
HBsAg testing at screening and are excluded if HBsAg is positive. 
[22] Participants with a past history (suspected or confirmed) of Hepatitis C (resolved >6 
months prior to enrollment) should have HCV RNA PCR testing at screening and 
are excluded if the HCV RNA PCR test is positive. 
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[23] History of clinically significant multiple or severe drug allergies, significant atopy, 
or severe posttreatment hypersensitivity reactions (including but not limited to 
erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal 
necrolysis, and/or exfoliative dermatitis). 
Imaging, Vital Signs, Electrocardiograms, Laboratory Tests, and Physical Examination 
[24] Have any clinically important abnormality at screening, as determined by the 
investigator, in physical or neurological examination, vital signs, ECG, or clinical 
laboratory test results that could be detrimental to the participant, could 
compromise the study, or show evidence of other etiologies for dementia. 
[25] Screening MRI that shows evidence of significant abnormality that would suggest 
another potential etiology for progressive dementia or a clinically significant 
finding that may impact the participant’s ability to safely participate in the study. 
[26] Have any contraindications for MRI, including claustrophobia or the presence of 
contraindicated metal (ferromagnetic) implants/cardiac pacemaker. 
[27] Sensitivity to flortaucipir F18. 
[28] Contraindication to PET and present or planned exposure to ionizing radiation that, 
in combination with the planned administration of study PET ligands, would result 
in a cumulative exposure that exceeds local recommended exposure limits. 
[29] Cardiovascular screening ECG criteria  
 heart rate less than 45 beats/min 
 Mobitz type 2 second-degree or third-degree AV block (uncorrected by 
cardiac pacemaker), and 
 ECG with QTc >450 msec in males and >470 msec in females.  
[30] Calculated creatinine clearance <30 mL/min (Cockcroft–Gault formula; Cockcroft 
and Gault 1976) at screening. 
[31] ALT ≥2x the ULN of the performing laboratory, AST ≥2x ULN, TBL ≥2x ULN, or 
ALP ≥2x ULN at screening. 
NOTE: Participants with TBL ≥2x ULN are not excluded if they meet all of 
the following criteria for Gilbert syndrome: 
a. bilirubin is predominantly indirect (unconjugated) at screening 
(direct bilirubin within normal limits). 
b. absence of liver disease. 
c. ALT, AST, and ALP ≤1x ULN at screening. 
d. hemoglobin is not significantly decreased at screening. 
Prior/Concomitant Therapy (Refer to Manual of Operations for complete lists) 
[32] Have known allergies to LY3372689, related compounds, or any components of the 
formulation; or history of significant atopy. 
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Prior/Concurrent Clinical Trial Experience 
[35] Are currently enrolled in any other interventional clinical trial involving an 
investigational product or any other type of medical research judged not to be 
scientifically or medically compatible with this study. 
[36] Have participated within the last 30 days in a clinical trial involving an 
investigational product. If the previous investigational product is scientifically or 
medically incompatible with this study (such as an anti-tau or anti-amyloid therapy) 
and has a long half-life, 3 months or 5 half-lives (whichever is longer) should have 
passed prior to screening. Participation in observational studies may be permitted 
upon review of the observational study protocol and approval by the sponsor. 
Other Exclusions 
[37] Are investigator site personnel directly affiliated with this study and/or their 
immediate families. Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted. 
[38] Are Lilly employees or are employees of TPOs involved in the study who require 
exclusion of their employees, or have study partners who are Lilly employees or are 
employees of TPOs involved in a study that requires exclusion of their employees. 
[44] Criterion deleted. 
[45] Criterion deleted. 
[46] Criterion deleted. 
5.3. 
Post-Treatment Safety Follow-up Period  
Exclusion criteria 
[47] Are currently enrolled in any other interventional clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or medically 
compatible with this study. 
5.4. 
Lifestyle Considerations  
Participants should refrain from donating blood or blood products from the time of their 
screening visit until 7 days following the last dose of IP. 
Participants should avoid excessive use of alcohol from the screening visit until the study ends. 
Excessive alcohol consumption is defined for men as consuming an average of more than 3 
drinks per day, or more than 21 drinks per week. For women, excessive use of alcohol is defined 
as consuming an average of more than 2 drinks per day, or more than 14 drinks per week. 
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5.5. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE.  
If the screen failure is due to a CDR global score <0.5, or due to non-eligible plasma P-tau or 
flortaucipir F18 PET scan, then 1 rescreen will be allowed after 24 weeks.   
Other reasons for screen failure will require sponsor approval for rescreen. 
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6. 
Study Intervention  
Study intervention is defined as any medicinal product(s) or medical device(s) intended to be 
administered to or used by a study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
Treatment Regimens, Double-Blind Treatment Period  
LY3372689 Dose (mg) 
Regimen 
0.75 
LY3372689: 0.75 mg dose once daily for up to 124 weeks (minimum of 76 
weeks) (Visit 2 [Week 0]–Visit 29 [Week 124]). 
3.0a 
 
LY3372689: 3.0 mg dose once daily for up to 124 weeks (minimum of 76 
weeks) (Visit 2 [Week 0]–Visit 29 [Week 124]). 
Placebo 
 
Placebo dose once daily for up to 124 weeks (minimum of 76 weeks) (Visit 2 
[Week 0]–Visit 29 [Week 124]). 
a Dose may be reduced from 3 to 1.5 mg if deemed necessary. Refer to Section 6.6. 
Investigational products used in this study are: 
 LY3372689, and 
 Placebo. 
Investigational products are administered orally once daily in the morning at approximately the 
same time each day. LY3372689 may be taken with or without food. All LY3372689 strengths 
and placebo will be identical tablets. 
This study will utilize a 76-week common close design. Under the common close design, all 
enrolled participants will remain on double-blind randomized treatment and complete 
assessments until the last enrolled participant that has not discontinued from treatment has 
achieved 76 weeks of assigned treatment. The maximum duration of treatment is 124 weeks. 
The table below lists the study interventions used in this clinical study. 
Intervention Name 
LY3372689 
Placebo 
Flortaucipir F18 
Authorized as defined by EU 
Clinical Trial Regulation 
Not authorized 
Not authorized 
Not authorized 
Packaging and Labeling 
Study intervention will be supplied by the sponsor or designee in accordance with current Good 
Manufacturing Practice. Clinical trial materials will be labeled according to the country’s 
regulatory requirements. All IPs will be stored, inventoried, reconciled, and destroyed according 
to applicable regulations. Clinical trial materials are manufactured in accordance with current 
Good Manufacturing Practices. 
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6.2. 
Preparation/Handling/Storage/Accountability  
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IP received and any discrepancies are reported and 
resolved before use of the IP. 
2. Only participants enrolled in the study may receive IP, and only authorized site staff or 
designee may supply or administer IP. 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 
site staff or designee. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused IP are provided by 
the sponsor.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
This is a double-blind study (study periods 2a and 2b), with design to maintain blinding to 
treatment. To preserve the blinding of the study, a minimal number of Lilly personnel will see 
the randomization table and treatment assignments before the study is complete.   
For between-group comparability, participant randomization will be stratified by the 
investigative site, tau burden (moderate versus high) as defined by flortaucipir PET, and by prior 
or current use of any approved disease-modifying therapy for AD. Enrollment of high tau burden 
participants will be capitated at a predetermined proportion of the total enrolled population. 
Hence, study eligibility based on flortaucipir PET scan results may change as the study 
progresses. Assignment to treatment groups will be determined using an interactive web 
response system (IWRS). The IWRS will be programmed using the dynamic allocation 
(minimization) method of Pocock and Simon (1975), to balance the treatment arms using three 
factors: investigative site, tau burden, and prior or current use of any approved disease-
modifying therapy for AD. This is to achieve balanced participant assignment between treatment 
arms as much as possible within each stratum and at the study level. Randomization into 1 
stratum may be discontinued at the discretion of the sponsor. 
Blinded site personnel will dispense study intervention and confirm that they have located the 
correct packages by entering a confirmation number found on the label into the IWRS. 
The independent external DMC is unblinded to randomization.  
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a 
Lilly-designated Medical Monitor for the participant to continue in the study. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event. The 
participant’s safety must always be the first consideration in making such a determination. If a 
participant’s treatment assignment is unblinded, Lilly must be notified immediately. If the 
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investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible. 
Participants who meet all criteria for enrollment will be assigned a study (participant) number at 
Visit 601 or Visit 1 and randomized to double-blind treatment at Visit 2. Participants will be 
randomized to LY3372689 low dose, LY3372689 high dose, or Placebo in a 1:1:1 ratio. 
Participants will remain blinded to the original treatment arms while participating in the post-
treatment safety follow-up period. 
6.4. 
Study Intervention Compliance  
Participant compliance with study medication will be assessed at each visit by direct questioning 
and/or counting returned tablets. The participant should be instructed to retain all empty drug 
packages after using up the medication in the package and to bring the empty packages and any 
unused medication to the clinic at each visit so that the clinic staff can record the amount of 
medication used since the last visit.  
Compliance for the double-blind study periods will be assessed at telephone visits via 
questioning of the participant and/or study partner. 
The administration of all study medication should be recorded in the appropriate sections of the 
eCRF. 
Participants who consume 80-100% of the prescribed daily dose during this study will be 
considered compliant. A participant will be considered significantly noncompliant if he or she is 
judged by the investigator to have intentionally or repeatedly taken more or less than the 
prescribed amount of medication. Participants regarded as non-compliant may be discontinued at 
the investigator’s discretion, in consultation with the Lilly-designated Medical Monitor. 
6.5. 
Concomitant Therapy  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded in the CRF, along with any changes to dose.   
The Lilly-designated Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Participants and their study partners will be instructed to consult the investigator or other 
appropriate study personnel at the site before initiation of any new medications or supplements 
and before changing dose of any current concomitant medications or supplements. 
Use of benzodiazepines for treatment on an as-needed basis for insomnia or daily dosing as 
anxiolytics is permitted. Use of sedatives or hypnotics should be avoided for 8 h before 
administration of the cognitive and functional tests unless they are given chronically. 
The following are prohibited concomitant medications during the study (refer to Manual of 
Operations for complete lists): 
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 Use of any investigational drug or device not specified in this study unless approved by 
the Lilly-designated medical monitor (topical may be permitted)  
 Use of any drug of abuse, including but not limited to illicit amphetamine, cocaine, illicit 
opiates, propoxyphene, methadone, methaqualone, phencyclidine, and illicit barbiturate. 
 Use of cannabis in a pattern of abuse.  
6.5.1. 
Standard of Care for Alzheimer’s Disease  
To ensure standard of care for AD, use of approved prescription treatments for AD is permitted 
(but not a requirement) in this study. The section below provides additional guidance on 
managing concomitant medication use. 
Double-Blind Period (Period 2a and 2b) 
Use of approved or standard-of-care treatments for AD is permitted (but not a requirement) 
during the study, provided that the dose has been unchanged for 1 month before Visit 1. If 
approved prescription AD medication is a disease-modifying therapy (e.g., anti-amyloid or anti-
tau), then dose must be stable for at least 3 months prior to V2. Doses of these medications 
should remain constant when possible, throughout the double-blind period (Visit 2 to 29). Any 
initiation or changes to standard-of-care medications should be done in consultation with the 
sponsor prior to implementing to determine if the participant would be allowed to continue in the 
study. 
Nonmedication treatments for AD such as behavioral management are permitted but are subject 
to the same restrictions as medication treatment taken for AD. 
Post-treatment Safety Follow-up Period (V802 and V803) 
Use of approved or standard-of-care treatments including both symptomatic and disease-
modifying therapies are permitted during the post-treatment safety follow-up period. Any 
changes to concomitant medication should be documented. Any concomitant medication used 
should be approved and used per the direction of the prescribing information. 
6.6. 
Dose Modification  
Dose modification of IP will be permitted for notable treatment-emergent AEs and AEs of 
special interest as determined by the study sponsor medical team, or as determined by the 
unblinded external DMC recommendations. Sponsor, site staff, and study participant will remain 
blinded to treatment assignments in all cases. A one-time dose reduction can be applied in a 
blinded fashion after sponsor safety review and/or an external DMC review (blinded or 
unblinded) on a case-by-case basis. Individual case dose reductions will result in individual 
participant reductions from 3.0 to 1.5 mg, or 0.75 mg to placebo, depending on the blinded 
treatment arm assignment of the participant. No change will be made for participants assigned to 
the placebo arm. If safety concerns remain for individual participants after dose reduction, a 
permanent discontinuation of study drug may be necessary. Based on a scheduled or ad-hoc 
safety review, the external DMC may also opt to trigger a dose reduction for the entire high-dose 
arm from 3.0 mg to a pre-established reduction dose of 1.5 mg for those participants assigned to 
the high-dose arm. There are no pre-established dose reductions for the low-dose arm. Study 
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team, participants, and blinded site staff will remain blinded to study dose and treatment arm in 
the event of dose reductions. In addition, treatment can be temporarily discontinued as an 
alternative to a dose reduction (see Section 7.1.1). 
6.7. 
Intervention after the End of the Study  
Study intervention will not be made available to participants after conclusion of the study. 
 
 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1. 
Discontinuation of Study Intervention  
In rare instances, it may be necessary for a participant to permanently discontinue IP. If IP is 
permanently discontinued, the participant may remain in the study (following the SoA, except as 
noted below) to be evaluated for safety and efficacy. 
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation for 
ET procedures and follow-up and for any further evaluations that need to be completed.  
Participants who permanently discontinued from IP but remain in the study should complete ET 
procedures (as indicated in the SoA), then continue to participate in subsequent scheduled visits 
and assessments, as appropriate. After ET visit, PK assessments should not be collected in 
participants that have permanently discontinued from IP. 
Investigational product may be discontinued for a participant for the following reasons (details 
given below):   
 clinical judgment  
 AEs 
 by request of the participant or participant’s designee (e.g., legal guardian)  
 severe noncompliance  
 the participant requires an excluded therapeutic agent and temporary discontinuation 
criteria cannot be met, and 
 pacemaker that is not MRI-compatible. 
Clinical Judgment 
AE or clinically significant laboratory value, ECG result, physical examination finding, MRI 
finding (such as symptomatic ischemic stroke), C-SSRS result, or vital sign measurement of such 
severity that, in the opinion of the investigator or Lilly-designated Medical Monitor, continued 
treatment is not in the best interest of the participant. 
Hepatic Event or Liver Test Abnormality 
Participants who are discontinued from IP due to a hepatic event or liver test abnormality should 
have additional hepatic safety data collected via the CRF. 
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a participant meets 1 of the following conditions after consultation with the Lilly-designated 
Medical Monitor:   
 
ALT or AST >8x ULN  
 
ALT or AST >5x ULN for more than 2 weeks  
 
ALT or AST >3x ULN and TBL >2x ULN or INR >1.5   
 
ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
 
ALP >3x ULN  
 
ALP >2.5x ULN and TBL >2x ULN  
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 
ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)  
C-SSRS  
In addition, IP may be discontinued if participants: 
 Answer “yes” to Question 4 or Question 5 on the “Suicidal Ideation” portion of the C-SSRS, 
or 
 Answer “yes” to any of the suicide-related behaviors on the Suicidal Behavior portion of the 
C-SSRS. 
A psychiatrist or appropriately trained professional may assist in the decision to discontinue the 
participant.   
ECG 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using QTcF, PR interval or new onset AV block) after enrollment, the 
investigator or qualified designee will determine if the participant can continue in the study and 
if any change in participant management is needed. This review of the ECG printed at the time of 
collection must be documented. Any new clinically relevant finding should be reported as an AE. 
Severe Noncompliance 
Severe noncompliance to the study protocol, that results in a safety concern, in the judgment of 
the investigator, may be reason for discontinuing IP. 
Excluded Therapeutic Agent 
The participant, for any reason, requires a treatment with an excluded therapeutic agent 
(Section 6.5) and temporary discontinuation criteria cannot be met (see Section 7.1.1). 
Pacemaker that is not MRI-compatible 
Participants who require a ferromagnetic implant or insertion of a cardiac pacemaker that is not 
MRI-compatible will be discontinued from IP and may remain in the study off IP with no further 
MRIs. 
7.1.1. 
Temporary Discontinuation  
Treatment can be temporarily discontinued (examples include short-term treatment using a 
prohibited drug, uncertain AE, hospitalization). Re-starting investigational product is based on 
Sponsor and the Principal Investigator's judgment. The maximum permissible treatment 
suspension is a total of 6 weeks over the duration of the study. Temporary treatment 
discontinuation and restarting needs to be documented. If temporary discontinuation is due to an 
AE, it should be reported to the Lilly-designated Medical Monitor. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
A participant may withdraw from the study:   
 
at any time at his/her own request  
 
at the request of his/her designee (e.g., legal guardian) 
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 
at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 
if the participant becomes pregnant during the study  
 
if the participant enrolls in any other clinical study involving an investigational 
medicinal product or enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study, and 
 
if participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and GCP. 
At the time of discontinuing from the study, if possible, an ET visit should be conducted, as 
shown in the SoA. See SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. The participant will be 
permanently discontinued both from the IP and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, he or she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants  
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment. 
Safety follow-up should be performed as outlined in Section 1.3 (Schedule of Activities), Section 
8.2 (Safety Assessments), and Section 8.3 (Adverse Events and Serious Adverse Events, and 
Product Complaints) of the protocol.  
7.3. 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel 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.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
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8. 
Study Assessments and Procedures  
● Study procedures and their timing are summarized in the SoA. Protocol waivers 
or exemptions are not allowed. 
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
8.1. 
Efficacy Assessments  
Cognitive and functional testing data will be documented using an eCOA tablet. The audio voice 
recordings of the rater’s questions and the participant’s and study partner’s responses will also be 
collected via the eCOA tablet during administration of the cognitive and functional testing for 
central monitoring of rater scale administration. Cognitive and functional testing for each 
participant should be performed at approximately the same time on each day, whenever possible, 
to reduce potential variability.  
Note that the CDR should be administered by a different rater than the ADAS-Cog13 and MMSE. 
The ADCS-ADL should be administered by the same rater as the CDR. Each rater should 
continue administering the same scale whenever possible to the same participant throughout the 
study. The PI has the responsibility of selecting the raters who will administer the instruments at 
the site and ensuring all training requirements have been met by those raters. The CDR rater 
should be blinded to AEs to avoid bias in the CDR assessment. 
When administered, cognitive and functional testing should be performed before medical 
procedures that could be stressful for the participant (e.g., blood draws). Note that some 
procedures (e.g., MRI, flortaucipir F18 PET imaging) can be conducted on other days within the 
visit window. 
8.1.1. 
Primary Efficacy Assessment  
The iADRS (Wessels et al. 2015) represents a composite that was developed using both a theory-
driven approach (incorporating measures of both cognition and function) and a data-mining 
approach (identifying the most sensitive combination of scales through analysis of data from the 
Alzheimer’s Disease Neuroimaging Initiative and the EXPEDITION, EXPEDITION2, and 
EXPEDITION3 studies).  
The iADRS is a simple linear combination of scores from 2 well-established, therapeutically 
sensitive, widely accepted measures in AD, the ADAS-Cog13, and the ADCS-iADL, measuring 
the core domains of AD. All items of these 2 scales are included without additional weighting of 
items, yielding face validity and ease of interpretation of the composite relative to its 
components. 
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The iADRS score will be derived from the ADAS-Cog13 and the ADCS-iADL. The 
ADAS-Cog13 and the ADCS-ADL will be the actual scales administered to participants. 
8.1.2. 
Secondary Efficacy Assessments  
8.1.2.1. 
MMSE  
The MMSE is a brief instrument used to assess cognitive function in participants (Folstein et al. 
1975). The instrument measures orientation, memory, and attention; the ability of the participant 
to name objects; follow verbal and written commands; write a sentence; and copy figures. The 
range for the total MMSE score is 0 to 30, with lower scores indicating greater level of 
impairment. 
8.1.2.2. 
ADAS-Cog13  
The ADAS-Cog13 is a rater-administered instrument that was designed to assess the severity of 
dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD 
(Rosen et al. 1984). The ADAS-Cog13 should be administered by the same rater from visit to 
visit to reduce potential variability.  
The cognitive subscale of the ADAS, the ADAS-Cog13, consists of 13 items assessing areas of 
cognitive function that are the most typically impaired in AD: orientation, verbal memory, 
language, praxis, delayed free recall, digit cancellation, and maze-completion measures (Mohs et 
al. 1997). The ADAS-Cog13 scale ranges from 0 to 85, with higher scores indicating greater 
disease severity. 
8.1.2.3. 
CDR-Sum of Boxes  
The CDR-SB is a semi-structured interview performed with the participant and study partner 
(informant) that integrates domains of cognition and function into a single overall score (Berg et 
al. 1992; Morris 1993). By assigning a severity score for each of the 6 domains, and then 
summating each domain, a total score known as “Sum of Boxes” is obtained. Higher scores 
indicate greater disease severity. 
The CDR global ratings, calculated using an algorithm, range from 0 (no dementia) to 3 (severe 
dementia) while CDR-SB scores, calculated by adding the box scores, range from 0 to 18 (with 
higher scores indicative of more impairment). The informant is queried about the participant’s 
memory, orientation, judgment and problem solving, community affairs, home and hobbies, and 
personal care. The participant’s memory, orientation, judgment, and problem-solving ability are 
assessed. This scale demonstrates acceptable psychometric characteristics (Coley et al. 2011; 
Cedarbaum et al. 2013) and has been shown to be sensitive enough to detect disease progression, 
even in populations with less advanced clinical disease (Williams et al. 2013; Wessels et al. 
2015). 
The CDR should be administered whenever possible by the same rater from visit to visit to 
reduce potential variability. The study partner and participant must be interviewed separately. 
The CDR must always be administered to the study partner first and then to the participant. 
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8.1.2.4. 
ADCS-ADL  
The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire that is to 
be answered by the participant’s study partner (Galasko et al. 1997, 2004). The ADCS-ADL 
should be administered by the same rater from visit to visit to reduce potential variability.  
The ADCS-ADL subset of items (items 6a and 7 to 23) for iADLs will be used as a secondary 
efficacy measure. The focus in the early symptomatic AD population is on the iADLs rather than 
the bADLs, which are thought to be affected in more severe stages of the disease. The range for 
the iADL score is 0 to 59, with lower scores indicating greater disease severity.  
For each of the specific items, the study partner is first asked if the participant attempted the 
ADL during the past 4 weeks. If the participant did attempt the ADL, the study partner is asked 
to rate the participant’s performance level based on a set of performance descriptions. Scores for 
each item and the overall score for the tool are calculated. The range for the total ADCS-ADL 
score is 0 to 78, with lower scores indicating greater level of impairment. Separate scores for the 
bADLs (0 to 19) will also be computed. 
8.1.3. 
Exploratory Assessments  
8.1.3.1. 
Digital Clock Drawing Test  
The traditional Clock Drawing Test is a well-established and widely used pen and paper 
cognitive assessment in which individuals draw the face of a clock showing a specific time on a 
blank page, then copy a pre-drawn clock. The Digital Clock Drawing Test revises this familiar 
test by combining digitizing pen technology with novel software to precisely measure nuances in 
cognitive performance beyond task completion (Souillard-Mandar et al. 2016).  
Thus, the innovation offered by this technology is the examination of detailed temporal cognitive 
processes obtained in real time that cannot be captured using the traditional pen and paper testing 
format. 
8.1.3.2. 
Digit Symbol Substitution Test  
The Digit Symbol-Coding test from the Wechsler Adult Intelligence Scale-IV (Wechsler et al. 
2008) engages multiple cognitive abilities, but most notably processing speed. The Digit 
Symbol-Coding is a paper and pencil test presented on a single sheet of paper that requires a 
participant to match symbols to numbers according to a key located on the top of the page. The 
participant copies the symbol into spaces below a row of numbers. The number of correct 
symbols within the allotted time (120 s) constitutes the score. Maximum coding total raw score is 
135 points. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations  
Physical examinations will be performed as indicated in the SoA (Section 1.3).  
The complete physical examination will include assessment of  
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 
general appearance 
 
skin, head, eyes, and neck 
 
lymph nodes 
 
thyroid 
 
abdomen (bowel sounds, liver, and spleen palpation) 
 
back (costovertebral angle tenderness), and 
 
musculoskeletal, cardiovascular, and respiratory systems.  
Neurological examinations will be performed as indicated in the SoA (Section 1.3).  
The examinations will include a thorough assessment of 
 
gait 
 
balance 
 
coordination 
 
cranial nerves 
 
sensory and motor systems, and 
 
reflexes.  
If necessary, given the training of the PI, a neurologist may be consulted in the event of 
significant new findings.  
If a clinically meaningful change in an MRI is noted during the study, an additional full 
neurological exam should be performed as soon as possible, along with any other medical 
follow-up deemed necessary by the investigator. 
8.2.2. 
Vital Signs  
Vital signs, including temperature, will be measured at visits indicated in the SoA (Section 1.3). 
Vital signs may be repeated as needed.   
8.2.2.1. 
Blood Pressure  
Sitting blood pressure and pulse will be measured after approximately 5 min in the sitting 
position only, as indicated in the SoA. In addition, orthostatic blood pressure and pulse will be 
measured supine and standing at designated visits, as detailed in the SoA (Section 1.3). 
For orthostatic blood pressure monitoring, participants should be supine for at least 5 min and 
then stand for at least 3 min prior to taking the respective measurements. If the participant feels 
unable to stand, only supine vital signs will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. 
8.2.2.2. 
Height, Weight, and Body Temperature  
Height and body weight will be measured. Measurements should be taken, when possible, with 
the same scale for all measurements. Body mass index will be calculated from the height and 
body weight.  
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Temperature will be recorded using an oral or tympanic (or another acceptable route) 
thermometer. 
Any body weight data entered into the CRF will be used for the overall data analysis. 
8.2.3. 
Electrocardiograms  
For each participant, 12-lead digital ECGs will be collected during the double-blind period, 
according to the SoA (Section 1.3). Participants must be supine for approximately 5 to 10 min 
before ECG collection and remain supine but awake during ECG collection. 
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs (replicates) than expected at a timepoint is allowed when needed to 
ensure high-quality records. 
Electrocardiograms will initially be interpreted by a qualified physician (the investigator or 
qualified designee) at the site as soon after the time of ECG collection as possible, and ideally 
while the participant is still present, to determine whether the participant meets entry criteria at 
the relevant visit(s) and for immediate participant management, should any clinically relevant 
findings be identified. 
After enrollment, if a clinically significant increase in the QT/QTc, PR, or AV block interval 
from baseline or other clinically significant quantitative or qualitative change from baseline is 
identified, the participant will be assessed by the investigator for symptoms (e.g., palpitations, 
near syncope, syncope) and, in consultation with the sponsor to determine whether the 
participant can continue in the study. The investigator or qualified designee is responsible for 
determining if any change in participant management is needed. The investigator or qualified 
designee must document his/her review of the ECG printed at the time of evaluation.  
All digital ECGs will be electronically transmitted to a designated central ECG laboratory. A 
cardiologist at the central ECG laboratory will then conduct a full overread. A report based on 
data from this overread will be issued to the investigative site. These data are not routinely 
reported back to the investigative site. All data from the overreads will be placed in the Lilly 
database for analytical and study report purposes. 
When there are differences in ECG interpretation between the investigator (or qualified 
designee) and the cardiologist at the central ECG laboratory, the investigator’s (or qualified 
designee’s) interpretation will be used for study entry and immediate participant management.  
Interpretations from the cardiologist at the central ECG laboratory will be used for data analysis 
and report writing purposes. 
The investigator (or qualified designee) must document his/her review of the ECG printed at the 
time of collection, the final overread ECG report issued by the central ECG laboratory, and any 
alert reports. 
8.2.4. 
Clinical Safety Laboratory Assessments  
● See Appendix 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 report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the case report form. The laboratory reports 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 last dose of 
IP should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or Lilly-designated Medical 
Monitor. 
○ If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
○ All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA, standard collection requirements and 
laboratory manual. 
 
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then report the information as an AE.  
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  
8.2.5. 
Magnetic Resonance Imaging  
Magnetic resonance imaging of the brain will be performed according to the SoA (Section 1.3) 
and as clinically indicated.  
This technology will be used to check for evidence of clinically relevant exclusion and safety 
findings (vMRI will also be used to calculate brain volumes, as noted in Section 9.4.3). 
The MRI scans will be reviewed by the investigator or qualified designee for immediate 
participant management. Any clinically significant findings noted at baseline that result in a 
diagnosis should be recorded as a preexisting condition or AE. After the MRI scan is read 
locally, the MRI scans will be sent for analysis to a centralized MRI vendor designated by Lilly. 
Final MRI eligibility at screening will be based on the centralized MRI read by the vendor, 
which will be reported to the site.  
Specific analyses of the scans, including calculations of brain volumes, will be interpreted by the 
centralized MRI vendor for data analysis and report writing purposes.  
Results of centrally read MRIs regarding participant care/safety will be reported back to sites. 
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8.2.6. 
Hepatic Safety Monitoring  
Close Hepatic Monitoring 
Laboratory tests (Section 10.4), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 h to 
confirm the abnormality and to determine if it is increasing or decreasing, if 1 or more of these 
conditions occur: 
If a participant with baseline results 
of ...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for participants with Gilbert’s syndrome) 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated Medical Monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (e.g., heart 
failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, and history of alcohol 
drinking and other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive Hepatic Evaluation   
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptoms*, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptoms*, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for participants with Gilbert’s syndrome)  
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Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for Prothrombin time and INR; tests for viral hepatitis 
A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (e.g., ultrasound 
or computed tomography [CT] scan).  
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated Medical Monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
serum phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy.   
8.2.7. 
Suicidal Ideation and Behavior Risk Monitoring  
Participants being treated with LY3372689 should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior, especially at 
the beginning and end of the course of intervention, or at the time of dose changes, either 
increases or decreases. Consideration should be given to discontinuing the study medication in 
participants who experience signs of suicidal ideation or behavior, following a risk assessment.  
Families and caregivers of participants being treated with LY3372689 should be alerted about 
the need to monitor participants for the emergence of unusual changes in behavior, as well as the 
emergence of suicidal ideation and behavior and to report such symptoms immediately to the 
study investigator. 
Baseline assessment of suicidal ideation and behavior/intervention emergent suicidal ideation 
and behavior will be monitored during Study MTAE using C-SSRS.   
C-SSRS 
Columbia Suicide-Severity Rating Scale is a scale that captures the occurrence, severity, and 
frequency of suicidal ideation and behavior during the assessment period via a questionnaire. 
The scale was developed by the National Institute of Mental Health trial group for the purpose of 
being counterpart to the Columbia Classification Algorithm of Suicide Assessment 
categorization of suicidal events. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3: 
 AEs 
 SAEs 
 PCs 
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AEs will be reported by the participant (or, when appropriate, by a caregiver, study partner, 
surrogate, or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE, and remain responsible for following 
up on AEs that are serious, considered related to the IP or study procedures, or that caused the 
participant to discontinue the IP (see Section 7). 
8.3.1. 
Timing Period and Frequency for Collecting AE and SAE Information  
All SAEs and AEs will be collected from the signing of the ICF through the time points specified 
in the SoA (Section 1.3). 
Medical occurrences that begin before the start of IP but after signing of the ICF will be recorded 
on the AE CRF. 
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to sponsor begins after the participant has signed the ICF and has received IP or 
PET tracer. However, if an SAE occurs after signing the ICF, but prior to receiving IP or PET 
tracer, it needs to be reported ONLY if it is considered reasonably possibly related to study 
procedures. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 h, as indicated in Section 10.3. The investigator will submit 
any updated SAE data to the sponsor within 24 h of it being available.   
Investigators are not obligated to actively seek AEs or SAEs after conclusion of study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he or she considers the event to be 
reasonably related to the IP or study participation, the investigator must promptly notify the 
sponsor. 
8.3.1.1. 
Adverse Event Monitoring with a Systematic Questionnaire  
Nonleading AE collection should occur prior to the collection of the C-SSRS.   
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form.   
If an AE is serious or leads to discontinuation, it needs to be included on the AE form and the 
process for reporting SAEs is followed. 
8.3.2. 
Method of Detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs and SAEs, and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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8.3.3. 
Follow-Up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in Section 8.3.6), 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3). Further information on follow-up procedures is 
provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs  
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of an IP 
under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an IP under clinical investigation. The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., 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. 
8.3.5. 
Pregnancy  
Women of childbearing potential are excluded from Study MTAE. Therefore, pregnancy is not 
expected to occur. However, if pregnancy does occur, follow the instructions below. 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of IP and until 90 days after the last dose of IP 
received. 
If a pregnancy is reported, the investigator should inform the sponsor within 24 h of learning of 
the pregnancy. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
8.3.6. Adverse Events of Special Interest  
Specific safety topics of interest for this study include, but are not limited to, the following: 
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The topics listed above, as well as other topics which may be subsequently determined by the 
sponsor, will be subject to enhanced surveillance activities. Additionally, the topics above will be 
analyzed for presentation in the CSR in accordance with the SAP. 
8.3.7. 
Complaint Handling  
Lilly collects product complaints on investigational medicinal products or investigational devices 
used in clinical trials in order to ensure the safety of study participants, to monitor quality, and to 
facilitate process and product improvements. 
Study participants will be instructed to contact the investigator as soon as possible if they have a 
complaint or problem with the investigational medicinal product so that the situation can be 
assessed. 
8.4. 
Treatment of Overdose  
In the event of an overdose, the investigator or treating physician should: 
1. Contact the Lilly-designated Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE, laboratory abnormalities, or ECG 
abnormalities.  
3. Obtain a plasma sample for PK analysis of IP if requested by the Lilly-designated 
Medical Monitor (determined on a case-by-case basis)]. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Lilly-designated medical monitor based on the clinical evaluation of the 
participant.  
8.5. 
Pharmacokinetics  
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine the plasma concentrations of LY3372689. A maximum of 3 blood samples per 
participant may be drawn at additional time points during the study, if warranted and agreed 
upon between both the investigator and sponsor. The actual date and time (24-h clock time) of 
each sample collected will be recorded. When a blood sample is collected at the time and date of 
last dose, and next to last dose administration (except at the initial dosing Visit 2), prior to blood 
sampling should be recorded. Instructions for the collection and handling of blood samples will 
be provided by the sponsor. 
A validated assay will be used to determine plasma LY3372689 concentrations from the blood 
samples collected. The blood samples will be analyzed at a laboratory approved by the sponsor. 
The samples will be retained for a maximum of 1 year following last  study visit for the study. 
During this time, any samples remaining after the bioanalysis is complete may be used for 
exploratory analyses, such as metabolism, protein binding, or bioanalytical method 
development/validation work. It is intended that blood samples collected from participants who 
have received placebo will not be analyzed to measure plasma concentrations of LY3372689. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
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8.6. 
Pharmacodynamics  
Biomarker Measures  
8.6.1. 
Imaging Measures  
Flortaucipir F18 PET Scan  
Change in the brain tau burden (as assessed by flortaucipir F18 PET) will be compared in 
LY3372689 and placebo-treated participants for those participants who undergo baseline and 
follow-up flortaucipir F18 scans as described in the SoA (Section 1.3). Flortaucipir F18 PET 
provides quantitative assessment of aggregated tau deposition in the brain and can serve as a PD 
biomarker of accumulation of tau deposits as AD progresses. 
Volumetric MRI 
Assessment of vMRI of the brain will be performed according to the SoA (Section 1.3). 
LY3372689 and placebo-treatment effects on MRI will be assessed and compared to evaluate the 
loss of brain volume that occurs in AD participants. 
8.6.2. 
Fluid Measures  
Plasma P-tau will be measured according to the SoA (Section 1.3). P-tau levels are associated 
with AD pathology, neurodegeneration, and cognitive worsening (Janelidze et al. 2020, 
Mattsson-Carlgren et al. 2020, Palmqvist 2020, Thijssen et al. 2020). The P-tau immunoassay is 
manufactured by Lilly and performed at a central laboratory. When used as a screening test, it is 
an investigational in vitro diagnostic and will serve to identify participants with increased 
likelihood of having AD tau pathology. It may not be available to all trial sites for screening 
purposes, in which case, screening samples from these sites will only be used for exploratory 
analyses. At study sites utilizing plasma P-tau for screening purposes, participants that meet P-
tau study eligibility criteria will have subsequent confirmation of brain tau pathology by 
flortaucipir F18 PET.  
8.6.2.1. 
Exploratory Biomarkers  
Exploratory biomarker samples will be collected at timepoints described in the SoA (Section 1.3) 
to  assess AD pathology, evidence of neurodegeneration and neuroinflammation, as well as to 
potentially assess additional novel and developing biomarkers of disease state, progression, and 
association with study treatment. For example, within the study at baseline and post baseline 
visits, plasma P-tau levels may serve as a disease relevant PD biomarker. Additionally, plasma 
neurofilament light chain (NFL) levels are believed to reflect neuronal damage and potentially 
serve as a pharmacodynamic marker for ongoing neurodegeneration in AD.  Glial fibrillary 
acidic protein (GFAP) is a marker of astroglial injury associated with neuroinflammatory 
changes in the CNS.  For these reasons, biomarkers may be tested from exploratory samples and 
compared in LY3372689 and placebo-treated participants. These may include but are not limited 
to  P-tau217, NFL, and GFAP. 
Final testing and analysis plan to be at sponsor discretion.  
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8.7. 
Genetics  
A blood sample for DNA isolation will be collected from participants at screening.  
See Appendix 10.7 for information regarding genetic research and Appendix 10.1.12 for details 
about sample retention and custody.  
8.7.1. 
Apolipoprotein E Genotyping  
ApoE genotyping is a mandatory part of this study, unless country-specific laws and regulations 
prohibit this type of testing. Blood sampling for ApoE genotyping will be performed as shown in 
the SoA (Section 1.3). Neither participants nor investigators will receive the genotype results 
unless there is a country-specific law or regulation that requires notification of the results.  
Failure to collect samples for ApoE will not be considered a protocol deviation if country-
specific regulations prohibit the testing of genetic material or transportation of such material 
outside of the country. 
8.7.2. 
Whole Blood Samples for Pharmacogenetic Research  
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3) where local regulations allow. 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples will be used to investigate variable response to LY3372689 and to 
investigate genetic variants thought to play a role in AD or other neurological conditions. 
Assessment of variable response may include evaluation of AEs or differences in efficacy. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last study visit for the study, or for a shorter period if local regulations and/or 
ERBs/IRBs impose shorter time limits. This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of LY3372689 or after LY3372689 becomes commercially 
available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, and candidate gene studies. Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section. 
8.8. 
Biomarkers  
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 
clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid, RNA, 
proteins, lipids, and other cellular elements. 
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8.8.1. 
Blood Sample Collection for Exploratory Biomarkers  
Serum, plasma, and whole blood RNA samples for biomarker research will be collected at the 
times specified in the SoA (Section 1.3) where local regulations allow. Additionally, as indicated 
in Section 8.6.2.1, based on emerging technology, biomarkers may be tested from the exploration 
biomarker samples collected from participants. These may include but are not limited to P-
tau217, NFL, and GFAP. 
Samples will be used for research on the drug target, disease process, variable response to 
LY3372689, pathways associated with AD and other neurodegenerative conditions, mechanism 
of action of LY3372689, and/or research method or in validating diagnostic tools or assay(s) 
related to AD or other neurodegenerative conditions. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last study visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits. This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3372689 or after LY3372689 becomes commercially available. 
8.9. 
Immunogenicity Assessments  
Not applicable.  
8.10. 
Medical Resource Utilization and Health Economics  
Dependence, or the level of assistance required by a participant, has been suggested as a 
construct for assessing the effect of AD treatment. The process of increasing dependence on 
others is intended as a complementary measure to existing clinical measures in order to help 
explain the impact of AD on economic issues such as the risk of institutionalization and 
caregiver burden (McLaughlin et al. 2010; Spackman et al. 2013).  
For this purpose, the ADCS-ADL scale will be used to assess changes in dependence levels in 
Study MTAE. The ADCS-ADL scores will be used to map individuals into 1 of 6 dependence 
levels (0 to 5):   
 
Level 0 – no iADL/bADL impairment 
 
Level 1 – some supervision needed on isolated iADLs 
 
Level 2 – supervision on multiple iADLs or loss of at least 1 household activity 
 
Level 3 – supervision on all types of iADLs or homebound 
 
Level 4 – supervision on some bADLs, and 
 
Level 5 – impaired transfer or complete incontinence (Kahle-Wrobleski et al. 2015).  
An approach to transforming continuous functional scale scores into discrete levels of 
dependence was examined previously in a longitudinal observational study, with preliminary 
results suggesting acceptable validity and progression in dependence level over time (Kahle-
Wrobleski et al. 2017). At baseline, 49.6% of those with mild AD dementia were dependence 
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level 2 and 42.7% were at levels 3 or 4. At 18 months, the proportion of participants at level 2 
declined to 31.2% while that at levels 3 and 4, rose to 58.8%.  
Analyses will be conducted to examine changes in dependence levels across the trial population 
as well as potential differences on dependence level by treatment group assignment. 
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9. 
Statistical Considerations  
The study population includes early symptomatic AD participants with evidence of elevated 
pathological tau. The primary efficacy objective of Study MTAE is to demonstrate that 
LY3372689 slows cognitive and/or functional decline in AD versus placebo as measured by the 
iADRS after 76 to 124 weeks in participants with moderate levels of tau pathology at screening. 
Participants with moderate levels of tau pathology are defined as those who meet tau PET 
inclusion criteria for evidence of tau pathology consistent with AD (Fleisher et al. 2020), but do 
not have widespread and high levels of cortical tau pathology. High levels of cortical tau 
pathology by flortaucipir PET is defined by the top quartile of quantitative standardized uptake 
value ratios in a population of amyloid positive Alzheimer’s patients and cognitively normal 
older controls (Pontecorvo et al. 2019). It is hypothesized that individuals with high tau 
pathology, representing a later pathological stage of disease, where aggregated neurofibrillary 
tau tangles have already spread throughout the brain, may be less likely to benefit from 
LY3372689. For this reason, the primary objective for this study focuses on a sub-population 
with moderate levels of tau pathology as defined by tau PET. The high tau sub-population will 
be included in key secondary analyses. The primary analyses will be conducted by a DPM, and 
MMRM will be performed as a sensitivity analysis.  
9.1. 
Statistical Hypotheses  
The null hypothesis for the primary analysis is that there is no difference in disease progression 
between LY3372689 and placebo as measured by iADRS through the end time point in the 
moderate tau pathology sub-population. The estimand of the primary analysis is the overall 
treatment effect of LY3372689 vs placebo as measured by percent slowing of disease 
progression on iADRS in all randomized participants with early symptomatic AD and moderate 
cortical tau pathology burden that receive up to 124 weeks of study assessments, regardless of 
study treatment discontinuation. 
9.2. 
Sample Size Determination  
Approximately 330 participants will be enrolled and randomized in a 1:1:1 ratio to the 3 
treatment arms (placebo and 2 active arms of LY3372689). It is expected that approximately 240 
participants (i.e., 75%) will complete the double-blind period 2a 76-week treatment period of the 
study (approximately 80 per treatment arm). Using a DPM model over the entire 124-week 
treatment period, this sample size will provide approximately 96.6% power
 
 
 
 
 
 
 
 If the active LY3372689 treatment arm progression 
rate is not different than the placebo treatment arm rate, the probability of passing the efficacy 
criterion specified above (i.e., false positive) is approximately 2.4% 
 
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 The simulation for the power calculation and sample size 
determination was carried out in the statistical program R, version 3.6.3. 
9.3. 
Populations for Analyses  
The following populations are defined: 
Population 
Description 
Entered 
All participants who sign the ICF. 
Enrolled/ITT 
All participants assigned to treatment, regardless of whether they 
take any doses of study treatment, or if they take the correct 
treatment. Participants will be analyzed according to the treatment 
group to which they were assigned. 
Efficacy evaluable 
For each assessment, the efficacy evaluable population will be 
defined as all participants with a baseline measurement and at least 
1 complete post-baseline measurement for that respective 
assessment. Participants will be grouped according to randomized 
treatment assignment (LY3372689 or placebo), even if the 
participant does not take the assigned treatment, does not receive 
the correct treatment, or otherwise does not follow the protocol.   
Biomarker evaluable 
Same population as efficacy evaluable.  
Safety 
All participants randomly assigned to IP and who take at least 1 
dose of IP.  
Pharmacokinetic analysis Same as safety. 
Abbreviations:  ICF = informed consent form; IP = investigational product. 
9.4. 
Statistical Analyses  
9.4.1. 
General Considerations  
Statistical analysis of this study will be the responsibility of the Sponsor or its designee. 
Unless otherwise noted, all pairwise tests of treatment effects will be conducted at a 2-sided 
alpha level of 0.05 (or equivalently, a 1-sided 0.025 alpha level); 2-sided CIs will be displayed 
with a 95% confidence level. All tests of interactions between treatment and other factors will be 
conducted at an alpha level of 0.05. 
Bretz’s graphical approach may be utilized to provide strong control of the study wise Type I 
error rate for the primary and key secondary hypotheses at an alpha level of 0.05 (Bretz et al. 
2009, 2011). Details on the graphical approach and testing strategy will be specified in the SAP. 
All efficacy analyses will follow the ITT principle unless otherwise specified.  An ITT analysis 
is an analysis of data by the groups to which participants are assigned by random allocation, even 
if the participant does not take the assigned treatment, does not receive the correct treatment, or 
otherwise does not follow the protocol. 
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When change from baseline is assessed, participants will be included in the analysis only if both 
a baseline and a postbaseline measure are available. Unless otherwise defined, a baseline 
measure is the last non-missing observation collected prior to the first administration of study 
medications. Endpoint is the last non-missing postbaseline measurement. 
For efficacy and biomarker analyses, observations collected at nonscheduled visits will not be 
included in the analyses unless the nonscheduled visit coincided with a protocol scheduled visit 
or the nonscheduled visit is within the tolerance window as pre-specified in the SAP. If any of 
the individual items for ADAS-Cog13 or ADCS-ADL or CDR-SB are missing or unknown, every 
effort will be made to obtain the score for the missing item or items. If either ADAS-Cog13 or 
ADCS-iADL is missing, iADRS score will be considered missing. For all other scales, if any 
item is missing, any total or sum involving that item will be considered missing.  For all scales, if 
a limited number of individual test items are missing, imputation using prorating will be 
implemented to obtain a total score. Details of this prorating and the circumstances in which it 
will be used are included in the SAP. 
A database lock is expected to occur after all randomized participants have had a chance to 
complete their final study visit in the double-blind period of the study (study period 2a/2b). 
Efficacy and safety analyses will be conducted based on data collected during the double-blind 
period. Data collected during post-treatment safety follow-up period (study period 3) will be 
summarized and analyzed separately.  
Additional database lock(s) may occur during the post-treatment safety follow-up period (study 
period 4). Efficacy and safety analyses will be conducted based on data collected during the 
double-blind and/or post-treatment safety follow-up period.   
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP and the CSR. Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 
The study will include 2 SAPs: a main study SAP (referred to as Study SAP) which will detail 
the analyses for the objectives for double-blinded, placebo-controlled phase, and post-treatment 
safety follow-up period; a supplemental SAP which will detail the additional exploratory 
analyses using data collected from post-treatment safety follow-up period.  
The main Study SAP will be finalized prior to unblinding of all participants in the placebo-
controlled phase, 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. 
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and in the SAPs, where appropriate. 
9.4.2. 
Primary Endpoint(s)  
Study MTAE has a 76-week common close design wherein all enrolled participants continue on 
study drug and complete study assessments until last enrolled participant that has not 
discontinued reaches 76 weeks of double-blind treatment. The maximum duration of treatment is 
124 weeks. 
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The primary objective of this study is to test the hypothesis that LY3372689 slows cognitive and 
functional decline in early symptomatic AD participants with moderate cortical tau burden as 
measured by iADRS compared with placebo through end time point (76-124 weeks). This will 
be assessed using DPM as the primary analysis, and MMRM analysis will be performed as a 
sensitivity analysis.  
The iADRS score at each scheduled postbaseline visit (according to the SoA) during the 
treatment period will be the dependent variable. The DPM is as follows: 
𝑌𝑖𝑗= 𝛾𝑖+ 𝑒𝜃𝑇𝑖∑𝛼𝑣
𝑗
𝑣=0
+ 𝜀𝑖𝑗, 𝑖= 1, 2, … 𝑘; 𝑗= 1, 2, … 𝑙 
where 𝑌𝑖𝑗 denotes the clinical outcome at visit j for participant i, clinical outcome scores at 
baseline (prior to treatment) is 𝑌𝑖0. 𝑇𝑖 denotes the treatment arm for participant i. The parameter 
𝛾𝑖 (i=1, 2, …, k) represents the subject-specific random effect for participant i. 𝑒𝜃𝑇 is the disease 
progression ratio (DPR) for treatment T and 𝑒𝜃𝑇= 1 for placebo; 𝑒𝜃1 and  𝑒𝜃2 represent the DPR 
of the low dose and the high dose, respectively. The parameter 𝛼𝑣 is the mean change of placebo 
response from visit v-1 to v. 𝜀𝑖𝑗 is the error term. Any stratification variables used for 
randomization such as investigator site and prior or current use of any approved disease-
modifying therapy for AD will be included in the model. Baseline score, baseline age,  
concomitant acetylcholinesterase inhibitor (AChEI)/memantine use (yes/no) will be included in 
the model as well. Diffuse priors will be used for the Bayesian inferences in the DPM analysis. A 
DPR less than 1 corresponds to a slowing of disease progression; similarly, a DPR greater than 1 
reflects some evidence of cognitive worsening. The DPM will be fitted to the data and Bayesian 
inferences will be summarized including posterior distribution of DPR and posterior probabilities 
of various DPR thresholds of interest (e.g., 0.75 which translates to 25% slowing of disease 
progression with LY3372689 group versus placebo). The null hypothesis is that the DPR 
between the LY3372689 group versus placebo equals 1.   
The primary endpoint will also be assessed using natural cubic spline model with degrees of 
freedom 2 (NCS2) and MMRM to serve as sensitivity analyses. Additional models/analyses may 
be considered if deemed appropriate. The SAP will describe the planned analyses in greater 
details. 
9.4.3. 
Secondary Endpoint(s)  
The key secondary objective of this study is to test the hypothesis that LY3372689 slows 
cognitive and functional decline in early symptomatic AD participants in the overall population 
as measured by iADRS compared with placebo through end time point (76-124 weeks). It will be 
analyzed using the NCS2, MMRM and the Bayesian DPM as described in Section 9.4.2, with the 
adjustment for tau burden (moderate versus high) as defined by flortaucipir PET.    
Other secondary efficacy outcomes include ADAS-Cog13, ADCS-iADL, CDR-SB, and MMSE. 
Each of these 4 secondary efficacy endpoints will be assessed using the same analysis method(s) 
applied to the primary endpoint iADRS and will be analyzed for both moderate tau sub-
population and the overall population.  The change from baseline score at each scheduled 
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postbaseline visit (according to the SoA) during the treatment period will be analyzed using the 
NCS2. Greater details of model specifications will be provided in the SAP. 
The change from baseline to Week 76 in tau deposition (as measured by flortaucipir F18 PET 
scan) will be analyzed using an ANCOVA model with terms of baseline value and treatment.   
Longitudinal change in vMRI parameters up to Week 76 will be analyzed using MMRM 
including the following terms in the model: treatment, visit, treatment-by-visit interaction, 
baseline vMRI, and intracranial volume. Other baseline covariates may be included. 
For data beyond Week 76, including flortaucipir F18 PET and MRI, MMRM may be used to 
analyze the data with terms of baseline value and treatment.   
An additional analyses of secondary efficacy and biomarkers endpoints may be performed and 
will be pre-specified in the SAP. 
9.4.4. 
Tertiary/Exploratory Endpoint(s)  
Exploratory endpoints and their respective analyses will be described in the SAP. 
9.4.5. 
Treatment Group Comparability  
9.4.5.1. 
Participant Disposition  
All participants who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. 
The reasons for discontinuation will be collected when the participant’s participation in the study 
ends and will be summarized by treatment group for all randomized participants.  The percentage 
of participants discontinuing from each treatment group will be compared between groups using 
Fisher’s exact test. The comparisons will be done for the overall percentage of participants who 
discontinue and for select specific reasons for discontinuation. 
9.4.5.2. 
Participant Characteristics  
The participant’s age, sex, race, height, body weight, body mass index (weight (kg)/[height 
(m)]2), tobacco use, alcohol use, caffeine use, years of education, work status, marital status, 
time since onset of first AD symptoms, time since diagnosis, baseline MMSE, ApoE genotype 
(e.g., E4 carrier versus non-carrier), having 1 or more first degree relatives with AD, and use of 
approved prescription AD medications will be recorded. 
Baseline characteristics will be summarized by treatment group, primary efficacy subpopulation, 
and overall population. Summaries will include descriptive statistics for continuous and 
categorical measures. Fisher’s exact test or Pearson’s chi-square test will be used for treatment-
group comparisons of categorical data. For continuous data, analysis of variance (ANOVA), with 
independent factors for treatment and investigator, will be used. 
9.4.5.3. 
Prior and Concomitant Therapy  
Prior medications are defined as those that stop before randomization (Visit 2). Concomitant 
medications are defined as those being taken on or after randomization (Visit 2). A summary of 
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concomitant medications will be presented as frequencies and percentages for each treatment 
group. Fisher’s exact test will be used to test for treatment differences between groups.  
If the start or stop dates of therapies are missing or partial to the degree that determination cannot 
be made of whether the therapy is prior or concomitant, the therapy will be deemed concomitant. 
Prior and concomitant medications will be listed. 
Summary tables will also be provided for concomitant anticholinergics that affect cognitive 
function and use of approved prescription AD medications. 
Medications will be coded using the World Health Organization drug dictionary. 
9.4.5.4. 
Treatment Compliance  
The proportion of participants who are significantly noncompliant as described in Section 6.4 of 
this protocol will be summarized and compared among all treatment groups using Fisher’s exact 
test. 
9.4.6. 
Safety Analyses(s)  
All safety analyses will be made on the Safety Population. Refer to the SAP for additional 
details. 
9.4.7. 
Other Analyses  
9.4.7.1. 
Pharmacokinetic/Pharmacodynamic Analyses  
LY3372689 plasma concentrations will be illustrated graphically and summarized descriptively.  
If warranted and based on availability of data, the exposure-response relationship of LY3372689 
concentrations to biomarkers, pharmacodynamic endpoints, efficacy endpoints, and/or safety 
endpoints may be explored. Data from other clinical studies evaluating LY3372689 may be 
combined with data from this study to support exposure-response analyses. Such analyses may 
be reported separately. 
9.4.7.2. 
Analysis of C-SSRS Data  
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide 
(CUIMC 2016). 
9.5. 
Interim Analyses  
Interim analyses may be conducted for Study MTAE; for example, when 50% of randomized 
participants have had a chance to complete 52 weeks of treatment (Visit 15), data may be used to 
evaluate whether to stop the study for futility. Operational details and a quantitative framework 
to provide information for these decisions will be documented in the SAP. 
Only the DMC is authorized to evaluate unblinded interim efficacy and safety analyses. Study 
sites will receive information about interim results only if they need to know for the safety of 
trial participants. 
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Unblinding details are specified in the unblinding plan section of the SAP or in a separate 
unblinding plan document. 
The timing of dissemination of data summaries based on interim analyses is addressed in Section 
10.1.6. 
9.6. 
Data Monitoring Committee  
For details on DMC, refer to Appendix 10.1.5 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
● This study will be conducted in accordance with the protocol and with the 
following: 
o consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
o applicable ICH GCP Guidelines,  
o regulation (EU) No. 536/2014, if applicable, and 
o other applicable laws and regulations. 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● The investigator will be responsible for the following: 
o providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
o notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures, 
o providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
o reporting to the sponsor or designee significant issues related to participant safety, 
participant rights, or data integrity. 
● Investigator sites are compensated for participation in the study as detailed in the 
CTA. 
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 
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certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
● The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study. 
● Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act 
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 re-consented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file.  
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection  
● Participants will be assigned a unique identifier by the sponsor to protect the 
participant’s personal data. Any participant information, such as records, datasets, 
or tissue samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 
● The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for his/her data to be used as described in the informed consent. This is 
done by the site personnel through the informed consent process. 
● The participant must be informed through the informed consent by the site 
personnel that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
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● The sponsor has processes in place to ensure information security, data integrity, 
and data protection. These processes address management of data transfer, and 
prevention and management of unauthorized access, disclosure, dissemination, 
alteration or loss of information or personal data. These processes include 
appropriate contingency plan(s) for appropriate and timely response in the event 
of a data security breach. 
 The transfer of personal data is subject to appropriate safeguards through contractual 
agreements and processes. The sponsor’s processes are compliant with local privacy laws 
and relevant legislations including the General Data Protection Regulation (GDPR). 
10.1.5. 
Committees Structure  
A DMC consisting of members external to Lilly will be established.  The purpose of the DMC is 
to conduct periodic monitoring of clinical trial data for Study MTAE. The DMC will consist of a 
minimum of 3 members, including a physician with expertise in AD and a statistician. 
No member of the DMC will have contact with study sites.  An SAC will prepare and provide 
unblinded data to the DMC.  The SAC members will be from a TPO designated by Lilly.  The 
SAC members will be external to the study team and will have no contact with sites and no 
privileges to influence changes to the ongoing studies.  The timing and frequency of the periodic 
clinical trial data review by the DMC will be detailed in a DMC charter. 
The DMC is authorized to separately evaluate unblinded interim efficacy and safety analyses.  In 
addition, the DMC may request key efficacy data to put safety observations into context and to 
assess a reasonable benefit/risk profile for ongoing participants in the study.  The DMC will 
make recommendation to the Lilly Research Laboratories Senior Management Designee, who 
may order the immediate implementation of the DMC recommendation, or may convene an 
internal review committee, which is independent from the study team, to review the 
recommendation according to standard Lilly policy.  Study sites will receive information about 
interim results ONLY if it is required for the safety of their participants. 
10.1.6. 
Dissemination of Clinical Study Data  
Reports  
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, 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 provides access to all individual participant data collected during the trial and after 
anonymization, with the exception of PK or genetic data.  Data are available for request 
6 months after the indication studied has been approved in the US and EU, and after primary 
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publication acceptance, whichever is later.  No expiration date of data requests is currently set 
once data are made available.    
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement.  Data and 
documents, including the study protocol, SAP, CSR, and blank or annotated CRFs, will be 
provided in a secure data sharing environment for up to 2 years per proposal.    
For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
Data Quality Assurance  
● All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 
● The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. This includes 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. 
 The investigator must review and confirm that data entries are accurate and complete 
throughout the duration of the study, by physically or electronically signing the CRF, as 
instructed by the sponsor. All completed CRFs must be signed prior to archival. 
● Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-
based monitoring), methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques, are provided in the 
Monitoring Plan. 
● The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
● The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations). 
● The sponsor or designee will perform monitoring to confirm that data transcribed 
into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
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● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the CTA 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
● In addition, Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by Sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An (EDC system will be used in this study for the collection of CRF data. The investigator 
maintains a separate source for the data entered by the investigator or designee into the 
sponsor-provided EDC system.  The investigator is responsible for the identification of any data 
to be considered source and for the confirmation that data reported are accurate and complete by 
signing the CRF. 
Additionally, COA data (participant-focused outcome instrument) will be collected by the 
participant and/or investigator site personnel, via a paper source document and will be 
transcribed by the investigator site personnel into the EDC system. 
Additionally, eCOA data (participant-focused outcome instrument) will be directly recorded by 
the investigator site personnel into an instrument (e.g., tablet).  The eCOA data will serve as the 
source documentation and the investigator does not maintain a separate, written, or electronic 
record of these data.     
Data collected via the sponsor-provided data capture system 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 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 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 the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
10.1.9. 
Study and Site Start and Closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to 
● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
● Inadequate recruitment of participants by the investigator, and 
● discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and assures 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy  
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.  
10.1.11. 
Investigator Information  
Physicians with a specialty in neurology, geriatrics, or psychiatry will participate as investigators 
in this clinical trial.  In addition, licensed clinicians who have clearly documented experience in 
AD may participate as investigators in this clinical study. 
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 LY3372689 or after LY3372689 become(s) commercially available. 
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Sample Type 
Custodian 
Retention Period after 
Last Study Visit* 
Exploratory biomarkers 
Sponsor or Designee 
15 years 
PK 
Sponsor or Designee 
2 years  
Genetics 
Sponsor or Designee 
15 years 
*Retention periods may differ locally.
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10.2. 
Appendix 2: Clinical Laboratory Tests  
 The tests detailed in the table below will be performed by the central laboratory (unless 
specified otherwise below). 
 Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as determined 
necessary by the investigator or as required by local regulations. 
 Investigators must document their review of each laboratory safety report. 
 Laboratory analyte results denoted below that could unblind the study will not be 
reported to investigative sites or other blinded personnel. 
Clinical Laboratory Tests  
Comments   
Hematology 
Assayed by Lilly-designated laboratory 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Leukocytes (WBCs)  
  
Differential 
  
   Neutrophils, segmented 
  
   Lymphocytes 
  
   Monocytes 
  
   Eosinophils 
  
   Basophils 
  
Platelets 
  
Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
  
Potassium 
  
Total bilirubin 
  
Direct bilirubin 
  
ALP 
  
ALT 
  
AST 
  
GGT 
  
BUN 
  
Creatinine  
  
CK 
  
Uric acid 
  
Albumin 
  
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Clinical Laboratory Tests  
Comments   
Calcium 
  
Glucose  
  
Cholesterol  
  
Hormone Panel 
Assayed by Lilly-designated laboratory 
FSH 
 
LH 
 
Inhibin B 
 
Testosterone 
 
Estrogen 
 
Urinalysis 
Assayed by Lilly-designated laboratory 
Specific gravity 
  
pH 
 
Protein 
 
Glucose 
 
Ketones 
 
Blood 
 
Urine leukocyte esterase 
 
Biomarkers 
Assayed by Lilly-designated laboratory.  Results will not be 
provided to the investigative sites. 
ApoE 
Neither participants nor investigators will receive the genotype 
results unless there is a country-specific law or regulation that 
requires notification of the results. 
NFL 
 
GFAP 
 
P-tau217 
 
Hepatic Testing 
Assayed by Lilly-designated laboratory   
HBsAg 
 
Hepatitis C virus RNA PCR 
 
Genetics sample 
Assayed by Lilly-designated laboratory.  Results will not be 
provided to the investigative sites. 
Stored Samples 
Assayed by Lilly-designated laboratory.  Results will not be 
provided to the investigative sites. 
Exploratory biomarker samples:   
 
  PaxGene Tube for RNA   
 
  Plasma 
 
  Serum 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; ApoE = apolipoprotein E; AST = 
aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatine kinase; FSH = follicle-stimulating 
hormone; GFAP = glial fibrillary acidic protein; GGT = gamma-glutamyl transferase; HBsAg = hepatitis B 
surface antigen; IgE = immunoglobulin E; LH = luteinizing hormone; NFL = neurofilament light chain; NMH = 
N-methylhistamine; RBC = red blood cell; PK = pharmacokinetics; P-tau = phosphorylated tau; RNA = 
ribonucleic acid; WBC = white blood cells. 
 
 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting  
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, or vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (i.e., not related to progression of underlying 
disease). 
 Exacerbation of a chronic or intermittent preexisting condition, including either an increase 
in frequency and/or intensity of the condition. 
 New condition(s) detected or diagnosed after IP administration, even though it may have 
been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. 
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE/SAE.  Such instances will be captured in the efficacy assessments.  
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as an AE/SAE if they fulfill the definition of an AE/SAE. 
 
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Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE  
If an event is not an AE per definition above, then it cannot be an SAE, even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease). 
An SAE is defined as any untoward medical occurrence that at any dose: 
a. Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires in participant hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to the 
hospital for observation and/or treatment that would not have been appropriate in the 
physician’s office or out participant setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious.  When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle), which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
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e. 
Is a congenital anomaly/birth defect 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
f. 
Other situations: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These events should usually be considered 
serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
g. Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
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. 
 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. 
 Device deficiencies are product complaints. 
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 (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
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 The investigator will then record all relevant AE/SAE/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 (e)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. 
 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 (e)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 1 of the following categories:  
 Mild: A type of AE 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 AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.  
Assessment of Causality 
 The investigator is obligated to assess the relationship between IP and each occurrence of 
each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to IP administration will be 
considered and investigated. 
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 The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee.  However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee. 
 The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible.  
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
postmortem findings, including histopathology.  
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 paper SAE data collection 
tool (see next section) in order to report the event within 24 h. 
 The site will enter the SAE data into the electronic system as soon as it becomes available. 
 After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Lilly-designated medical monitor by telephone. 
 SAE reporting is done through the eCRF. 
 
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SAE Reporting via Paper CRF 
 Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Lilly-designated Medical Monitor. 
 In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
 Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found on the paper CRF. 
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 evaluate the reported SAEs, including confirmation of 
relatedness and assessment of expectedness. The sponsor has processes for safety reports 
for identification, recording, and expedited reporting of SUSARs according to local 
regulatory requirements. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/ IEC, and 
investigators. 
● An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., 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. 
EU-specific regulatory reporting requirements 
The sponsor has processes for safety reports for identification, recording, and expedited 
reporting of SUSARs according to EU regulatory requirements. The sponsor will comply with 
applicable regulatory requirements relating to safety reporting to the regulatory authority, per 
European Union Clinical Trial Regulation 536/2014 submission of SUSARs to the 
EudraVigilance database. 
 
 
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10.4. 
Appendix 4:  Liver Safety:  Suggested Actions and Follow-Up 
Assessments  
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with participants in consultation with the Lilly, or its designee, CRP. 
Hepatic Evaluation Testing 
See Section 8.2.6 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs) 
ALP 
Leukocytes (WBCs) 
ALT 
Differential: 
AST 
    Neutrophils, segmented 
GGT 
    Lymphocytes 
CK 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
EtOH 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
HAV testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
PEth 
HBV testing: 
Urine Chemistry 
HBsAg 
Drug screen 
    anti-HBs 
EtG 
    anti-HBc 
Other Serology 
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    Hepatitis B core IgM antibody 
ANA 
    Hepatitis B core IgG antibody 
ASMA a 
    HBV DNA d 
Anti-actin antibody b 
HCV testing: 
EBV testing: 
    HCV antibody 
    EBV antibody 
    HCV RNA d 
    EBV DNA d 
HDV testing: 
 CMV testing: 
    HDV antibody 
    CMV antibody 
HEV testing: 
    CMV DNA d 
    HEV IgG antibody 
HSV testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNA d 
    HSV (Type 1 and 2) DNA d 
Microbiology c 
LKM-1 antibody 
Culture: 
 
    Blood 
 
    Urine 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANA = anti-nuclear antibody; 
anti-HBc = hepatitis B core total antibody; anti-HBs = hepatitis B surface antibody; 
ASMA = anti-smooth muscle antibody; AST = aspartate aminotransferase; CK = creatine kinase;  
CMV = cytomegalovirus; EBV = Epstein-Barr virus; EtG = ethyl glucuronide; EtOH = ethyl alcohol; 
GGT = gamma-glutamyl transferase; HAV = hepatitis A virus; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; 
HSV = herpes simplex virus; LKM-1 = liver kidney microsomal type 1, Peth = phosphatidylethanol; 
RBC = red blood cell; WBC = white blood cell 
Footnotes:
 
a 
Not required if anti-actin antibody is tested. 
b 
Not required if anti-smooth muscle antibody (ASMA) is tested. 
c 
Assayed ONLY by investigator-designated local laboratory; no central testing available. 
d 
Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
 
 
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10.5. 
Appendix 5:  Flortaucipir F18 Tau PET Imaging  
Flortaucipir F18 PET scans will be performed as part of the study eligibility criteria and as 
indicated in the SoA (Section 1.3). 
For inclusion and exclusion criteria related to the flortaucipir F18 PET scans, refer to 
Sections  5.1 and 5.2. 
Site investigators, participants, and study partners will only be informed of the eligibility results 
of PET scans obtained prior to randomization, as they relate to the study, and will not be 
informed of scan results obtained post-randomization. Any significant findings that may be of 
potential medical concern will be provided for appropriate follow-up.   
PET Scan-Specific Information 
PET Scan Procedures 
Specific imaging acquisition protocols designed to ensure consistency across sites will be 
provided in a PET Imaging Manual.  
Scan Safety 
The primary risk related to flortaucipir F18 PET is radiation exposure.  Details on the amount of 
exposure estimated to occur on each imaging occasion and cumulatively are shown in the table 
below and will be provided.  Details on the clinical information to date regarding flortaucipir F18 
exposure will be provided in the ICF.  More detailed information about the known and expected 
benefits and risks of flortaucipir F18 can be found in the IB. 
Participants must minimize movement during each PET procedure, which can last approximately 
30 min for each scan.  Most state-of-the-art imaging systems are designed to reduce head motion 
and participant discomfort. 
The table below shows the effective radiation dose of the Study MTAE’s PET scans. 
 
Effective Dose 
(mSv) per 
Scana,b 
Number of 
Scans in First 
Year 
Effective Dose 
(mSv) for 
Scans in First 
Year 
Number of 
Scans in 
Second Yeara 
Effective Dose 
(mSv) for 
Scans in 
Second Year 
Sum of 
Effective Dose 
(mSv) for 
Years 1 and 2 
Flortaucipir 
F18 Scan (10 
mCi IV) 
9.10 
1 
9.10 
2 
18.20 
27.30 
Abbreviations:   IV = intravenous infusion; PET = positron emission tomography. 
a All participant will receive at least one scan in second year, a second scan in Year 2 will occur for those who will 
reach Week 100 in Period 2b.   
b Dose shown includes radiation exposure from the radiotracer and assumes a nonclinical CT scan is obtained 
(estimated at 0.4 mSv) as part of the PET scan attenuation correction process when the scan is done on a PET/CT 
scanner.  A clinical CT scan is not needed during the PET scan session and, because it will add additional radiation 
exposure, it is not recommended.  
Note:  In the event a repeat scan is required (e.g., the scan is not analyzable), 1 additional flortaucipir F18 scan may 
be received in 1 year.  
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10.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information  
Please see Section 5.1 for details on contraceptive guidance.  
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
● The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study intervention. 
● After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 h of learning of the partner’s pregnancy. 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 fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Female Participants who become pregnant 
Women of childbearing potential are excluded from Study MTAE. Therefore, pregnancy is not 
expected to occur. However, if a female participant becomes 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 h 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 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 8.3.4. 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. 
● Any female participant who becomes pregnant while participating in the study  will be 
withdrawn from the study.  
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10.7. 
Appendix 7: 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/saliva sample 
will be collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to study intervention or indication and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related to 
study intervention and/or interventions of this drug class and indication. 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 planned analyses. 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 study intervention or study interventions of this class to understand study 
disease or related conditions. 
● The results of genetic analyses may be reported in the CSR or in a separate study summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
● The samples will be retained while research on study intervention 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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10.8. 
Appendix 8. 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 conditions in which notification 
is required. To protect the safety of study participants, urgent changes may be implemented 
before approval but need to be reported as soon as possible. All approvals must be retained in the 
study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for Making a Change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study.  
Informed Consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period  
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in Study Conduct during Exceptional Circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
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Visits referenced below are indicative of visits that are not otherwise indicated in the SoA as 
televisits or remote visits. These changes are for additional televisits and remote visits under 
exceptional circumstances. 
The following changes in study conduct will not be considered protocol deviations. 
Remote Visits 
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. 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. Furthermore, 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. 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner may include the 
assessments below.  
Clinician-Administered Assessments (Electronic)  
 ADAS-Cog13 
 ADCS-ADL 
 CDR 
 MMSE 
 DSST, and 
 Digital Clock. 
Clinician-Administered Assessment (Paper)  
 C-SSRS baseline 
 C-SSRS Since Last Visit 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the sponsor. Procedures performed at 
such visits include, but are not limited to,  
 Physical Evaluation 
 Laboratory Tests, and 
 Sample Collections.  
Other alternative locations:  Procedures that may be done at an alternate location, other than 
listed above include 
 Physical Evaluation 
 Laboratory Tests, and  
 Sample Collections.  
Local Laboratory Testing Option 
Local laboratory testing may be conducted in lieu of some central laboratory testing.   
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 Obtain local labs for safety (hematology, chemistry, hormone panel, and urinalysis) 
when applicable, as per the SoA.   
 All labs will be reviewed by the investigators. Lilly Medical should be informed of 
any labs that meet criteria for temporary or permanent study drug discontinuation.   
 Sign and date review of local labs per normal process and follow-up with the 
participant as needed.  Results will not be recorded in the eCRF.   
 Safety labs should be obtained as specified in the SoA. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Study Intervention and Ancillary Supplies  
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions.  These actions may 
include   
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken: 
 Alternate delivery of IP should be performed in a manner that does not compromise 
treatment blinding and ensures product integrity. The existing protocol requirements 
for product accountability remain unchanged, including verification of participant’s 
receipt of study supplies. 
 When delivering supplies to a location other than the study site (e.g., participant’s 
home), the investigator, sponsor, or both should ensure oversight of the shipping 
process to ensure accountability and product quality (i.e., storage conditions 
maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
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 90 days. The following rules will be applied for 
active, nonrandomized participants whose participation in the study must be paused due to 
exceptional circumstances: 
 If paused for less than 90 days from screening, the participant will proceed to the next 
study visit per the usual SoA, provided that randomization visit must be conducted 
within 90 days from first screening  
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. 
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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 paused for more than 90 days from screening: the participant must be discontinued 
because of screening interruption due to an exceptional circumstance.  This is 
documented as a screen failure in the CRF.  This screen fail is allowed in addition to 
the main protocol screen fail. The participant can reconsent and be rescreened as a 
new participant. The screening procedures per the usual SoA should be followed, 
starting at screening visit to ensure participant eligibility by randomization visit. 
Adjustments to Visit Windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
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. 
This table describes the allowed adjustments to visit windows. 
Visit Number Tolerance 
For Study 
Periods 2a 
and 2b  
±14 days from intended visit date for all visits.  
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.  
Documentation 
Changes to study conduct will be documented: 
 Sites will identify and document the details of how participants, visit types, and 
conducted activities were affected by exceptional circumstances. 
Dispensing/shipment records of study intervention and relevant communications, 
including delegation, should be filed with site study records. 
 Source documents 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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10.9. 
Appendix 9: Abbreviations  
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADAS-Cog13 
Alzheimer’s Disease Assessment Scale - Cognitive subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living Inventory 
ADCS-iADL 
Alzheimer’s Disease Cooperative Study - instrumental Activities of Daily Living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ApoE 
apolipoprotein E 
AST 
aspartate aminotransferase 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004  or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, 
which is used as an investigational medicinal product 
bADLs 
basic Activities of Daily Living 
blinding/masking 
a single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the 
participants are aware of the treatment received. 
MMRM 
Mixed model for repeated measures 
CDR-SB 
Clinical Dementia Rating Scale - Sum of Boxes 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
central nervous system 
COA 
clinical outcome assessment 
complaint 
a complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
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Term 
Definition 
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. 
CSR 
clinical study report 
CTA 
clinical trial agreement 
DART 
Developmental and Reproductive Toxicology 
DMC 
Data Monitoring Committee 
DPM 
disease progression model 
ECG 
electrocardiogram 
eCOA 
electronic Clinical Outcome Assessment 
EDC 
electronic data capture 
enroll 
the act of assigning a participant to a treatment.  Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
EO 
enzyme occupancy 
GCP 
good clinical practice 
HBsAg 
Hepatitis B surface antigen 
iADRS 
integrated Alzheimer’s Disease Rating Scale 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICE 
Independent Ethics Committees 
ICH 
International Council for Harmonisation 
INR 
international normalized ratio 
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. 
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Term 
Definition 
Informed consent 
a process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate.  Informed consent is 
documented by means of a written, signed and dated informed consent form. 
interim analysis 
an interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
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.” 
IP 
investigational product 
IRB 
Institutional Review Boards 
ITT 
intention to treat: the principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that participant allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment. 
IWRS 
interactive web-response system 
MAD 
multiple ascending dose 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or more 
of the five “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication's labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MMSE 
Mini Mental State Examination 
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Term 
Definition 
NFL 
neurofilament light chain 
NIMP 
non-investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
OGA 
O-linked N-acetyl glucosaminidase 
O-GlcNAc 
O-linked β-N-acetyl glucosamine 
OLE 
open-label extension 
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 
PET 
Positron emission tomography 
PK/PD 
pharmacokinetics/pharmacodynamics 
PPS 
per-protocol set:  The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model. 
PRO/ePRO 
participant-reported outcomes/electronic participant-reported outcomes 
QD 
once daily 
QTc 
corrected QT interval 
SAC 
statistical analysis center 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
screen 
the act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SoA 
schedule of activities 
SUSARs 
suspected unexpected serious adverse reactions 
Refers to an adverse event that occurs in a clinical trial participant, which is assessed by 
the sponsor and or study investigator as being unexpected, serious and as having a 
reasonable possibility of a causal relationship with the study intervention. 
TBL 
total bilirubin level 
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Term 
Definition 
TPO 
third-party organization 
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 
vMRI 
volumetric magnetic resonance imaging 
 
 
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10.10. Appendix 10: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [d] (18-Apr-2024) 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment 
The main rationale for this amendment is to make corrections as specified in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
6.1 Study 
Intervention(s) 
Administered 
Deleted sentence about supplying 
blister packaging. 
To provide flexibility in the packaging to be 
used. 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Deleted sentence about supplying 
blister packaging. 
To provide flexibility in the packaging to be 
used. 
7.3 Lost to Follow-Up 
Deleted Note about operations for 
lost to follow-up. 
To provide flexibility in operations. 
Amendment [c] (22-Mar-2024) 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the 
● safety or the rights of the study participants, and 
● reliability and robustness of the data generated in the clinical study. 
Overall Rationale for the Amendment: 
The main rationale of this amendment is to update the study design with the addition of an 
optional open-label extension period and an optional substudy for flortaucipir F18 PET imaging 
and MRI scans to assess long term safety and extended biomarker.   
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Revised flortaucipir PET at all 
instances to reflect: 
flortaucipir F18 PET 
For consistency and clarity 
Title Page 
Regulatory Agency Identifier 
Number(s): 
Added EU CT number 
Compliance with EU-CTR 
Added subsections: 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
 Regulatory Agency Identifier 
Numbers (IND, EudraCT, and EU 
CT number) 
 Study Population 
 Ethical Considerations of 
Benefit/Risk 
Deleted language from Rationale 
For conciseness 
Objectives and Endpoints subsection: 
Deleted exploratory objectives and 
endpoint 
Added table and corresponding 
abbreviations depicting the objectives 
and endpoints for the open-label 
extension (OLE) period 
 
For conciseness 
 
To reflect the changes in the modified open-
label study design 
Overall design subsection: 
Updated the overall design as per the 
modified study design and deleted the 
disclosure statement. 
Intervention Groups and Duration 
subsection: 
 Modified total study duration 
from “137 weeks” to “217 
weeks” 
 Added duration and follow-up 
for the OLE period 
1.2. Schema 
New figure and corresponding 
footnote have been added for the 
OLE period 
To reflect the changes in the modified open-
label study design 
1.3. Schedule of 
Activities (SoA) 
1.3.1. Study Period 2a- 
Treatment Period 
1.3.2. Study Period 2b- 
Treatment Period 
Added table headings 
Clarification 
1.3.1. Study Period 2a- 
Treatment Period 
Laboratory tests and sample 
collection row: 
Added hormone panel testing 
(testosterone, LH, FSH, Inhibin B) at 
Visit 21 
 
 Added footnote ‘c’ detailing 
specifics for ET MRI scan  
 Updated footnote ‘h’ with 
specifics for hormone panel 
collection 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3.2. Study Period 2b- 
Treatment Period 
Laboratory tests and sample 
collection row: 
 Added hormone panel testing 
(testosterone, LH, FSH, Inhibin 
B) at Visit 23, 25, 27, 29, ET, 
V801 and added applicable 
comments 
 Added footnote ‘d’ and ‘i’ 
detailing specifics for ET MRI 
scan and hormone panel 
collection 
 
1.3.3. Study Period 4-
Open-Label Extension 
Period (newly added 
section) 
Added study activities and 
procedures to be performed in the 
OLE period. Also, added 
corresponding footnote 
To reflect the changes in the modified open-
label study design 
3. Objectives and 
Endpoints 
Added objectives and endpoints to be 
evaluated in the OLE period 
4.1. Overall Design 
 Modified total study duration 
 Added duration and follow-up 
for the OLE period  
 Added criteria for participants 
who will be offered to enter 
OLE Study MTAE 
4.1.5. Optional 
Extension Period (newly 
added section) 
Added eligibility criteria, dosing, and 
follow-up duration for the OLE 
period 
4.2. Scientific Rationale 
for Study Design 
Added paragraph on rationale for the 
modified study design 
4.3. Justification for 
Dose 
Added rationale for the OLE dose 
selection 
5.3. Open-Label 
Extension Period (newly 
added section) 
Added new criterion 44, 45, and 46 to 
assess eligibility of participants for 
the OLE period 
6. Study Intervention 
Added table describing authorization 
as defined by EU-CTR for 
LY3372689 and placebo, and 
updated the definition for study 
intervention 
Compliance with EU-CTR 
Packaging and Labeling subsection: 
Added a statement for supply of 
study interventions by the sponsor or 
designee in accordance with current 
Good Manufacturing Practice 
Added treatment regimen table for 
OLE period 
To reflect the changes in the modified open-
label study design 
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Section # and Name 
Description of Change 
Brief Rationale 
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Added “study periods 2a and 2b” to 
reiterate the duration of double-blind 
Added for clarity 
Updated the information in the 
section based on addition of OLE 
period 
To reflect the changes in the modified open-
label study design 
6.4. Study Intervention 
Compliance 
Indicated that the telephone visits are 
applicable only for the double-blind 
study periods 
Added for clarity 
6.5.1. Standard of Care 
for Alzheimer’s Disease 
Revised visit number for double-
blind period from “33” to “29” 
Error correction 
Specified that approved prescription 
treatments for AD is permitted but 
not a requirement in this study 
Added for clarity 
 New paragraph added for 
permitted standard-of-care 
treatments during the OLE 
period 
 Added a heading to clearly 
segregate the double-blind study 
period and the OLE period 
(newly added paragraph) 
To reflect the changes in the modified open-
label study design 
6.6. Dose Modification 
Updated the information in the 
section based on OLE 
6.7. Intervention after 
the End of the Study 
7.2.1. Discontinuation of 
Inadvertently Enrolled 
Participants 
Deleted statement which allows 
inadvertently enrolled participants to 
receive study intervention 
For compliance with sponsor’s internal 
procedure 
 
7.3. Lost to Follow-up 
Deleted paragraph on site personnel 
or an independent third party 
attempting to collect vital status of 
participants 
Added a note regarding actions that 
will be taken by the investigative site 
personnel when they are unable to 
contact the participant 
Clarification 
8.5. Pharmacokinetics 
Replaced collection of “serum” with 
“plasma” samples of LY3372689 
Error correction 
8.6.2.1. Exploratory 
Biomarkers 
8.8.1. Blood Sample 
Collection for 
Exploratory Biomarkers 
Added language for additional testing 
of plasma P-tau217, NFL, and GFAP 
from the exploratory biomarker 
samples 
Specifying biomarkers to be tested 
Added “neuroinflammation” 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
8.6.2.1. Exploratory 
Biomarkers 
Deleted “gene expression of the OGA 
gene” 
Change in assay availability and 
prioritization of biomarkers for primary data 
base lock 
9. Statistical 
Considerations 
9.2. Sample Size 
Determination 
Changed “bMMRM” to “MMRM” 
No longer using bMMRM for sensitivity 
analysis to the primary endpoint nor to other 
analyses that were previously planned to use 
bMMRM 
9.4.1. General 
Considerations 
Updated the information in the 
section based on OLE 
To reflect the changes in the modified open-
label study design 
 Added a statement for handling of 
missing, unused, and spurious 
data 
 Deleted duplicate statement 
For EU-CTR compliance 
9.4.2 Primary 
Endpoint(s) 
Updated to be specific regarding 
covariates that will be adjusted in the 
primary analysis and additional 
sensitivity analysis 
For clarify  
9.4.3. Secondary 
Endpoint(s) 
Updated the analytic models that will 
be used for secondary endpoints 
To reflect the latest analysis plan for 
secondary endpoints and for clarity.  
9.4.6. Other Safety 
Analyses(s) 
Deleted “Other” from the heading 
For clarity 
9.5. Interim Analyses 
Added statement cross referencing to 
Section 10.1.6. on timing of 
dissemination of data summaries 
To reinforce awareness of the content in 
Section 10.1.6. 
10.1.1. Regulatory and 
Ethical Considerations 
Added specific statement that the 
clinical trial will be conducted in 
compliance with European 
Regulation (EU) No 536/2014, if 
applicable 
For EU-CTR compliance 
Added a bullet point regarding 
reporting of significant issues related 
to participant’s safety, rights, and 
data integrity 
10.1.4. Data Protection 
Updated the section with required 
language on data protection 
10.1.6. Dissemination of 
Clinical Study Data 
Added a new paragraph under 
“Reports” 
Data subsection: 
 Added “ or genetic data” which 
cannot be provided by the 
sponsor  
 Updated the website to submit 
data request 
As per Lilly template requirements 
10.1.7. Data Quality 
Assurance 
Updated section 
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Section # and Name 
Description of Change 
Brief Rationale 
10.2. Appendix 2: 
Clinical Laboratory 
Tests 
Additional biomarker testing has 
been included which comprises of  
NFL, GFAP, and P- tau217 
Specifying biomarkers to be tested 
10.3.1. Definition of AE 
Updated events meeting the AE 
definition and events not meeting the 
AE definition 
For EU-CTR compliance 
10.3.3. Definition of 
Product Complaints 
Updated definition 
As per Lilly template requirements 
10.3.6. Regulatory 
Reporting Requirements 
 Updated section 
 Added a new paragraph to add 
information for SAE regulatory 
reporting 
For EU-CTR compliance 
10.5. Appendix 5: 
Flortaucipir F18 Tau 
PET Imaging 
 Referenced footnote ‘b’ for 
effective dose (mSv) per scan 
 Deleted footnote ‘b’ from number 
of scans in second year 
Error correction 
10.9. Appendix 9: 
Abbreviations 
Added terms and definitions 
including abuse, authorized IMP, 
IMP, medication error, misuse, SoA, 
and SUSAR 
For EU-CTR compliance 
Revised “bMMRM” to “MMRM” 
No longer using bMMRM for sensitivity 
analysis to the primary endpoint nor to other 
analyses that were previously planned to use 
bMMRM 
Added “OLE” to the list 
To update list of abbreviations 
10.10. Appendix 10: 
Flortaucipir F18 PET 
Imaging and MRI 
Substudy (newly added 
section) 
Added new section for flortaucipir 
F18 PET imaging and MRI scans  
substudy which will be performed in 
approximately 80 participants 
To collect additional PET and MRI scans in 
participants enrolled in the open-label 
extension period of Study MTAE on a 
voluntary basis 
Throughout 
Minor formatting and editorial 
changes 
Minor, therefore, not detailed 
 
 
Amendment [b]: (02-Sep-2021)   
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The main rationale of this amendment is to make an administrative change regarding reference to 
an unblinded pharmacist.   
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Removed reference to drug 
being made available by 
unblinded site personnel and 
being given by blinded nurse. 
Reference to the pharmacy 
manual also removed. 
Minor correction and 
clarification.  
Language corrected regarding 
blinded and unblinded site 
personnel for drug dispensing. 
Updated text to use dynamic 
allocation (minimization) 
method of Pocock and Simon 
(1975) in randomization 
scheme to achieve as much 
balance as possible across the 
arms on the stratified factors at 
the study level.  
Section 11 References 
Added Pocock and Simon, 
1975. 
Additional reference for the 
additions made in Section 
6.3. 
Amendment [a]:   (09-Jun-2021) 
Overall Rationale for the Amendment: 
The main rationale of this amendment is to change the primary endpoint from the CDR-SB to 
iADRS to improve efficacy signal detection and to add some flexible language for use of P-tau 
as a screening tool considering the potential limited or delayed availability in some countries. In 
addition, the mention of specific biomarker assay in exploratory objectives and endpoints has 
been removed. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Changed primary outcome and 
language related to P-tau use in 
screening and as endpoint 
measure. 
Removed mention of specific 
biomarker assay in exploratory 
objectives and endpoints. 
Updated to reflect changes in 
objectives, Schedule of 
Activities, and design related 
to primary endpoint and P-
tau. 
Section 1.3 Schedule of 
Activities 
Clarified study schedule to 
reflect timing for blood-based 
exploratory biomarker 
collections. 
To allow for accommodation 
of emergent technology. 
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Section # and Name 
Description of Change 
Brief Rationale 
Updated table to add language 
related to P-tau use in screening 
and as endpoint measure. 
To reflect changes in 
objectives. 
Updated tolerance interval for 
visit 801. 
Correction. 
Section 3 Objectives and 
Endpoints 
 
Modified objectives and 
endpoints to include iADRS 
assessment as primary objective 
and CDR-SB assessment as 
secondary objective. 
Primary endpoint changed 
from CDR-SB to iADRS to 
reflect recent data reviews 
suggesting improved 
capability of iADRS in 
detecting treatment effects in 
this population. 
Removed mention of specific 
biomarker assay in exploratory 
objectives and endpoints. 
To allow for accommodation 
of emergent technology. 
Section 4.1.1 Lead-In and 
Screening period (V601 and 
V1) 
Updated wording to clarify that 
sites can continue with 
flortaucipir F18 PET scanning 
without meeting the P-tau 
screening criterion if the P-tau 
testing is not available at site.  
Added protocol flexibility to 
allow for not performing P-
tau as a prescreen prior to tau 
PET in cases where it may 
not be available. All 
participants will be required 
to meet P-tau PET criteria 
for enrollment. 
Section 4.2 Scientific 
Rationale for Study Design 
Removed text related to CDR-
SB. 
To remove redundancy and 
change of endpoint 
measures. 
Section 5 Study Population 
Section 5.1 Inclusion 
Criteria 
 
Updated wording to allow 
flexibility for P-tau assay use. 
Provided information on assay 
status. 
Added protocol flexibility to 
allow for not performing P-
tau as a prescreen prior to tau 
PET in cases where it may 
not be available. All 
participants will be required 
to meet Tau PET criteria for 
enrollment. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 Study 
Intervention(s) 
Administered 
Corrected visit number. 
Error correction. 
Section 6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Updated text related to 
stratification of participant 
randomization. 
To allow for potential 
stratification needs for 
emerging approved disease-
modifying therapies. 
Section 6.7 Intervention 
after the End of the Study 
Updated text to indicate that an 
active treatment extension may 
be offered. 
Added flexibility for open-
label extension option to be 
determined at a later date. 
Section 8.1 Efficacy 
Assessments 
Updated text to include iADRS 
assessment as primary endpoint 
analyses and CDR-SB 
assessment as secondary 
endpoint analyses. 
Updated text to indicate that 
rater should be different for 
CDR assessment and ADAS-
Cog13 and MMSE assessments. 
To reflect recent data 
reviews suggesting improved 
capability of iADRS in 
detecting treatment effects in 
this population.  
Added flexibility. 
Section 8.6.2 Fluid 
Measures 
Updated text to remove 
mention of specific assay being 
used as endpoint measures. 
To allow for accommodation 
of emergent technology. 
Section 9.2 Sample Size 
Determination 
Updated power calculation to 
align with the change in 
primary endpoint. 
To reflect change in primary 
endpoint. 
Section 9.4 Statistical 
Analyses 
 
Modified text to include 
iADRS assessment as primary 
endpoint analyses and CDR-SB 
assessment as secondary 
endpoint analyses. 
To reflect recent data 
reviews suggesting improved 
capability of iADRS in 
detecting treatment effects in 
this population. 
Minor edits to the model 
description for the primary 
analysis. Added brief 
description in the statistical 
model for the sensitivity 
analysis. 
Clarification. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Removed plasma NfL, plasma 
P-tau, and OGA gene 
expression sample assays. 
To allow for accommodation 
of emergent technology. 
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Protocol I9X-MC-MTAE(e) 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.8 Appendix 8 
Provisions for Changes in 
Study Conduct During 
Exceptional Circumstances 
Deleted Self-Harm Supplement 
Form and Self-Harm Follow-
Up Form. 
Standard Operating 
Procedures update. 
Throughout the Protocol 
Medical monitor changed to 
Lilly-designated medical 
monitor. 
Minor editorial changes made 
throughout the protocol. 
Correction 
 
 
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