Clinical trial NCT03019536
Conditions: Alzheimer Disease
Sponsor: Eli Lilly and Company
Start date: 2017-01-31; Completion date: 2019-06-05
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study involves repeated doses of LY3303560 given by infusion for 49 weeks. The study will examine how safe repeated doses of LY3303560 are, whether they cause side effects in participants with mild cognitive impairment or Alzheimer's Disease, and how LY3303560 is handled by the body and acts in the body. This study will last up to 65 weeks, not including screening. Screening is required within 90 days prior to the start of the study.

Detailed description:

Arms: arm 1: 70 milligram (mg) LY3303560 administered intravenously (IV) every 4 weeks for 25 weeks with the option of continuing treatment up to 49 weeks (up to 6 further doses), followed by a 16-week follow-up period. arm 2: 210 mg LY3303560 administered IV every 4 weeks for 25 weeks with the option of continuing treatment up to 49 weeks (up to 6 further doses), followed by a 16-week follow-up period. arm 3: Placebo administered intravenously (IV) every 4 weeks for 25 weeks with the option of continuing treatment up to 49 weeks (up to 6 further doses),, followed by a 16-week follow-up period.
Interventions: intervention 1: LY3303560 - IV intervention 2: Placebo - IV intervention 3: Florbetapir F 18 intervention 4: Flortaucipir F18
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV intervention 3: Administered IV during the Positron Emission Tomography (PET) scan performed during screening. intervention 4: Administered IV during the PET scan performed during the study.

Protocol documents:
Prot_000.pdf: 
Protocol (d) LMDD 
 
Multiple-Dose, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of LY3303560 in Patients with Mild Cognitive Impairment due to 
Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease 
 
 
NCT03019536 
 
 
Approval date: 02-May-2018 


I8G-MC-LMDD(d) Clinical Pharmacology Protocol
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LY3303560
Protocol I8G-MC-LMDD(d)
Multiple-Dose, Dose-Escalation Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
LY3303560 in Patients with Mild Cognitive Impairment due to 
Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease
EudraCT Number:  2016-002102-39
Confidential Information
The information contained in this protocol 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 
LY3303560, 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. 
LY3303560
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:
14 October 2016
Amendment (a) Electronically Signed and Approved by Lilly:  08 December 2016
Amendment (b) Electronically Signed and Approved by Lilly:  15 January 2018  
Amendment (c) Electronically Signed and Approved by Lilly:  12 April 2018
Amendment (d) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 02-May-2018 GMT


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Table of Contents
Multiple-Dose, Dose-Escalation Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
LY3303560 in Patients with Mild Cognitive Impairment due to 
Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease
Section
Page
Protocol I8G-MC-LMDD(d) Multiple-Dose, Dose-Escalation Study to 
Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of LY3303560 in Patients with Mild Cognitive 
Impairment due to Alzheimer’s Disease or Mild to Moderate 
Alzheimer’s Disease ...........................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................9
2.
Schedule of Activities .......................................................................................................11
2.1.
Screening (Visit 1) .......................................................................................................12
2.2.
MAD Treatment Period (Visits 2 to 19)........................................................................13
2.3.
Follow-up Assessments (Visits 20 to 24)......................................................................18
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................21
3.2.1.
Clinical Data........................................................................................................21
3.2.1.1.
Study I8G-MC-LMDA ...................................................................................21
3.2.1.2.
Study I8G-MC-LMDD ...................................................................................22
3.3.
Benefit/Risk Assessment..............................................................................................22
4.
Objectives and Endpoints..................................................................................................24
5.
Study Design.....................................................................................................................26
5.1.
Overall Design .............................................................................................................26
5.1.1.
Screening and Randomisation for all Cohorts.......................................................28
5.1.2.
Dosing for all Cohorts..........................................................................................28
5.1.3.
Treatment Phase...................................................................................................28
5.1.4.
Japanese Patients..................................................................................................29
5.2.
Number of Participants.................................................................................................29
5.3.
End of Study Definition ...............................................................................................29
5.4.
Scientific Rationale for Study Design...........................................................................29
5.5.
Justification for Dose ...................................................................................................30
6.
Study Population...............................................................................................................32


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6.1.
Inclusion Criteria..........................................................................................................32
6.2.
Exclusion Criteria ........................................................................................................34
6.3.
Lifestyle and/or Dietary Requirements .........................................................................37
6.3.1.
Meals and Dietary Restrictions.............................................................................37
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................37
6.3.3.
Activity................................................................................................................38
6.4.
Screen Failures.............................................................................................................38
7.
Treatment..........................................................................................................................39
7.1.
Treatment Administered...............................................................................................39
7.1.1.
Packaging and Labeling .......................................................................................40
7.2.
Method of Treatment Assignment ................................................................................40
7.2.1.
Timing of Doses...................................................................................................40
7.3.
Blinding .......................................................................................................................40
7.4.
Dose Modification........................................................................................................41
7.4.1.
Dose Decision/Escalation.....................................................................................41
7.4.2.
Special Treatment Considerations ........................................................................42
7.4.2.1.
Premedication for Infusions............................................................................42
7.4.2.2.
Management of Infusion Reactions.................................................................42
7.5.
Preparation/Handling/Storage/Accountability...............................................................43
7.6.
Treatment Compliance .................................................................................................43
7.7.
Concomitant Therapy...................................................................................................43
7.8.
Treatment after the End of the Study............................................................................43
8.
Discontinuation Criteria ....................................................................................................44
8.1.
Discontinuation from Study Treatment.........................................................................44
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................44
8.2.
Discontinuation from the Study....................................................................................44
8.3.
Patients Lost to Follow-up............................................................................................45
9.
Study Assessments and Procedures ...................................................................................46
9.1.
Efficacy Assessments...................................................................................................46
9.2.
Adverse Events ............................................................................................................46
9.2.1.
Serious Adverse Events........................................................................................47
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................47
9.2.2.
Complaint Handling.............................................................................................48
9.3.
Treatment of Overdose.................................................................................................48
9.4.
Safety...........................................................................................................................48
9.4.1.
Laboratory Tests ..................................................................................................48
9.4.2.
Vital Signs ...........................................................................................................48
9.4.3.
Electrocardiograms ..............................................................................................48


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9.4.4.
Neurological Examinations ..................................................................................49
9.4.5.
Magnetic Resonance Imaging...............................................................................50
9.4.6.
Columbia Suicide Severity Rating Scale...............................................................50
9.4.7.
PET Imaging........................................................................................................51
9.4.7.1.
Radiation Doses Associated with PET Imaging ..............................................51
9.4.8.
Safety Monitoring ................................................................................................52
9.4.9.
Immunogenicity Assessments ..............................................................................53
9.5.
Pharmacokinetics .........................................................................................................53
9.5.1.
Cerebrospinal Fluid Sampling ..............................................................................54
9.5.2.
Bioanalysis...........................................................................................................54
9.6.
Pharmacodynamics ......................................................................................................54
9.6.1.
Exploratory Cognitive and Functional Assessments .............................................55
9.6.1.1.
Alzheimer’s Disease Assessment Scale-Cognitive 
Subscale .........................................................................................................55
9.6.1.2.
Neuropsychological Test Battery....................................................................55
9.6.1.3.
Mini–Mental Scale Examination.....................................................................56
9.6.1.4.
Clinical Dementia Rating................................................................................56
9.6.1.5.
Alzheimer's Disease Cooperative Study/Activities of 
Daily Living Scale Adapted for MCI Patients.................................................56
9.6.1.6.
Free and Cued Selective Reminding Test with Immediate 
Recall.............................................................................................................56
9.6.1.7.
Digital Clock Drawing Test ............................................................................56
9.7.
Genetics .......................................................................................................................57
9.8.
Biomarkers...................................................................................................................58
9.9.
Health Economics ........................................................................................................58
10.
Statistical Considerations and Data Analysis.....................................................................59
10.1. Sample Size Determination ..........................................................................................59
10.2. Populations for Analyses..............................................................................................59
10.2.1.
Study Participant Disposition ...............................................................................59
10.2.2.
Study Participant Characteristics ..........................................................................59
10.3. Statistical Analyses ......................................................................................................59
10.3.1.
Safety Analyses....................................................................................................60
10.3.1.1.
Clinical Evaluation of Safety..........................................................................60
10.3.1.2.
Statistical Evaluation of Safety.......................................................................60
10.3.2.
Pharmacokinetic Analyses....................................................................................61
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................61
10.3.3.
Imaging Analyses.................................................................................................61
10.3.4.
Exploratory Pharmacodynamic Analyses .............................................................61
10.3.4.1.
Pharmacodynamic Parameter Estimation ........................................................61


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10.3.4.2.
Cognition Analyses ........................................................................................62
10.3.4.3.
Evaluation of Immunogenicity........................................................................62
10.3.5.
Exploratory Pharmacokinetic/Pharmacodynamic Analyses...................................62
10.3.6.
Interim Analyses..................................................................................................62
11.
References ........................................................................................................................64


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List of Tables
Table
Page
Table LMDD.1. Objectives and Endpoints ..............................................................................24
Table LMDD.2. Margin of Safety for Intravenous Administration of LY3303560 
after 6 months of Dosing Based on Administered Dose and 
Predicted Human Exposure............................................................................31
Table LMDD.3. Treatments Administered...............................................................................39
Table LMDD.4. Scoring of Neurological Examinations...........................................................50
Table LMDD.5. Radiation Doses Associated with PET Imaging .............................................52


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List of Figures
Figure
Page
Figure LMDD.1. Illustration of study design.............................................................................27


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LY3303560
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions .......................................................................66
Appendix 2.
Clinical Laboratory Tests...............................................................................71
Appendix 3.
Study Governance, Regulatory and Ethical Considerations ............................74
Appendix 4.
Blood and CSF Sampling Summary...............................................................77
Appendix 5.
Management of Infusion Reactions................................................................78
Appendix 6.
Protocol Amendment I8G-MC-LMDD(d) Summary
Multiple-Dose, Dose-Escalation Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
LY3303560 in Patients with Mild Cognitive Impairment due to 
Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease.....................80


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LY3303560
1. Protocol Synopsis
Title of Study:
Multiple-Dose, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of LY3303560 in Patients with Mild Cognitive Impairment due to Alzheimer’s Disease or Mild to Moderate 
Alzheimer’s Disease
Rationale: 
Lilly is developing LY3303560 for the treatment of Alzheimer’s disease (AD).  This study (I8G-MC-LMDD 
[LMDD]) will be the second clinical study of LY3303560 and will evaluate the effects of repeated every 4 week 
(Q4W) administrations in patients with mild cognitive impairment (MCI) due to AD or mild to moderate AD over 6 
months (7 doses), with the option of extending the treatment period up to 12 months (up to 6 further doses).
The study aims to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple 
doses of LY3303560 to define an appropriate dose range for further clinical research.  
Objectives/Endpoints:
Objectives
Endpoints
Primary
To assess the safety and tolerability after 16 weeks of 
multiple doses of LY3303560 in patients with MCI 
due to AD or mild to moderate AD
Safety and tolerability will be assessed by monitoring 
treatment-emergent adverse events (TEAEs)
Secondary

To assess the PK of LY3303560 in serum 
following multiple intravenous (IV) doses of 
LY3303560 in patients with MCI due to AD or 
mild to moderate AD 
Maximum serum concentration (Cmax) and the area 
under the serum concentration time curve during the 
dosing interval (AUC)
Summary of Study Design:
This is a Phase 1b, multi-site, patient- and investigator-blind, placebo controlled, parallel-group study in patients 
with MCI due to AD or mild to moderate AD to assess the safety, tolerability, PK and PD of multiple IV doses of 
LY3303560.
Treatment Arms and Duration:
Patients will receive either LY3303560 or placebo as an IV infusion every 4 weeks (7 doses), after which they will 
be given the option of continuing the treatment up to 49 weeks (up to 6 further doses); the planned doses for Cohorts 
1 and 2 are 70 and 210 mg, respectively.


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LY3303560
Number of Patients:
A maximum of 24 patients will be enrolled.
In each cohort, up to 12 patients may be enrolled so that approximately 8 patients per cohort (6 LY3303560:  2 
placebo) provide safety and PK data to steady state.
Statistical Analysis:
Safety:  All summary statistics will be provided by cohort and visit. Patients who received placebo from both 
cohorts may be pooled into 1 group.
Safety parameters will be assessed including adverse events (AEs), magnetic resonance imaging (MRI), safety 
laboratory parameters, vital signs, and electrocardiogram (ECG) parameters.  The parameters will be listed and 
summarised using standard descriptive statistics.  Additional analysis will be performed if warranted upon review of 
the data.
Shift tables will be constructed for each dose group to assess the incidence of and changes in vasogenic oedema and 
microhaemorrhage counts pre- and post-dose based on MRI.
Suicide-related thoughts and behaviours based on the Columbia Suicide Severity Rating Scale (C-SSRS) will be 
listed by patient.  Only time points and patients that show suicidal ideation/behaviour will be displayed (i.e., not all
of the “no” responses will be displayed).
Potential QTc prolongation will be assessed using plots of PK data versus QTc values and providing frequencies by 
treatment for the following: the number of patients experiencing a maximum increase from baseline in QTcF 
interval according to the following categories - >30 ms and >60 ms; the number of patients with QTcF postdose 
values according to the following categories -  >450 ms, >480 ms and >500 ms.
Pharmacokinetics:  Pharmacokinetic parameters, including maximum drug concentration (Cmax) and area under the 
concentration curve during the dosing interval (AUC), will be calculated using standard non-compartmental 
methods of analysis and/or model-based approaches.
Imaging:  Summary statistics of the flortaucipir F 18 standardised uptake value ratio (SUVr) will be provided by 
treatment (70 and 210 mg, and placebo) and visit (baseline and Visit 13 or Visit 20). Summary statistics of change 
from baseline and percentage change from baseline in SUVr will also be provided. Summary statistics may also be 
provided for SUVrs in individual and other composite brain regions if needed.
Changes in regional brain volume and functional connectivity in brain networks captured by MRI over the course of 
the study will be explored and summarised.  Magnetic resonance imaging will be obtained every 8-12 weeks; 
therefore, a mixed model repeated measures (MMRM) may be conducted fitting baseline, treatment and study visit 
as fixed effects.
Additionally, the relationship between LY3303560 serum exposure and imaging endpoints may be explored 
graphically or by a modeling approach.


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2. Schedule of Activities


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LY3303560
2.1.
Screening (Visit 1)
Study Schedule Protocol I8G-MC-LMDD (Screening Period) 
Comments
Visit 
V1
Screening tests may occur up to 90 days before study drug 
administration.  Tests may be conducted over approximately 
3-5 screening visit days.
Day Relative to First Dose
-90
Study Entry and Administrative Procedures
Informed consent (before procedures/tests)
X
Patient number assigned 
X
Demographics, height, weight, and habits
X
Inclusion/exclusion review
X
Previous/concomitant medications
X
Preexisting conditions/AEs
X
Cognitive Assessments
MMSE
X
Cognitive assessments need not be done on the same visit day, 
but should be completed in the following order if done on the 
same day:  
1) MMSE, 2) FCSRT-IR, 3) CDR, and 4) dCDT
FCSRT-IR
X
CDR
X
dCDT
X
Safety Assessments
Physical/neurological exam
X
Single 12-lead digital ECG
X
Vital signs 
X
Supine blood pressure and pulse rate
C-SSRS (child)/SHSF
X
If the investigator determines that suicide-related behaviours
have occurred, the Lilly SHSF and SHFU forms will be used 
to collect additional information to allow for a more complete 
assessment of these behaviours
Laboratory Assessments (local laboratory)
Coagulation tests 
X
Clinical laboratory tests
X
See Appendix 2, Clinical Laboratory Tests, for details.
Imaging
Lumbar x-ray
X
A lumbar x-ray may be performed to rule out potential 
contraindications to an LP.  If an x-ray was performed within 
12 months of screening, it may be used.
MRI
X
Amyloid scan (if not previously performed)
X
Any previously taken positive amyloid scan must be reviewed 
by central reader to confirm amyloid status.  Amyloid PET 
tracers may include, but are not limited to, florbetapir, 
florbetaben, flutemetamol.
Abbreviations:  AE = adverse event; CDR = Clinical Dementia Rating; C-SSRS = Columbia-Suicide Severity 
Rating Scale; dCDT = digital clock drawing test; ECG = electrocardiogram; FCSRT-IR = Free and Cued 
Selective Reminding Test with Immediate Recall; MMSE = Mini-Mental State Examination; MRI = magnetic 
resonance imaging; PET = positron emission tomography; SHSF = Self-Harm Supplement Form; SHFU = Self-
Harm Follow-Up.


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LY3303560
2.2.
MAD Treatment Period (Visits 2 to 19)


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LY3303560
Study Schedule Protocol I8G-MC-LMDD 
MAD Treatment Period (Visits 2 through 19)
Visit
V2a
Rand
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
Day Relative to First Dose
-8
1b
2
4
8
15
29b
57b
85b
113b
141b
169b
197b
225b
253b
281b
309b
337b
Week
1
1
1
2
3
5
9
13
17
21
25
29
33
37
41
45
49
Tolerance Interval for Visit (days)
7a
0
+4 h
1
1
1
4
4
7
7
7
7
7
7
7
7
7
7
Dosing
Study medication administered
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Administrative Procedures
Body weight
X
0
0
Previous/concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion review
X
Preexisting conditions/AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cognitive Assessments and Functional Scalesc,d
ADAS-Cog14
X
X
ADCS-MCI-ADL24
X
X
MMSE
X
X
NTB
X
X
dCDT
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
Vital signs
X
0, 0.5, 
2
24
72
X
X
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
C-SSRS/SHSF 
X
0
X
X
X
X
0
0
0
0
0
0
0
0
0
0
0
0
Physical examination
0
X
0
0
0
0
0
0
0
0
0
0
0
Neurological examination
0
24
X
X
0
0
0
0
0
0
0
0
0
0
0
0
Triplicate 12-lead digital ECG
X
0, 0.5, 
2
24
72
X
X
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
0, 0.5, 
2
continued


I8G-MC-LMDD(d) Clinical Pharmacology Protocol
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LY3303560
Study Schedule Protocol I8G-MC-LMDD 
MAD Treatment Period (Visits 2 through 19) (concluded)
Visit
V2a
Rand
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
Day Relative to First Dose
-8
1b
2
4
8
15
29b
57b
85b
113b
141b
169b
197b
225b
253b
281b
309b
337b
Week
1
1
1
2
3
5
9
13
17
21
25
29
33
37
41
45
49
Tolerance Interval for Visit (days)
7a
0
+4 h
1
1
1
4
4
7
7
7
7
7
7
7
7
7
7
Dosing
Study medication administered
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Imaging
MRIf
X
X
X
X
X
Flortaucipir F 18 PETd,h
Xg
Xh
Xh
Laboratory Assessments (central laboratory unless otherwise noted)
Lumbar punctured,j
Xi
Xl
Xl
Blood RNA
X
X
X
Pharmacogenetic sample
X
Clinical laboratory tests 
X 
(local 
lab)
0
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation tests (local 
laboratory)j,k
X
X
X
Serum LY3303560 PK (hours)e
0.5, 2, 
4, 8
24
X
X
0, 0.5, 
2, 4, 8
0, 0.5, 
2, 4, 8
0
0
0, 0.5, 
2, 4, 8
0
0, 0.5, 
2, 4, 8
Serum for immunogenicity
X
X
X
0
X
0
0
0
Plasma Tau PD (hours)e
0, 0.5, 
2, 4, 8
24
X
X
0, 0.5, 
2, 4, 8
0, 0.5, 
2, 4, 8
0
0 
0, 0.5,
2, 4, 8
0
0, 0.5, 
2, 4, 8
Stored EDTA plasma and serum
0
24
X
0
0
0
0
0
0
0
0
Stored serum for possible 
exploratory immune safety 
laboratory tests
X
X
X
X


I8G-MC-LMDD(d) Clinical Pharmacology Protocol
Page 16
LY3303560
Abbreviations:  ADAS-Cog14 = 14-item Alzheimer's Disease Assessment Scale – Cognition; ADCS-MCI-ADL24 = 24-question Alzheimer's Disease 
Cooperative Study/Activities of Daily Living scale adapted for MCI patients; AE = adverse event; CDR = Clinical Dementia Rating; CRF = case report form; 
CSF = cerebrospinal fluid; C-SSRS = Columbia-Suicide Severity Rating Scale; D = dose; dCDT = digital clock drawing test; ECG = electrocardiogram; ED = 
early discontinuation; EDTA = ethylene diamine tetraacetic acid; FU = follow-up; IV = intravenous; LP = lumbar puncture; MMSE = Mini-Mental State 
Examination; MRI = magnetic resonance imaging; NTB = Neuropsychological Test Battery; PD = pharmacodynamics; PET = positron emission tomography; 
PK = pharmacokinetics; rand = randomisation; RNA = ribonucleic acid; SC = subcutaneous; SHSF = Self-Harm Supplement Form.
Note:
(i) PK time points indicated as zero (0) denote trough samples immediately prior to study drug infusions/injections.  Other assessments denoted as “0” will be 
collected prior to study drug infusions/injections.  Samples listed as non-zero numbers refer to hours after the start of the IV infusion.
(ii) The timings of safety, PK, and PD sampling are given as targets to be achieved within reasonable limits.  Modifications may be made to the time points based 
upon the safety and PK information obtained.  The scheduled time points may be subject to minor alterations; however, the actual time must be correctly 
recorded in the CRF. Failure to obtain samples due to clinical issues, such as problems with venous access, will not be considered a protocol violation.
(iii) Order of assessments should be as follows:  ECGs, vital signs (after appropriate rest), PK (when applicable).
a
Tests may be conducted over approximately 3-5 visit days.
b
Patients may be admitted on Day -1, to perform pre-dose tests, at the discretion of the site.  For the first 6 infusions, patients must be observed closely for at 
least 4 hours following each infusion of LY3303560. After the first 6 infusions, a minimum post-infusion observation time of 2 hours will be required for all 
subsequent infusions. If any patient shows symptoms of an infusion reaction, the observation time will be increased to a minimum of 8 hours for that infusion 
and all future infusions. If deemed necessary, for safety or feasibility reasons, patients may remain in the investigative site for a longer duration at the 
discretion of the investigator.
c
Assessments need not be done on the same visit day but should be completed in the following order if done on the same day (with approximately 4 hours 
separating NTB and ADAS-Cog14 to avoid testing fatigue):  1) ADAS-Cog14, 2) ADCS-MCI-ADL24, 3) MMSE, 4) NTB, and 5) dCDT.  All cognitive and 
functional assessments must be performed before LP if on the same day; therefore, some of this testing may need to be performed on a separate day.
d
When the flortaucipir F 18 PET scan and LP have been scheduled on the same visit, the PET scan should be performed at least 24 hours after the LP.  
Cognitive assessments must be performed before LP if done on the same day.
e
Pharmacokinetic sample time points are relative to the beginning of the IV infusion. The 0.5 h PK sample should be collected immediately after the 0.5 h IV 
infusion is completed as close as possible to the end of the infusion), followed by ECGs and vital signs 5 to 10 minutes later.  On the day of dosing, postdose 
samples should be collected from the opposite arm to that used to administer study drug for IV infusion.
f
If a patient discontinues before the MRI, the patient will be requested to return for this procedure even though all other study evaluations may be forgone.
The MRI must be performed before a LP if conducted on same day.
g
The V2 flortaucipir F 18 PET scan must be performed, and notification of adequate technical scan quality received from the PET imaging core laboratory,
before dosing.  The scan is performed after the patient qualifies based on the results of the amyloid PET scan and other screening tests.  It may be performed 
up to 28 days prior to dosing once all screening assessments have been completed.


I8G-MC-LMDD(d) Clinical Pharmacology Protocol
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LY3303560
h
The flortaucipir F 18 PET scan should be conducted at Visit 13 should the patient follow the 25-week treatment regimen or at Visit 19 for the 49-week
treatment regimen. The flortaucipir F 18 PET scan should be completed at Visit 20 if the patient discontinues treatment after Visit 13 and before Visit 19.
Patients permanently discontinued from study treatment due to initiation of a prohibited medication known to prolong the QT-interval should not have an ED 
flortaucipir F 18 scan unless the scan can be performed prior to initiation of the prohibited medication.  Patients who have continued on study after 
introduction of a drug known to prolong QT interval (with sponsor approval) need a minimum of 14 days or 5 half-lives, whichever is longer, without that 
drug prior to the flortaucipir scan.  
i
The baseline V2 LP will be performed no closer than 24 hours before first dose.  Dosing may not proceed until patient has been at least 12 hours free of 
symptoms of post-LP headache, if present.  Refer to Section 9.5.1 for details of sampling.
j
Coagulation test results should be reviewed before each LP.  Concomitant medications should be reviewed to ensure that no changes to anticoagulation or 
antiplatelet therapy have occurred since the last coagulation test.
k
LPs are scheduled at either Visits 13, 19, 20, or early discontinuation. The corresponding coagulation test is required up to 2 weeks prior to the next 
scheduled LP.
l
The LP should be conducted at Visit 13 should the patient follow the 25-week treatment regimen or at Visit 19 for the 49-week treatment regimen. The LP 
should be completed at Visit 20 if the patient discontinues treatment after Visit 13 and before Visit 19.


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LY3303560
2.3.
Follow-up Assessments (Visits 20 to 24)
Study Schedule Protocol I8G-MC-LMDD - MAD Treatment Period; Follow-up Assessments (Visits 20 to 24)
Visit
V20
V21
V22
V23
V24
ED
Day Relative to First Dose (for 25-week 
treatment phase)a
189
203
231
259
287
Week (for 25-week treatment)a
27 
29
33
37 
41
Day Relative to First Dose (for 49-week 
treatment phase)a
351
365
393
421
449
Week (for 49-week treatment)a
51
53
57
61
65
Tolerance Interval for Visit (days)
7
7
7
7
7
Administrative Procedures
Body weight
X
X
Previous/concomitant medications
X
X
X
X
X
X
Inclusion/exclusion review
Preexisting conditions/AEs
X
X
X
X
X
X
Cognitive Assessments and Functional Scalesb,c
ADAS-Cog14
X
ADCS-MCI-ADL24
X
MMSE
X
NTB
X
dCDT
X
X
X
Safety Assessments
Vital signs
X
X
X
X
X
C-SSRS/SHSF 
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Neurological examination
X
X
X
X
X
Triplicate 12-lead digital ECG
X
X
X
X
X
Imaging
MRI
X
X
Flortaucipir F 18 PETc,d
X (if not done 
at V13 or 19)
X
Laboratory Assessments (central laboratory unless otherwise noted)
Lumbar puncturec,e,g
X (if not done 
at V13 or 19)
X
Blood RNA
X
Pharmacogenetic sample
Clinical laboratory tests 
X
X
X
X
X
Coagulation tests (local laboratory)e
X (if not done 
at V13 or 19)
X
Serum LY3303560 PK (hours)f
X
X
X
X
X
X
Serum for immunogenicity
X
X
Plasma Tau PD (hours)f
X
X
X
X
X
Stored EDTA plasma and serum
X
Stored serum for possible exploratory 
immune safety laboratory tests
X


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LY3303560
Abbreviations:  ADAS-Cog14 = 14-item Alzheimer’s Disease Assessment Scale – Cognition; ADCS-MCI-ADL24 = 
24-question Alzheimer’s Disease Cooperative Study/Activities of Daily Living scale adapted for MCI patients; 
AE = adverse event; CRF = case report form; C-SSRS = Columbia-Suicide Severity Rating Scale; D = dose; 
dCDT = digital clock drawing test; ECG = electrocardiogram; ED = early discontinuation; EDTA = ethylene 
diamine tetraacetic acid; IV = intravenous; LP = lumbar puncture; MAD = multiple ascending dose; MMSE = 
Mini-Mental State Examination; MRI = magnetic resonance imaging; NTB = Neuropsychological Test Battery;
PD = pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; rand = randomisation; 
RNA = ribonucleic acid; SC = subcutaneous; SHSF = Self-Harm Supplement Form.
Notes:
(i) Patients who have completed at least the 25-week treatment period will be followed up for 16 weeks after 
completion of dosing (Visits 20 to 24) as per the Schedule of Activities.
(ii) Pharmacokinetic time points indicated as zero (0) denote trough samples immediately prior to study drug 
infusions/injections.  Other assessments denoted as “0” will be collected prior to study drug infusions/injections.  
Samples listed as non-zero numbers refer to hours after the start of the IV infusion.
(iii) The timings of safety, PK, and PD sampling are given as targets to be achieved within reasonable limits.  
Modifications may be made to the time points based upon the safety and PK information obtained.  The 
scheduled time points may be subject to minor alterations; however, the actual time must be correctly recorded in 
the CRF. Failure to obtain samples due to clinical issues, such as problems with venous access, will not be
considered a protocol violation.
(iv) Order of assessments should be as follows:  ECGs, vital signs (after appropriate rest), PK (when applicable).
a
All patients will be dosed for 25 weeks (Visits 3 to 13), after which they will be given the option to continue the 
treatment up to 49 weeks (Visits 14 to 19); the follow-up visits (Visits 20 to 24) for all patients will be conducted
accordingly relative to their first dose.
b
Assessments need not be done on the same visit day but should be completed in the following order if done on 
the same day (with approximately 4 hours separating NTB and ADAS-Cog14 to avoid testing fatigue):  1) ADAS-
Cog14, 2) ADCS-MCI-ADL24, 3) MMSE, 4) NTB, and 5) dCDT.  All cognitive and functional assessments must 
be performed before LP if on the same day; therefore, some of this testing may need to be performed on a 
separate day.
c
When the flortaucipir F 18 PET scan and LP have been scheduled on the same visit, the PET scan should be 
performed at least 24 hours after the LP.  Cognitive assessments must be performed before LP if done on the 
same day.
d
The flortaucipir F 18 PET scan should be conducted at Visit 13 should the patients follow the 25-week treatment 
or at Visit 19 for the 49 week treatment period. The flortaucipir F 18 PET scan should be completed at Visit 20 if 
the patient discontinues treatment after Visit 13 and before Visit 19. Patients permanently discontinued from 
study treatment due to initiation of a prohibited medication known to prolong the QT interval should not have an 
ED flortaucipir F 18 scan unless the scan can be performed prior to initiation of the prohibited medication.  
Patients who have continued on study after introduction of a drug known to prolong QT interval (with sponsor 
approval) need a minimum of 14 days or 5 half-lives, whichever is longer, without that drug prior to the 
flortaucipir scan.
e
Coagulation test results should be reviewed before each LP.  Concomitant medications should be reviewed to 
ensure that no changes to anticoagulation or antiplatelet therapy have occurred since the last coagulation test.  
The coagulation test is required up to 2 weeks prior to the LP, if LP is performed at Visit 20.
f
Pharmacokinetic sample time points are relative to the beginning of the IV infusion. The 0.5 h PK sample should 
be collected immediately after the 0.5 h IV infusion is completed as close as possible to the end of the infusion.  
On the day of dosing, postdose samples should be collected from the opposite arm to that used to administer 
study drug for IV infusion.
g
The LP should be conducted at Visit 13 should the patients follow the 25-week treatment or at Visit 19 for the 
49-week week treatment period. The LP should be completed at Visit 20 if the patient discontinues treatment 
after Visit 13 and before Visit 19.


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LY3303560
3. Introduction
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterised by a 
progressive decline in cognitive function and ability to perform activities of daily living, and 
ultimately can lead to death due to complications of the disease.  Pathologic hallmarks of AD 
identified at autopsy include the presence of neuritic amyloid-β (Aβ) plaques, neurofibrillary 
tangles (NFTs) (Hyman et al. 2012), and neuronal loss in brain regions important for cognition, 
such as the hippocampus and temporal cortex (Selkoe 1991).
Tau is an axonal microtubule binding protein that normally promotes microtubule assembly and 
stability.  In AD and other tauopathies, hyperphosphorylated misfolded tau is hypothesised to
induce tau aggregation, NFT formation, microtubule destabilisation, and neuronal toxicity.  In 
AD, aggregated misfolded tau forms intraneuronal NFTs, which tend to spread sequentially from 
transentorhinal, to limbic, then neocortical regions, and correlate with severity of dementia and 
extent of neuronal loss.  The stereotypical, temporal and neuroanatomical progression of 
neurofibrillary pathology in AD suggests that misfolded tau propagates along neuronal networks.  
The capability of misfolded tau “seeds” to spread across synapses and generate new aggregates is 
supported by cell culture and mouse models. 
LY3303560 is a humanised monoclonal antibody that binds to aggregated tau from patients with 
AD and other tauopathies, such as progressive supranuclear palsy. In preclinical in vitro and in 
vivo studies, LY3303560 reduced trans-cellular spread of tau seeds and tau pathology 
propagation. By binding to aggregated tau, LY3303560 is hypothesised to block or delay trans-
cellular spread of aggregated tau, NFT formation and neuronal loss, and may have the potential 
to slow the progression of tau-related diseases.
3.1.
Study Rationale
Lilly is developing LY3303560 for the treatment of AD.  This study (I8G-MC-LMDD [LMDD]) 
will be the second clinical study of LY3303560 and will evaluate the effects of repeated every 4 
week (Q4W) administrations in patients over 6 months (7 doses), with the option of extending 
the treatment period up to 12 months (up to 6 further doses).  
The study aims to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics 
(PD) of multiple doses of LY3303560 in patients with mild cognitive impairment (MCI) due to 
AD or mild to moderate AD.In this amendment (b), the higher dose cohorts of LY3303560 (700 
and 1400 mg) have been removed based on an update to the PK/PD model originally used to 
predict the LY3303560 efficacious dose range. The ongoing single-dose I8G-MC-LMDA
(LMDA) study is exploring single doses of LY3303560 up to 5600 mg. Future multiple-dose 
studies with LY3303560 will evaluate higher dose levels using a Q4W dosing regimen. In 
addition, the duration of dosing in the LMDD study has been reduced from 12 to 6 months, 
based on emerging longitudinal and baseline data using tau positron emission tomography (PET)
imaging, which suggests that the study is now insufficiently powered to assess the effects of 
LY3303560 on progression of tau pathology using flortaucipir F 18 PET over 12 months (see 
Appendix 6). 


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LY3303560
3.2.
Background
LY3303560 binds preferentially to aggregated misfolded tau, with minimal binding to 
monomeric tau by an enzyme-linked immunosorbent assay (ELISA) and Biacore measurements 
(>100-fold selectivity for aggregated tau over monomeric tau).
In vitro, LY3303560 inhibits cell-based tau propagation, binds to brain sections derived from 
patients with AD and other tauopathies, and does not interfere with the binding of flortaucipir to 
neurofibrillary tangles.  In vivo, LY3303560 inhibits tau propagation when co-injected with tau 
seeds in mice.  The high affinity surrogate murine antibody (MC-1-3C9) reduced tau pathology 
following systemic dosing in 2 tau transgenic mouse models (JNPL3 and Tg4510).
3.2.1. Clinical Data
3.2.1.1.
Study I8G-MC-LMDA
Study LMDA is an ongoing study assessing the safety, tolerability, PK, and PD of LY3303560 
following single intravenous (IV) doses ranging from 7 to 5600 mg, and a single subcutaneous 
(SC) dose of 210 mg.
As of 06 November 2017, 54 subjects have completed the study and preliminary safety data 
indicate that IV doses up to 1400 mg and the SC 210-mg dose of LY3303560 have been well
tolerated. A total of 28 treatment-emergent adverse events (TEAEs), regardless of causality, 
were observed in 12 subjects (28.6%) in the treated cohorts and a total of 5 TEAEs in 4 subjects 
(33%) in the pooled placebo group.  All TEAEs were mild in severity and none were serious and 
no subject has withdrawn from the study because of an adverse event (AE). Across the treated 
cohorts, regardless of causality, upper respiratory tract infection was reported by 3 subjects 
(7.1%).  Back pain, contusion, headache, and influenza-like illness were all reported by 2 
subjects.  All other TEAEs were reported by 1 subject each.  Five subjects reported 1 TEAE each 
that was considered related to study treatment:  hot flush, swelling, headache, bradyphrenia, and 
palpitations.
The decision to dose escalate to IV 5600 mg was made after the safety review of all 8 subjects in 
the IV 2800 mg was completed and determined that there were no safety concerns. As of 30 
November 2017, 2 subjects have been dosed in the 5600-mg IV cohort.  There have been no 
clinically significant changes in magnetic resonance imaging (MRI) scans and no infusion 
reactions have been observed to date.  There have been no clinically significant findings with 
vital signs, electrocardiograms (ECGs), safety laboratory assessments or neurological 
examinations. 
Preliminary interim PK data from Study LMDA following single doses of 7 to 2800 mg were 
evaluated in Caucasian and Japanese subjects.  Overall, the PK parameters from Caucasian and 
Japanese subjects were similar.  The initial estimate for clearance was approximately 0.2 L/day, 
volume of distribution at steady state was 3 to 5 L and mean half-life was 2 to 3 weeks.  The PK 
of LY3303560 appears to be linear across the dose range studied. These draft data are consistent 
with the PK properties of immunoglobulin G (IgG) antibodies, and thus, the expected PK 
properties of LY3303560.  


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LY3303560
3.2.1.2.
Study I8G-MC-LMDD
In this current study, as of 06 November 2017, data up to at least Day 57 from 9 patients, of 
whom 6 patients have received IV 70 mg LY3303560 Q4W, have been reviewed. The following 
blinded summary includes all TEAEs reported from the first dose to when the sixth patient 
received their third dose of LY3303560. A total of 16 TEAEs were observed in 5 out of 9 
patients, all of which were mild to moderate in severity and none of which were serious.  The 
most common TEAEs reported were bradycardia (n=4) and contact dermatitis (n=2); all reported 
by the same patient.  The patient experienced 4 episodes of bradycardia, which were observed on 
infusion Days 29, 57, and 85.  All episodes of bradycardia were asymptomatic and there were no 
clinically significant changes in ECGs.  There were no other clinically significant changes in 
other safety measures for this patient, including MRI, vital signs, safety laboratory assessments, 
and neurological monitoring. The patient also had a history of bradycardia.  There have been no 
infusion reactions observed to date.
Based on a review of the 70-mg LY33030560 safety data, it was deemed appropriate to dose 
escalate to the 210-mg LY3303560 cohort, which is ongoing.
Preliminary PK data from the first cohort (70 mg Q4W) of Study LMDD have been assessed. 
The PK observed following the first dose of 70 mg was consistent with the preliminary results of 
Study LMDA. In this preliminary assessment, minimal accumulation (as assessed using
maximum drug concentration [Cmax]) was observed between the first and second doses, with no 
additional accumulation apparent between the second and third doses. The accumulation ratio, 
as assessed between the first and third doses is 1.22, consistent with the value predicted using 
single dose data (1.26). 
3.3.
Benefit/Risk Assessment
The safety of LY3303560 was assessed in 5-week and 6-month toxicology studies in 
cynomologus monkeys, which included evaluation of safety pharmacology parameters and 
toxicokinetics.  The administration of LY3303560 in monkeys up to a maximum dose of 
200 mg/kg/week (bolus IV injection) for 5 weeks or 6-months resulted in no drug-related adverse 
findings.  The safety of LY3303560 was also assessed in 5-week and 6-month toxicology studies 
in a transgenic mouse model (Tg4510) expressing human 4-repeat tau with P301L mutation that 
is linked to hereditary tauopathy.  The administration of LY3303560 in transgenic Tg4510 mice 
up to a maximum SC dose of 200 mg/kg resulted in no drug-related adverse findings.
Procedure-related microscopic findings were observed for the IV and SC injection sites of 
monkeys, and SC injection sites of mice, and were consistent with the skin and vessels’ response 
to venipuncture and administration of foreign material.
Administration of SC or IV LY3303560 may lead to injection-site or infusion reactions, 
respectively. Injection-site reactions may include pain, swelling, redness, or irritation at the site 
of injection.  Infusion reactions may include fever, chills, nausea, headache, bronchospasm, 
hypotension, angioedema, throat irritation, rash, pruritus, myalgia, and dizziness.  Patients should 
be monitored for injection-site and infusion reactions and provided with appropriate intervention 
or supportive care if reactions do not promptly resolve.


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LY3303560
The potential for immunogenicity exists as administration of LY3303560 may cause the 
development of antibodies to LY3303560.  Formation of antibodies against LY3303560 could be 
associated with infusion reactions, lower exposure to LY3303560, or the blocking or prolonging 
of any PD effect seen with LY3303560.
This multiple-dose study (LMDD) will evaluate the safety, tolerability, and PK of repeated doses 
of LY3303560 over  6 months (with the option to extend the treatment up to 12 months).  The 
study will also investigate the potential PD effect of LY3303560, primarily on the basis of 
progression of tau pathology using the tau tracer, flortaucipir F 18.  Flortaucipir F 18 is an 
investigational tracer and was positive in the in vitro human ether-a-go-go-related gene (hERG)
assay.  However, the cardiovascular assessments performed during the dog toxicology studies 
showed no evidence that flortaucipir F 18 prolongs the QT interval at high multiples of relevant 
clinical doses.  Nonetheless, until sufficient human cardiovascular data are available, subjects 
with a history of risk factors for Torsades de Pointes and subjects taking drugs known to prolong 
the QT interval are excluded from studies with this tracer.  Long-term animal studies to assess 
the risk of cancer from Flortaucipir F 18 have not been conducted. The non-radioactive version 
of Flortaucipir F 18 has been tested in bacteria and short-term animal studies to assess the risk of 
cancer. In laboratory tests with bacteria cells, Flortaucipir F 18 showed positive results for 
genotoxicity (damage to genes). Damage to genes can lead to the development of cancer. 
However, further studies conducted in living animals with Flortaucipir F 18 at doses over 750 
times the maximum human dose did not produce any evidence for damage to genes.
The estimated exposure to ionising radiation from flortaucipir and amyloid PET scans is 
25.63 mSv based on a total of 3 PET scans.
As this is a Phase 1 study, it is anticipated that patients will not receive any clinical benefit.  
Cognitive and functional outcomes are incorporated into the study as exploratory measures and 
patients will be assessed regularly during their participation in the study.  While changes in 
biomarkers of tau pathology may be observed after treatment with LY3303560, the exact clinical 
significance of any change in tau is unknown at present. 
The dose range chosen for Study LMDD is based upon preclinical data and preliminary safety, 
tolerability and PK data from the ongoing single-dose study (LMDA).  The highest planned dose 
is 210 mg, which is lower than the administered doses in Study LMDA that have been shown to 
be well tolerated. Preliminary data from Study LMDA indicate that LY3303560 is well tolerated 
up to 2800 mg when administered as a single IV dose, with no dose-limiting safety or tolerability 
findings to date.  In Study LMDD, multiple IV doses of 70 mg have been administered to 9
patients with AD (7 LY, 2 placebo), and to date, no SAEs or infusion-related reactions have been 
reported.
In this current study, safety data for a particular dose cohort will be reviewed prior to dose 
escalation to the subsequent cohort (see Section 5.1.3).  Safety data will be reviewed periodically 
during the treatment and follow-up periods. 
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of LY3303560 are to be found in the Investigator’s Brochure (IB).


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LY3303560
4. Objectives and Endpoints
Table LMDD.1 shows the objectives and endpoints of the study.
Table LMDD.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective of this study is to assess the safety 
and tolerability after 16 weeks of multiple doses of 
LY3303560 in patients with MCI due to AD or mild to 
moderate AD
Safety and tolerability will be assessed by monitoring 
treatment-emergent adverse events (TEAEs)
Secondary

To assess the PK of LY3303560 in serum following 
multiple IV doses of LY3303560 in patients with 
MCI due to AD or mild to moderate AD 
Maximum serum concentration (Cmax) and the area 
under the serum concentration time curve during the 
dosing interval (AUC)
Exploratory Objectives

To evaluate the effects of multiple doses of 
LY3303560 on cognitive function in patients with 
MCI due to AD or mild to moderate AD

To evaluate the effects of multiple doses of
LY3303560 on brain atrophy in patients with MCI 
due to AD or mild to moderate AD

To evaluate the effects of multiple doses of
LY3303560 on brain functional connectivity in 
patients with MCI due to AD or mild to moderate 
AD

To evaluate the immunogenicity of multiple doses 
of LY3303560 in patients with MCI due to AD or 
mild to moderate AD

To evaluate the effects of multiple doses of
LY3303560 on plasma and CSF biomarkers in 
patients with MCI due to AD or mild to moderate 
AD

To evaluate the effects of multiple doses of 
LY3303560 on tau pathology using the tau tracer 
flortaucipir F 18 in patients with MCI due to AD or 
mild to moderate AD

To determine the CSF concentration of LY3303560 
following multiple IV doses in patients with MCI 
due to AD or mild to moderate AD
ADAS-Cog14, ADCS-MCI-ADL24, NTB, MMSE, 
dCDT
Quantitative measures of brain atrophy derived from 
volumetric MRI scans
Quantitative measures of brain functional connectivity 
derived from functional MRI scans
Detection of anti-drug antibodies (ADA) 
Plasma tau concentration; CSF concentration of tau, p-
tau, Aβ1-42, and neurogranin
Quantitative endpoints from flortaucipir F 18 PET scans
Mean LY3303560 concentrations in CSF


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LY3303560
Exploratory Objectives (continued)

To explore the safety and tolerability of LY3303560
in Japanese subjects in relation to non-Japanese 
subjects

To explore the PK of LY3303560 in Japanese 
subjects in relation to non-Japanese subjects
Safety and tolerability will be assessed by monitoring 
TEAEs
Cmax and AUC


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LY3303560
5. Study Design
5.1.
Overall Design
This is a Phase 1b, multi-site, patient- and investigator-blind, placebo-controlled, parallel-group
study in patients with MCI due to AD or mild to moderate AD to assess the safety, tolerability, 
PK and PD following multiple IV doses of LY3303560.
The planned IV doses of LY3303560 are 70 and 210 mg; however, dose levels may be adjusted 
based on emerging data from Study LMDA and from this current study, if indicated (Section 
7.4).
Patients will be dosed Q4W for 25 weeks (7 doses) with LY3303560 or placebo, after which 
they will be given the option of continuing the treatment up to 49 weeks (up to 6 further doses), 
followed by a 16-week follow-up period after completion of dosing.  Detail on the number of 
participants is given in Section 5.2 and Figure LMDD.1.


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LY3303560
Abbreviations:  IAD = interim access to data; IV = intravenous; LY = LY3303560; MRI = magnetic resonance imaging; Q4W = 
every 4 weeks; PET = positive emission tomography; PL = placebo. 
Figure LMDD.1.
Illustration of study design.
Visit 16ǂ
Visit 13@
Visit 20**
Visit 23ǂ
Visit 2#
Visit 8ǂ
Visit 10ǂ
Cohort 1 
70 mg IV Q4W
6LY:2PL
Cohort 2 
210 mg IV Q4W 
6LY:2PL
Biomarkers
Visit 1
Screening
16-week 
safety/PK IAD
49-week treatment phase (13 doses)
16-week follow-up
16-week follow-up
Visit 1 (Screening):
Amyloid scan (diagnosis)
Cognition
MRI
ǂVisits 8, 10, 16, 23:  MRI
@Visit 13:
Cognition
MRI
Flortaucipir PET
**Visit 20:
Flortaucipir PET (if not done at Visit 13 or 19)
Cognition
Visit 1
Screening
#Visit 2:
Flortaucipir PET
Cognition
Visit 19*
Visit 16ǂ
Visit 13@
Visit 20**
Visit 8ǂ
Visit 10ǂ
49-week treatment phase (13 doses)
Visit 19*
Visit 23ǂ
Visit 2#
Note:  Subsequent cohorts will be initiated following a review of the safety data from a minimum of 4 patients having received at least 2 
doses of LY3303560 and 1 patient having received at least 2 doses of placebo at the prior dose level
16-week 
safety/PK IAD
*Visit 19:
MRI
Flortaucipir PET


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5.1.1. Screening and Randomisation for all Cohorts
At Visit 1, patients will undergo the screening tests outlined in the Schedule of Activities 
(Section 2).  The screening tests may be conducted over approximately 3-5 screening visit days.  
For the screening amyloid scan, a prior positive amyloid PET scan using a validated tracer can 
also satisfy the inclusion criterion for amyloid-positivity as long as the scan is available for 
review by the central reader. Similar to the screening Visit 1, the Visit 2 randomisation tests 
may be conducted over 3-5 visit days. Patients will undergo a flortaucipir F 18 PET scan as part 
of Visit 2.  
5.1.2. Dosing for all Cohorts
Patients will receive their study drug at the investigational site after all predose procedures have 
been completed and must be observed closely for at least 4 hours following each infusion of 
LY3303560 for the first 6 infusions.  After the first 6 infusions, a minimum post-infusion 
observation time of 2 hours will be required for all subsequent infusions. If any patient shows 
symptoms of an infusion reaction, the observation time will be increased to a minimum of 8 
hours for that infusion and all subsequent infusions.
If deemed necessary, for safety or feasibility reasons, patients may remain in the investigative 
site for a longer duration at the discretion of the investigator.
5.1.3. Treatment Phase
Each cohort will consist of 8 patients randomised (6 LY3303560:  2 placebo) to a 25-week MAD 
treatment period (7 doses), after which they will be given the option of continuing the treatment 
up to 49 weeks (up to 6 further doses, Visits 14 to 19). Patients who have completed at least the 
25-week treatment period will be followed up for 16 weeks after completion of dosing (Visits 20 
to 24) as per the Schedule of Activities in Section 2.
Safety and PK will be assessed throughout the study for each cohort.
Safety will be monitored by AEs, ECGs, vital signs (blood pressure and pulse rate), MRIs, 
neurological examinations, Columbia Suicide Severity Rating Scale (C-SSRS), and safety 
laboratory tests.  In addition, blood samples for the assessment of immunogenicity will be taken 
at regular intervals throughout the dosing and follow-up periods.  Each patient will have 1 
screening (baseline) MRI prior to dosing with LY3303560, another after approximately 4 weeks, 
and then at approximately 12-week intervals thereafter as specified in the Schedule of Activities 
(Section 2), for the assessment of any potential imaging abnormalities.  Tau imaging using 
flortaucipir F 18, cognitive and functional assessments (Neuropsychological Test Battery [NTB], 
the 14-item Alzheimer's Disease Assessment Scale – Cognition [ADAS-Cog14], Mini-Mental 
State Examination [MMSE], digital clock drawing test [dCDT], and 24-question Alzheimer's 
Disease Cooperative Study/Activities of Daily Living scale adapted for MCI patients [ADCS-
MCI-ADL24]), and cerebrospinal fluid (CSF) (via single lumbar puncture) will be 
assessed/obtained as detailed in the Schedule of Activities in Section 2. If scheduled on the same 
day, the cognitive/functional testing should be conducted before the lumbar puncture (LP), and 
the LP should occur no closer than 24 hours before dosing.  The patient must be free from any 


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post-LP headache for at least 12 hours before dosing.  If the LP is performed on a separate day 
before the cognitive testing, the cognitive/functional testing should be performed at least 24 
hours after the LP, and the patient must be free from any post-LP headache for at least 12 hours 
before dosing (see Section 9.5.1 for detail on CSF sampling).
As detailed in Section 7.4.1, dose escalation decisions will be made following a review of the 
safety data from a minimum of 4 patients having received at least 2 doses of LY3303560 and 1 
patient having received at least 2 doses of placebo at the prior dose level. The subsequent cohort 
will not begin dosing until all 8 patients from the previous cohort have started dosing.
5.1.4. Japanese Patients
This study was designed to support further development of LY3303560 in Japanese patients.  It 
was intended that approximately 3 Japanese patients would be enrolled in each cohort; however, 
recruitment to a cohort will not be contingent upon fulfilling these requirements.  Japanese 
patient enrolment into these cohorts should ensure sufficient exposures at applicable doses to 
support future dosing (at least 1 Japanese patient exposed to LY3303560 in each cohort).  
Evaluation of safety data from patients before dose escalation in Japan must include at least 
1 Japanese patient on LY3303560.  To avoid unblinding, there must be at least 2 Japanese 
patients in a cohort.  Therefore, if fewer than 2 Japanese patients are enrolled in the cohort of 
patients evaluated for dose escalation, then dose escalation outside Japan will proceed, and 
additional Japanese patients will be recruited to allow dose escalation in Japan.  Once the 
Japanese patients have the required safety evaluations, then patients in Japan may join in the 
ongoing dose-escalation cohort (see Section 5.1.3).  For the purpose of safety evaluation in 
Japanese patients during the study, Japanese patients at sites in Japan and up to third-generation 
Japanese patients at sites outside of Japan will be included.  The definition of up-to-third-
generation Japanese is provided in Section 6.  If necessary to make the judgment of dose 
escalation in the Japanese population, additional Japanese patients may be recruited and dosed to 
support the decision.
5.2.
Number of Participants
In each cohort, up to 12 patients may be enrolled so that approximately 8 patients per cohort (6 
LY3303560:  2 placebo) provide safety and PK data to steadystate.  
A maximum of 24 patients will be enrolled.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
This study will investigate the safety, tolerability, PK and PD of multiple IV doses of
LY3303560 in patients with MCI due to AD and mild to moderate AD.  Only patients with 
evidence of amyloid deposition will be recruited into the study as it has been shown that 


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advanced stages of tau pathology are associated with the presence of amyloid (Scholl et al. 2016; 
Schwarz et al. 2016), and both amyloid and tau are defining pathologies of AD (Montine et al. 
2012).  The presence of amyloid deposition will be confirmed by amyloid PET imaging using
National Institute on Aging and Alzheimer’s Association work group consensus guidelines 
(Albert et al. 2011; McKhann et al. 2011).  
Placebo is included as the control, in a blinded manner for investigator/site staff and patients, to 
allow an unbiased assessment of the safety and PD data generated. 
Magnetic resonance imaging is commonly used to detect amyloid-related imaging abnormalities 
(ARIAs), which have been associated with anti-amyloid therapy.  Both ARIA-E (vasogenic 
oedema) and ARIA-H (microhaemorrhage) have been reported after administration of several 
amyloid antibodies.  While there is no evidence of imaging abnormalities with therapies
targeting tau from the preclinical data for LY3303560 or from other tau therapeutics in the 
literature, MRI scans will be taken at predose, and thereafter at times specified in the Schedule of 
Activities (Section 2) after dosing with LY3303560 or placebo, in order to assess the potential 
for imaging changes, including, but not restricted to, vasogenic oedema and microhaemorrhage. 
The inclusion of Japanese patients in this trial will facilitate the inclusion of Japanese patients in 
subsequent clinical trials.
The primary objective of investigating safety and tolerability of LY3303560 at steady state after 
administration of multiple IV doses will be evaluated, with evaluation of safety data from 8 
patients (6 LY3303560:  2 placebo) in each cohort. It is anticipated that steady-state 
concentrations of LY3303560 will be achieved after approximately 4 months of dosing (4 doses), 
and so the minimum safety and PK data required to support future studies are up to Day 113.
5.5.
Justification for Dose
Doses of 70 and 210 mg are planned for this study.  The doses were selected based upon the 
preliminary safety and PK data at doses ranging from 7 to 2800 mg from Study LMDA, as well 
as nonclinical PK, efficacy and toxicology data from studies conducted in Tg4510 tau transgenic 
mice and cynomolgus monkeys. 
In Study LMDA, single doses administered up to 70 mg LY3303560 have been well-tolerated 
(see Section 3.2.1), thus, the safety data up to 70 mg supports the starting dose of 70 mg in this
study. Furthermore, safety data from higher single doses of LY3303560 in Study LMDA will be 
available prior to initiating the corresponding dose level in this study.
In humans, the predicted steady state concentration (Css) at the highest planned dose of 210 mg 
in Study LMDD is predicted to be 41.8 g/mL (see Table LMDD.2). The calculated Css in 
monkey is 6,726 µg/mL at the NOAEL (200 mg/kg IV dosing) determined in the 6-month repeat 
dosing toxicity study (Study 8326196), which is approximately 160 times higher than the 
predicted human Css at 210 mg.  The calculated Css in the Tg4510 mice is 2,208 µg/mL at the
NOAEL (200 mg/kg SC dosing) determined in the 6-month repeat dosing toxicity study (Study 
8326195) which is approximately 52 times higher than the predicted human Css at the highest 
dose of 210 mg IV (41.8 µg/mL) planned in Study LMDD.  


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Overall, the exposures and lack of findings in the 6-month toxicology studies in both the Tg4510 
mice and monkeys, and the AE profile and preliminary PK in humans from Study LMDA,
support the doses proposed in this study.
Table LMDD.2.
Margin of Safety for Intravenous Administration of LY3303560 after 
6 months of Dosing Based on Administered Dose and Predicted
Human Exposure
Dose
Dose
Multiplea
(Maximum Dose)
Cavg
(µg/mL)
Exposure
Multiplea
(Maximum Dose)
Human Maximum Doseb
210 mg (3 mg/kg)
–
41.8
–
Tg4510 Mouse NOAELc
200 mg/kg
266xf
2,208.3
e
52
Monkey NOAELd
200 mg/kg
266xf
6,726.2
e
160
Abbreviations:  Cavg = average steady-state serum concentration; NOAEL = no-observed-adverse-effect level.
a
Dose multiple is the dose in animals divided by the dose in humans on a mg/kg basis.  Exposure multiple is the 
calculated Cavg in animals divided by the predicted Cavg in humans after intravenous dosing. Multiples are 
rounded down to the nearest integer.
b
Clinical (IV) dose multiple calculation assumes a 70-kg subject. Projected AUCτ at 210 mg Q4W is 
1170 µg·day/mL. 
c
NOAEL was determined in a 6-month SC repeat-dose toxicity study (Study 8326195).
d
NOAEL was determined in a 6-month IV repeat-dose toxicity study (Study 8326196).
e
Cavg is the mean of male and female.
f
Preclinical dosing was weekly/human dose was monthly (200 mg/kg x 4 weeks / 3 mg/kg).


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6. Study Population
Eligibility of patients for study enrolment will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, ECG, and the research disease 
diagnostic criteria.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 90 days prior to the first dose.
Patients recruited at the Japan sites must be Japanese.  Japanese patients recruited outside of 
Japan should be up to third-generation Japanese to be included in the analysis as Japanese, 
defined as all of the patient’s biological grandparents are of exclusive Japanese descent and were
born in Japan.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible for inclusion in the study only if they meet all of the following criteria at 
screening:
[1]
MCI due to AD or mild-to-moderate AD based on National Institute of Aging 
and Alzheimer’s Association diagnostic criteria (Albert et al. 2011; McKhann 
et al. 2011):

gradual and progressive change in memory function reported by patients 
or study partner over more than 6 months

objective evidence of significantly impaired episodic memory 
characteristic of hippocampal dysfunction on testing: 
o Free and Cued Selective Reminding Test with Immediate Recall
(FCSRT-IR):  <27 for free recall (The episodic memory impairment 
can be isolated or associated with other cognitive changes at the 
onset or as the disease advances) (Auriacombe et al. 2010; Grober 
et al. 2010), and
o Clinical Dementia Rating (CDR) of 0.5 to 2, global score; memory 
box score ≥0.5, and 
o MMSE of 16 to 30

Has a florbetapir or other amyloid PET scan consistent with amyloid 
pathology at screening (the amyloid PET scan must be available to the 
central reader).


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[2a] male patients:

must abstain from intercourse for 24 hours after PET scans

agree to use an effective method of contraception and will not donate 
sperm during the study and for approximately 6 months following the last 
dose of investigational medicinal product (IMP).  At least one effective 
method of contraception will be used (for example, condoms with 
spermicide, oral contraceptives, intrauterine device, male sterilisation, 
etc.).  The subject may choose to use a barrier method of contraception.  
Barrier protection methods without concomitant use of a spermicide are 
not an effective or acceptable method.  Thus, each barrier method must 
include use of a spermicide (i.e., condom with spermicide, diaphragm with 
spermicide, female condom with spermicide).  It should be noted however 
that the use of male and female condoms as a double barrier method is not 
considered acceptable due to the high failure rate when these barrier 
methods are combined.
[2b] female patients: 
women not of child-bearing potential may participate, and include those who are:
a) Infertile due to surgical sterilisation (hysterectomy, bilateral oophorectomy, or, 
for countries outside of Japan, tubal ligation), congenital anomaly such as 
mullerian agenesis; or
b) Postmenopausal – postmenopausal is defined as women at least 50 years of age 
with an intact uterus who have not taken hormones or oral contraceptives within 1 
year, who have had either cessation of menses for at least 1 year, or 6 to 12 
months of spontaneous amenorrhea with follicle-stimulating >40 mIU/mL.
[3]
are at least 50 years old at the time of screening
[4]
have a body weight of at least 50 kg (except for Japanese sites) and have a 
body mass index (BMI) of 18.0 to 35.0 kg/m2 (for all sites), inclusive, at 
screening  
[5]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[6]
have venous access sufficient to allow for blood sampling and/or 
administration of the IMP for IV administration as per the protocol
[7]
have adequate premorbid literacy, vision, and hearing for neuropsychological 
testing in the opinion of the investigator
[8]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[9]
are able and willing to give signed informed consent


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[10] have up to 2 reliable study partners who are in frequent contact with the 
patient (defined as at least 10 hours per week), one of whom at any one 
occasion:  will accompany the patient to the study visits, will be available by 
telephone at designated times, and will provide a separate written informed 
consent to participate. A study partner should carry out his/her responsible 
part of the ADCS-MCI-ADL assessment.  If a patient has more than 1 study 
partner, it is preferred that one of them will be primarily responsible for this 
assessment. 
If the study partner(s) are not able to accompany the patient in person because 
of an unavoidable circumstance, they must be available by telephone for the 
following assessments:

AEs and concomitant medications;

relevant portions of the C-SSRS/self-harm supplement and follow-up 
forms, and

CDR and ADCS-MCI-ADL (primary study partner if possible)
If any study partner familiar with the study cannot continue, 1 replacement for 
each study partner is allowed, or more at the investigator’s discretion.  The 
replacement(s) will also need to sign a separate informed consent on the visit 
he/she accompanies the patient to participate.  
Study partners must be able to communicate with site personnel and be 
willing to comply with protocol requirements, and in the investigator’s 
opinion must have adequate literacy to complete the protocol-specified 
questionnaires.  
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
[11] are investigative site personnel directly affiliated with this study or immediate 
family members of investigative site personnel (immediate family is defined 
as a spouse, biological or legal guardian, child, or sibling)
[12] are Lilly employees or employees of third-party organisation(s) (TPOs) 
involved with the study who require exclusion of their employees; or have 
study partners who are Lilly employees or employees of TPOs involved in the 
study who require exclusion of their employees
[13] are currently enrolled in a clinical trial involving an IMP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study


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[14] have participated, within the last 30 days (3 months and 4 months for sites in 
the EU and Japan, respectively) in a clinical trial involving an IMP.  If the 
previous IMP has a long half-life, 3 months (4 months for sites in Japan) or 5 
half-lives (whichever is longer) should have passed
[15] have previously completed or withdrawn from this study or any other study 
investigating LY3303560, and have previously received the IMP
[16] have known allergies to LY3303560, related compounds or any components 
of the formulation, or history of significant atopy
[17] have significant allergies to humanised monoclonal antibodies,
diphenhydramine, adrenaline, or methylprednisolone; or have a history of 
clinically significant multiple or severe drug allergies, or intolerance to topical 
corticosteroids, or severe post treatment hypersensitivity reactions (including, 
but not limited to, erythema multiforme major, linear immunoglobulin A 
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis)
[18] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[19] have an abnormal blood pressure or pulse rate as determined by the 
investigator
[20] show evidence of clinically significant active neuropsychiatric disease, 
deemed to be a risk to subject participation in the study, in the opinion of  the 
investigator  
[21] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening that cannot be explained by regular concomitant medications
[22] have donated blood of more than 500 mL within the last month before start of 
dosing.  For sites in Japan, have donated 400 mL or more blood in the last 12 
weeks (males) or in the last 16 weeks (females), or any blood donation 
(including apheresis) within the last 4 weeks, or total volume of blood 
donation within 12 months is 1200 mL (males) / 800 mL (females) or more at 
screening
[23] have an average weekly alcohol intake that exceeds 14 units, or are unwilling 
to stop alcohol consumption 48 hours before dosing until at least 24 hours 
after dosing 
[24] have an increased risk of seizures as evidenced by a history of head trauma 
with loss of consciousness within the last 5 years or any seizure (except 
childhood febrile seizure); prior electroencephalogram with epileptiform 
activity; surgery to the cerebral cortex; or history within the last 5 years of a 
serious infectious disease affecting the brain (including neurosyphilis, 
meningitis, or encephalitis)
[25] have any contraindications for MRI studies, including claustrophobia, or the 
presence of metal (ferromagnetic) implants or a cardiac pacemaker


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[26] have a brain MRI (centrally read) demonstrating either:  greater than 4 
cerebral microhaemorrhages on a T2*-weighted gradient-echo sequence, 
regardless of their anatomical location; any macrohaemorrhage or prior 
evidence of macrohaemorrhage; or any other major intracranial pathology 
(except:  atrophy, meningiomas without mass effect, benign pituitary 
microadenomas, and/or mild-to-moderate white-matter hyperintensities on 
fluid attenuation inversion recovery (FLAIR))
[27] have a history of intracranial haemorrhage, cerebrovascular aneurysm, or 
arteriovenous malformation, carotid artery occlusion, or epilepsy
[28] in the opinion of the investigator, the patient has a history of clinically 
significant stroke that is deemed to be a risk for study participation
[29] show evidence of clinically significant suicidal ideation as assessed by the C-
SSRS
[30] have current serious or unstable illnesses including hepatic disease (cirrhosis, 
hepatitis A, B, or C [presence of antibody to hepatitis B surface antigen in the 
setting of hepatitis B immunisation is not exclusionary; the presence of 
hepatitis C antibody a normal liver function tests and a negative hepatitis C 
polymerase chain reaction is not exclusionary]); renal, gastroenterologic,
respiratory, cardiovascular disease (active ischemic heart disease [stable or 
unstable angina], intermittent atrial fibrillation); endocrinologic disease (stable 
non-insulin-dependent diabetes or stable thyroid disease is not an exclusion);
neurologic disease (other than AD); immunologic, infectious disease (human 
immunodeficiency virus [HIV], tuberculosis, Lyme, or haematologic disease 
[including transfusion within past year]), or other conditions that, in the 
investigator’s opinion, could interfere with the analyses of safety in this study
[31] have had any prior exposure to active or passive immune therapies directed 
against tau or Aβ protein
[32] have had a ventriculoperitoneal shunt within the last year
[33] have had gamma globulin (IgG) therapy within the last 6 months
[34] have received treatment with biologic agents (such as monoclonal antibodies, 
including marketed drugs) within 3 months or 5 half-lives (whichever is 
longer) prior to dosing
[35] have received acetylcholinesterase inhibitors (AChEIs), memantine, and/or 
other AD therapy for less than 4 weeks, or have less than 4 weeks of stable 
therapy on these treatments by time of randomisation (including less than 4 
weeks since stopping AChEIs and/or memantine); or have received 
medications that affect the central nervous system, except treatments for AD, 
for less than 4 weeks at a stable dose
[36] have used stable medical therapy for less than 2 months by the time of 
randomisation for any concurrent medical condition that is not exclusionary


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[37] are currently using or intend to use drugs known to significantly prolong the 
QT interval, or who have a known risk factor for Torsades de Pointes. A 
subject will not be excluded if they have been using stable medication that is 
known to potentially cause significant prolongation of the QT interval, but 
does not present with any clinically significant prolongation of the QT interval 
at screening, in the opinion of the investigator
[38] have previous (within last 12 months) and planned exposure to ionising 
radiation that, in combination with the planned administration of study PET 
ligands, would result in a cumulative exposure that exceeds local 
recommended exposure limits
[39] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
[40] show clinically significant abnormalities in lumbar spine previously known or 
determined by screening lumbar x-ray (if performed)
[41] have a history of clinically significant back pain, back pathology and/or back 
injury (for example, degenerative disease, spinal deformity or spinal surgery) 
that may predispose to complications or technical difficulty with lumbar 
puncture
[42] have other criteria that would preclude a lumbar puncture, such as allergy to 
local anaesthetics (such as lidocaine (Xylocaine®) or its derivatives); have a 
local infection at the intended site of the lumbar puncture; have <100 GI/L 
(100,000/mm3) platelets or clinically significant coagulation abnormality or 
significant active bleeding; or have had treatment with an anticoagulant or 
treatment with 2 or more antiplatelet agents or other drugs that affect 
coagulation or platelet function within 14 days before lumbar puncture
[43] history of cancer within the past 5 years, with the exception of non-metastatic 
basal and/or squamous cell carcinoma of the skin, in situ cervical cancer, 
non-progressive prostate cancer, or other cancers with low risk of recurrence 
or spread
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, patients may undergo medical assessments and review of compliance with 
the following requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Patients should be adequately hydrated throughout the study.  Therefore, patients should be 
encouraged to drink several glasses of water each day.
6.3.2. Caffeine, Alcohol, and Tobacco
Consumption of caffeine-containing products is allowed.


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Patients will not be permitted to consume alcohol from 48 hours before visits until at least 24 
hours after dosing with study drug.  When not at the investigative site, patients should be advised 
to limit alcohol consumption to no more than 14 units per week.  Also, patients should be 
advised to limit alcohol consumption to no more than 3 units in any one day.
Patients will not be permitted to smoke at the investigative site and should not smoke for 48 
hours prior to visiting the investigative site. 
6.3.3. Activity
Patients should avoid strenuous exercise and/or activity from 48 hours before visits until after 
leaving the investigational site and, for 24 hours after the LP.
On LP days, movement will be restricted during the procedure and for an appropriate time after
the LP, as determined by the investigator (see Section 9.5.1). Patients may also be required to 
stay overnight at the investigative site for monitoring following completion of the LP procedure.
6.4.
Screen Failures
Patients who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 times following a discussion between the investigator and sponsor.  The 
interval between rescreening should be at least 8 weeks.  Each time rescreening is performed, the 
individual must sign a new informed consent form (ICF). A repeat scan for technical reasons is 
not considered a rescreen. If a patient is unable to participate in a cohort due to the cohort being 
fully enrolled, he/she may be enrolled into a subsequent cohort after re-consenting to that cohort. 
Screening tests conducted in the previous cohort screening may be used for the subsequent 
cohort, as long as the screening tests are within the screening window of the subsequent cohort. 
All safety assessments that fall out of the screening window need to be repeated. Other 
assessments may not need to be repeated, including cognitive assessments, lumbar x-ray and 
florbetapir PET scan, based on consultation with the Lilly clinical pharmacologist/CRP.  


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of LY3303560 and placebo, with the planned doses of 70 and 
210 mg.  Table LMDD.3 shows the treatment regimens. Detailed instructions for the 
preparation, handling, and administration of LY3303560 will be provided by the sponsor in a 
pharmacy binder.
The IMP will be administered as a slow IV infusion over at least 30 minutes.
The minimum time for close observation at the investigative site following dosing is 4 hours for 
the first 6 IV infusions and 2 hours for subsequent IV infusions. If any patient shows symptoms 
of an infusion reaction, the observation time will be increased to 8 hours for that infusion and all 
subsequent infusions. The site must have resuscitation equipment, emergency drugs, and 
appropriately trained staff available during dosing and while patients are under observation after 
dosing.  
All IMP provided to the investigator will be stored in a secure location, and allocated and 
dispensed by appropriately trained, unblinded site personnel.  The allocation and dispensing of 
the IMP will be fully documented and verified by a second person.  Detailed records of the 
amounts of IMP received, dispensed and remaining at the end of the study will be maintained.  
The actual time of all dose administrations will be recorded in the patient’s case report form 
(CRF).
For purposes of scheduling, “dosing time” refers to the start of infusion.
Table LMDD.3.
Treatments Administered
Treatment Name
LY3303560
Placebo
Dosage Formulation
lyophilised powder in vial
liquid in vial
Unit dose strength(s)/Dosage Level(s)
each vial can deliver 90 mg 
LY3303560
0.9% normal saline
Route of Administration
intravenous infusion 
intravenous infusion 
Dosing instructions
Refer to pharmacy binder
The investigator’s designee is responsible for:

explaining the correct use of the IMP to the site personnel, 

verifying that instructions are followed properly,

maintaining accurate records of IMP dispensing and collection,

and returning all unused medication to Lilly or its designee at the end of the study.


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Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.
7.1.1. Packaging and Labeling
The IMP will be manufactured in accordance with good manufacturing practices and will be 
labeled according to applicable local regulatory requirements.
7.2.
Method of Treatment Assignment
A patient number will be assigned to each patient after the ICF is signed and dated.  This 
identification number must appear on all patient-related documents.  Assignment to treatment 
groups will be determined by a computer-generated random sequence within each dose cohort 
using an interactive web response system (IWRS).
7.2.1. Timing of Doses
Doses should be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the patient’s CRF.  For IV infusions, the actual 
duration time of the infusion will be recorded in the CRF.  If the infusion is interrupted or
terminated, this should be recorded in the CRF.
7.3.
Blinding
This is a patient- and investigator-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomisation table and treatment assignments before the study is complete.  
Investigative site pharmacists or pharmacy staff will be unblinded due to their involvement in 
dose preparation.  In order to maintain the blind, these unblinded investigative site staff will not 
be involved in clinical assessments of patients or general conduct of the study.
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.  All 
actions resulting in an unblinding event are to be recorded and reported by the IWRS.
If a patient’s study treatment assignment is unblinded, the patient must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist or 
clinical research physician (CRP) for the patient to continue in the study.  During the study, 
emergency unblinding should occur only by accessing the patient’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  Patient’s
safety must always be the first consideration in making such a determination.  If the investigator 
decides that unblinding of a study patient’s treatment assignment is warranted, it is the 
responsibility of the investigator to promptly document the decision and rationale and notify 
Lilly as soon as possible.  


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All events resulting in an unblinding event must be recorded and reported through the IWRS.  
7.4.
Dose Modification
7.4.1. Dose Decision/Escalation
Safety data (see below) will be the primary criteria for the dose escalation. The available PK 
data for LY3303560 obtained during the study may be used to assist in dose escalation decisions 
but these data are not required for every decision.  No dose escalation can occur without prior 
discussion between investigator(s) and the Lilly clinical pharmacologist/CRP.  In the case of 
disagreement, the decision of the investigator(s) will be followed, except in a situation where 
Lilly’s proposal is the more conservative action (for example, where the investigator wishes to 
escalate and the Lilly clinical pharmacologist/CRP does not) in which case, the Lilly proposal 
will be followed. 
Safety data (including MRI scans) up to Day 85 from the minimum number of subjects (see 
Section 5.1.3) will be reviewed by the sponsor and investigator(s) to determine if the current 
dose was well tolerated and the proposed dose level for the next cohort is appropriate (see 
Section 10.3.6).  The safety data reviewed will include AEs, ECGs, vital signs (blood pressure 
and pulse rate), MRIs, neurological examinations, C-SSRS, and safety laboratory tests. See 
Section5.1.4 for details of the dose escalation for Japanese patients.
Safety data, in particular TEAEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator, and will be considered related to the IMP unless 
there is clear evidence that the event is not related.  
After review of these data, an agreement on the appropriate dose for the next cohort will be made 
by the investigator(s) and sponsor.  For doses above 70 mg, the dose level of LY3303560 
selected should also have been shown to be well tolerated with no safety concerns when 
administered as a single dose in the ongoing LMDA study, prior to initiating dosing at that dose 
level in this study. 
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be discontinued:
1) One or more patient experiences an SAE that is considered related to LY3303560
administration
2) Two or more patients experience a clinically significant event (CSE) that is 
considered related to LY3303560 administration. (A CSE will be defined as a 
moderate-to-severe AE, abnormal clinical sign, or clinical laboratory finding that 
may pose a risk to the well-being of the subject)
3) Two or more patients at a dose level experience moderate or severe AEs that 
impair normal activities, and are considered related to LY3303560, but do not 
meet the CSE criteria


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4) After the introduction of premedication in accordance with the protocol, 2 or 
more patients develop (according to Common Terminology Criteria for Adverse 
Events [CTCAE]) Grade 2 acute AEs related to the infusion, during the infusion 
or within 2 hours of completion, that do not resolve with a reduced infusion rate 
and/or supportive care.
7.4.2. Special Treatment Considerations
7.4.2.1.
Premedication for Infusions
Premedication for the infusions is not planned.  However, if an infusion reaction occurs, 
appropriate medication may be used as determined by the study investigator(s).  If infusion 
reactions are observed, but review of the data suggests that dose escalation may continue, 
administration of paracetamol/acetaminophen (500 to 1000 mg) and/or an antihistamine, and/or 
methylprednisolone (or other corticosteroid) may be administered orally 30 to 60 minutes prior 
to the start of infusion for subsequent patients.
Any decision to implement premedication for infusions in subsequent cohorts will be made by 
the investigator(s) and sponsor and recorded in the study documentation, along with the dose-
escalation decision.
Any premedications given will be documented as a concomitant therapy (see Section 7.7).
7.4.2.2.
Management of Infusion Reactions
There is a risk of an infusion reaction with any biological agent; therefore, all patients should be 
monitored closely.  Symptoms and signs that may occur as part of an infusion reaction include, 
but are not limited to, fever, chills, nausea, headache, bronchospasm, hypotension, angio-
oedema, throat irritation, rash, pruritus, myalgia, and dizziness.  In the event that a significant 
infusion reaction occurs, the following guidance should be followed:

the IMP infusion should be slowed or stopped, depending on the symptoms/signs present:
o
if slowed, the infusion should be completed at the slower rate (at least 50% of the 
original infusion rate [for example, an infusion rate of 100 mL/hr becomes 
50 mL/hr or slower]), as tolerated and documented in the CRF.  The slower rate 
of infusion will be used for subsequent infusions for that patient
o
if stopped, no further attempts to administer the IMP for that patient will be made, 
and this will be documented in the CRF

supportive care should be employed in accordance with the symptoms/signs.
Management of the infusion reaction should proceed according to the severity of the reaction as 
per the flowchart in Appendix 5.  This may include, but is not limited to, rescue medications 
such as diphenhydramine, adrenaline, and/or methylprednisolone.
Stored serum samples for possible exploratory immune safety laboratory testing (including but 
not limited to Beta tryptase, total immunoglobulin E, and immune complex testing) will be 
collected at time points indicated in the Schedule of Activities (Section 2).  


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Additionally, stored serum samples for possible exploratory immune safety laboratory testing 
should be collected approximately 60-120 minutes and 4-6 weeks after moderate or severe 
infusion reactions.  Unscheduled samples may also be collected as needed.
Standardised clinical information from the infusion should be collected in the CRF.
7.5.
Preparation/Handling/Storage/Accountability
Only participants enrolled in the study may receive the IMP and only authorised site staff may 
supply or administer study treatment.  All study treatments should be stored in an
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to authorised site staff.
The investigator or the head of the medical institution (where applicable) is accountable for study 
treatment accountability, reconciliation, and record maintenance (such as receipt, reconciliation 
and final disposition).
7.6.
Treatment Compliance
The IMP will be administered at the investigative site, and documentation of treatment 
administration will occur at the site.
7.7.
Concomitant Therapy
Patients on stable concomitant medication for treatment of AD and other chronic conditions at 
the time of study entry should continue their regular, unchanged dose throughout the study.  
Additional drugs for patients should be avoided during the study unless required for a study 
procedure, to treat an AE, or for the treatment of an ongoing medical problem (refer to Exclusion 
Criteria, Section 6.2).  Occasional paracetamol/acetaminophen and antihistamine use, without 
prior consultation with a Lilly clinical pharmacologist, will be allowed.  
If an infusion reaction occurs, rescue medications may be administered at the discretion of the 
investigator (see Section 7.4.2.2).
Use of drugs known to significantly prolong the QT interval are not permitted within 14 days or 
5 half-lives, whichever is longer, prior to flortaucipir scans (refer to the PET Technical 
Operations Manual for a list of excluded drugs).
If the need for concomitant medication arises, inclusion or continuation of the patient may be at 
the discretion of the investigator after consultation with a Lilly clinical pharmacologist or CRP.  
Any additional medication used during the study must be documented.
7.8.
Treatment after the End of the Study
Not applicable.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Patients will be discontinued from the IMP in the following circumstances:
o
an SAE occurs that is related to study drug
o
an SAE occurs during the infusion of the study drug, irrespective of causality; in 
this event, the drug is to be discontinued immediately.  No re-dosing or 
completion of dosing is to be considered for that patient if the SAE is deemed to 
be related to study drug  
o
a clinically significant systemic hypersensitivity reaction occurs following 
administration of the IMP (for example, drug-related symptomatic bronchospasm, 
allergy-related oedema/angio-oedema, or hypotension), that requires parenteral 
medication, does not respond to symptomatic medication, or results in clinical 
sequelae or an anaphylactic reaction
o
symptomatic or asymptomatic cerebral vasogenic oedema 
o
symptomatic cerebral microhaemorrhage or an increase in the number of cerebral 
microhaemorrhage >2 over baseline or such that the total number of 
microhaemorrhages is >4
o
a clinically significant neurological finding 
o
an occurrence of suicidal ideation, as defined by a “yes” answer to Questions 4 or 
5 on the Suicidal Ideation portion of the C-SSRS
Patients who discontinue the study drug early should complete all remaining scheduled visits 
(omitting dosing) if feasible or, at a minimum, the early discontinuation procedures as shown in 
the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrolment criteria and was 
inadvertently enrolled, the patient must be discontinued from the study following the early 
discontinuation procedures, as detailed in the Schedule of Activities (Section 2).  
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

Enrolment in any other clinical trial involving an IMP or enrolment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision


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o
the investigator decides that the patient should be discontinued from the study
o
the patient, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication; in this 
event, discontinuation from the study occurs prior to introduction of the new 
agent

Patient Decision
o
the patient (or designee, for example, study partner) requests that the patient be 
withdrawn from the study
Patients who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
Investigative sites will report emerging clinically significant events (including but not limited to 
SAEs, clinically significant infusion/injection site reactions and clinically significant MRI 
abnormalities) to Lilly as soon as possible after they occur, and no later than the timing for 
expedited AE reporting.  Lilly will inform all sites across all geographies of any clinically 
significant events and/or related decisions as soon as possible after notification, but no later than 
the timing for expedited AE reporting.
In the case where the decision is taken to suspend dosing in the trial or terminate due to safety 
findings, this decision will be immediately (within 1 hour) communicated by Lilly to all 
investigators (for example, by phone and/or email).  It will be a requirement that investigators 
respond upon receipt to confirm they understand and have taken the appropriate action prior to 
dosing any patients with study treatment. Any investigator not responding will be followed up 
by Lilly personnel within 24 hours and prior to any planned dosing.
8.3.
Patients Lost to Follow-up
A patient 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 are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IMP or the 
study, or that caused the patient to discontinue the IMP before completing the study.  The patient 
should be followed until the event resolves, stabilises with appropriate diagnostic evaluation, or 
is reasonably explained.  The frequency of follow-up evaluations of the AE is left to the 
discretion of the investigator.
After the ICF is signed, study site personnel will record, via CRF, the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause-and-effect relationship between 
the IMP, study device and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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If a patient’s IMP is discontinued as a result of an AE, study site personnel must report this to 
Lilly or its designee via CRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalisation

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

events considered significant by the investigator based upon appropriate medical 
judgment
Study site personnel must alert Lilly, or its designee, of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Although all AEs are recorded in the CRF after signing informed consent, SAE reporting begins 
after the patient has signed informed consent and has received IMP.  However, if an SAE occurs 
after signing informed consent, but prior to receiving IMP, AND is considered Reasonably 
Possibly Related to a study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to IMP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to IMP or procedure.  Suspected 
unexpected serious adverse reactions must be reported according to United States 21 CFR 312.32 
and European Union Clinical Trial Directive 2001/20/EC and the associated detailed guidances
or national regulatory requirements in participating countries.  Lilly has procedures that will be 
followed for the recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.


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9.2.2. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3303560 is considered any dose higher than the 
dose assigned through randomisation.  There is no known antidote for LY3303560; subjects 
should receive appropriate supportive care.
Refer to the IB for LY3303560.
9.4.
Safety
9.4.1. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
9.4.2. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).
Supine blood pressure and pulse rate should be measured after at least 5 minutes resting in the 
supine position.
If orthostatic measurements are required, patients should be supine for at least 5 minutes and 
then stand for at least 3 minutes.  If the patient feels unable to stand, supine vital signs only will 
be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted and agreed upon between the sponsor and investigator.
9.4.3. Electrocardiograms
For each patient, ECGs should be collected according to the Schedule of Activities (Section 2). 
Any clinically significant findings from ECGs that result in a diagnosis, and that occur after the 
patient receives the first dose of the IMP, should be reported to Lilly, or its designee, as an AE 
via the CRF.  Any clinically significant findings that do not result in a diagnosis should be 
commented on and appropriately documented.  If a clinically significant change is seen, 
additional ECGs may be added at appropriate intervals to follow return to baseline.  Any new 
clinically significant findings should be reported as an AE. 
Electrocardiograms must be recorded before collecting any blood for safety or PK tests.  Patients
must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but 
awake during ECG collection.  Electrocardiograms may be obtained at additional times, when 


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deemed clinically necessary.  Collection of additional ECGs at a particular time point is allowed 
to ensure high quality records.  All screening ECGs should be stored at the investigational site.
At screening, a single ECG will be obtained and does not need to be transmitted to the ECG 
vendor.  The screening ECG will be interpreted by the investigator or qualified designee at the 
site to determine whether the patient meets entry criteria.
At all other time points, ECGs will be obtained in triplicate at approximately 1-minute intervals 
and will be transmitted to and stored at the central ECG vendor.  Electrocardiograms will be 
interpreted by a qualified physician (the investigator or qualified designee) at the site as soon 
after the time of ECG collection as possible, and ideally while the patient is still present, to 
determine whether the patient meets entry criteria at the relevant visit(s), and for immediate 
patient management should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the patient can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point.
Digital ECGs will be electronically transmitted to and stored at the central ECG laboratory
designated by Lilly.  The central ECG laboratory will perform a basic quality control check (for 
example, of demographics and study details) then store the ECGs in a database.  At a future time, 
the stored ECG data may be overread at the central ECG laboratory for further evaluation of 
machine-read measurements or to meet regulatory requirements.
The machine-read ECG intervals and heart rate may be used for data analysis and report-writing 
purposes unless a cardiologist overread of the ECGs is conducted before completion of the final 
study report (in which case the overread data would be used).
9.4.4. Neurological Examinations
A directed neurological examination will be performed by a physician, nurse practitioner, or 
physician’s assistant at the time points specified in the Schedule of Activities (Section 2).  If 
abnormalities are noted at these time points, additional examinations should be performed at 
daily intervals until the patient has returned to baseline.  The examiner should be familiar with 
the patient’s baseline examination.  Mandated elements of the examination include inspection for 
tremor, extraocular movements, brachial and patellar deep tendon reflexes, finger-nose pointing, 
and Romberg’s sign.
Table LMDD.4 presents the scoring of the neurological examination findings.  For patients with 
mild (1+) tremor or nystagmus at baseline, increases in these findings should not be scored at a 
higher level unless the examiner judges them to be significantly exacerbated compared to 
baseline.


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Table LMDD.4.
Scoring of Neurological Examinations
Score
0
1
2
3
4
Tremor
Absent
Visible with limb 
extension and/or 
careful inspection
Visible 
without limb
extension
Interferes 
with motor 
function
Nystagmus
Absent
1-3 beats on 
lateral gaze
>3 beats on 
lateral gaze
Present on 
forward gaze
Reflexes (brachial or patellar)
Absent
Trace
Normal
Increased
Clonic
Finger-nose
Normal
Abnormal
Romberg’s sign
Absent
Present
9.4.5. Magnetic Resonance Imaging
The MRI scans will be obtained at time points indicated in the Schedule of Activities (Section 2).
Magnetic resonance imaging safety monitoring will include sequences appropriate for detecting 
vasogenic oedema and microhaemorrhage.
Specifics of the MRI acquisition protocol will be provided in an MRI Technical Operations 
Manual.  A 3T scanner is preferred but a 1.5T scanner may be used if a 3T scanner is not 
available.  However, the same scanner should be consistently used throughout the study for any 
particular patient.  All MRI scans will be analysed by a central reader blinded to treatment.
9.4.6. Columbia Suicide Severity Rating Scale
By industry guidance regarding suicidality (US Food and Drug Administration [FDA]), any 
assessment of suicide-related thoughts and behaviours must map to the Columbia Classification 
Algorithm for Suicide Assessment (Posner et al. 2007).  The C-SSRS was developed by the 
National Institute of Mental Health trial group to map directly to the Columbia Classification 
Algorithm for Suicide Assessment and therefore was chosen to assess suicide-related thoughts 
and behaviours in this study.
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicide-related 
thoughts and behaviours during the assessment period.  The scale includes suggested questions to 
solicit the type of information needed to determine whether a suicide-related thought or 
behaviour has occurred.  The C-SSRS will be administered as specified in the Schedule of 
Activities by appropriately trained site personnel.
The C-SSRS is available in adult and child versions; however, there is no version of the C-SSRS 
for a cognitively impaired population.  The adult version contains a more elaborate “Intensity of 
Ideation” section that requires memory of past thoughts in a temporal context, and a cognitively 
impaired population may be unable to give an accurate response.  The child version of the C-
SSRS has condensed this section into 1 question.  The suggested wording for the scale questions 
has also been simplified.  For these reasons, the child version has been chosen for this study.  
The child version of the C-SSRS should be administered to the patient with the study partner 
present or available by phone.  Responses from both the study partner and patient should be 


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considered when administering the scale.  If a suicide-related thought or behaviour is identified 
at any time during the study, a thorough evaluation should be performed by a study physician, 
and appropriate medical care should be provided.
The Lilly Self-Harm Supplement Form should be completed every time the C-SSRS is 
administered. If the investigator determines that suicide-related behaviours have occurred, the 
Lilly Self-Harm Follow-Up form will be used to collect additional information to allow for a 
more complete assessment of these behaviours.  Patients with any clinically significant changes 
as determined by the investigator will be referred to a mental health professional.
9.4.7. PET Imaging
An amyloid PET scan, utilising florbetapir F 18 (or florbetaben F 18 or flutemetamol F 18, if the 
sponsor approves) will be performed at screening if amyloid PET confirming amyloid pathology 
has not been conducted previously (and scans are not available to the central reader).  Details of 
the acquisition protocols for each amyloid tracer will be provided in the PET Technical 
Operations Manual.  
A total of 2 flortaucipir F 18 PET scans will be performed at time points specified in the 
Schedule of Activities (Section 2).  At each flortaucipir F 18 PET imaging visit, patients will 
receive a single IV administration of approximately 370 MBq (10 mCi) flortaucipir F 18, with 
the scan being acquired approximately 75 minutes post injection.  Details of the acquisition 
protocol will be provided in the PET Technical Operations Manual. 
Patients with a history of risk factors for Torsades de Pointes or taking medications known to 
prolong the QT interval (as listed in the PET Technical Operations Manual) should not have a 
flortaucipir F 18 scan. 
9.4.7.1.
Radiation Doses Associated with PET Imaging
The estimated exposure to ionising radiation per patient enrolled in this study (effective dose) is 
summarised in Table LMDD.5.  This includes contributions from amyloid PET imaging (either 
florbetapir F 18, florbetaben F 18 or flutemetamol F 18) and flortaucipir F 18 PET imaging with 
flortaucipir F 18, along with a low-dose CT scan at each imaging session required for attenuation 
correction.  
For flortaucipir F 18 scans only, if the image is not interpretable based on predetermined criteria 
outlined at the central lab (for example, scanner failure, patient motion, etc.), the patient may be 
asked to schedule an additional visit requiring an additional injection of flortaucipir F 18.  Each
patient will undergo a maximum of 1 additional flortaucipir F 18 PET scan beyond those 
scheduled in this protocol.  The additional PET scan will not be considered out of window or a 
protocol deviation.


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Table LMDD.5.
Radiation Doses Associated with PET Imaging
Injected 
Radioactive Dose
per Scan, mCi
Injected 
Radioactive Dose
per Scan, MBq
Effective Dose 
(mSv) per Scan
Number 
of Scans
Total 
Effective 
Dose (mSv) 
Florbetapira scan
10
370
7.43
1
  7.43
Flortaucipir F 18 scan
10
370
9.1
2
18.2
Totals
3
  25.63
Abbreviations:  CT = computed tomography; PET = positron emission tomography.
Note:  Doses shown include radiation exposure from the radiotracer and also assume a non-clinical 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
Amyloid PET scanning using florbetapir F 18 represents the likely maximum effective dose in this study.  Use of 
alternate radioligands is associated with lower effective doses (florbetaben F 18 injects 8.1 mCi/300 MBq 
radioactive dose per scan with an effective dose of 6.2 mSv; flutemetamol F 18 injects 5 mCi/185 MBq 
radioactive dose per scan with an effective dose of 6.32 mSv).
9.4.8. Safety Monitoring
The Lilly clinical pharmacologist or CRP will monitor safety data throughout the course of the 
study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or research physician will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist when appropriate, and 
periodically review:

trends in safety data

laboratory analytes 

AEs including monitoring of imaging abnormalities by MRI, infusion reactions, and
injection site reactions.
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, clinical and laboratory monitoring should be initiated by the investigator.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient safety and compliance with regulatory guidance, the 
investigator is to consult with the Lilly-designated clinical pharmacologist or CRP regarding 
collection of specific recommended clinical information and follow-up laboratory tests.
The levels of tau protein in plasma have been shown to be associated with AD, age, BMI, 
diabetes, hypertension, atrial fibrillation, and head injuries (traumatic brain injury, sports related 
concussion) (Zetterberg et al. 2013; Shahim et al. 2014).  Therefore, patients should be 
monitored for any changes or occurrences of these variables during the study as they may impact 
the assessment of one of the PD biomarkers, plasma tau.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the Unblinding/Blinding Plan.


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9.4.9. Immunogenicity Assessments
As detailed in the Schedule of Activities (Section 2), blood samples for immunogenicity testing 
will be collected to determine antibody production against LY3303560.  Additional samples may 
be collected if there is a possibility that an AE is immunologically mediated.  In case of a 
hypersensitivity reaction, serum drug concentrations will also be measured to aid interpretation 
of the immunogenicity data.  
Additional samples for immunogenicity testing will be taken approximately every 3 months after 
the last follow-up visit when: 
1) Patients have an anti-drug antibody (ADA) titre of 1:5120 or higher at the final follow-up 
visit.  Samples for immunogenicity will be taken approximately every 3 months until the 
titres drop below 1:5120, for up to a maximum of 1 year after last dose
2) Patients have increasing ADA titres at the final follow-up visit compared to previous 
titres.  Samples for immunogenicity will be taken up to a maximum of 1 year after the 
last dose or until the titres begin to decrease (and also drop below 1:5120, if the titre was 
1:5120 or higher at the final follow-up visit)
3) Patients had an immunologically mediated AE judged to be potentially associated with 
ADAs at any time during treatment and have a positive ADA titre at the last follow-up 
visit.  Samples for immunogenicity will be taken up to a maximum of 1 year after the last 
dose.
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of LY3303560. Antibodies may be further characterised and/or evaluated for their ability to 
neutralise the activity of LY3303560. 
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and Ethical Review Boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
LY3303560.  Any samples remaining after 15 years will be destroyed.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), blood samples will be 
collected to determine the serum concentrations of LY3303560.  A maximum of 5 samples may 
be collected at additional time points during the study if warranted and agreed upon between 
both the investigator and sponsor.  Instructions for the collection and handling of blood samples 
will be provided by the sponsor.  The actual date and time (24-hour clock time) of each sampling 
will be recorded.
On the day of dosing, PK samples should be collected from the arm that did not receive the IV 
infusion of study drug.
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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9.5.1. Cerebrospinal Fluid Sampling
A lumbar x-ray may be performed at screening to rule out potential contraindications to an LP, 
such as significant osteoarthritic disease and bone overgrowth.  If an x-ray was conducted within 
12 months of screening, it may be used.
The LP procedure will be conducted under local anaesthesia by an appropriately qualified 
person.  At each LP, a maximum of 20 mL (including up to 5 mL for local laboratory testing) of 
CSF will be collected.  The first 5 mL of CSF will be collected in a separate container and sent to 
a local laboratory for testing of white blood cell count, red blood cell count (where possible), 
total protein, and glucose.  In addition, each CSF sample will be visually inspected for evidence 
of blood contamination.  The results of the visual inspection and local laboratory CSF analyses 
are to be documented on the electronic CRF (eCRF).  Grossly evident blood by visual inspection 
will be reported as positive and documented in the CRF. 
Any sample that shows visual or laboratory evidence of blood contamination may be excluded 
from the PK and statistical analyses if the level of contamination is estimated to be sufficient to 
produce misleading results.
The remaining CSF will be collected to measure concentrations of CSF biomarkers in all patients 
and LY3303560 concentrations in patients who are assigned to receive LY3303560.  All CSF 
aliquots remaining after analysis will be stored for exploratory work (Section 9.8).  
Patients will be carefully monitored for post-LP headaches.  The investigator may use hydration, 
analgesics, and blood patch to treat any headaches, as clinically indicated.
9.5.2. Bioanalysis
Samples will be analysed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3303560 will be assayed using a validated ELISA method.  Analyses of 
samples collected from placebo-treated patients are not planned.
Bioanalytical samples collected to measure IMP concentrations will be retained for a maximum 
of 1 year following last patient visit for the study.  
9.6.
Pharmacodynamics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected for measurement of plasma tau concentrations if a suitable assay exists.  A 
maximum of 5 additional time points per patient may be drawn during the study at the discretion 
of the investigator or sponsor.  These additional samples may be drawn to measure LY3303560, 
tau or exploratory PD biomarker concentrations.  Cerebrospinal fluid samples for exploratory PD 
will be collected as described in Section 9.5.1.
Plasma concentrations of tau and CSF concentrations of tau, p-tau, neurogranin, and Aβ1-42 will 
be determined using validated immunoassay methods.  The samples will be stored for a 
maximum of 15 years after the last patient visit for the study at a facility selected by the sponsor.  


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Plasma and CSF samples collected for PD measurements will have aliquots stored for future 
exploratory biomarker work for a maximum of 15 years after last patient visit for the study.  Any 
sample remaining after this period will be destroyed.  Research will be limited to investigation of 
the safety and PD of LY3303560, biomarkers relevant to neurodegenerative diseases, and the 
mechanism of action of LY3303560.  Instructions for the collection and handling of blood 
samples will be provided by the sponsor.  The actual date and time (24-hour clock time) of each 
sampling will be recorded.
On the day of dosing, for all cohorts, PD samples should be collected from the arm that did not 
receive the IV infusion of study drug.
9.6.1. Exploratory Cognitive and Functional Assessments
The tests of cognitive function (ADAS-Cog14, NTB, MMSE, CDR, ADCS-MCI-ADL24, dCDT, 
and FCSRT-IR) will be performed during the study at the times specified in the Schedule of 
Activities (Section 2). These tests are performed as a safety and exploratory measure to 
document any substantial change associated with treatment, as it is not anticipated that these tests 
should have significant changes associated with LY3303560 in this small patient population.
Cognitive and functional tests may be conducted on separate days within the particular visit’s 
allowed window.  However, tests that are performed on the same day should be done in a 
specific order.  Screening tests should be completed in this order:  1) MMSE, 2) FCSRT-IR, 3) 
CDR, and 4) dCDT.  Tests during the study, if done on the same day, should be performed in this 
order with a minimum of 4 hours separating ADAS-Cog14 and NTB testing to avoid testing 
fatigue:  1) ADAS-Cog14, 2) ADCS-MCI-ADL24, 3) MMSE, 4) NTB, and 5) dCDT.  The study 
partner (or one of the study partners if there are 2) should be present or available by telephone
for the assessment of CDR and ADCS-MCI-ADL (this should be the primary study partner for 
ADCS-MCI-ADL).  When cognitive/functional assessments and LP are scheduled on the same 
day, all cognitive/functional assessments must be performed before the LP.
9.6.1.1.
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
The ADAS is a rater-administered instrument that was designed to assess the severity of the 
dysfunction in the cognitive and non-cognitive behaviours characteristic of persons with AD
(Rosen et al. 1984); ADAS-Cog refers to the cognitive subscale which was originally designed 
with 11 items (the ADAS-Cog11). An expanded version that includes 3 additional items more 
sensitive to patients at earlier stages of AD, the ADAS-Cog14 (Mohs et al. 1997), will be used in 
this study.  It consists of 14 items assessing areas of cognitive function most typically impaired 
in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation, and 
maze-completion measures. The ADAS-Cog14 scale ranges from 0 to 90, with higher scores 
indicating greater disease severity.
9.6.1.2.
Neuropsychological Test Battery
The NTB is a cognitive tool for clinical trials in the field of AD.  The NTB is a collection of 
several written and oral tests that examines verbal and non-verbal brain functions.  The NTB 
shows linear annual cognitive changes across a wide range of MMSE scores as compared to the 


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ADAS-Cog14 and is more sensitive than the ADAS-Cog14 among patients with mild impairment 
(Harrison et al. 2007).
9.6.1.3.
Mini–Mental Scale Examination
The MMSE is one of the most widely used screening instruments for cognitive impairment and 
provides a total score ranging from 0 to 30, with lower scores indicative of greater cognitive 
impairment (Folstein et al. 1975).
9.6.1.4.
Clinical Dementia Rating
The CDR is a clinical staging instrument for dementia (Morris 1993).  It characterises 6 domains 
of cognitive and functional performance:  memory, orientation, judgment and problem solving, 
community affairs, home and hobbies, and personal care.  The necessary information to make 
each rating is obtained through a semistructured interview of the patient and a reliable informant 
or collateral source (e.g., a family member).  The CDR table provides descriptive anchors that 
guide the clinician in making appropriate ratings based on interview data and clinical judgment.
In addition to ratings on a 5-point scale for each domain (except for personal care, which is rated 
on a 4-point scale), an overall CDR score is derived by standard algorithm.  This score is useful 
for globally staging the level of impairment:  0 indicates no impairment; 0.5, 1, 2, and 3 indicate 
very mild, mild, moderate, and severe dementia, respectively.
The CDR and Clinical Dementia Rating-Sum of Boxes (CDR-SB) will be evaluated at screening.  
The CDR-SB is considered a more detailed quantitative general index than the global score and 
has reasonable accuracy to discriminate between patients with very early AD and those with 
MCI.
9.6.1.5.
Alzheimer's Disease Cooperative Study/Activities of Daily Living Scale
Adapted for MCI Patients
The ADCS-MCI-ADL is a 24-item questionnaire that attempts to detect milder functional 
impairments and represent a modification of the original activities of daily living scale (Galasko 
et al. 1997).
9.6.1.6.
Free and Cued Selective Reminding Test with Immediate Recall
The FCSRT-IR is a 16-item instrument version of controlled learning (Grober and Buschke 
1987) and will be evaluated at screening only.  The FCSRT-IR performance as an indicator of 
early AD comes from correlations with abnormalities in structural and functional imaging and 
with neurofibrillary lesions in parahippocampal regions that are the earliest targets of AD 
pathology. Only Form A of the FCSRT-IR will be used in this study.
9.6.1.7.
Digital Clock Drawing Test
The Clock Drawing Test (CDT) is used to measure constructional, spatial, and executive 
abilities, and deficits in the conception of time.  On a blank sheet of paper, the patient will be 
asked to draw a clock showing 10 minutes past 11 (the “command” clock).  Next, the patient will 
be asked to copy a pre-drawn clock showing the same time (the “copy” clock).  This test requires 
different cognitive capabilities in the 2 drawing conditions:  the command clock relies more 
heavily on memory and language; the copy clock relies more on executive function and visual-
spatial perception (Rouleau et al. 1996). 


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The dCDT uses a novel digitising ballpoint pen that functions in the subject’s hand as an 
ordinary ballpoint pen, but digitally records its position on the paper and encrypts the data.  
Changes in pen position (that cannot be seen by the naked eye) are measured and data are time-
stamped to enable the system to capture the entire sequence of behaviours, for example, every 
stroke, pause or hesitation (Souillard-Mandar et al. 2016).
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), 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 tested for the apolipoprotein E (APOE) genotype (ε2, ε3, 
ε4) to determine whether these genetic variants are potentially associated with a pharmacological 
response to LY3303560.  Apolipoprotein E genotype has been demonstrated even in small 
sample sizes to be associated with vasogenic oedema complications.  In addition, where local 
regulations allow, the sample will be stored and analysis may be performed on other genetic 
variants thought to play a role in response to LY3303560, response to antidementia concomitant 
therapy, and/or molecular subtypes of AD to test their association with observed clinical 
outcomes when taking the study drug.  While it is unlikely that signals from small trials can be 
suggested by genetic variance, samples may be saved for analysis particularly for retrospective 
review if future studies detect associations or other researchers report significant findings.  At the 
current time, possible target genes include, but are not limited to, FcγRII, FCγRIII, CLU, CR1, 
PICALM, MAPT, BIN1, PSEN1, and PSEN2.
In the event of an unexpected AE or the observation of unusual pharmacological response, the 
pharmacogenetic samples may be genotyped and analysis may be performed to evaluate a 
genetic association with response to LY3303560.  These investigations may be limited to a 
focused candidate gene study or, if appropriate, genome wide analysis may be performed to 
identify regions of the genome associated with the variability observed in drug response.  The 
pharmacogenetic samples will only be used for investigations related to disease and drug or class 
of drugs under study in the context of this clinical programme.  They will not be used for broad 
exploratory unspecified disease or population genetic analysis.
Other samples may be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to disease process, pathways associated with disease state, and/or
mechanism of action of the IPs.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs/IRBs impose shorter time limits, for the study at a 
facility selected by Lilly or its designee.  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 LY3303560 or after LY3303560 is commercially available.  


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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, multiplex assays, and candidate gene studies.  
Regardless of technology utilised, data generated will be used only for the specific research 
scope described in this section. 
9.8.
Biomarkers 
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PDs, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements.
Serum, plasma, CSF, and whole blood ribonucleic acid (RNA) samples for non-pharmacogenetic 
biomarker research will be collected at the times specified in the Schedule of Activities (Section 
2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3303560, pathways associated with LY3303560, mechanism of action of LY3303560, and/or 
research method development, or for validating diagnostic tools or assay(s) related to 
neurodegenerative diseases.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs/IRBs impose shorter time limits, at a facility selected by 
Lilly or its designee.  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 LY3303560 or after LY3303560 is commercially available.  
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
A total of 24 patients may be enrolled to ensure 16 complete the study. The sample sizeis
customary for Phase 1 studies evaluating safety, PK and/or PD parameters.
It is expected that at least 4 Japanese patients will be enrolled into the study. Patients will be 
stratified by Japanese/non-Japanese but not by disease severity at randomisation.
Patients who are randomised but do not complete the study may be replaced to ensure that 
enough patients complete the study (see Section 5.2).
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of patient disposition will be provided at the end of the study. 
All patients 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.
10.2.2. Study Participant Characteristics
The patient’s age, sex, race, weight, height, APOE status, and/or other demographic 
characteristics will be recorded and may be used in the PK, PD, and safety analyses as 
quantitative or classification variables.  These characteristics will be listed and summarised at 
baseline, with the exception of weight, which will also be summarised over time.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on the full analysis set.  This set includes all data 
from all randomised patients receiving at least 1 dose of the IMP according to the treatment the 
patients actually received.  Safety analyses will be conducted for all enrolled patients, whether or 
not they completed all protocol requirements. Pharmacodynamic analyses will be conducted on 
all randomised participants who take at least 1 dose of study treatment and have at least 1 
postdose PD measurement relevant to the endpoint.
Summary statistics, data tabulations, and data graphs by population (Japanese and non-Japanese, 
and combined) will be provided as appropriate.
Analyses will be reported by  dose.  Patients receiving placebo will be pooled into 1 group.  
All total and subscale scores will be derived from individual items.  If any individual item is 
missing, the corresponding total and subscale scores will be considered missing, except for the 


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ADAS-Cog14, which will be imputed.  The imputation algorithm will be specified in the 
statistical analysis plan (SAP).
No formal hypothesis tests are planned.Additional exploratory analyses of the data will be 
conducted as deemed appropriate. 
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IMP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarised using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IMP as perceived by the investigator.  Symptoms reported to occur prior to randomisation
will be distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.
The number of IMP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include AEs, MRI, safety laboratory parameters, vital 
signs, and ECG parameters.  The parameters will be listed and summarised using standard 
descriptive statistics.  Additional analysis will be performed if warranted upon review of the 
data.  Outliers will also be identified and listed where appropriate.  Additional analyses may be 
performed if warranted upon review of the data. All planned safety analyses will be detailed in 
the SAP.
Shift tables will be constructed for each dose group to assess the incidence of and changes in
vasogenic oedema and microhaemorrhage counts pre- and post-dose (by time) based on MRI.
Suicide-related thoughts and behaviours based on the C-SSRS will be listed by patient.  Only 
time points and patients that show suicidal ideation/behaviour will be displayed (i.e., not all of 
the “no” responses will be displayed).
An assessment of potential QTc prolongation will be carried out in 2 ways:
1. A summary of the number of patients experiencing a maximum increase from baseline in 
QTcF interval will be summarised for each treatment according to the following 
categories:  >30 ms and >60 ms.  In addition, there will be a summary by treatment of the
number of patients with QTcF postdose values in the following categories:  >450 ms, 
>480 ms and >500 ms.
2. Scatter plots will be created of QTcF versus LY3303560 concentration and change from 
baseline QTcF versus LY3303560 concentration (for time points where there is matched 
LY3303560 concentration and QTcF available).  Placebo data will be included in the plot 
with concentration imputed to zero.  The reference line of 450, 480, and 500 ms will be 
used for the QTcF versus concentration plot; the reference line will be 10, 30 and 60 ms 
for the QTcF change from baseline versus concentration plot.  Analysis will be performed 


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to assess the mean change in QTcF as a function of plasma drug concentration.  The 
average of the triplicate QTcF measurements will be computed at each of the scheduled 
time points, and baseline will be the mean of the triplicate measurements collected prior 
to dosing at time 0 in each treatment period.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Standard non-compartmental methods of analysis and model-based approaches using non-linear 
mixed effects modeling (NONMEM) or other appropriate software may be implemented to 
estimate PK parameters including Cmax, area under the concentration curve during the dosing 
interval (AUC), half-life, clearance, and volume of distribution after IV administration of 
LY3303560.  The accumulation ratio, expressed as either AUC, Cmax, or minimum observed 
drug concentration (Cmin), may be reported.  
An analysis of the effect of dose, concentration or demographic factors on the PK parameters 
may be conducted.  
An analysis relating LY3303560 serum exposure to LY3303560 CSF concentrations may be 
conducted.
Exploratory PK analysis comparing Japanese and non-Japanese subjects may be conducted.
10.3.3. Imaging Analyses
Summary statistics of the flortaucipir F 18 standardised uptake value ratio (SUVr) will be 
provided by treatment (70 and 210 mg, and placebo) and visit (baseline and Visit 13 or Visit 20). 
Summary statistics of change from baseline and percentage change from baseline in SUVr will 
also be provided. Summary statistics may also be provided for SUVrs in individual and other 
composite brain regions if needed.
Changes in regional brain volume and functional connectivity in brain networks captured by 
MRI over the course of the study will be explored and summarised.  Magnetic resonance 
imaging will be obtained every 8-12 weeks; therefore, a mixed model repeated measures 
(MMRM) may be conducted fitting baseline, treatment and study visit as fixed effects.
Additionally, the relationship between LY3303560 serum exposure and imaging endpoints may 
be explored graphically or by a modeling approach.
10.3.4. Exploratory Pharmacodynamic Analyses
10.3.4.1. Pharmacodynamic Parameter Estimation
The concentration of plasma tau, and the concentration of CSF biomarkers, including tau, p-tau, 
Aβ1-42 and neurogranin, will be determined. Plasma and CSF biomarker data will be 
summarised statistically and/or illustrated graphically by time and dose.  The mean change in 
concentration of the plasma and CSF biomarkers from predose will be evaluated.
No formal statistical analyses of biomarkers are planned.


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10.3.4.2. Cognition Analyses
ADAS-Cog14, NTB, MMSE, dCDT, and ADCS-MCI-ADL24 will all be summarised and may 
be analysed using an MMRM with preinfusion cognitive measures as a baseline covariate and 
fixed effects of dose and study visit.  All cognition analyses are exploratory and underpowered to 
detect a clinically meaningful effect.
Correlations between cognition endpoints and flortaucipir F 18 SUVr may be explored.
10.3.4.3. Evaluation of Immunogenicity
The frequency of antibody formation to LY3303560 will be determined.  If a neutralisation assay 
is performed, the frequency of neutralising antibodies will be determined.  The relationship 
between the presence (or absence) of antibodies and clinical parameters (AEs, efficacy measures, 
and so on) will be assessed.  Likewise, the relationship between the presence of antibodies and 
the PK parameters and PD response to LY3303560 will be assessed.  
10.3.5. Exploratory Pharmacokinetic/Pharmacodynamic Analyses 
A model-based approach may be implemented using NONMEM or other appropriate software to 
estimate PK/PD parameters.  Exploratory analyses may be conducted to characterise the 
relationship between changes in cognition endpoints, plasma and/or CSF biomarkers, and 
exposure of LY3303560.  
10.3.6. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.
The Lilly study team will review safety data obtained on an ongoing basis, to assure patient 
safety. 
Safety and/or PK interim access to data (IAD) reviews are scheduled to occur throughout the 
study. 
The investigator(s) and the Lilly study team will make the determination regarding dose 
escalation based on their review of the safety and tolerability data, along with available PK data, 
as applicable.  Anti-drug antibody titres will also be reviewed, if available.  The investigator will 
remain blinded and the Lilly study team will be unblinded during these reviews for dose 
escalation.  The specifics about the timing of the dose escalation reviews and the procedures for 
selecting doses are described in the study design and dose modification sections of the protocol 
(Sections 5 and 7.4, respectively).
For each cohort, IADs for review of safety data, including ADA titres (if available), and PK data 
will be conducted at 16 weeks (4 weeks after the fourth dose [Day 113]) to evaluate the safety, 
PK and PD of LY3303560 at steady state.  Across the study, a review of safety data, including 
ADA titres (along with PK data, if applicable) will be conducted at approximately quarterly
intervals throughout the treatment and follow-up period.  These IADs may align with (and be 
included in) other pre-planned IADs or may be separate.


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Additional IADs may also be conducted to summarise data for internal decision-making and/or 
support of subsequent clinical studies/regulatory agency submissions/IB annual updates, as 
required.
There will be regular reviews of PD data by the Lilly study team.


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11.
References
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Albert MS, Dekosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, 
Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild 
cognitive impairment due to Alzheimer’s disease: recommendations from the National 
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Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270-279.
Auriacombe S, Helmer C, Amieva H, Berr C, Dubois B, Dartigues JF. Validity of the free and 
cued selective reminding test in predicting dementia: The 3C study. Neurology. 
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Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, Ferris S. An inventory to 
assess activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s 
Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S33-S39.
Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol. 1987;3(1):13-
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Grober E, Sanders AE, Hall C, Lipton RB. Free and cued reminding identifies very mild 
dementia in primary care. Alzheimer Dis Assoc Disord. 2010;24(3):284-290.
Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M. A neuropsychological 
test battery for use in Alzheimer disease clinical trials. Arch Neurol. 2007;64(9):1323-1329.
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, 
Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, 
Trojanowski JQ, Vinters HV, Montine TJ. National Institute on Aging – Alzheimer's 
Association guidelines on neuropathologic assessment of Alzheimer's disease. Alzheimers 
Dement. 2012;8(1):1-13.
Lichtenstein L, Ron Y, Kivity S, Ben-Horin S, Israeli E, Fraser GM, Dotan I, Chowers Y, 
Confino-Cohen R, Weiss B. Infliximab-related infusion reactions: systematic review. J Crohns 
Colitis. 2015;9(9):806-815.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, 
Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, 
Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer’s 
disease: recommendations from the National Institute on Aging-Alzheimer’s Association 
workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 
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Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, Sano M, Bieliauskas 
L, Geldmacher D, Clark C, Thal LJ. Development of cognitive instruments for use in clinical 
trials of antidementia drugs: additions to the Alzheimer’s Disease Assessment Scale that 
broaden its scope. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord. 
1997;11(suppl 2):S13-S21.
Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch 
MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, 
Hyman BT; National Institute on Aging; Alzheimer’s Association. National Institute on 
Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's 
disease: a practical approach. Acta Neuropathol. 2012;123(1):1-11.
Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 
1993;43(11):2412-2414.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-1043.
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry.
1984;141(11):1356-1364.
Rouleau I, Salmon DP, Butters N. Longitudinal analysis of clock drawing in Alzheimer's disease 
patients. Brain Cogn. 1996;31:17-34.
Scholl M, Lockhart SN, Schonhaut DR, O'Neil JP, Janabi M, Ossenkoppele R, Baker SL, Vogel 
JW, Faria J, Schwimmer HD, Rabinovici GD, Jagust WJ. PET Imaging of Tau Deposition in 
the Aging Human Brain. Neuron. 2016;89(5):971-982.
Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, Joshi AD, Devous MD Sr, 
Mintun MS. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key 
features of Braak histopathological stages. Brain. 2016;139(Pt 5):1539-1550.
Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron. 1991;6(4):487-498.
Shahim P, Tegner Y, Wilson DH, Randall J, Skillback T, Pazooki D, Kallberg B, Blennow K, 
Zetterberg H: Blood biomarkers for brain injury in concussed professional ice hockey players.
JAMA neurology. 2014;71:684-692.
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. 
Confidence interval criteria for assessment of dose proportionality. Pharm Res.
2000;17(10):1278-1283.
Souillard-Mandar W, Davis R, Rudin C, Au R, Libon DJ, Swenson R, Price CC, Lamar M, 
Penney DL. Learning Classification Models of Cognitive Conditions from Subtle Behaviors in 
the Digital Clock Drawing Test. Mach Learn. 2016;102:393-441.
Zetterberg H, Wilson D, Andreasson U, Minthon L, Blennow K, Randall J, Hansson O. Plasma 
tau levels in Alzheimer's disease. Alzheimers Res Ther. 2013;5(2):9.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
Aβ
Amyloid-beta (amyloid-β)
AD
Alzheimer’s disease
ADA
Anti-drug antibody
ADAS-Cog14
14-item Alzheimer's Disease Assessment Scale – Cognition
ADCS-MCI-ADL24
24-question Alzheimer's Disease Cooperative Study/Activities of Daily Living scale 
adapted for patients with MCI
AE
Adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product.
ARIA
amyloid-related imaging abnormality
assent
Agreement from a child or other individual who is not legally capable of providing 
consent, but who can understand the circumstances and potential risks involved in 
participating in a study (required by some institutional review boards [IRBs]/ethical 
review boards [ERBs]). 
blinding
A procedure in which one or more parties to the trial are kept unaware of the 
treatment assignment(s).  Unless otherwise specified, blinding will remain in effect 
until final database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not. A double-blind 
study is one in which neither the patient nor any of the investigator or sponsor staff 
who are involved in the treatment or clinical evaluation of the subjects are aware of 
the treatment received
BMI
body mass index
CDR/CDR-SB
Clinical Dementia Rating/CDR-Sum of Boxes
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum drug concentration
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 the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.


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confirmation
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Lilly is confident that results 
are accurate.  Confirmation will either occur immediately after initial testing or will 
require that samples be held to be retested at some defined time point, depending on 
the steps required to obtain confirmed results.
CP
Clinical Pharmacologist
CRF
Case report form
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.
CSE
clinically significant event
CSF
Cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
dCDT
Digital clock drawing test
ECG
Electrocardiogram
EDTA
Ethylene diamine tetraacetic acid
enrol
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial 
are those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.[
ERB
Ethical review board
FCSRT-IR
Free and Cued Selective Reminding Test with Immediate Recall
Florbetaben
Florbetapir
Flutemetomol
PET scanning radiopharmaceutical compounds containing the radionuclide fluorine-
18 approved by the FDA as a diagnostic tool for AD.
Flortaucipir F 18 (18F-
AV-1451, also known as 
[F-18]T807 or 
LY3191748)
Investigational PET scanning radiopharmaceutical compound containing the 
radionuclide fluorine-18 that binds with high affinity and selectivity to aggregated 
tau pathology.
GCP
Good clinical practice
IAD
Interim access to data
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation


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IMP
investigational medicinal product
IND
Investigational New Drug:  An application to the FDA to allow testing of a new drug 
in humans.
informed consent
A process by which a patient voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial 
that are relevant to the patient’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form.  
Investigational 
medicinal product (IMP)
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 authorised form, or 
marketed products used for an unauthorised indication, or marketed products used to 
gain further information about the authorised form.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IV
Intravenous
IWRS
interactive web response system
LP
Lumbar puncture
MAD
Multiple-ascending dose
MCI
Mild cognitive impairment
MMRM
mixed model repeated measures
MMSE
Mini-Mental State Examination
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
MUBADA
Multi-block barycentric discriminant analysis
NFT
Neurofibrillary tangle
Non-investigational 
medicinal product (non-
IMP)
A product that is not being tested or used as a reference in the clinical trial, but is 
provided to subjects and used in accordance with the protocol, such as:  concomitant 
or rescue/escape medication for preventative, diagnostic, or therapeutic reasons, 
medication to ensure adequate medical care, and/or products used to induce a 
physiological response.
NTB
Neuropsychological Test Battery
PET
Positron emission tomography
PK/PD
Pharmacokinetic(s)/pharmacodynamic(s)


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Q4W
every 4 weeks
QTc/QTcF
corrected Q-T interval/Q-T interval corrected using the Fridericia formula
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
subcutaneous
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 trial.
SHFU
Self-harm follow-up assessment  
SHSF
Self-harm supplement form
SUSARs
Suspected unexpected serious adverse reactions
SUVr
Standardised uptake value ratio
TEAE
Treatment-emergent adverse event:  Any 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 
TPO
third-party organisation


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Appendix 2.
Clinical Laboratory Tests


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Laboratory Tests at Screening and During the Study (Performed at Local Laboratory)
Haematology:
Clinical chemistry:
Haematocrit
Sodium
Haemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonated
Mean cell volume 
Chloride
Mean cell haemoglobin 
Calcium
Mean cell haemoglobin concentration 
Glucose (random)
Leucocytes (WBC)
Blood urea nitrogen 
Cell morphology (absolute or relative % counts)
Total protein
Neutrophils
Albumin
Lymphocytes
Total bilirubin
Monocytes
Alkaline phosphatase
Eosinophils
Aspartate aminotransferase (SGOT)
Basophils
Alanine aminotransferase (SGPT)
Platelets
Creatinine
Urinalysis:
Ethanol testingb,c
Specific gravity
Urine drug screenc
pH
Hepatitis B surface antigene
Protein
Hepatitis C antibodye
Glucose
HIVe
Ketones
Bilirubin
FSH (females only; if required to confirm 
postmenopausal status)e
Urobilinogen
Blood
Nitrite
Microscopic examination of sedimenta
Coagulation:
Prothrombin time/international normalised ratio
Activated partial thromboplastin time
Abbreviations:  CRU = clinical research unit; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; SGOT = serum glutamic oxaloacetic transaminase; SGPT = glutamic-pyruvic transaminase; RBC = red 
blood cell; WBC = white blood cell.
a
Test only if dipstick result is abnormal.
b
At site discretion this may be a serum, breath, or urine sample.
c
Urine drug screen and ethanol level may be repeated before admission to the CRU.
d
May not be collected in Japan.
e
Performed at screening only.  


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Laboratory Tests During the Study (Performed at Central Laboratory)
Haematologya:
Clinical chemistrya:
Haematocrit
Sodium
Haemoglobin
Potassium
Erythrocyte count (RBC)a
Bicarbonatec
Mean cell volume 
Uric acid
Mean cell haemoglobin 
Chloride
Mean cell haemoglobin concentration 
Calcium
Leucocytes (WBC)
Glucose 
Cell morphology (absolute or relative % counts)
Blood urea nitrogen 
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase
Basophils
Aspartate aminotransferase (SGOT)
Platelets
Alanine aminotransferase (SGPT)
Creatinine
Urinalysisa:
Total cholesterol
Specific gravity
Low-density lipoprotein cholesterol
pH
High-density lipoprotein cholesterol
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Anti-LY antibodies/immunogenicityd
Blood
Exploratory immune safety laboratory testse
Nitrite
Microscopic examination of sedimentb
Abbreviations:  LY = LY3303560; SGOT = serum glutamic oxaloacetic transaminase; SGPT = glutamic-pyruvic 
transaminase; RBC = red blood cells; WBC = white blood cells.
a
Results will be validated by the central laboratory at the time of initial testing.
b
Test only if dipstick result is abnormal.
c
May not be collected in Japan.
d
Results will be validated by the central laboratory.
e
If testing ordered, will be performed at central laboratory.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient/study partner understands the potential risks and benefits of 
participating in the study.

ensuring that informed consent is given by each patient/study partner or legal 
representative.  This includes obtaining the appropriate signatures and dates on the 
informed consent form (ICF) prior to the performance of any protocol procedures and 
prior to the administration of investigational product.

answering any questions the patient/study partner may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the patient’s 
willingness to continue his or her participation in the trial.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by ICH guidelines and other applicable laws and 
regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the International 
Conference on Harmonisation (ICH) guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure (IB) and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organisation.


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Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and
send a copy of the signed page to a Lilly representative.
Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most enrolled patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.


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Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Blood and CSF Sampling Summary
The following tables summarise the approximate number of venipunctures and blood volumes 
for all blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
In addition, CSF sampling during the study is also summarised.  Fewer venipunctures and blood 
draws and CSF draws may actually occur, but this will not require a protocol amendment.
Protocol I8G-MC-LMDD Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
26
1
26
Clinical laboratory testsa
12
20
240
Blood RNA
10
4
40
Coagulation tests
6
2
12
Serum LY3303560 PKb
3
35 (+5)
105 (15)
Blood discard for cannula patency
3
24
72
Serum for immunogenicity 
6
9
54
Pharmacogenetic sample
10
1
10
Plasma for Tau PDb
2
35 (+5)
70 (10)
Stored EDTA plasma sample
10
12
120
Stored serum sample
2
12
24
Serum sample for exploratory 
immune safety
14
5
70
Total
843 (868)
Total for clinical purposes (rounded to nearest 10 mL)
850 (870)
a
Additional samples may be drawn if needed for safety purposes.
b
A maximum of 5 samples may be collected at additional time points during the study if warranted and agreed 
upon between both the investigator and sponsor.
Protocol I8G-MC-LMDD CSF Sampling Summarya
Purpose
Maximum CSF Volume 
per Sample (mL)
Maximum Number 
of CSF Samples
Maximum Total 
Volume (mL)
CSF PK and PD
20b
3
60
Total
60
Total for clinical purposes (rounded up to nearest 10 mL)
60
Abbreviations:  CSF = cerebrospinal fluid; PD = pharmacodynamics(s); PK = pharmacokinetics.
a
Additional samples may be drawn if needed for evidence of CSF contamination.
b
For Japan sites, 10 mL.


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Appendix 5.
Management of Infusion Reactions


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Abbreviations:  BP = blood pressure; IM = intramuscular; IV = intravenous; NSAID = nonsteroidal anti-
inflammatory drug; PO = by mouth.
Continue supportive care in accordance with the symptoms/signs (Section 7.4.2.2).
Source:  Adapted from Lichtenstein et al. 2015.


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Appendix 6.
Protocol Amendment I8G-MC-LMDD(d) 
Summary
Multiple-Dose, Dose-Escalation Study to Assess the 
Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of LY3303560 in Patients with Mild 
Cognitive Impairment due to Alzheimer’s Disease or 
Mild to Moderate Alzheimer’s Disease
Overview
Protocol I8G-MC-LMDD “Multiple-Dose, Dose-Escalation Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of LY3303560 in Patients with Mild 
Cognitive Impairment due to Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease”
has been amended.  The new protocol is indicated by Amendment (d) and will be used to 
conduct the study in place of any preceding version of the protocol.
The overall changes made to this protocol are as follows:

In the Schedule of Activities in Section 2, the lumbar puncture at Visit 13, which was 
removed in protocol amendment (c), has been reinstated to accommodate patients who 
are following the 25-week dosing period.  A flortaucipir F 18 PET scan has been added to 
Visit 13 for the same reason.

The Schedule of Activities in Section 2 has been amended to show the LP and 
flortaucipir F 18 PET scan are not required at Visit 20 for patients who have had an LP or 
PET scan at Visits 13 or 19.  A flortaucipir F 18 PET scan has been added to Visit 19 for 
patients following the 25-week treatment period.

The Schedule of Activities (Section 2) has been amended to show that, after a patient has 
had 6 infusions with no infusion reaction, the observation period for subsequent infusions 
is reduced. However, should any infusion reaction occur for any patient, the monitoring 
period will be increased to at least 8 hours for all subsequent infusions.  To date, there 
have been no infusion reactions observed in 9 subjects in Cohort 1 (70 mg LY3303560) 
who have reached at least 6 months of dosing and 9 subjects in Cohort 2 (210 mg 
LY3303560) who have reached at least 3 months of dosing. 


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
Section 2.2.
MAD Treatment Period (Visits 2 to 19)


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Study Schedule Protocol I8G-MC-LMDD 
MAD Treatment Period (Visits 2 through 19) (concluded)
Visit
V2a
Rand
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
Day Relative to First Dose
-8
1b
2
4
8
15
29b
57b
85b
113b
141b
169b
197b
225b
253b
281b
309b
337b
Week
1
1
1
2
3
5
9
13
17
21
25
29
33
37
41
45
49
Tolerance Interval for Visit (days)
7a
0
+4 h
1
1
1
4
4
7
7
7
7
7
7
7
7
7
7
Imaging
Flortaucipir F 18 PETd,h
Xg
Xh
Xh
Laboratory Assessments (central laboratory unless otherwise noted)
Lumbar punctured,j
Xi
Xl
Xl
b
Patients may be admitted on Day -1, to perform pre-dose tests, at the discretion of the site.  For all dosing daysthe first 6 infusions, patients must be observed 
closely for at least 4 hours following each infusion of LY3303560.after dosing and will remain in the investigative site for at least 8 hours after dosing.After 
the first 6 infusions, a minimum post-infusion observation time of 2 hours will be required for all subsequent infusions.  If any patient shows symptoms of an 
infusion reaction, the observation time will be increased to a minimum of 8 hours for that infusion and all future infusions.  If deemed necessary, for safety or 
feasibility reasons, patients may remain in the investigative site for a longer duration at the discretion of the investigator.
h
The flortaucipir F 18 PET scan should be conducted at Visit 13 should the patient follow the 25-week treatment regimen or at Visit 19 for the 49-week 
treatment regimen. The flortaucipir F 18 PET scan should be completed at Visit 20 if the patient discontinues treatment after Visit 13 and before Visit 19.
Patients permanently discontinued from study treatment due to initiation of a prohibited medication known to prolong the QT-interval should not have an ED 
flortaucipir F 18 scan unless the scan can be performed prior to initiation of the prohibited medication.  Patients who have continued on study after 
introduction of a drug known to prolong QT interval (with sponsor approval) need a minimum of 14 days or 5 half-lives, whichever is longer, without that 
drug prior to the flortaucipir scan.
k
LPs are scheduled at either Visits 13, 19, 20, or early discontinuation. The corresponding coagulation test is rRequired at leastup to 2 weeks prior to the next 
scheduled LP. (Visit 20 or early discontinuation).
l
The LP should be conducted at Visit 13 should the patient follow the 25-week treatment regimen or at Visit 19 for the 49-week treatment regimen. The LP 
should be completed at Visit 20 if the patient discontinues treatment after Visit 13 and before Visit 19.


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2.3.
Follow-up Assessments (Visits 20 to 24)
Study Schedule Protocol I8G-MC-LMDD - MAD Treatment Period; Follow-up Assessments (Visits 20 to 24)
Visit
V20
V21
V22
V23
V24
ED
Day Relative to First Dose (for 25-week 
treatment phase)a
189
203
231
259
287
Week (for 25-week treatment)a
27 
29
33
37 
41
Day Relative to First Dose (for 49-week 
treatment phase)a
351
365
393
421
449
Week (for 49-week treatment)a
51
53
57
61
65
Tolerance Interval for Visit (days)
7
7
7
7
7
Imaging
MRId
X
X
Flortaucipir F 18 PETc,d
X (if not done 
at V13 or 19)
X
Laboratory Assessments (central laboratory unless otherwise noted)
Lumbar puncturec,e,g
X (if not done 
at V13 or 19)
X
Notes:
(i) Patients who have completed at least the 25-week treatment period will be followed up for 16 weeks after 
completion of dosing (Visits 20 to 24) and will return to the investigational site for safety assessments, PK, and 
plasma tau (PD) sampling on Visits 20 to 24 as per the Schedule of Activities.
d
The flortaucipir F 18 PET scan should be conducted at Visit 13 should the patients follow the 25-week treatment 
or at Visit 19 for the 49 week treatment period. The flortaucipir F 18 PET scan should be completed at Visit 20 if 
the patient discontinues treatment after Visit 13 and before Visit 19. Patients permanently discontinued from 
study treatment due to initiation of a prohibited medication known to prolong the QT interval should not have an 
ED flortaucipir F 18 scan unless the scan can be performed prior to initiation of the prohibited medication.  
Patients who have continued on study after introduction of a drug known to prolong QT interval (with sponsor 
approval) need a minimum of 14 days or 5 half-lives, whichever is longer, without that drug prior to the 
flortaucipir scan. If patients have had a flortaucipir F 18 PET scan at Visit 13 (as per amendment (b)), they will 
not be required to have another scan at Visit 20.
e
Coagulation test results should be reviewed before each LP.  Concomitant medications should be reviewed to 
ensure that no changes to anticoagulation or antiplatelet therapy have occurred since the last coagulation test.  
The coagulation test is required up to 2 weeks prior to the LP, if  LP is performed at Visit 20.
g
The LP should be conducted at Visit 13 should the patients follow the 25-week treatment or at Visit 19 for the  
49-week week treatment period. The LP should be completed at Visit 20 if the patient discontinues treatment 
after Visit 13 and before Visit 19.


I8G-MC-LMDD(d) Clinical Pharmacology Protocol
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LY3303560
5.1.
Overall Design
Previous diagram:
Visit 16ǂ
Visit 13@
Visit 20**
Visit 23ǂ
Visit 2#
Visit 8ǂ
Visit 10ǂ
Cohort 1 
70 mg IV Q4W
6LY:2PL
Cohort 2 
210 mg IV Q4W 
6LY:2PL
Biomarkers
Visit 1
Screening
16-week 
safety/PK IAD
49-week treatment phase (13 doses)
16-week follow-up
16-week follow-up
Visit 1 (Screening):
Amyloid scan (diagnosis)
Cognition
MRI
ǂVisits 8, 10, 16, 19, 23:  MRI
@Visit 13:
Cognition
MRI
Flortaucipir PET
**Visit 20:
Flortaucipir PET (if not done at Visit 13)
Cognition
Visit 1
Screening
#Visit 2:
Flortaucipir PET
Cognition
Visit 19ǂ
Visit 16ǂ
Visit 13@
Visit 20**
Visit 8ǂ
Visit 10ǂ
49-week treatment phase (13 doses)
Visit 19ǂ
Visit 23ǂ
Visit 2#
Note:  Subsequent cohorts will be initiated following a review of the safety data from a minimum of 4 patients having received at least 2 
doses of LY3303560 and 1 patient having received at least 2 doses of placebo at the prior dose level
16-week 
safety/PK IAD


I8G-MC-LMDD(d) Clinical Pharmacology Protocol
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Revised diagram:
Figure LMDD.1.
Illustration of study design.
Visit 16ǂ
Visit 13@
Visit 20**
Visit 23ǂ
Visit 2#
Visit 8ǂ
Visit 10ǂ
Cohort 1 
70 mg IV Q4W
6LY:2PL
Cohort 2 
210 mg IV Q4W 
6LY:2PL
Biomarkers
Visit 1
Screening
16-week 
safety/PK IAD
49-week treatment phase (13 doses)
16-week follow-up
16-week follow-up
Visit 1 (Screening):
Amyloid scan (diagnosis)
Cognition
MRI
ǂVisits 8, 10, 16, 23:  MRI
@Visit 13:
Cognition
MRI
Flortaucipir PET
**Visit 20:
Flortaucipir PET (if not done at Visit 13 or 19)
Cognition
Visit 1
Screening
#Visit 2:
Flortaucipir PET
Cognition
Visit 19*
Visit 16ǂ
Visit 13@
Visit 20**
Visit 8ǂ
Visit 10ǂ
49-week treatment phase (13 doses)
Visit 19*
Visit 23ǂ
Visit 2#
Note:  Subsequent cohorts will be initiated following a review of the safety data from a minimum of 4 patients having received at least 2 
doses of LY3303560 and 1 patient having received at least 2 doses of placebo at the prior dose level
16-week 
safety/PK IAD
*Visit 19:
MRI
Flortaucipir PET


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LY3303560
5.1.2. Dosing for all Cohorts
Patients will receive their study drug at the investigational site after all predose procedures have 
been completed and must be observed closely for at least 4 hours following each infusion of 
LY3303560 for the first 6 infusions.  After the first 6 infusions, a minimum post-infusion 
observation time of 2 hours will be required for all subsequent infusions, and remain in the 
investigative site for at least 8 hours, after each administration. If any patient shows symptoms of 
an infusion reaction, the observation time will be increased to a minimum of 8 hours for that 
infusion and all subsequent infusions.
5.1.3. Treatment Phase
Each cohort will consist of 8 patients randomised (6 LY3303560:  2 placebo) to a 25-week MAD 
treatment period (7 doses), after which they will be given the option of continuing the treatment 
up to 49 weeks (up to 6 further doses, Visits 14 to 19).  Patients who have completed at least the 
25-week treatment period will be followed up for 16 weeks after completion of dosing (Visits 20 
to 24) and will return to the investigational site for safety assessments and PK and biomarker 
sampling throughout Visits 20 to 24 as per the Schedule of Activities (seein Section 2 for the 
Schedule of Activities).
7.1.
Treatment Administered
[…]
The minimum time for close observation at the investigative site following dosing is 4 hours for 
the first 6 IV infusions and 2 hours for subsequent IV infusions.  If any patient shows symptoms 
of an infusion reaction, the observation time will be increased to 8 hours for that infusion and all 
subsequent infusions.  The site must have resuscitation equipment, emergency drugs, and 
appropriately trained staff available during dosing and while patients are under observation after 
dosing.


Leo Document ID = 14983b1d-b9d2-43e0-b83d-6c209b7b1b15
Approver: 
Approval Date & Time: 02-May-2018 17:37:25 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 02-May-2018 17:37:25 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan Version 2 LMDD 
 
Multiple-Dose, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of LY3303560 in Patients with Mild Cognitive Impairment due to Alzheimer’s 
Disease or Mild to Moderate Alzheimer’s Disease 
 
 
 NCT03019536 
 
Approval date: 27-Jun-2018 


I8G-MC-LMDD Statistical Analysis Plan Version 2
Page 1
LY3303560
Statistical Analysis Plan for Clinical Studies:  
I8G-MC-LMDD:  Study Title Multiple-Dose, Dose-Escalation Study to 
Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of LY3303560 in Patients with Mild Cognitive 
Impairment due to Alzheimer’s Disease or Mild to Moderate 
Alzheimer’s Disease
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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..
LY3303560
Phase 1 MAD study to assess the safety, PK and PD of LY3303560 in patients in MCI and 
AD.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8G-MC-LMDD
Phase 1
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below.
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:  20-
December-2016.
Approval Date: 27-Jun-2018 GMT


I8G-MC-LMDD Statistical Analysis Plan Version 2
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LY3303560
1.
Table of Contents
Section
Page
Statistical Analysis Plan for Clinical Studies:   I8G-MC-LMDD:  Study 
Title Multiple-Dose, Dose-Escalation Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
LY3303560 in Patients with Mild Cognitive Impairment due to 
Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease ..........................................1
1.
Table of Contents................................................................................................................2
2.
Revision History .................................................................................................................5
3.
Study Objectives.................................................................................................................6
4.
Study Design.......................................................................................................................8
4.1.
Method of Assignment to Treatment ..............................................................................8
5.
A Priori Statistical Methods ................................................................................................9
5.1.
General Considerations ..................................................................................................9
5.1.1.
Handling of Dropouts or Missing Data...................................................................9
5.1.2.
Multicentre Studies ................................................................................................9
5.1.3.
Multiple Comparisons/Multiplicity.........................................................................9
5.2.
Patient Disposition .......................................................................................................10
5.2.1.
Patient Characteristics..........................................................................................10
5.3.
Protocol deviations.......................................................................................................10
5.3.1.
Japanese and non-Japanese Patients .....................................................................11
5.3.2.
Subgroup Analyses ..............................................................................................11
5.3.3.
Concomitant Therapy...........................................................................................11
5.3.4.
Extent of Exposure...............................................................................................11
5.4.
Safety Analyses............................................................................................................11
5.4.1.
Adverse Events ....................................................................................................11
5.4.2.
Safety MRI ..........................................................................................................12
5.4.3.
Evaluation of Immunogenicity .............................................................................12
5.4.4.
C-SSRS................................................................................................................12
5.4.5.
QTcF ...................................................................................................................12
5.5.
Pharmacokinetic Parameter Estimation.........................................................................13
5.5.1.
Pharmacokinetic Statistical Inference...................................................................13
5.6.
Imaging Analyses.........................................................................................................13
5.6.1.
Flortaucipir SUVr ................................................................................................13
5.6.2.
Brain volume and functional connectivity ............................................................15
5.6.3.
Amyloid scans .....................................................................................................15
5.7.
Exploratory Pharmacodynamic Analyses......................................................................15


I8G-MC-LMDD Statistical Analysis Plan Version 2
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LY3303560
5.7.1.
Pharmacodynamic Parameter Estimation..............................................................15
5.7.2.
Cognition Analyses..............................................................................................15
5.7.3.
Exploratory Pharmacokinetic/Pharmacodynamic Analyses...................................16
5.7.4.
Interim Analyses..................................................................................................16
5.7.4.1.
Safety reviews for dose escalation, 16 week reviews per 
cohort, quarterly safety reviews and end of cohort 
reviews...........................................................................................................16
5.7.4.2.
Internal decision making IAD for Phase 2/3 trigger ........................................16
5.7.5.
Other IADs ..........................................................................................................16
5.8.
Clinical Trial Registry Analyses...................................................................................16
6.
References ........................................................................................................................18


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Table of Contents
Table
Page
Table LMDD.1.
Description of Programmable Protocol Deviations....................................10


I8G-MC-LMDD Statistical Analysis Plan Version 2
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LY3303560
2.
Revision History
SAP Version 1 was approved prior to first patient visit and prior to unblinding
SAP Version 2 was approved prior to prior to unblinding and final database lock.  Changes 
reflect the changes made to the LMDD protocol as defined in LMDD (b) and (d).
Briefly, in amendment (b), the higher dose cohorts of LY3303560 (700 and 1400 mg) have been
removed based on an update to the PK/PD model originally used to predict the LY3303560
efficacious dose range.  In addition, the duration of dosing in the LMDD study has been reduced 
from 12 months to 6 months, based on emerging longitudinal and baseline data using tau 
positron emission tomography (PET) imaging, which suggests that the Part B of the study is now 
insufficiently powered to assess the effects of LY3303560 on progression of tau pathology using 
the tau tracer flortaucipir F 18 PET over 12 months.  However the effects using the tau tracer on 
tau pathology of repeated every 4 week (Q4W) administrations in patients over approximately 6 
months (7 doses), with the option of extending the treatment period to up to 12 months (up to 6 
further doses), in the two remaining doses of Part A.
A decision was made by the team to not implement amendment c because the cohort 2 subjects 
would have had a LP at V13 per amendment b after which amendment c would be implemented 
and another LP would have been required at V20 per amendment c.  This is would have meant 
an extra LP for these subjects.
The overall changes made to protocol amendment b to create LMDD (d) are as follows:

In the Schedule of Activities in Section 2, the lumbar puncture at Visit 13, which was 
removed in protocol amendment (c), has been reinstated to accommodate patients who
are following the 25-week dosing period.  A flortaucipir F 18 PET scan has been added to 
Visit 13 for the same reason.

The Schedule of Activities in Section 2 has been amended to show the LP and 
flortaucipir F 18 PET scan are not required at Visit 20 for patients who have had an LP or 
PET scan at Visits 13 or 19.  A flortaucipir F 18 PET scan has been added to Visit 19 for 
patients following the 25-week treatment period.

The Schedule of Activities (Section 2) has been amended to show that, after a patient has 
had 6 infusions with no infusion reaction, the observation period for subsequent infusions
has been reduced to 2 hours.  However, should any infusion reaction occur for any 
patient, the monitoring period will be increased to at least 8 hours for all subsequent 
infusions.  To date, there have been no infusion reactions observed in 9 subjects in 
Cohort 1 (70 mg LY3303560) who have reached at least 6 months of dosing and 9 
subjects in Cohort 2 (210 mg LY3303560) who have reached at least 3 months of dosing.


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3.
Study Objectives
Primary
The primary objective of this study is to assess the safety 
and tolerability after 16 weeks of multiple doses of 
LY3303560 in patients with MCI due to AD or mild to 
moderate AD
Safety and tolerability will be assessed by monitoring 
treatment-emergent adverse events (TEAEs) 
Secondary

To assess the PK of LY3303560 in serum following 
multiple IV doses of LY3303560 in patients with 
MCI due to AD or mild to moderate AD 
Maximum serum concentration (Cmax) and the area 
under the serum concentration time curve during the 
dosing interval (AUC)
Exploratory Objectives

To evaluate the effects of multiple doses of 
LY3303560 on cognitive function in patients with 
MCI due to AD or mild to moderate AD

To evaluate the effects of multiple doses of 
LY3303560 on brain atrophy in patients with MCI 
due to AD or mild to moderate AD

To evaluate the effects of multiple doses of 
LY3303560 on brain functional connectivity in 
patients with MCI due to AD or mild to moderate 
AD

To evaluate the immunogenicity of multiple doses 
of LY3303560 in patients with MCI due to AD or 
mild to moderate AD

To evaluate the effects of multiple doses of 
LY3303560 on plasma and CSF biomarkers in 
patients with MCI due to AD or mild to moderate 
AD

To evaluate the effects of multiple doses of 
LY3303560 on tau pathology using the tau tracer 
flortaucipir F 18 in patients with MCI due to AD or 
mild to moderate AD

To determine the CSF concentration of LY3303560 
following multiple IV doses in patients with MCI 
due to AD or mild to moderate AD
ADAS-Cog14, ADCS-MCI-ADL24, NTB, MMSE, 
dCDT
Quantitative measures of brain atrophy derived from 
volumetric MRI scans
Quantitative measures of brain functional connectivity 
derived from functional MRI scans
Detection of anti-drug antibodies (ADA) 
Plasma tau concentration; CSF concentration of tau, p-
tau, Aβ1-42, and neurogranin
Quantitative endpoints from flortaucipir F 18 PET scans
Mean LY3303560 concentrations in CSF


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Exploratory Objectives (continued)

To explore the safety and tolerability of LY3303560 
in Japanese subjects in relation to non-Japanese 
subjects

To explore the PK of LY3303560 in Japanese 
subjects in relation to non-Japanese subjects
Safety and tolerability will be assessed by monitoring 
TEAEs
Cmax and AUC


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4.
Study Design
This is a Phase 1b, multi-site, patient- and investigator-blind, placebo-controlled, parallel-group
study in patients with MCI due to AD or mild to moderate AD to assess the safety, tolerability, 
PK and PD following multiple IV doses of LY3303560.  
The planned doses of LY3303560 are:  70 and 210, mg; however, dose levels may be adjusted 
based on emerging data from Study LMDA and from this current study, if indicated. 
Dose escalation decisions will be made following a review of the safety data from a minimum of 
4 patients having received at least 2 doses of LY3303560 and 1 patient having received at least 2 
doses of placebo at the prior dose level. The subsequent cohort will not begin dosing until all 8 
patients from the previous cohort have started dosing.  For each cohort, IADs for review of 
safety data, including ADA titres (if available), and PK data will be conducted at 16 weeks to 
evaluate the safety, PK and PD of LY3303560 at steady-state.
4.1.
Method of Assignment to Treatment
Assignment to treatment groups will be determined by a computer-generated random sequence 
within each dose cohort using an interactive web response system (IWRS).
For Cohorts 1 to 2, up to 12 patients may be enrolled so that approximately 8 patients per cohort 
(6 LY3303560:  2 placebo) provide data to Day 113.  The randomization will be such that the 
placebo assignments for the cohorts enrolling Japanese and non-Japanese subjects will be 
balanced between these 2 populations.


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5.
A Priori Statistical Methods
5.1.
General Considerations
Pharmacokinetic analyses will be conducted on the full analysis set (not including placebo).  
This set includes all data from all subjects receiving at least one dose of the investigational 
product.
Safety analyses will be conducted for all enrolled subjects who took study medication, whether
or not they completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  As this is 
a Phase 1 study and there will be no formal statistical hypothesis testing, any changes to the
planned analysis will not necessitate a protocol amendment and will be detailed in the study
report.  Summary statistics, data tabulations, and data graphs by ethnicity (Japanese and non-
Japanese, and combined) will be provided as appropriate.
Safety reporting will be conducted by Covance; with the exception of QTcF statistical analyses
which will be conducted by Eli Lilly.  All drug effects, PK, PD, imaging, cognition and 
exploratory reporting and analyses will be conducted by Eli Lilly.
Where two cohorts are given the same dose and formulation the patients will be pooled together 
and reported under the same dose levels.  Placebo will be pooled across all cohorts.
In recognition that there are now only two dose cohorts in this study, any statistical models 
detailed in the analysis plan may still be carried out in order to estimate parameters, in particular 
where changes from baseline are being considered.  Without recourse to statistical models, only 
those patients with both baseline and at least one post-baseline measurement can be included in 
any summary.  Estimates from statistical models may provide additional information, if 
interpreted appropriately.
5.1.1. Handling of Dropouts or Missing Data
Subjects or patients who discontinue may be replaced at the discretion of the sponsor and 
investigator.  The ethnicity of the replacement subject (Japanese or non-Japanese) should match 
the ethnicity of the discontinued patient, where possible.  Replacement patients will be allocated 
the same treatment as the dropout patient.
There will be no imputation of missing data.
5.1.2. Multicentre Studies
Due to this being a safety and tolerability study with low patient numbers per dose there is no
plan to fit centre as a covariate in any of the models.  The demographic/disposition listings will
make it clear which sites each patient were attributed to.
5.1.3. Multiple Comparisons/Multiplicity
No adjustments will be made for multiplicity.


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5.2.
Patient Disposition
A detailed description of patient disposition will be provided at the end of the study.  All patients
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.
5.2.1. Patient Characteristics
The patient’s age, sex, race, weight, height, APOE4 status or other demographic characteristics 
will be recorded and may be used in the PK, PD, and safety analyses as quantitative or 
classification variables.  These characteristics will be listed and summarised at baseline, with the 
exception of weight which will also be summarised over time.
5.3.
Protocol deviations
All clinically relevant programmable protocol deviations will be listed by pre-determined 
categories (e.g., inclusion/exclusion criteria, non-compliance with protocol procedures, use of 
excluded treatments, informed consent/assent process, continuing after meeting withdrawal 
criteria, or other).  The following protocol deviations relevant to this study have been identified 
in Table LMDD.1. 
Table LMDD.1.
Description of Programmable Protocol Deviations
Category 
Source
Methods of Identification 
Category:  Informed Consent 
Informed Consent Not 
Obtained/Missing/Late
Programmable 
(clinical database)
Compare all assessment dates to ICD date 
(except those assessments that may occur 
before ICD, e.g., disease assessments)
from SDTM datasets
Category:  Eligibility 
Participation of a subject(s) 
that did not meet study 
inclusion/exclusion criteria
Mixed 
(Monitoring and 
clinical database)
Review of the following programmable 
and relevant protocol inclusion/exclusions 
criteria:  [1] CDR, FSCRT, MMSE and 
amyloid, [3] Age [4] BMI [29]C- SSRS  
[35] stable concomitant medications.
Discontinuation due to 
protocol violation during 
the study
Mixed 
(Monitoring and 
clinical database)
Review of reasons for discontinuation  
Category:  Study Procedures
Excluded concomitant 
medications
Mixed 
(Monitoring and 
clinical 
Study specific definition:  a list with all 
concomitant medication will be 
generated, and CRP will flag those 


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LY3303560
database)
excluded (the flagged medications will 
be used in programming to flag 
important protocol deviations)  
Abbreviations:  CRP = clinical research physician; ICD = informed consent document.
5.3.1. Japanese and non-Japanese Patients
In addition to combined summaries selected TFLs will be reproduced in triplicate for Japanese
and non-Japanese subjects (All subjects, Japanese only subjects and Non-Japanese only
subjects.).  These will include demography and baseline characteristics, AE summaries,
frequency of increases in QTc intervals (greater than 30msec and greater than 60msec) and 
maximum QTc values exceeding 450msec, 480msec and 500msec.  If differences are observed 
between Japanese and non-Japanese then further analyses and/or split summaries maybe 
produced.
5.3.2. Subgroup Analyses
Any subgroup analyses will be exploratory (posthoc) in nature.
5.3.3. Concomitant Therapy
Concomitant medication will be coded using the WHO drug dictionary.  Concomitant
medications will be listed and summarised by treatment.
5.3.4. Extent of Exposure
Dosing information for each individual subject will be listed.
5.4.
Safety Analyses
Safety parameters that will be assessed include AEs, MRI, safety laboratory parameters, vital 
signs, and ECG parameters.  The parameters will be listed and summarised using standard 
descriptive statistics for values at each time point as well as changes from baseline.  A listing of 
all patients’ lab values and a listing of abnormal lab values (for that parameter) during the 
treatment period will be provided and results will be summarised.  Outliers will also be identified 
and listed where appropriate.  Additional analyses may be performed if warranted upon review 
of the data.  
5.4.1. Adverse Events
All investigational product and protocol procedure AEs will be listed, and if the frequency of
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to randomization will
be distinguished from those reported as new or increased in severity during the study.  Each


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LY3303560
symptom will be classified by the most suitable term from the medical regulatory dictionary.  
The number of IP-related SAEs will be reported.
5.4.2. Safety MRI
Shift tables will be constructed for each dose group to assess the incidence of and changes in 
vasogenic oedema and microhaemorrhage counts pre- and post-dose (by time) based on MRI.
5.4.3. Evaluation of Immunogenicity
Antibody formation will be listed and summarized as well as presented graphically over time by
patient and treatment. Exposure and antibody formulation may also be explored graphically.  If 
a neutralization assay is performed, the frequency of neutralizing antibodies will be determined.  
The relationship between the presence (or absence) of antidrug antibodies and clinical 
parameters (e.g., infusion reaction AEs) may be assessed.  Likewise, the relationship between the 
presence of antidrug antibodies and the PK parameters and PD response to LY3303560 may be 
assessed.
5.4.4. C-SSRS
Suicide-related thoughts and behaviours based on the C-SSRS will be listed by patient.  Only 
time points and patients that show suicidal ideation/behaviour will be displayed (i.e., not all of 
the “no” responses will be displayed).
5.4.5. QTcF
The number of patients experiencing a maximum increase from baseline in QTcF interval will be 
summarised for each treatment according to the following categories:  >30 ms and >60 ms.  In 
addition, the number of patients with QTcF postdose values, according to the following
categories:  >450 ms, >480 ms and >500 ms, will be summarised by treatment.
Analyses of QTc using QTcF from ECG monitoring will be performed to judge the extent and/or 
risk of QT prolongation.  An assessment of potential QTc prolongation will be performed using 
plots of PK data versus QTc values.  Scatter plots will be created of QTcF versus LY3303560 
concentration and change from baseline QTcF versus LY3303560 concentration (for timepoints 
where there is matched LY3303560 concentration and QTcF available).  Placebo data will be 
included in the plot with concentration imputed to zero.  The reference line of 450, 480, and 500 
ms will be used for the QTcF versus concentration plot; while 10, 30 and 60 ms for QTcF change 
from baseline versus concentration plot.  Analysis will be performed to assess the mean change 
in QTcF as a function of plasma drug concentration.  The average of the triplicate QTcF 
measurements will be computed at each of the scheduled time points, and baseline will be the 
mean of the triplicate measurements collected prior to dosing at time 0 in each treatment period.
A mixed-effect model may be fitted to the QTcF change from baseline, with log –transformed 
plasma-drug concentration and dose included as fixed effects.  The model will be run for the 
following ECG/PK time matched visits and time points in separate models; Visit 3(Day 1), Visit 
8 (Day 27), Visit 9 (Day 57), Visit 13 (Day 169), Visit 19 (Day 337).


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The following SAS code may be utilized:
proc mixed data=dose_sim;
by visit;
class patient;
model qtcresult = pkresult / outp=resdat s cl alpha=0.1;
random patient;
ods output solutionf=sol;
run;
A second model may be run following the same model but combining all the visits above 
together.  Other time matched measures from non PK/ECG intensive days may also be 
considered for inclusion.
Further exploratory analyses may be conducted if required.
5.5.
Pharmacokinetic Parameter Estimation
Standard non-compartmental methods of analysis and model-based approaches using non-linear 
mixed effects modeling (NONMEM) or other appropriate software may be implemented to 
estimate PK parameters including maximum drug concentration (Cmax), area under the 
concentration curve during the dosing interval (AUC), half-life, clearance and volume of 
distribution after IV administration of LY3303560.  Parameters such as time to Cmax (tmax), 
Cmax, bioavailability, apparent clearance, apparent volume of distribution and half-life after SC 
administration may be reported.  The accumulation ratio, expressed as either AUCor minimum 
observed drug concentration (Cmin), following IV and SC routes may be reported.  
When plotted Japanese and non-Japanese subjects will be identified in the same plot with
different symbol types. 
An analysis of the effect of dose, route of administration, concentration or demographic factors 
on the PK parameters may be conducted.  
An analysis relating LY3303560 serum exposure versus LY3303560 CSF concentrations may be 
conducted.
5.5.1. Pharmacokinetic Statistical Inference
With just two doses no statistical inferential analyses will be carried out on PK parameters.
5.6.
Imaging Analyses
5.6.1. Flortaucipir SUVr
Whilst the following proposed analyses are not intended to test any hypotheses, they will be 
carried out to estimate the extent of changes from baseline of the flortaucipir F 18 SUVr after 
treatment with LY3303560. 
The data will be analysed by an Analyses of Covariance (ANCOVA).  Fixed effects of treatment
doses (LY3303560 and placebo) will be fitted and a baseline covariate adjustment will be used.  


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The primary comparison is between LY3303560 and placebo for change from baseline in 
composite SUVr at last flortaucipir F 18 imaging visit.  Covariates such as (but not limited to) 
APOE status, MMSE baseline score, diagnosis and age may be explored.  
The following SAS code may be utilized:
proc mixed data=tau_sim;
class patient treatment;
model change_from_baseline_SUVR_month12 = treatment baseline_SUVR APOE, MMSE_baseline 
diagnosis age / outp=resdat s cl solution residual;
lsmeans treatment /pdiff cl alpha=0.05;
ods output lsmeans=lsmean1 diffs=diff1  covparms=cov1; 
run;
In addition to the ANCOVA analysis, a Bayesian posterior probability may be computed for 
each LY3303560 dose compared to placebo, it is essentially a Bayesian interpretation of the 
results assuming a non-informative prior.  The credible interval will be computed for each dose 
relative to placebo.  For each dose of LY3303560, the posterior probability that the SUVr 
difference to placebo is less than or equal to a certain value (X) will be calculated as the 
appropriate tail area in the t distribution, e.g., Prob(LY xmg - Placebo <=X) = prob t ((X– d) / 
sed, df) where d is the estimated difference, sed is the standard error of the estimated difference 
and df is the degrees of freedom associated with this difference.  This Bayesian inference is 
justified on the assumption of vague priors for all parameters in the model.  Values of interest for 
X may be a 0%, 10%, 30%, 50% and 100% reduction in accumulation of tau compared to 
placebo.
This analysis may be repeated for SUVrs in individual and other composite brain regions if 
needed. 
Additional analyses may explore if there is an optimum baseline SUVr value that can be used as 
an inclusion criterion for future studies, i.e., do those with a higher baseline SUVr accumulate 
more tau burden over time and hence have high propensity to respond to treatment.  To 
investigate this, the above analyses may be conducted on; all patients, patients with baseline 
SUVrs >1.05, SUVrs >1.1 and SUVrs >1.2.  These cutoffs are subject to change based on data 
received and any analyses will consider the current literature and the in-house method study 
findings (A05 from AVID).  Given the small sample sizes this is very exploratory and the 
findings may not be reported in the CSR.
Early withdrawals
It is anticipated that each patient has a baseline (screening) and week 51 value.    All postbaseline 
scans from the screening scan will be considered to be included in the analyses.  If the data 
suggest it is appropriate, a calculated annualized rate of change may be considered and analyses 
will be done with and without these dropouts included.


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5.6.2. Brain volume and functional connectivity 
If data is available then changes in regional brain volume and functional connectivity in brain 
networks captured by MRI over the course of the study will be explored and summarised.  MRI 
will be obtained every 8-12 weeks; therefore, an MMRM may be conducted fitting treatment and 
study visit and the interaction as fixed effects, the baseline will also be included and the 
baseline*visit interaction will be assessed for potential inclusion.  The following SAS code may 
be utilized for each relevant endpoint:
proc mixed data=MRI_sim;
class patient treatment visit;
model change_from_baseline_volume = treatment treatment*visit baseline_volume visit
baseline*visit / outp=resdat s cl solution residual;
random intercept/subject= patient type=un;
lsmeans treatment*visit treatment /pdiff cl alpha=0.05;
ods output lsmeans=lsmean1 diffs=diff1  covparms=cov1; 
run;
Additionally, the relationship between LY3303560 serum exposure and imaging endpoints may 
be explored graphically or by a modeling approach.
5.6.3. Amyloid scans
Patients require an amyloid scan at screening (if they haven’t previously had one for another 
purpose).  This data will listed; it will be stated if the scan is historic or denovo.  If numeric 
SUVr data is available this data may also be summarised and potential explored by correlations 
to tau burden and/or disease status.
5.7.
Exploratory Pharmacodynamic Analyses
5.7.1. Pharmacodynamic Parameter Estimation
The concentration of plasma tau, and the concentration of CSF biomarkers, including tau, p-tau, 
Aβ1-42 and neurogranin, will be determined.  Since protocol approval an additional parameter 
will be added to the assay; neurofilament light chain in CSF, this measure will be collected and 
treated as per the other parameters.  Plasma and CSF biomarker data will be summarised 
statistically and/or illustrated graphically by time and dose.  The mean change in concentration 
of the plasma and CSF biomarkers from predose will be evaluated.
No formal statistical analyses of these exploratory CSF/plasma biomarkers are planned.
5.7.2. Cognition Analyses
ADAS-Cog14, NTB, MMSE, dCDT, and ADCS-MCI-ADL24 will all be summarised and may be 
analysed using an MMRM with preinfusion cognitive measures as a baseline covariate and fixed 
effects of dose and study visit.  All cognition analyses are exploratory and underpowered to 
detect a clinically meaningful effect.
The digital clock test (dCDT) will be summarised by parameter and treatment, an MMRM may 
be applied. 


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Correlations between cognition endpoints (including dCDT) and flortaucipir F 18 SUVr, other
imaging endpoints and plasma tau may be explored.
5.7.3. Exploratory Pharmacokinetic/Pharmacodynamic Analyses 
A model-based approach may be implemented using NONMEM or other appropriate software to 
estimate PK/PD parameters.  Exploratory analyses may be conducted to characterise the 
relationship between changes in cognition endpoints, plasma and/or CSF biomarkers and 
exposure of LY3303560.  
5.7.4. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, clinical research physician/investigator, or designee 
will consult with the appropriate medical director or designee to determine if it is necessary to 
amend the protocol.
The Lilly study team will review safety data obtained on an ongoing basis, to assure patient 
safety.  Safety and/or PK interim access to data (IAD) reviews are scheduled to occur throughout 
the study. 
Changes to any Safety reviews/IADs will not constitute a SAP amendment.
5.7.4.1.
Safety reviews for dose escalation, 16 week reviews per cohort, quarterly 
safety reviews and end of cohort reviews
For safety reviews it is planned that the draft site data will be loaded into Spotfire to look for 
trend over time and treatment.  The endpoints to review will include (but not restricted to):  vital
signs, QTc, laboratory values, PK, and MRI scans.  ADA titres will be reviewed as and when 
available.  AEs, Conmeds and site feedback will also be reviewed (not in Spotfire)
The investigator will remain blinded and the Lilly study team will be unblinded during these 
reviews for dose escalation.  
5.7.4.2.
Internal decision making IAD for Phase 2/3 trigger
No longer applicable.
5.7.5. Other IADs
Additional IADs may also be conducted to summarise data for internal decision making and/or 
supporting subsequent clinical studies/regulatory agency/IB annual updates, as required by the 
Lilly study team and will be articulated in the snapshot plan.
5.8.
Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:


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Summary of adverse events, provided as a dataset which will be converted to an XML file.  
Both Serious Adverse Events and ‘Other’ Adverse Events are summarised:  by treatment 
group, by MedDRA preferred term.

An adverse event is considered ‘Serious’ whether or not it is a treatment emergent 
adverse event (TEAE).

An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth.AE reporting is consistent with other document disclosures for 
example, the CSR, manuscripts, and so forth. 


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6.
References 
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue 
ST.Confidence interval criteria for assessment of dose proportionality. 
PharmRes.2000;17(10):1278-1283.


Leo Document ID = 8ec20fd6-4ae9-40e8-a909-9f6a89b22ec4
Approver: 
Approval Date & Time: 27-Jun-2018 17:21:54 GMT
Signature meaning: Approved
PPD