Clinical trial NCT02754830
Conditions: Alzheimer's Disease
Sponsor: Eli Lilly and Company
Start date: 2016-04-25; Completion date: 2018-07-10
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of the study drug, LY3303560. Side effects and laboratory results will be monitored. This study will involve single doses of LY3303560 administered intravenously (IV), meaning into a vein or subcutaneously (SC), meaning under the skin.

Screening is required within 28 days before the start of the study for healthy participants and within 70 days before the start of the study for AD participants. The study requires about 16 weeks of each participant's time including a 4 day clinical research unit (CRU) admission and 10 follow-up appointments.

This is the first time that this study drug is being given to participants. This study is for research purposes only, and is not intended to treat any medical condition.

Detailed description:

Arms: arm 1: Single IV infusion 7 milligram (mg), 21 mg, 70 mg, 210 mg, 700 mg, 1400 mg, 2800 mg, and 5600 mg of LY3303560 on Day 1 in healthy participants. arm 2: Single IV infusion of saline solution to match LY3303560 on Day 1 in healthy participants. arm 3: Single SC injection of 210 mg LY3303560 on Day 1 in healthy participants.
Interventions: intervention 1: LY3303560 - IV intervention 2: Saline Solution - IV intervention 3: LY3303560 - SC
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered IV intervention 3: Administered SC

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan I8G-MC-LMDA Version 1 
Single-Dose, Dose-Escalation Study with LY3303560 to Evaluate the Safety, Tolerability, and 
Pharmacokinetics in Healthy Subject and Patients with Mild Cognitive Impairment due to 
Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease 
NCT02754830 
Approval Date: 14-Apr-2016 


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 1
LY3303560
Statistical Analysis Plan:  
I8G-MC-LMDA:  Single-Dose, Dose-Escalation Study with 
LY3303560 to Evaluate the Safety, Tolerability and 
Pharmacokinetics in Healthy Subjects and 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
Single-Dose, Dose Escalation Study with LY3303560 to Evaluate the Safety, Tolerability 
and Pharmacokinetics in Healthy Subjects and Patients with MCI and AD to mild/moderate 
AD.
Approval Date: 14-Apr-2016 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8G-MC-LMDA
Phase 1
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 2
LY3303560
1.
Table of Contents
Section
Page
Statistical Analysis Plan:   I8G-MC-LMDA:  Single-Dose, Dose-
Escalation Study with LY3303560 to Evaluate the Safety, 
Tolerability and Pharmacokinetics in Healthy Subjects and 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 .................................................................................................................4
3.
Study Objectives.................................................................................................................5
4.
Study Design.......................................................................................................................6
4.1.
Summary of Study Design..............................................................................................6
4.2.
Determination of Sample Size ........................................................................................7
4.3.
Method of Assignment to Treatment ..............................................................................7
5.
A Priori Statistical Methods ................................................................................................8
5.1.
General Considerations ..................................................................................................8
5.2.
Handling of Dropouts or Missing Data...........................................................................8
5.3.
Multicenter Studies ........................................................................................................8
5.4.
Multiple Comparisons/Multiplicity.................................................................................8
5.5.
Patient and Subject Disposition ......................................................................................8
5.6.
Patient and Subject Characteristics.................................................................................9
5.7.
Japanese and non Japanese subjects................................................................................9
5.8.
Subgroup Analyses.........................................................................................................9
5.9.
Concomitant Therapy.....................................................................................................9
5.10. Safety Analyses..............................................................................................................9
5.10.1.
Extent of Exposure.................................................................................................9
5.10.2.
Adverse Events ......................................................................................................9
5.10.3.
Safety MRI ..........................................................................................................10
5.10.4.
Evaluation of Immunogenicity .............................................................................10
5.10.5.
C-SSRS................................................................................................................10
5.10.6.
Electrocardiograms ..............................................................................................10
5.11. Pharmacokinetic Parameter Estimation.........................................................................11
5.11.1.
Pharmacokinetic Statistical Inference...................................................................11
5.12. Exploratory Pharmacodynamic Analyses......................................................................12
5.12.1.
Pharmacodynamic Parameter Estimation..............................................................12
5.12.2.
Pharmacodynamic Statistical Inference ................................................................12
5.13. Pharmacokinetic/Pharmacodynamic Analyses (Cohorts 8 & 9).....................................12


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 3
LY3303560
5.13.1.
Planned Exploratory Analyses  (Cohorts 8 and 9).................................................12
5.13.2.
Imaging................................................................................................................12
5.13.3.
vMRI ...................................................................................................................13
5.13.4.
Cognition Analyses..............................................................................................13
5.14. Interim Analyses and Data Monitoring.........................................................................13
5.15. Clinical Trial Registry Analyses...................................................................................14
6.
Unblinding Plan................................................................................................................15
7.
References ........................................................................................................................16
8.
Appendix ..........................................................................................................................17
8.1.
Derivations of Scores for Cognition Questionnaires .....................................................17
8.1.1.
CDR Domain scores.............................................................................................17
8.1.1.1.
CDR Global score...........................................................................................17
8.1.2.
Mini Mental State Examination (MMSE).............................................................18
MMSE Total score (range 0-30) .......................................................................................18
8.1.3.
FCSRT-IR............................................................................................................18
Free Recall18
Cued Recall......................................................................................................................18
Total Recall......................................................................................................................18
Free Recall / Total Recall .................................................................................................18
Total Recall / Maximum Possible Recall ..........................................................................18


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 4
LY3303560
2.
Revision History
This is SAP Version 1


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 5
LY3303560
3.
Study Objectives


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 6
LY3303560
4.
Study Design 
4.1.
Summary of Study Design
This is a Phase I, subject-/patient- and investigator-blind, placebo-controlled, randomized,
parallel, single-ascending dose (SAD) study in healthy subjects and patients with mild cognitive
impairment (MCI) due to AD or mild to moderate AD. The study has been designed to assess the 
safety, tolerability, and PK of single intravenous (IV) and subcutaneous (SC) doses of
LY3303560. The planned doses to be explored are 7, 21, 70, 210, 700 and 1400 mg.
Cohorts 1 to 7 will consist of healthy subjects. The planned number of subjects per cohort will be 
8 (6:2, LY3303560: placebo), except for Cohort 5 (6 subjects on LY3303560). For each IV
cohort, the intention is to enroll 4 subjects of Japanese origin (first generation) and 4 subjects of
non-Japanese origin, but enrollment to a cohort will not be contingent upon fulfilling these
requirements. The minimum requirement is to enroll 4 Japanese subjects to at least 3 of the IV
cohorts, including the highest dose level cohort (a minimum of 12 Japanese subjects in total).
However, if enrollment of Japanese subjects is slower than anticipated, cohorts may complete
enrollment with non-Japanese subjects and proceed to dose escalation without waiting for the
desired number of Japanese subjects to be enrolled. If 4 subjects of Japanese origin are not
included in a cohort initially, additional subjects may subsequently be enrolled to achieve a
maximum of 4 subjects of Japanese origin, if agreed between the sponsor and investigator.
Cohorts 8 and 9 will consist of patients with MCI due to AD or mild to moderate AD. The 
number of patients (LY3303560: placebo) in each cohort will be 6:2 patients.


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 7
LY3303560
4.2.
Determination of Sample Size
The sample size is customary for Phase 1 studies evaluating safety, PK, and/or PD parameters,
and at the conclusion of the trial confidence intervals for PK, PD, and cognition endpoints may
be computed in order to evaluate the precision of the estimates where appropriate.
Up to 70 healthy subjects may be enrolled to ensure that approximately 54 subjects (8 subjects
per cohort, except for Cohort 5 [n=6]) reach at least Day 29 of the study.
For each of the IV healthy subject cohorts, the intention is to include at least 4 non-Japanese 
subjects (preferred non-Asian) and up to 4 Japanese subjects to support the development of 
LY3303560 in Japan.
Up to 20 patients with AD may be enrolled to ensure that 16 patients (8 patients in each cohort)
complete Cohorts 8 and 9.
4.3.
Method of Assignment to Treatment
Computer-generated randomization tables will be prepared by a statistician. 
Cohorts 1-7 (Healthy Volunteers, Single Site): 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.
Cohorts 8-9 (AD Patients, 2 Sites): The randomization will be such that the placebo assignments 
for the patient cohorts will be balanced between these 2 populations.  Japanese subjects are not 
required for these cohorts and hence no split for Japanese/Non-Japanese will be made in the 
randomisation.


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 8
LY3303560
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 allprotocol 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 and exploratory reporting and 
analyses will be conducted by Eli Lilly.
5.2.
Handling of Dropouts or Missing Data
Subjects or patients who discontinue the study before completing the Day 29 assessment may be
replaced at the discretion of the sponsor and investigator. Subjects or patients who discontinue
after Day 29 may also be considered for replacement to ensure sufficient data are available for
final data analysis. 
The ethnicity of the replacement subject (Japanese or non-Japanese) should match the ethnicity 
of the discontinued subject, where possible. Replacement subjects will be allocated the same 
treatment as the dropout subject. 
There will be no imputation of missing data.
5.3.
Multicenter 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.
5.4.
Multiple Comparisons/Multiplicity
No adjustments will be made for multiplicity.
5.5.
Patient and Subject Disposition
A detailed description of healthy subject and patient disposition will be provided at the end of the


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 9
LY3303560
study.
All patients/healthy subjects 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.
5.6.
Patient and Subject Characteristics
The patient’s/healthy subject’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 summarized at
baseline, with the exception of weight which will also be summarized over time.
5.7.
Japanese and non Japanese subjects
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 30ms and greater than 60ms) 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.
5.8.
Subgroup Analyses
Any subgroup analyses will be exploratory (posthoc) in nature
5.9.
Concomitant Therapy
Concomitant medication will be coded using the WHO drug dictionary. Concomitant 
medications will be listed.
5.10. Safety Analyses
Safety parameters that will be assessed include safety laboratory parameters, vital signs and ECG 
parameters. The parameters will be listed and summarized 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.
5.10.1. Extent of Exposure
Dosing information for each individual subject will be listed.
5.10.2. 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


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 10
LY3303560
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
symptom will be classified by the most suitable term from the medical regulatory dictionary.The 
number of IP-related SAEs will be reported.
5.10.3. Safety MRI
A shift table for each IV dose will be constructed to assess the MRI measurement pre- and 
postdose for changes and additions of vasogenic edema and microhemorrhages  in AD Cohorts 
8/9 and for clinically significant changes including potentially vaogenic edema and 
microheamorrhages in HVs.
5.10.4. Evaluation of Immunogenicity
Antibody formation will be listed and summarized as well as presented graphically over time by
subject/patient and treatment. If trends following the dosing of LY3303560 are observed, then a
mixed effect model will be used, fitting dose and day and the interaction between day and dose
as a fixed effects and the dependent variable as the log transformed change from baseline in
antibody formulation following dosing of LY3303560. 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.
5.10.5. C-SSRS
For Cohorts 8 and 9, suicide-related thoughts and behaviors based on the C-SSRS will be listed
by patient. Only time points and patients that show ideation/behavior of suicide will be
displayed, that is, all ‘no’s will not be displayed.
5.10.6. Electrocardiograms
An assessment of potential prolongation will be performed using plots of PK data versus QTc
values. The frequency of subjects with a maximum increase from baseline in QTcF interval will
be summarized for each treatment according to the following categories: >30 ms and >60 ms.
In addition, the frequency of subjects with QTcF postdose values, according to the following
categories: >450 ms, >480 ms and >500 ms, will be summarized by treatment.
Analyses of QTc using QTcF from ECG monitoring in a Phase 1 trial will be performed to judge
the extent and/or risk of QT prolongation. Scatter plots will be created of QTcF versus
LY3303560 concentration and change from baseline QTcF versus LY3303560 concentration for 
matched timepoints.
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


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 11
LY3303560
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. Japanese and non Japanese subjects will be identified in the same plot 
with different symbol types.
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 following SAS code may be 
utilized:
proc mixed data=dose_sim;
class subject;
model qtcresult = pkresult / outp=resdat s cl alpha=0.1;
random subject;
ods output solutionf=sol;
run;
Further exploratory analyses may be conducted if required. Separate analysis may be conducted 
for healthy subjects and patients with AD as required.
5.11. Pharmacokinetic Parameter Estimation
It is intended that PK parameter estimates for LY3303560 in serum and CSF will be calculated
by standard noncompartmental methods of analysis. The primary serum and CSF parameters for
analysis will be maximum drug concentration (Cmax), area under the concentration versus time
curve from time 0 to infinity (AUC0-∞) and AUC from time 0 to the last measurable
concentration (AUC0-tlast) of LY3303560. Other serum PK parameters, such as half-life,
clearance, and volume of distribution may be reported after IV administration of LY3303560.
Serum PK parameters such as bioavailability, apparent clearance, apparent volume of
distribution and half-life may be reported after SC administration.
A model-based approach may also be implemented using nonlinear mixed effects modeling
(NONMEM) or other appropriate software to estimate serum and/or CSF PK parameters.
Exploratory analyses of the effect of dose, route of administration, concentration or demographic
factors, including healthy subjects versus patients, on the PK parameters may be conducted, and
modeling analyses may be performed for characterization purposes. Exploratory analyses
relating LY3303560 serum exposure versus LY3303560 CSF concentrations may be conducted.
5.11.1. Pharmacokinetic Statistical Inference
The serum PK parameters, Cmax and AUC0-∞ or AUC0-tlast, for LY3303560 obtained for
healthy subjects (IV only) will be evaluated to estimate the dose-exposure proportionality of
LY3303560 using a linear effects power model (Smith et al. 2000). In this model, log
transformed dose will be the independent variable, and subject will be a random effect. Both
Cmax and AUC will be log-transformed prior to analysis. The least-square means for each
treatment together with the treatment differences and associated 90% confidence intervals (CIs)
will be estimated from the model. These estimates will be back-transformed to present
geometric means, the ratios of geometric means, and the corresponding 90% CIs. Dose-exposure


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 12
LY3303560
analysis will be conducted using the healthy subject IV cohorts (Cohorts 1, 2, 3, 4, 6, and 7).
The following SAS code may be utilized:
proc mixed ;
class subject;
by day;
model log_pk= log_dose/ ddfm=kr s cl alpha=0.1;
random intercept/subject=subject;
estimate ‘ldose’ logdose 1 / cl alpha=0.10 e;
ods output estimates=est covparms=cov;
run;
When plotted Japanese and non Japanese subjects will be identified in the same plot with 
different symbol types. Exploratory analyses of Japanese and non-Japanese subjects may be 
conducted. Additional
dose-exposure analyses may be conducted using patient data.
5.12. Exploratory Pharmacodynamic Analyses
5.12.1. Pharmacodynamic Parameter Estimation
For the healthy subjects, if data are available, plasma tau will be summarized and/or illustrated 
graphically by time and dose/formulation.
For the patient cohorts (Cohorts 8 and 9), if data are available, the concentration of the plasma 
and/or CSF biomarkers, including tau, p-tau, Aβ, and neurograinin, will be summarized and/or 
illustrated graphically based on availability of data. The mean change in concentration of the 
biomarkers from predose will be evaluated. Further analyses may be conducted if trends are 
observed in the data.
5.12.2. Pharmacodynamic Statistical Inference
No statistical analysis of PD parameters are planned.
5.13. Pharmacokinetic/Pharmacodynamic Analyses (Cohorts 8 & 9)
Exploratory correlational analyses may be conducted to describe the relationship between 
systemic and/or central LY3303560 exposure and changes in the florbetapir SUVr; MRI of 
whole brain,ventricle, and hippocampus volumes; CSF concentrations of Aβ, tau and p-tau; and 
number AEs related to infusion reactions.  It is intended that these analyses will initially be 
descriptive graphs in nature as a function of LY3303560 dose, exposure, and/or time from study 
entry.  If appropriate,these relationships may also be described using a modeling approach.
5.13.1. Planned Exploratory Analyses  (Cohorts 8 and 9)
5.13.2. Imaging 
18F-AV-1451 SUVR data will be summarized and/or plotted by region of interest as appropriate. 
Change from baseline of tau burden within regions of interested will be calculated and 
summarised, however, no formal analyses is planned to be conducted due to single dose nature 
of the study.


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 13
LY3303560
Amyloid status at baseline will be summarized and may be used as a factor in plots of other
endpoints.
In addition to these analyses, correlation analyses between changes in CSF biomarkers (Aβ1-40, 
Aβ1-42, total tau, phospho-tau), or imaging endpoints (MRI measures, or SUVr from florbetapir 
scans) with posthoc serum AUC estimates derived from the PK model (or an alternative measure 
of exposure if deemed appropriate) may be completed.  For SUVr, this will be conducted for the 
individual regions (if collected) and the total SUVr.  Additionally, CSF and/or serum 
LY3002813 exposures may be related to CSF biomarkers, as appropriate.
5.13.3. vMRI 
Magnetic resonance imaging changes in volume over the course of the study will be explored, 
and exploratory evaluation of whole brain and anatomically localized structural changes will be 
summarized (including, but not limited to, whole brain, ventricle, and hippocampus).  Magnetic
resonance imaging volumetric assesssments will be obtained at baseline, Day 15 and end of 
study. If data warrants further analyses then an MMRM will be constructed by fitting treatment
and study visit as fixed effects.  Response variables are brain structural changes of whole brain, 
ventricle, and hippocampal volumes.
5.13.4. Cognition Analyses 
Cognition endpoints collected at screening and Day 85 may be summarized and correlated with
imaging and CSF endpoints. The data are collected to provide information on cognition changes
in a 2-3 month timeframe will not be used to assess efficacy of the molecule.
5.14. Interim Analyses and Data Monitoring 
Select individuals may gain access to unblinded data, prior to the interim data access review or 
final database lock, in order to initiate the final population PK/PD model development processes 
for interim or final analyses. The individuals and unblinded data are as specified in the 
unblinding plan.
Information that may unblind the study during the analyses will not be reported to study sites or
blinded study team until the study has been unblinded.
Safety and/or PK interim access to data (IAD) is scheduled to occur throughout the study. The
purpose of these IAD reviews is to examine the safety data and guide dose selections. The
investigator and the Lilly study team will make the determination regarding dose escalation
based on their review of the safety and tolerability data, along with PK data, as applicable.
An interim review of safety and PK data is planned after healthy subjects in Cohort 3 complete
the 28-day postdose PK blood draw. Additional interim PK data reviews may be performed as
required during study conduct. The PK data obtained during the study may be used to assist in


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 14
LY3303560
dose-escalation decisions, but such data are not required for dose escalation.]
5.15. Clinical Trial Registry Analyses
Additional analyses may be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
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 summarized: 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. 


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 15
LY3303560
6.
Unblinding Plan 
This is a subject-/patient- and investigator-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the
randomization table and treatment assignments before the study is complete.
Randomization tables for allocation of LY3303560 and placebo will be prepared by the Lilly
statistician and provided to the study site pharmacists or pharmacy staff involved in dose
preparation. Blinding will be maintained throughout the conduct of the trial until all data are
cleaned to an acceptable level of quality and locked. 
Emergency codes will be available to the investigator. A code, which reveals the treatment
group for a specific study subject/patient, may be opened during the study only if the
subject/patient’s well-being requires knowledge of the subject/patient’s treatment assignment.
No formal interim analyses are planned for this study. If an unplanned interim analysis is
deemed necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate
medical director or designee to determine if it is necessary to amend the protocol.
Interim access to the data is detailed in the protocol.


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 16
LY3303560
7.
References
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.


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 17
LY3303560
8. Appendix
8.1. Derivations of Scores for Cognition Questionnaires
Note: These derivations are draft to facilitate programming and any changes will not warrant a 
SAP amendment
8.1.1. CDR Domain scores
6 domains scored by clinician (based on a structured interview) as follows:
8.1.1.1. CDR Global score
The global CDR 
CCI
is derived from the scores in each of the six categories ("boxscores") as 
follows.


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 18
LY3303560
Memory (M) is considered the primary category and all others are secondary. CDR = M if at
least three secondary categories are given the same score as memory. Whenever three or more
secondary categories are given a score greater or less than the memory score, CDR = score of
majority of secondary categories on whichever side of M has the greater number of secondary
categories.
When three secondary categories are scored on one side of M and two secondary categories
are scored on the other side of M, CDR=M. When M = 0.5, CDR = 1 if at least three of the other
categories are scored one or greater. If M = 0.5, CDR cannot be 0; it can only be 0.5 or 1. If M =
0, CDR = 0 unless there is impairment (0.5 or greater) in two or more secondary categories, in
which case CDR = 0.5
8.1.2. Mini Mental State Examination (MMSE)
MMSE Total score (range 0-30)
Sum of questions: Orientation (0-10), Registration (0-3), Attention and Calculation (0-5), Recall 
(0-3), Language (0-8) and Copying (0-1)
8.1.3. FCSRT-IR
The test provides two basic measures of memory and learning: Free Recall and Total Recall.
Total Recall is obtained by adding Cued Recall to Free Recall on each trial.. Free Recall is a
measure of self-organized retrieval. Total recall is a measure of maximum retrieval that
provides an estimate of encoding and retention.
Free Recall
Enter the number of items retrieved by Free Recall on each trial.
Enter the sum of Free Recall on trials 1 + 2 + 3.
Cued Recall
Enter the number of items retrieved by Cued Recall on each trial.
Enter the sum of Cued Recall on trials 1 + 2 + 3.
Total Recall
Add Cued Recall to Free Recall on each trial. Enter the sum of Total
Recall on trials 1 + 2+ 3.
Free Recall / Total Recall
The proportion of Total Recall obtained by Free Recall provides a measure of the efficacy of
Free Recall or retrieval. Divide Free Recall on each trial by Total Recall on each trial. For “Sum
1+2+3” divide the sum of Free Recall on Trials 1 + 2 + 3 by
the sum of Total Recall on Trials 1 + 2+ 3.
Total Recall / Maximum Possible Recall
The proportion of maximum possible recall obtained by Total Recall provides a measure of the


I8G-MC-LMDA Statistical Analysis Plan Version 1
Page 19
LY3303560
efficacy of Total Recall or encoding and retention. This proportion may also be regarded as a
measure of the efficacy of Cued Recall, assuming that words retrieved by Free Recall would also
have been retrieved by Cued Recall.
Divide Total Recall on each trial by 16. For “Sum 1+2+3” divide the sum of Total Recall on
Trial 1 + 2 + 3 by 48.


PPD
Leo Document ID = ddcc1362-fe06-4d89-8879-98163d554f60
Approver: 
Approval Date & Time: 14-Apr-2016 10:01:20 GMT
Signature meaning: Approved

Prot_000.pdf: 
Protocol I8G-MC-LMDA(b) 
 
Single-Dose, Dose-Escalation Study with LY3303560 to Evaluate the Safety, Tolerability, and 
Pharmacokinetics in Healthy Subject and Patients with Mild Cognitive Impairment due to 
Alzheimer’s Disease or Mild to Moderate Alzheimer’s Disease 
 
NCT02754830 
 
Approval Date: 31-Jul-2017 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 1
LY3303560
Protocol I8G-MC-LMDA(b)
Single-Dose, Dose-Escalation Study with LY3303560 to 
Evaluate the Safety, Tolerability, and Pharmacokinetics in 
Healthy Subjects and Patients with Mild Cognitive 
Impairment due to Alzheimer’s Disease or Mild to Moderate 
Alzheimer’s Disease
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:
10 February 2016
Amendment (a) Electronically Signed and Approved by Lilly: 26 May 2016
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 31-Jul-2017 GMT


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 2
LY3303560
Table of Contents
Single-Dose, Dose-Escalation Study with LY3303560 to 
Evaluate the Safety, Tolerability, and Pharmacokinetics in 
Healthy Subjects and Patients with Mild Cognitive 
Impairment due to Alzheimer’s Disease or Mild to Moderate 
Alzheimer’s Disease
Section
Page
Protocol I8G-MC-LMDA(b) Single-Dose, Dose-Escalation Study with 
LY3303560 to Evaluate the Safety, Tolerability, and 
Pharmacokinetics in Healthy Subjects and 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 .......................................................................................................12
3.
Introduction ......................................................................................................................18
3.1.
Study Rationale............................................................................................................18
3.2.
Background..................................................................................................................18
3.2.1.
Preliminary Data from Cohorts 1 through 7..........................................................19
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.2.
Number of Participants.................................................................................................24
5.3.
End of Study Definition ...............................................................................................25
5.4.
Scientific Rationale for Study Design...........................................................................25
5.5.
Justification for Dose ...................................................................................................26
6.
Study Population...............................................................................................................28
6.1.
Inclusion Criteria..........................................................................................................28
6.2.
Exclusion Criteria ........................................................................................................31
6.3.
Lifestyle and/or Dietary Requirements .........................................................................34
6.3.1.
Meals and Dietary Restrictions.............................................................................34
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................34
6.3.3.
Activity................................................................................................................34
6.4.
Screen Failures.............................................................................................................34
7.
Treatment..........................................................................................................................35


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 3
LY3303560
7.1.
Treatment Administered...............................................................................................35
7.1.1.
Packaging and Labeling .......................................................................................36
7.2.
Method of Treatment Assignment ................................................................................36
7.2.1.
Selection and Timing of Doses.............................................................................36
7.3.
Blinding .......................................................................................................................36
7.4.
Dose Modification........................................................................................................37
7.4.1.
Dose Decision/Escalation.....................................................................................37
7.4.2.
Special Treatment Considerations ........................................................................38
7.4.2.1.
Premedication for Infusions............................................................................38
7.4.2.2.
Management of Infusion Reactions.................................................................38
7.5.
Preparation/Handling/Storage/Accountability...............................................................39
7.6.
Treatment Compliance .................................................................................................39
7.7.
Concomitant Therapy...................................................................................................39
8.
Discontinuation Criteria ....................................................................................................41
8.1.
Discontinuation from Study Treatment.........................................................................41
8.1.1.
Discontinuation of Inadvertently Enrolled Subject/Patients ..................................41
8.2.
Discontinuation from the Study....................................................................................41
8.3.
Patients/Subjects Lost to Follow-up..............................................................................42
9.
Study Assessments and Procedures ...................................................................................43
9.1.
Efficacy Assessments...................................................................................................43
9.2.
Adverse Events ............................................................................................................43
9.2.1.
Serious Adverse Events........................................................................................44
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................44
9.2.2.
Complaint Handling.............................................................................................45
9.3.
Treatment of Overdose.................................................................................................45
9.4.
Safety...........................................................................................................................45
9.4.1.
Laboratory Tests ..................................................................................................45
9.4.2.
Vital Signs ...........................................................................................................45
9.4.3.
Electrocardiograms ..............................................................................................46
9.4.4.
Other Tests...........................................................................................................47
9.4.4.1.
Neurological Examinations.............................................................................47
9.4.4.2.
Alertness and Attention Assessments (Cohorts 10 and 
11)..................................................................................................................47
9.4.4.2.1.
Bond and Lader VAS................................................................................47
9.4.4.2.2.
Digit Span Forward and Backward Test....................................................47
9.4.4.3.
Magnetic Resonance Imaging.........................................................................48
9.4.4.4.
Injection-Site Assessments (Cohort 5) ............................................................48


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 4
LY3303560
9.4.4.5.
Columbia Suicide Severity Rating Scale (Cohorts 8 and 
9)....................................................................................................................48
9.4.4.6.
Imaging (Cohorts 8 and 9)..............................................................................49
9.4.4.6.1.
Radiation Doses Associated with PET Imaging.........................................49
9.4.5.
Safety Monitoring ................................................................................................50
9.4.6.
Immunogenicity Assessments ..............................................................................51
9.5.
Pharmacokinetics .........................................................................................................51
9.5.1.
Cerebrospinal Fluid Sampling (Cohorts 8 and 9)..................................................51
9.5.2.
Bioanalysis...........................................................................................................52
9.6.
Exploratory Pharmacodynamics ...................................................................................53
9.6.1.
Exploratory Cognitive and Functional Scales (Cohorts 8 and 
9) .........................................................................................................................53
9.6.1.1.
Mini–Mental Scale Examination.....................................................................53
9.6.1.2.
Clinical Dementia Rating–Sum of Boxes........................................................54
9.6.1.3.
Free and Cued Selective Reminding Test with Immediate 
Recall.............................................................................................................54
9.7.
Genetics .......................................................................................................................54
9.8.
Biomarkers...................................................................................................................55
9.9.
Health Economics ........................................................................................................55
10.
Statistical Considerations and Data Analysis.....................................................................56
10.1. Sample Size Determination ..........................................................................................56
10.2. Populations for Analyses..............................................................................................56
10.2.1.
Study Participant Disposition ...............................................................................56
10.2.2.
Study Participant Characteristics ..........................................................................56
10.3. Statistical Analyses ......................................................................................................56
10.3.1.
Safety Analyses....................................................................................................57
10.3.1.1.
Clinical Evaluation of Safety..........................................................................57
10.3.1.2.
Statistical Evaluation of Safety.......................................................................57
10.3.2.
Pharmacokinetic Analyses....................................................................................58
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................58
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................58
10.3.3.
Exploratory Pharmacodynamic Analyses .............................................................59
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................59
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................59
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses (Cohorts 8 
and 9)...................................................................................................................59
10.3.5.
18F-AV-1451 Imaging and Cognition Analyses (Cohorts 8 
and 9)...................................................................................................................59
10.3.6.
Evaluation of Immunogenicity .............................................................................59


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 5
LY3303560
10.3.7.
Interim Analyses..................................................................................................60
11.
References ........................................................................................................................61


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 6
LY3303560
List of Tables
Table
Page
Table LMDA.1.
Objectives and Endpoints .......................................................................21
Table LMDA.2.
Margin of Safety for Subcutaneous/Intravenous Administration of 
LY3303560 Based on Administered Dose and Predicted Exposure.........27
Table LMDA.3.
Treatments Administered........................................................................35
Table LMDA.4.
Scoring of Neurological Examinations....................................................47
Table LMDA.5.
Radiation Doses Associated with PET Imaging ......................................50
Table LMDA.6.
Margin of Safety for Subcutaneous/Intravenous Administration of 
LY3303560 Based on Administered Dose and Predicted Exposure.........85


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 7
LY3303560
List of Figures
Figure
Page
Figure LMDA.1.
Illustration of study design for Protocol I8G-MC-LMDA. ......................24


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 8
LY3303560
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................63
Appendix 2.
Clinical Laboratory Tests........................................................................68
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................69
Appendix 4.
Blood Sampling Summary......................................................................72
Appendix 5.
Management of Infusion Reactions.........................................................73
Appendix 6.
Protocol Amendment I8G-MC-LMDA(b) Summary [Single-Dose, 
Dose-Escalation Study with LY3303560 to Evaluate the Safety, 
Tolerability, and Pharmacokinetics in Healthy Subjects and 
Patients with Mild Cognitive Impairment due to Alzheimer’s 
Disease or Mild to Moderate Alzheimer’s Disease] ................................74


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 9
LY3303560
1. Protocol Synopsis
Title of Study:
Single-Dose, Dose-Escalation Study with LY3303560 to Evaluate the Safety, Tolerability, and Pharmacokinetics in 
Healthy Subjects and Patients with Mild Cognitive Impairment due to Alzheimer’s Disease (AD) or Mild to 
Moderate AD
Rationale: 
Lilly is developing LY3303560, a humanized monoclonal antibody that targets aggregated tau, for the treatment of 
AD .  It is believed that targeting aggregated tau will reduce tau propagation, and in so doing, may delay the 
progression of tau-related diseases like AD.
LY3303560 has not been administered to humans.  This first-in-human study will investigate the safety, tolerability, 
and pharmacokinetics (PK) of LY3303560 in healthy subjects and patients with AD.  Safety and tolerability 
evaluations will be conducted over a wide range of single doses and dose escalation will not proceed until safety 
data from previous doses have been reviewed.  This study will aim to assess whether a maximum-tolerated dose 
(MTD) can be established or to demonstrate the tolerability of a dose greater than the expected therapeutic dose.  
The data generated in this study will be used to help design subsequent clinical studies.  The inclusion of Japanese 
subjects in this study will facilitate the inclusion of Japanese patients in subsequent clinical trials.
Objectives/Endpoints:  
Objectives
Endpoints
Primary
The primary objective of this study is to assess the safety 
and tolerability following single doses of LY3303560 in 
healthy subjects and patients with Mild Cognitive 
Impairment due to Alzheimer’s Disease (AD) or Mild to 
Moderate AD.
Safety and tolerability will be assessed by monitoring 
adverse events (AEs).
Secondary

To assess the serum pharmacokinetics (PK) of 
LY3303560 in healthy subjects, including those of 
Japanese origin, following single doses of 
LY3303560.

To assess the cerebrospinal fluid (CSF) PK of 
LY3303560 in patients with AD following single 
doses of LY3303560.

To assess the effect of single doses of LY3303560 
on the QTc interval in healthy subjects and patients 
with AD.
The primary parameters for analysis will be maximum 
drug concentration (Cmax), area under the concentration 
versus time curve from time 0 to infinity (AUC0-), and 
AUC from time 0 to the last measurable concentration 
(AUC0-tlast) of LY3303560.
QT/QTc interval mean change from baseline


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 10
LY3303560
Summary of Study Design:
Study I8G-MC-LMDA is a Phase I, subject-/patient- and investigator-blind, placebo-controlled, randomized, 
single-ascending dose (SAD) study in healthy subjects and patients with mild cognitive impairment (MCI) due to 
Alzheimer’s Disease (AD) or mild to moderate AD.  The study has been designed to assess the safety, tolerability, 
and PK of single intravenous (IV) and subcutaneous (SC) doses of LY3303560.
Treatment Arms and Duration:  
For all cohorts (except Cohort 5), subjects or patients will receive either LY3303560 or placebo as an IV single 
dose; the planned doses are 7, 21, 70, 210, 700, 1400, 2800, and 5600 mg.  In Cohort 5, it is intended that subjects 
will receive a single SC dose of 210 mg LY3303560, dependent on the observed safety profile from previous 
cohorts.
Number of Subject/Patients:
Cohorts 1 to 7, 10, and 11 (Healthy subjects): Up to 90 subjects may be enrolled so that approximately 70 subjects 
(8 subjects per cohort, except for Cohort 5 [n=6]), reach at least Day 29 of the study.
Cohorts 8 and 9 (Patients with AD): Up to 20 patients may be enrolled in order that 16 patients (8 patients per 
cohort) reach at least Day 29 of the study.
Subjects or patients who discontinue the study before completing the Day 29 assessment may be replaced at the 
discretion of the sponsor and investigator.  Subjects or patients who discontinue after Day 29 may also be considered 
for replacement to ensure sufficient data are available for final data analysis.
Statistical Analysis:
Safety:  Safety parameters that will be assessed include adverse events (AEs), safety laboratory parameters, vital 
signs, and electrocardiogram (ECG) parameters.  The parameters will be listed and summarized using standard 
descriptive statistics for values at each time point as well as changes from baseline.  Additional analyses may be 
performed if warranted upon review of the data.  
For Cohorts 8 and 9, suicide-related thoughts and behaviors based on the Columbia Suicide Severity Rating Scale
(C-SSRS) will be listed by patient.  Only time points and patients that show ideation/behavior of suicide will be 
displayed, that is, all ‘no’s will not be displayed.
An assessment of potential QT prolongation will be performed using plots of PK data versus QTc values using 
Fridericia’s formula (QtcF).  The frequency of subjects with a maximum increase from baseline in QTcF interval 
will be summarized for each treatment according to the following categories:  >30 ms and >60 ms.  In addition, the 
frequency of subjects with QTcF postdose values, according to the following categories:  >450 ms, >480 ms and 
>500 ms, will be summarized by treatment.
Analyses of (QTcF from ECG monitoring in a Phase 1 trial will be performed to judge the extent and/or risk of QT 
prolongation.  Scatter plots will be created of QTcF versus LY concentration and change from baseline QTcF versus 
LY concentration.  
Pharmacokinetic:  PK parameter estimates for LY3303560 in serum and CSF will be calculated by standard 
noncompartmental methods of analysis.  The primary parameters for analysis will be maximum drug concentration 
(Cmax) and area under the concentration versus time curve from time 0 to infinity (AUC0-∞) of LY3303560.  Other 
serum PK parameters such as half-life, clearance, and volume of distribution may be reported after IV 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 11
LY3303560
administration of LY3303560.  Serum PK parameters such as bioavailability, apparent clearance, apparent volume 
of distribution and half-life may be reported after subcutaneous administration.  The primary CSF PK parameters 
will be Cmax and AUC, estimated by standard noncompartmental methods of analysis.  A model-based approach 
may also be implemented using nonlinear mixed effects modeling (NONMEM) or other appropriate software to 
estimate serum and/or CSF PK parameters.  
The serum PK parameters, Cmax and AUC0-∞, for LY3303560 obtained for healthy subjects (IV only) will be 
evaluated to estimate the dose-exposure proportionality of LY3303560 using a linear-effect power model.
18F-AV-1451 Imaging Analyses (Cohorts 8 and 9):  18F-AV-1451 SUVR data will be summarized and/or plotted 
by region of interest as appropriate, further details will be given in the statistical analysis plan.  Change from 
baseline of tau burden within regions of interested will be calculated, however, no formal analyses are planned to be 
conducted due to single dose nature of the study.
Additionally, the relationship between LY3303560 serum exposure and imaging endpoints may be explored 
graphically or by a modeling approach.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 12
LY3303560
2. Schedule of Activities


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 13
LY3303560
Study Schedule Protocol I8G-MC-LMDA (Cohorts 1 to 7, 10, and 11, Healthy Subjects)
Screen
ED
Study Day
-28 to -1
-1
1
2
3
4
5
6
7
15
22
29
43
57
71
85
113
141
Visit Window (days)
±1 ±2 ±2 ±3 ±3 ±3 ±3 ±3
±3
Informed consent
X
Admit to CRU
X
Discharge from CRU
X
LY3303560/placebo dosinga
X
Prior/concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Xl
X
Preexisting conditions/AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Xl
X
Injection-site assessment (Cohort 5 only)
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
Neurological examination
X
X
0
24j
72j
X
X
X
X
X
Alertness and attention assessments
(Cohorts 10 and 11 only)
X
0
72j
X
X
X
X
X
Weight/heightb
X
0
X
X
X
X
Vitals (hours)c,d
X
X
0e, 0.5k, 
3, 12
24
48
72
X
X
X
X
X
X
X
X
X
X
Xl
Xl
X
12-lead electrocardiogram (hours)d,f
X
X
0e, 0.5k,
3, 12
24
48
72
144 
X
X
X
X
Ethanol and urine drug screens
X
X
Clinical laboratory tests 
X
0
24
72
X
X
X
X
X
X
X
Immunogenicityg
0
X
X
X
X
Xg
Xg
Stored serum for possible exploratory 
immune safety laboratory testsh
X
X
X
Magnetic Resonance Imaging
X
X
X
X
LY3303560 serum PK (hours)i
0e, 0.5k, 
2, 4, 12
24
48
72
96
120 144
X
X
X
X
X
X
X
Xl
Xl
X
Plasma tau PD samples (hours)i
X
0e,0.5k, 2, 
4, 12
24
48
72
96
120 144
X
X
X
X
X
Xl
Xl
Plasma PD storage samples (hours)i
X
0, 2, 4, 12
24
48
72
96
120 144
X
X
X
X
X
Serum PD storage samples (hours)i
X
0, 12
48
96
144
Sample for genetic testing
X
RNA testing (hours)
X
144
Abbreviations:  AE = adverse event; CRU = clinical research unit; ED = early discontinuation; PD = pharmacodynamics; PK = pharmacokinetics.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 14
LY3303560
Time 0 is predose.
a
Subjects in Cohorts 1 to 4, 6, 7, 10, and 11 will receive an IV single dose; subjects in Cohort 5 will receive a single SC dose.
b
Height will be measured only at screening.
c
Screening vital signs will be obtained in the sitting position (after at least 5 minutes sitting).  For vital signs after study entry, subjects will rest in the supine 
position for at least 5 minutes and undergo supine blood pressure and pulse rate measurements.  Subjects will sit for approximately 2 minutes then stand for 
approximately 2 minutes and undergo standing blood pressure and pulse rate measurements.  If subjects are unable to stand, supine vital signs only will be 
recorded.
d
The timing of the vital sign and ECG collections may be adjusted after review of these data or PK data.
e
Performed predose (for ECG measurements, 4 sets of triplicate ECGs within 60 minutes).
f
At screening and all timepoints post-Day 7, a single ECG will be obtained locally and stored at the investigational site. At all other time points, ECGs will be 
obtained in triplicate at approximately 1-minute intervals and will be transmitted and stored at the central ECG vendor.  ECGs must be recorded before 
collecting any blood samples for safety evaluations, PK and PD, and close to the time of the blood draw.
g
Up to 3 additional blood samples for immunogenicity evaluation per subject may be drawn during the study at the discretion of the investigator or sponsor.
h
Stored serum samples for possible immune safety laboratory testing (including but not limited to β tryptase, total Immunoglobulin E, and immune complex 
testing) will be collected.  In the event of a moderate or severe infusion reaction event, additional stored serum samples should be collected approximately 60-
120 minutes and 4-6 weeks after moderate or severe infusion reactions.  Failure to collect these samples will not qualify as a protocol violation.  Unscheduled 
samples may also be collected as needed.
i
A maximum of 5 additional blood samples per subject may be drawn during the study at the discretion of the investigator or sponsor.
j
To be conducted ± 1 hour. 
k
Performed at the end of the infusion.
l
Cohorts 10 and 11 only.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 15
LY3303560
Study Schedule Protocol I8G-MC-LMDA (Cohorts 8 and 9, Patients with AD)
Screen
ED
Study Day
-70 to -1
-1
1
2
3
4
5
6
7
15
22
29
43
57
71
85
Visit Window (days)
±1 ±2 ±2 ±3 ±3 ±3 ±3
Informed consent
X
Admit to CRUa
X
Discharge from CRU
X
LY3303560/placebo IV dose
X
Prior/concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Preexisting conditions/AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS/SHSFa,b
X
X
X
X
X
X
X
X
X
X
X
X
Injection-site assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
Neurological examination
X
X
0
72n
X
X
X
X
X
Weight/heightc
X
X
X
X
X
X
Vitals (hours)d,e
X
X
0f, 0.5o, 3, 12
24, 
36
72
X
X
X
X
X
X
X
X
X
X
X
12-lead electrocardiogram (hours)e,g
X
X
0f, 0.5o, 3, 12
24, 
36
72
X
X
X
X
X
Ethanol and urine drug screens
X
X
Clinical laboratory tests
X
0
24
72
X
X
X
X
X
X
X
Immunogenicityl
0
X
X
X
X
Xl
Xl
Stored serum for possible exploratory 
immune safety laboratory testsh
X
X
X
Magnetic Resonance Imaging
X
X
X
X
LY3303560 serum PK (hours)i
0f, 0.5o, 2, 4, 12
24
48
72
96
120 144
X
X
X
X
X
X
X
X
Plasma tau PD samples (hours)i
X
0f, 0.5o, 2, 4, 12
24
48
72
96
120 144
X
X
X
X
X
Plasma PD storage samples (hours)i
X
0, 2, 4, 12
24
48
72
96
120 144
X
X
X
X
X
Serum PD storage samples (hours)
X
0,  12
48
96
144
Sample for genetic testing
X
RNA testing (hours)
X
144
continued


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 16
LY3303560
Study Schedule Protocol I8G-MC-LMDA (Cohorts 8 and 9, Patients with AD) (concluded)
Screen
ED
Study Day
-42 to -1
-1
1
2
3
4
5
6
7
15
22
29
43
57
71
85
Visit Window (days)
±1 ±2 ±2 ±3 ±3 ±3 ±3
CSF sampling for PK and PD evaluations 
(hours)m
0f, 2, 4, 12
24,
36
Lumbar X-rayj
X
Florbetapir PET scan
X
18F-AV-1451 PET scan
X
X
Cognitive scalesa,k
MMSE
X
X
FCSRT-IR
X
X
CDR-SB
X
X
Abbreviations:  AE = adverse event; CDR-SB = Clinical Dementia Rating-Sum of Boxes; CRU = clinical research unit; CSF = cerebrospinal fluid; 
C-SSRS = Columbia Suicide Severity Rating Scale; CRU = clinical research unit; ED = early discontinuation; FCSRT-IR = Free and Cued Selective 
Reminding Test with Immediate Recall; MMSE = Mini-Mental State Examination; IV = intravenous; PD = pharmacodynamics; PET = positron emission 
tomography; PK = pharmacokinetics; SHSF = Self-Harm Supplemental Form.
Time 0 is predose.
a
The caregiver/study informant is required to accompany the patient for the dosing day and for all days that the C-SSRS/SHSF and cognitive and functional 
scales are administered.  If the caregiver/study informant is not able to accompany the patient in person because of an unavoidable circumstance, he/she must 
be available by telephone to answer questions regarding AEs and concomitant medications, and to answer the questions for the caregiver portions of any 
rating scales or questionnaires for that visit, such as the C-SSRS.  The caregiver/study informant must accompany the patient to screening, baseline (Day -1), 
final study visit (Day 85 or ED), and cognitive outcome assessments (screening).  If any caregiver/study informant familiar with the study cannot continue,
1 replacement will be allowed.  More than 1 replacement may be allowed per investigator's discretion.
b
The SHSF form will be completed at any visit, including baseline, when a suicidal or nonsuicidal self-injurious behavior is identified on the C-SSRS.
c
Height will be measured only at screening.
d
Screening vital signs will be obtained in the sitting position (after at least 5 minutes sitting).  For Visits 1 to 3, vital signs will be taken in the supine position 
only. For all other vital signs after study entry, subjects will rest in the supine position for at least 5 minutes and undergo supine blood pressure and pulse rate 
measurements.  Subjects will sit for approximately 2 minutes then stand for approximately 2 minutes and undergo standing blood pressure and pulse rate 
measurements.  If subjects are unable to stand, supine vital signs only will be recorded.
e
The timing of the vital sign and ECG collections may be adjusted after review of these data or PK data.
f
Performed predose (for ECG measurements, 4 sets of triplicate ECGs within 60 minutes).


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 17
LY3303560
g
At screening and all timepoints post-Day 7, a single ECG will be obtained locally and stored at the investigational site. At all other time points, ECGs will be 
obtained in triplicate at approximately 1-minute intervals and will be transmitted and stored at the central ECG vendor.  ECGs must be recorded before 
collecting any blood samples for safety evaluations, PK and PD, and close to the time of the blood draw.
h
Stored serum samples for possible immune safety laboratory testing (including but not limited to β tryptase, total Immunoglobulin E, and immune complex 
testing) will be collected.  In the event of a moderate or severe infusion reaction event, additional samples should be collected approximately 60 to 
120 minutes and 4 to 6 weeks after moderate or severe infusion reactions.  Failure to collect these samples will not qualify as a protocol violation.  
Unscheduled samples may also be collected as needed.
i
A maximum of 5 additional blood samples per subject may be drawn during the study at the discretion of the investigator or sponsor.
j
Patients may have a lumbar x-ray conducted at screening.  If an x-ray was done within 12 months of screening, this may be used.
k
Cognitive tests should be completed in the following order if done on the same day:  (1) MMSE; (2) FCSRT-IR; (3) CDR-SB.
l
Up to 3 additional blood samples for immunogenicity evaluation per subject may be drawn during the study at the discretion of the investigator or sponsor.
m The timing of the CSF sampling may be adjusted after review of serum PK data from previous cohorts.
n
To be conducted ± 1 hour.
o
Performed at the end of the infusion.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 18
LY3303560
3. Introduction
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized 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 causes tau 
aggregation, tau seeding, NFT formation, microtubule destabilization, and neuronal toxicity.  
Over time, tau accumulates in the brains of patients with AD, and forms intraneuronal NFTs, 
with tau pathology spreading in sequence from transentorhinal, to limbic, then neocortical 
regions.  The spread of tau pathology is highly correlated with neuronal loss, clinical symptoms 
and progression in AD and other neurodegenerative diseases such as progressive supranuclear 
palsy (PSP) (tauopathies).
LY3303560 is a humanized monoclonal antibody that binds to aggregated tau from patients with 
AD and other tauopathies, such as PSP.  In preclinical in vitro and in vivo studies, LY3303560
reduces trans-cellular spread of tau seeds and tau pathology propagation.  By binding to 
aggregated tau, LY3303560 is hypothesized 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, a humanized monoclonal antibody that targets aggregated tau
for the treatment of AD.
Prior to this study, LY3303560 had not been administered to humans.  This first-in-human study 
will investigate the safety, tolerability, and pharmacokinetics (PK) of LY3303560 in healthy 
subjects and patients with AD.  Safety and tolerability evaluations will be conducted over a wide 
range of single doses and dose escalation will not proceed until safety data from previous doses 
have been reviewed.  This study will aim to assess whether a maximum-tolerated dose (MTD) 
can be established or to demonstrate the tolerability of a dose greater than the expected 
therapeutic dose.  The data generated in this study will be used to help design subsequent clinical 
studies.  The inclusion of Japanese subjects in this study will facilitate the inclusion of Japanese 
subjects in subsequent clinical trials.
3.2.
Background
LY3303560 is a humanized monoclonal antibody engineered from the MC-1 antibody, which 
was identified among mouse monoclonal antibodies as the best antibody to target tau 
propagation in vitro and in vivo.  LY3303560 binds preferentially to aggregated tau, with 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 19
LY3303560
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 or tauopathy, and does not interfere with the binding of the tau positron 
emission tomography (PET) tracer AV-1451 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. Preliminary Data from Cohorts 1 through 7
As of 07 February 2017, the single-dose escalation up to 1400 mg has been completed (Cohorts 
1 to 7). A single subcutaneous (SC) cohort of 210 mg has also been completed (Cohort 5). No 
serious adverse events (SAEs) have been reported, and no subject has withdrawn from the study 
because of an adverse event (AE). A total of 27 AEs have been reported by a total of 16 
subjects, irrespective of causality. The most common AEs reported were headache (4), upper 
respiratory infection (2), contact dermatitis (2), back pain (2), and influenza (2). A total of 7 
AEs were deemed related to study drug by the investigator:  headache (2) and hot flashes, feeling 
swollen, upper respiratory infection, vomiting, and cloudy mind (1 each). There have been no 
infusion reactions reported to date, and there have been no clinically significant findings in 
magnetic resonance imaging (MRI) scans. In addition, there have been no clinically significant 
changes in vital signs, electrocardiograms (ECGs), neurological examinations, and safety 
laboratory tests.
Preliminary PK data following single intravenous (IV) doses indicated that the exposure of 
LY3303560 was approximately linear up to 1400 mg. The observed clearance was 
approximately 180 mL/day, with a half-life of 2 to 3 weeks. A relative bioavailability of 
approximately 60% was calculated based on PK data from the 210-mg SC cohort. The observed 
PK profile of LY3303560 is consistent with the PK properties of an immunoglobulin (Ig) G
antibody.  
3.3.
Benefit/Risk Assessment
The nonclinical safety information for LY3303560 detailed in the Investigator’s Brochure (IB) 
adequately supports the transition from preclinical status to a clinical, single-dose study.  On the 
basis of the nonclinical data, LY3303560 is not considered to be a high-risk compound.  This 
protocol reflects the fact that LY3303560 had not been administered to humans prior to this 
study, and to mitigate this risk, the study has been designed to be conducted in accordance with 
principles outlined in the Guideline on Strategies to Identify and Mitigate Risks for First-in-
Human Clinical Trials with Investigational Medicinal Products. It is intended that sentinel 
dosing will be conducted for the first dose cohort to minimize risk to subjects. Sentinel dosing 
will also be conducted for Cohorts 10 and 11 (2800 and 5600 mg), the additional cohorts 
introduced in Amendment (b). Based on preliminary PK data from Cohorts 1 to 7, the mean
exposure of LY3303560 at a dose of 5600 mg in Cohort 11 is predicted to approximate the no-
observed-adverse-effect level (NOAEL) exposure observed in the monkey (see Section 5.5). 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 20
LY3303560
Accordingly, in addition to review of safety data, the PK data from the 2800-mg dose will be 
analyzed and the projected exposure of 5600 mg will be reviewed prior to dose escalation. In 
addition, for Cohorts 10 and 11, alertness and attention assessments will be administered to 
assess potential central nervous system (CNS) effects. 
Risks around immunogenicity and infusion reactions are considered to be monitorable and 
manageable at the planned dose range of 7 to 5600 mg for LY3303560 in healthy subjects and 
patients with AD.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of LY3303560 is to be found in the IB.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 21
LY3303560
4. Objectives and Endpoints
Table LMDA.1 shows the objectives and endpoints of the study.
Table LMDA.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective of this study is to assess the safety 
and tolerability following single doses of LY3303560 in 
healthy subjects and patients with Mild Cognitive 
Impairment due to Alzheimer’s Disease (AD) or Mild to 
Moderate AD.
Safety and tolerability will be assessed by monitoring 
adverse events.
Secondary

To assess the serum pharmacokinetics (PK) of 
LY3303560 in healthy subjects, including those of 
Japanese origin, following single doses of 
LY3303560.

To assess the cerebrospinal fluid (CSF) PK of 
LY3303560 in patients with AD following single 
doses of LY3303560.

To assess the effect of single doses of LY3303560 
on the QTc interval in healthy subjects and patients 
with AD
The primary parameters for analysis will be maximum 
drug concentration (Cmax), area under the concentration 
versus time curve from time 0 to infinity (AUC 0-), 
and AUC from time 0 to the last measurable 
concentration (AUC0-tlast) of LY3303560.
QT/QTc interval mean change from baseline
Exploratory Objectives

To evaluate changes in plasma, serum and CSF 
biomarkers following single doses of LY3303560
(Cohorts 8 and 9).

To evaluate the effects of single doses of 
LY3303560 on cognitive function (Cohorts 8 and 
9).

To evaluate changes in MRI measures.

To evaluate the immunogenicity of single doses of 
LY3303560
Plasma and serum biomarkers, including tau, and 
neurogranin will be assessed if suitable assays are 
available.  CSF biomarkers, including tau, p-tau, Aβ, 
neurogranin will be assessed if suitable assays are 
available. 
MMSE, FCSRT-IR, CDR-SB
Presence of amyloid related imaging abnormalities 
(ARIA)-E (vasogenic edema) and ARIA-H 
(microhemorrhage).  Exploratory analyses of brain 
volume changes may also be performed.
Treatment-emergent anti-LY3303560 antibody titers.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 22
LY3303560
5. Study Design
5.1.
Overall Design
This is a Phase I, subject-/patient- and investigator-blind, placebo-controlled, randomized, 
parallel, single-ascending dose (SAD) study in healthy subjects and patients with mild cognitive 
impairment (MCI) due to AD or mild to moderate AD.  The study has been designed to assess 
the safety, tolerability, and PK of single IV and SC doses of LY3303560.  The planned doses to 
be explored are 7, 21, 70, 210, 700, 1400, 2800, and 5600 mg.
Cohorts 1 to 7, 10, and 11 will consist of healthy subjects.  The planned number of subjects per 
cohort will be 8 (6:2, LY3303560:placebo), except for Cohort 5 (6 subjects on LY3303560).  For 
each IV cohort, the intention is to enroll 4 subjects of Japanese origin (first generation) and 4 
subjects of non-Japanese origin, but enrollment to a cohort will not be contingent upon fulfilling 
these requirements.  The minimum requirement is to enroll 4 Japanese subjects to at least 3 of the 
IV cohorts, including the highest dose level cohort (a minimum of 12 Japanese subjects in total). 
However, if enrollment of Japanese subjects is slower than anticipated, cohorts may complete 
enrollment with non-Japanese subjects and proceed to dose escalation without waiting for the 
desired number of Japanese subjects to be enrolled.  If 4 subjects of Japanese origin are not 
included in a cohort initially, additional subjects may subsequently be enrolled to achieve a 
maximum of 4 subjects of Japanese origin, if agreed between the sponsor and investigator.  
Although not required, it is preferred that the non-Japanese subjects are not Asian.  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.  Cohorts 8 and 9 will 
consist of patients with MCI due to AD or mild to moderate AD.  The number of patients 
(LY3303560:placebo) in each cohort will be 6:2 patients.  
Subjects/patients will be admitted to the clinical research unit (CRU) on Day -1 and eligibility 
will be confirmed.  Safety will be monitored by AEs, ECGs, vital signs (blood pressure and heart 
rate), physical examinations, neurological examinations, and safety laboratory tests; and 
additionally for Cohorts 10 and 11, the Bond and Lader, and the Digit Span Forward and 
Backward test. The Columbia Suicide Severity Rating Scale (C-SSRS) will be assessed in 
Cohorts 8 and 9.  Subjects/patients will remain resident in the CRU and safety will be monitored 
daily until discharge from the CRU on Day 4 at the earliest, then at regular intervals thereafter
(see the Schedule of Activities in Section 2).  In addition, each subject/patient will have 1 
baseline MRI scan prior to dosing with LY3303560 or placebo, then approximately 2 weeks and 
3 months after dosing, primarily for the assessment of any potential imaging abnormalities.  In 
Cohorts 8 and 9, cerebrospinal fluid (CSF) will be obtained by an indwelling lumbar catheter
prior to dosing with LY3303560 or placebo, and up to 48 hours after dosing with LY3303560 or 
placebo to measure CSF levels of LY3303560 and tau related pharmacodynamic (PD)
biomarkers.  
For all cohorts (except Cohort 5), subjects or patients will receive either LY3303560 or placebo 
as an IV single dose; in Cohort 5, it is intended that subjects will receive a single SC dose of 
210 mg LY3303560, dependent on the observed safety profile from previous cohorts.  


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 23
LY3303560
Subjects/patients will be followed for up to 12-weeks after dosing to evaluate single-dose safety 
and PK.  Dose escalation to the next dose cohort will be triggered by a review of safety data from 
a minimum of 5 subjects (4 on LY3303560 and 1 on placebo) completing the 2-week safety 
evaluation procedures (see Section 7.4.1).  This process is repeated until the final cohort of the 
dose escalation is complete.  Patients in Cohorts 8 and 9 will not be dosed until equal or greater 
doses have been found to be well tolerated in healthy subjects (Cohorts 1 to 7).  The doses 
selected for Cohorts 8 and 9 (intended to be 210 and 700 mg, respectively) are predicted to be 
within the efficacious dose range.  The actual doses administered in Cohorts 8 and 9 will depend 
on observed safety and PK data from Cohorts 1 to 7, but the maximum dose will not exceed 
1400 mg.  These patient cohorts should confirm whether the safety and PK of LY3303560 is 
similar between patients with AD and healthy subjects, and support the dose range for future 
studies in patients with AD.
Sentinel dosing will be performed for Cohorts 1, 10, and 11.  Two subjects will be dosed initially 
(1 assigned to LY3303560 and 1 to placebo) and followed to 48 hours postdose before the 
remaining subjects in that cohort are dosed.  The remaining 6 subjects may be dosed on the same 
day, at appropriate intervals.  If there are no issues with the first cohort, subjects in Cohorts 2 to 
9 may be dosed on the same day at appropriate intervals, or on separate days, as practical, 
however, the timing of dosing will be staggered such that subjects will not be dosed 
simultaneously.
The highest dose may be adjusted based on emerging data, but it is intended that the magnitude 
of the escalation between dose levels will not exceed a half-log interval (approximately 3-fold) 
and a maximum dose of 5600 mg LY3303560 will not be exceeded.  All subjects in a particular 
cohort must have been dosed and safety data for 2 weeks after dosing must be reviewed from at 
least 4 subjects on LY3303560 and 1 subject on placebo, prior to dose escalation. Additionally, 
PK data from Cohort 10 will be reviewed prior to escalation to Cohort 11. If criteria for stopping 
rules are not met (see Section 7.4.1), then the next dose cohort will be enrolled with next planned
dose increases until 5600 mg or stopping criteria are met.  If a termination dose is reached, a 
dose reduction of at least one-half of the termination dose may be tested in one of the remaining
dose cohorts, if deemed appropriate.
The PK data for LY3303560 obtained during the study may be used to assist in dose escalation 
decisions, but such data are not required for dose escalation, except for dose escalation from 
Cohorts 10 and 11.  If the PK data reveal that the current sampling schedule does not allow for 
an adequate characterization of the PK profile, the blood sampling schedule for subsequent dose 
administrations may be adjusted.  A maximum of 5 additional PK samples per subject may be 
allowed if indicated by emerging data.  See Section 10.3.7 for further information about PK 
reviews.
Figure LMDA.1 illustrates the study design.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 24
LY3303560
Abbreviations:  AD = patients with Alzheimer’s disease; HS = healthy subjects; IV = 
intravenous; LY = LY3303560; PK = pharmacokinetics; PL = placebo; SAD = single-
ascending dose; SC = subcutaneous.
Figure LMDA.1.
Illustration of study design for Protocol I8G-MC-LMDA.
5.2.
Number of Participants
For Cohorts 1 to 7, 10, and 11, up to 90 healthy subjects may be enrolled so that approximately 
70 subjects (8 subjects per cohort, except for Cohort 5 [n=6]) reach at least Day 29 of the study.  
For Cohorts 8 and 9, up to 20 patients with AD may be enrolled so that approximately 
16 patients (8 patients in each cohort) reach at least Day 29 of the study. 
Subjects or patients who discontinue the study before completing the Day 29 assessment may be 
replaced at the discretion of the sponsor and investigator.  Subjects or patients who discontinue 
SAD 1 (HS)
7 mg IV
6 LY: 2 PL
(sentinel dosing)
SAD 2 (HS)
21 mg IV
6 LY: 2 PL
SAD 3 (HS)
70 mg IV
6 LY: 2 PL
SAD 5 (HS)
210 mg SC
6 LY
SAD 8 (AD)
IV Dose TBD 
6 LY: 2 PL
SAD 4 (HS)
210 mg IV
6 LY: 2 PL
SAD 6 (HS)
700 mg IV
6 LY: 2 PL
SAD 7 (HS)
1400 mg IV
6 LY: 2 PL
SAD 9 (AD)
IV Dose TBD
6 LY: 2 PL
2 wk
safety
2 wk
safety
2 wksafety
2 wk safety
2 wk safety
2 wk safety
2 wk safety/PK
2 wk safety
SAD 10 (HS)
2800 mg IV
6 LY: 2 PL 
(sentinel dosing)
2 wk safety
SAD 11 (HS)
5600 mg IV
6 LY: 2 PL 
(sentinel dosing)
2 wk safety 
and PK


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 25
LY3303560
after Day 29 may also be considered for replacement to ensure sufficient data are available for 
final data analysis.  The ethnicity of the replacement subject (Japanese or non-Japanese) should 
match the ethnicity of the discontinued subject, where possible.
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 subject/patient.
5.4.
Scientific Rationale for Study Design
This study will be conducted to investigate the safety, tolerability, and PK of a single IV
administration of LY3303560 in healthy subjects and patients with AD. Sentinel dosing will be 
implemented for the first cohort, where only 1 subject is dosed with LY3303560 in parallel with
1 subject dosed with placebo and these 2 subjects are observed for at least 48 hours before any 
other subjects are dosed.  The remaining subjects may be dosed on the same day, at appropriate 
intervals.  Also a minimum 4-day in-patient stay after dosing with study drug provides further 
risk management. 
Given planned doses for Cohorts 10 and 11 will approximate the NOAEL exposure in monkeys, 
sentinel dosing will also be conducted in these cohorts. In addition, the Bond and Lader, and 
Digit Span Forward and Backward test will be measured in these cohorts to assess potential CNS 
effects.
Due to the anticipated long half-life of LY3303560, separate groups of subjects will be 
randomized to each dose cohort in a parallel design rather than using a crossover study design 
within subjects.  Two subjects per cohort will be administered an IV infusion of placebo to allow 
for a blinded, placebo-controlled assessment of effects. 
Cohort 5 (SC dose) will allow for a determination of SC exposure relative to IV, and to assess 
safety.  It is intended that the dose administered in Cohort 5 will be 210 mg LY3303560, but the 
actual dose will be dependent on the observed safety and PK profile of previously administered 
doses.  However, the dose will not exceed 700 mg or the highest well-tolerated dose in the prior 
ascending IV cohorts. 
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 for imaging abnormalities with tau target 
therapies from the preclinical data for LY3303560 or from other tau therapeutics in the literature, 
MRI scans will be taken predose and then approximately 2 weeks and 3 months after dosing with
LY3303560, in order to assess the potential for LY3303560 induced tau related imaging 
changes, including, but not restricted to, vasogenic oedema and microhaemorrhage, in both 
healthy subjects and patients with AD. 
It is intended that this study will support further development of LY3303560 in Japanese
patients, therefore, it is planned that healthy Japanese subjects may be enrolled in each cohort.  If 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 26
LY3303560
the recruitment of Japanese subjects becomes limiting for a particular cohort, then cohorts may 
complete enrollment with non-Japanese subjects and proceed to dose escalation without waiting 
for the desired number of Japanese subjects to be enrolled.  Japanese subjects may subsequently 
be enrolled to fulfill the desired number of Japanese subjects at the discretion of the sponsor and 
investigator.  It is preferred that non-Japanese subjects be non-Asian.
5.5.
Justification for Dose
The proposed dose range is 7  to 5600 mg LY3303560.  The doses were selected based upon the 
analysis of nonclinical PK, efficacy and toxicology data from studies conducted in Tg4510 tau 
transgenic mice expressing human four-repeat tau with the P301L mutation that is linked to 
hereditary tauopathy and cynomolgus monkeys. 
A mechanistic PK/PD model was used to predict a clinically relevant LY3303560 dose range by 
estimating the steady-state reduction in aggregated tau in CSF at various doses.  The CSF was 
used as a surrogate matrix to understand the disposition of aggregated tau in the CNS.  Model 
predictions suggested a clinical dose of 10.5 mg LY3303560 administered every 4 weeks (Q4W) 
and 385 mg LY3303560 Q4W will decrease CSF aggregated tau by approximately 20% and 
90%, respectively.  However, an update to the PK/PD model based on recent nonclinical findings 
in monkey suggest that the predicted clinical dose of LY3303560 may be higher than what was 
previously predicted.  As such, the maximum dose to be evaluated in this study has been 
increased from 1400 to 5600 mg.  A dose of 10.5 mg (20% decrease in CSF aggregated tau) is 
defined as the minimally anticipated biological effect level (MABEL).  Therefore, a starting dose 
of 7 mg LY3303560 (approximately 0.1 mg/kg for a 70-kg person) is below the MABEL and 
thus considered an appropriate starting dose.
The safety of LY3303560 was assessed in 5-week and 6-month toxicology studies in 
cynomolgus monkeys which included evaluation of safety pharmacology and toxicokinetics.  
The cynomolgus monkey is an appropriate large animal species to evaluate the safety of
LY3303560 with respect to monomeric tau.  The administration of LY3303560 in monkeys up to 
a maximum dose of 200 mg/kg/week (bolus IV) for 5 weeks or 6 months resulted in no 
compound-related adverse findings. It is anticipated that the mean exposure resulting from doses 
of LY3303560 to be administered in Cohorts 10 and 11 will approximate the mean exposure in 
monkeys dosed 200 mg/kg LY3303560 (the NOAEL), see Table LMDA.2. The safety and PK 
data from doses up to 1400 mg LY3303560 also support dosing in Cohorts 10 and 11. The 
safety of LY3303560 was also assessed in 5-week and 6-month toxicology studies in a Tg4510 
mouse model.  The Tg4510 transgenic mouse is an appropriate species to evaluate the safety of 
LY3303560 with respect to binding aggregated tau and small tau fibrils.  The administration of 
LY3303560 to Tg4510 mice up to a maximum SC dose of 200 mg/kg resulted in no compound-
related adverse findings.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 27
LY3303560
Table LMDA.2.
Margin of Safety for Subcutaneous/Intravenous Administration of 
LY3303560 Based on Administered Dose and Predicted Exposure
Dose
Dose
Multiplea
(Starting dose/
Maximum dose)
AUC0-
168hr
(µg•day/mL)
Exposure
Multiplea
(Starting dose/
Maximum dose)
Humanb
Starting Dose
Maximum Dose
7 mg (0.1 mg/kg)
5600 mg (80 mg/kg)
–
–
36.1c
35,400
–
–
Tg4510 mouse NOAELd
200 mg/kg
2000/2.5
15,458e
428/0.4
Monkey NOAELf
200 mg/kg
2000/2.5
47,083e
1304/1.3
Abbreviations:  AUC0-168hr = area under the serum concentration time curve from time zero through 168 hours 
postdose; NOAEL = no-observed-adverse-effect level.
a
Dose multiple is the dose in animals divided by the dose in humans based on mg/kg basis.  Exposure multiple is 
the calculated AUC in animals divided by the predicted AUC in humans.
b
Clinical dose assumes a 70 kg subject; 7 mg = 0.1 mg/kg, 5600 mg = 80 mg/kg.
c
Observed data from Study LMDA (preliminary).
d
NOAEL determined in a 6-month repeat dose toxicity study (Study 8326195).
e
AUC is mean of male and female.
f
NOAEL determined in a 6-month repeat dose toxicity study (Study 8326196).
Overall, the proposed starting dose of 7 mg LY3303560 is considered appropriate as it is below 
the calculated MABEL.  The projected mean exposure at the highest planned dose of 5600 mg is 
expected to approximate the NOAEL exposure observed in the 6-month toxicology study in 
cynomolgus monkeys.  Prior to dosing Cohort 11 (5600 mg), LY3303560 PK data from Cohort 
10 (2800 mg) will be reviewed and the exposure for Cohort 11 (5600 mg) will be predicted.  The 
dose to be administered in Cohort 11 may be adjusted if necessary to ensure the projected mean 
exposure does not exceed the mean monkey NOAEL exposure of 47,083 µg•day/mL.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 28
LY3303560
6. Study Population
Eligibility of healthy subjects and patients for study enrollment will be based on the results of 
screening medical history, physical examination, vital signs, clinical laboratory tests, ECG, 
clinical imaging tests, and, for patients, the research disease diagnostic criteria.  Additionally for 
patients, a cognitive examination will be performed.
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 28 days before enrollment for Cohorts 1 to 7, 10, and 11 (healthy 
subjects).  Subjects who are not enrolled within 28 days of screening may be subjected to an 
additional medical assessment and/or clinical measurements to confirm their eligibility.
Screening may occur up to 70 days before enrollment for Cohorts 8 and 9 (patients with AD).  
Patients who are not enrolled within 70 days of screening may be subjected to an additional 
medical assessment and/or clinical measurements to confirm their eligibility and exceptions to 
the 70-day screening window may be granted as follows:

free and cued selective reminding test with immediate recall (FCSRT-IR), Mini 
Mental State Examination (MMSE), and Clinical Dementia Rating (CDR):  90 days

florbetapir imaging:  120 days
Patients should only proceed to the next screening test when the patient passes the prior
screening test.  The screening tests are to occur in the following order:
1. all screening tests except MRI and PET scans
2. MRI
3. florbetapir PET
Japanese healthy subjects will be recruited at a site outside of Japan and, for the purpose of 
analysis, should be first generation Japanese (defined as the subject, the subject’s biological 
parents, and all of the subject’s biological grandparents are of exclusive Japanese descent and 
were born in Japan).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects/patients are eligible for inclusion in the study only if they meet all of the following 
criteria at screening and/or enrollment:
[1a]
For Cohorts 1 to 7, 10, and 11, are overtly healthy, as determined by medical 
history and physical examination


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 29
LY3303560
[1b]
For Cohorts 8 and 9, have mild cognitive impairment 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 informants over more than 6 months

objective evidence of significantly impaired episodic memory 
characteristic of hippocampal dysfunction on testing: 
o FCSRT-IR:  ≤22 for free recall or ≤42 for total recall
o CDR of 0.5 to 2, global score
o MMSE of 16 to 30

positive florbetapir PET scan
[2a]
male subjects/patients:
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 product (IP)
At least one effective method of contraception will be used (for example, 
condoms with spermicide, oral contraceptives, intrauterine device (IUD), 
male sterilization, 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 subjects/patients:
women not of child-bearing potential may participate, and include those who 
are:
a) Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
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 hormone 
>40 mIU/mL.
[3]
are at least 30 years old at the time of screening for Cohorts 1 to 7, 10, and 11.  
For Cohorts 8 and 9, are at least 50 years old at the time of screening
[4]
have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, at screening


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 30
LY3303560
[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 administration 
of IP for IV administration as per the protocol
[7]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures and research unit policies
[8]
for healthy subjects (Cohorts 1 to 7, 10, and 11):  are able and willing to give 
signed informed consent.  For Cohorts 8 and 9, patients not capable of 
providing consent must provide assent; informed consent must be provided by 
a legally authorized representative
[9]
for patients with AD (Cohorts 8 and 9):  have adequate vision and hearing for 
neuropsychological testing in the opinion of the investigator
[10]
for patients with AD (Cohorts 8 and 9):  have a reliable caregiver/study 
informant who provides a separate written informed consent to participate.  
The caregiver/study informant is required to accompany the patient for 
screening, all dosing days and for all days that the C-SSRS/Self-Harm 
Supplemental Form (SHSF) and cognitive and functional scales are 
administered.  If the caregiver/study informant is not able to accompany the 
patient in person because of an unavoidable circumstance, he/she must be 
available by telephone to answer questions regarding AEs and concomitant 
medications, and to answer the questions for the caregiver portions the C-
SSRS/SHSF.  If any caregiver/study informant familiar with the study cannot 
continue, 1 replacement is allowed.  More than 1 replacement may be allowed 
per investigator's discretion.  The replacement(s) will also need to sign a 
separate written informed consent on the visit he/she accompanies the patient 
to participate.  The caregiver(s)/study informant(s) must be in frequent contact 
with the patient (defined as at least 10 hours per week), willing to accompany 
the patient to the office and/or be available by telephone at designated times, 
and willing to monitor administration of prescribed medications
Note:  The caregiver(s)/study informant(s) 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.  Participants living in an assisted-living 
facility may be included if regular contact with a caregiver who accompanies 
the patient is maintained.  If it is known that the caregiver could change and 
the 2 caregivers are available (in the same location), both should be advised of 
the study procedures and may attend the visits with the patient.  In addition, 
both will have to sign an informed consent form (ICF) (see Appendix 3)


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 31
LY3303560
6.2.
Exclusion Criteria
Subjects/patients will be excluded from study enrollment if they meet any of the following 
criteria at screening and/or enrollment:
[11]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.  For Cohorts 8 and 9, have caregivers who are 
investigator site personnel directly affiliated with this study
[12]
are Lilly employees or employees of third-party organizations (TPOs)
involved with the study who require exclusion of their employees, or have 
caregivers (Cohorts 8 and 9) who are Lilly employees or employees of TPOs 
involved in study who require exclusion of their employees
[13]
are currently enrolled in a clinical trial involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study.  
[14]
have participated, within the last 30 days, in a clinical trial involving an IP.  If 
the previous IP has a long half-life, 3 months or 5 half-lives (whichever is 
longer) should have passed
[15]
have previously completed or withdrawn from this study 
[16]
have known allergies to LY3303560, related compounds or any components 
of the formulation, or history of significant atopy
[17]
have significant allergies to humanized monoclonal antibodies, 
diphenhydramine, epinephrine, or methylprednisone
[18]
have clinically significant multiple or severe drug allergies, or intolerance to 
topical corticosteroids, or severe post treatment hypersensitivity reactions 
(including, but not limited to, erythema multiforme major, linear IgA
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis)
[19]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[20]
have persistent abnormal blood pressure as determined by the investigator
[21]
have a history or presence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the IP; or of interfering with the 
interpretation of data
[22]
show evidence of significant active neuropsychiatric disease
[23]
regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 32
LY3303560
[24]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[25]
show evidence of hepatitis C and/or positive hepatitis C antibody
[26]
show evidence of hepatitis B and/or positive hepatitis B surface antigen
[27]
are women who are lactating
[28]
for healthy subjects (Cohorts 1 to 7, 10, and 11):  have used or intend to use 
over-the-counter or prescription medication (including herbal medications) 
within 7 days prior to dosing or during the study with the exception of 
vitamins and mineral supplements (not providing >100% of the recommended 
dietary allowance); thyroid replacement and/or estrogen hormone 
replacement; and occasional paracetamol/acetaminophen.  If this situation 
arises, inclusion of an otherwise suitable subject may be at the discretion of 
the sponsor.  
[29]
have donated blood of more than 500 mL within the last month before dosing
[30]
have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (males over 65 and females), or are 
unwilling to stop alcohol consumption 48 hours before dosing until discharge 
from the CRU (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 
oz or 45 mL of distilled spirits)
[31]
have 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.
[32]
have an increased risk of seizures as evidenced by a history of head trauma 
with loss of consciousness within the last 5 years or ≥1 seizure (except 
childhood febrile seizure); prior electroencephalogram with epileptiform 
activity; stroke; 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)
[33]
have any contraindications for MRI studies, including claustrophobia, the 
presence of metal (ferromagnetic) implants/cardiac pacemaker, or 
contraindication for gadolinium contrast
[34]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
Additional criteria for patients with AD (Cohorts 8 and 9):
[35]
show abnormalities in lumbar spine previously known or determined by 
screening lumbar x-ray (if conducted)


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 33
LY3303560
[36]
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
[37]
MRI demonstrating presence of macrohemorrhage or >4 microhemorrhages or 
pathology inconsistent with AD or clinically significant finding that may 
impact patient’s ability to safely participate in the study
[38]
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 randomization (Note:  If a patient has 
recently stopped AChEIs and/or memantine, he or she must have discontinued 
treatment at least 4 weeks before time of randomization) or has received 
medications that affect the CNS, except treatments for AD, for less than 4 
weeks; that is, doses of chronic medications that affect the CNS should be 
stable for at least 4 weeks before randomization.  Any intended concomitant 
or concurrent medication use will be evaluated by the investigator in 
consultation with the Lilly clinical pharmacologist
[39]
have criteria that would preclude a lumbar puncture, such as allergy to all 
local anesthetics (such as lidocaine); have a local infection at the site of the 
lumbar puncture; have <100 GI/L (100,000/mm3) platelets or clinically 
significant coagulation abnormality or significant active bleeding; or treatment 
with an anticoagulant or treatment with >2 antiplatelet agents
[40]
have history of intracranial hemorrhage, cerebrovascular aneurysm, or 
arteriovenous malformation, carotid artery occlusion, stroke, or epilepsy
[41]
show evidence of suicidal ideation as assessed by the C-SSRS
[42]
have current serious or unstable illnesses including hepatic, renal, 
gastroenterologic, respiratory, cardiovascular (including ischemic heart 
disease), endocrinologic, neurologic (other than AD), psychiatric, 
immunologic, or hematologic disease and other conditions that, in the 
investigator’s opinion, could interfere with the analyses of safety and efficacy 
in this study
[43]
have history within the past 5 years of a primary or recurrent malignant 
disease with the exception of resected cutaneous squamous cell carcinoma in 
situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer 
with a normal prostate-specific antigen postresection
[44]
any prior exposure to or participation in clinical trials of active or passive 
immune therapies directed against tau Aβ protein 
[45]
have had a ventriculperitoneal shunt within the last year
[46]
have had gamma globulin (IgG) therapy within the last year


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 34
LY3303560
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects/patients may undergo medical assessments and review of 
compliance with requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Subjects/patients should fast for at least 4 hours prior to study drug administration and are 
required to remain recumbent for approximately 2 hours (unless otherwise required for 
procedures) after study drug administration and remain sedentary in a bed or chair for the 
subsequent 2 hours for observation.  Subjects/patients are permitted to have a meal 
approximately 2 hours following dosing.  While resident in the CRU, a standardized diet will be 
provided.  When outpatient, a subject’s/patient’s typical diet may be consumed at all other meal 
times during the study.
6.3.2. Caffeine, Alcohol, and Tobacco
Consumption of caffeine- and xanthine-containing products is allowed, provided that the 
subject’s/patient’s consumption has been consistent for the past 30 days.
Subjects/patients will not be permitted to consume alcohol from 48 hours before CRU admission
to leaving the CRU. Subjects/patients will not exceed their habitual alcohol consumption during 
the study.  When not resident in the CRU, male subjects/patients should be advised to limit 
alcohol consumption to no more than 21 units per week and males older than 65 years and
female subjects/patients to no more than 14 units per week, and all subjects/patients should be 
advised to limit alcohol consumption to no more than 3 units in a day.
Subjects/patients will not be permitted to smoke from 48 hours before visiting the CRU until 
discharge from the CRU.
6.3.3. Activity
On CSF sampling days in Cohorts 8 and 9, movement will be restricted during the procedure and 
for an appropriate time after removal of the lumbar catheter, as determined by the investigator
(see Section 9.5.1).  Patients will be monitored following removal of the lumbar catheter until 
discharge from the CRU on Day 4.  Dosing cannot proceed if dural puncture headache is present 
after insertion of the catheter.
6.4.
Screen Failures
Healthy subjects who do not meet the criteria for participation in this study (screen failure) may 
not be re-screened.  
Patients with AD who do not meet the criteria for participation in this study (screen failure) may 
be rescreened up to 2 times.  The interval between rescreening should be at least 1 week.  Each 
time rescreening is performed, the individual must sign a new ICF and will be assigned a new 
identification number.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 35
LY3303560
7. Treatment
7.1.
Treatment Administered
This study involves a comparison of LY3303560 and placebo, over a planned dose range of 7 to 
5600 mg.  Table LMDA.3 shows the treatment regimens.
For all cohorts except Cohorts 5, 7, 10, and 11, the IP will be administered as a slow IV infusion 
over at least 30 minutes.  Every attempt should be made to complete the infusion within 60 
minutes.  The infusion time for Cohorts 7 and 10 should be at least 60 minutes, and for Cohort
11, at least 90 minutes.
For Cohort 5, the planned 210 mg dose of IP will be administered SC as two 1.4 mL injections of 
105 mg each.
The minimum time for close observation in the CRU following dosing is 4 hours. The site must 
have resuscitation equipment, emergency drugs, and appropriately trained staff available during 
dosing and for at least 24 hours after dosing.  
All IP provided to the investigator will be stored in a secure location, and allocated and 
dispensed by appropriately trained persons.  The allocation and dispensing of the IPs will be 
fully documented and verified by a second person.  Detailed records of the amounts of IP
received, dispensed and remaining at the end of the study will be maintained.  Detailed 
instructions for the preparation and handling of LY3303560 will be provided by the sponsor in a 
pharmacy manual.
The actual time of all dose administrations will be recorded in the subject’s or patient’s case 
report form (CRF).
Study procedures scheduled relative to dosing time are to occur from time of start of infusion or 
the start of SC injection.  For example, 3 hours postdose would be 3 hours after the start of the 
IV infusion/SC injection.
Table LMDA.3.
Treatments Administered
Treatment Name
LY3303560
Placebo
Dosage Formulation
lyophilized 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 
or
subcutaneous injection
intravenous infusion 
or
subcutaneous injection
Dosing instructions
single administration
single administration
The investigator or designee is responsible for:

explaining the correct use of the IPs to the subject/patient/patient’s caregiver, 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 36
LY3303560

verifying that instructions are followed properly,

maintaining accurate records of IP dispensing and collection,

and returning all unused medication to Lilly or its designee at the end of the study.
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
Investigational product 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
Treatment assignment will be determined according to a randomization schedule.
7.2.1. Selection and Timing of Doses
The actual time of all dose administrations will be recorded in the subject’s/patient’s CRF.  For 
IV infusions, the actual duration time of the infusion will be recorded in the CRF.  If the infusion 
is terminated, this should be recorded in the CRF.
7.3.
Blinding
This is a subject-/patient- and investigator-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.  
Randomization tables for allocation of LY3303560 and placebo will be prepared by the Lilly 
statistician and provided to the study site pharmacists or pharmacy staff involved in dose 
preparation.  Blinding will be maintained throughout the conduct of the trial until all data are 
cleaned to an acceptable level of quality and locked.  The details are included in the 
Blinding/Unblinding Plan.
Emergency codes will be available to the investigator.  A code, which reveals the treatment 
group for a specific study subject/patient, may be opened during the study only if the 
subject/patient’s well-being requires knowledge of the subject/patient’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a subject/patient’s treatment assignment is warranted for medical management of 
the event.  Subject/patient’s safety must always be the first consideration in making such a 
determination.  If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact the Lilly clinical pharmacologist or clinical research physician
(CRP) prior to unblinding a study subject/patient’s treatment assignment unless this could delay 
emergency treatment of the patient.  If a study subject/patient’s treatment assignment is 
unblinded, Lilly must be notified immediately.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 37
LY3303560
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
7.4.1. Dose Decision/Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
MTD is determined or the highest planned dose has been administered. The highest dose level 
that is tolerated will be designated as the MTD.
Safety data will be the primary criteria for the dose escalation.  In addition, if available at the 
time of dose escalation decision, PK (Cmax, AUC, and total clearance [CL]) results will be used 
as supporting data for dose escalation, but such data are not required, aside from dose escalation
from Cohort 10 to 11 (see below).  No dose escalation can occur without prior discussion and 
agreement between the investigator and the Lilly clinical pharmacologist/CRP.  
Safety data collected up to 2 weeks after dosing will be evaluated from at least 4 subjects on 
LY3303560 and 1 subject on placebo prior to each dose escalation.  The safety data reviewed 
will include:  AEs, MRI, neurological monitoring, safety laboratories, ECGs and vital signs.
Safety data, in particular AEs and adverse laboratory abnormalities, will be independently 
assessed by the investigator, and will be considered related to the IP unless there is clear 
evidence that the event is not related.  After review of these data, an agreement on the 
appropriate dose escalation will be made by the investigator and sponsor for the next cohort.  
The magnitude of the dose escalation may be reduced following data review, but subsequent 
escalations cannot be increased by more than approximately 3-fold (a half-log increment).
At a minimum, safety data from Cohort 4 (210 mg IV LY3303560) will be reviewed prior to 
starting Cohorts 5 and 8. For Cohort 5, PK data from up to Cohort 3 (70 mg LY3303560) will 
also be reviewed prior to dosing this cohort. Cohort 9 will only be initiated after review of safety 
data from Cohorts 6 (700 mg LY3303560) and 8.  
For dose escalation from Cohort 10 to 11, LY3303560 PK data from Cohort 10 will be analyzed 
and the exposure at 5600 mg LY3303560 re-projected based on the observed PK at 2800 mg 
LY3303560.  The PK projection will be reviewed before escalation to Cohort 11 and the dose to 
be administered in Cohort 11 may be adjusted if necessary to ensure the projected mean 
exposure does not exceed the mean monkey NOAEL exposure of 47,083 µg•day/mL.
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be discontinued:
1) Two or more subjects experience a SAE (aside from a SAE occurring during the 
infusion/SC delivery, see below) or 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, or


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 38
LY3303560
2) Two or more subjects at a dose level experience moderate or severe AEs that 
impair normal activities, but do not meet the CSE criteria, and are considered 
related to study treatment.  
3) After the introduction of premedication in accordance with the protocol, 2 or 
more subjects develop (according to Common Terminology Criteria for Adverse 
Events) Grade 2 acute AEs related to the infusion, during or within 2 hours of 
completing the infusion, that do not resolve with a reduced infusion rate and 
supportive care.
4) If an SAE occurs during the infusion or SC delivery of the study drug, 
irrespective of causality, the drug is discontinued immediately.  No re-dosing or 
completion of dosing is considered for that subject.  If the infusion SAE is 
considered related to LY3303560 then the remaining cohort is not dosed.
It is important to note that when any of the above criteria are met, the dosing at the same and 
higher dose levels will be stopped, but any ongoing dose level that is below the dose that 
triggered the stopping rule may continue when considered appropriate by the sponsor.
In the event of an SAE that is related to the IP, other than precautionary in-patient observation, 
dosing will be suspended, for that cohort and higher cohorts, pending notification of the ethical 
review board (ERB) and appropriate regulatory authorities. Dosing will only resume, per 
protocol, after the ERB, investigator, and sponsor agree on the appropriateness of further dosing.
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 acetaminophen, 500 to 1000 mg and/or an antihistamine may be administered 
orally 30 to 60 minutes prior to the start of infusion for subsequent subjects.
The decision to implement premedication for infusions in subsequent cohorts will be made by 
the investigator 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, angioedema, 
throat irritation, rash, pruritus, myalgia, and dizziness.  In the event that a significant infusion 
reaction occurs, the following guidance should be followed:

the IP infusion should be slowed or stopped, depending on the symptoms/signs present


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 39
LY3303560
o
if slowed, the infusion should be completed at the slower rate, as tolerated and 
documented in the CRF
o
if stopped, no further attempts to administer the IP for that subject 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, epinephrine, and/or methylprednisolone.
Stored serum samples for possible immune safety laboratory testing (including but not limited to 
Beta tryptase, total IgE, and immune complex testing) will be collected at time points indicated 
in the Schedule of Activities (Section 2).  
Additionally, stored serum samples for possible immune safety laboratory testing (including but 
not limited to β tryptase, total IgE, and immune complex testing) should also be collected 
approximately 60 to 120 minutes and 4 to 6 weeks after moderate or severe infusion reactions.  
Unscheduled samples may also be collected as needed.
Standardized 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 IP and only authorized 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 the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
Prohibited medications are summarized in the inclusion and exclusion criteria (Section 6).  Use
of vitamins/mineral supplements (not providing more than 100% of the RDA), thyroid 
replacement, and/or estrogen hormone replacement is allowed.  Occasional 
paracetamol/acetaminophen use without prior consultation with a Lilly clinical pharmacologist 
will be allowed.  Patients with AD on stable concomitant medication at the time of study entry 
should continue their regular, unchanged dose throughout the study.  Additional drugs for 
subjects/patients should be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical problem.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 40
LY3303560
If the need for concomitant medication arises, inclusion or continuation of the subject/patient 
may be at the discretion of the investigator after consultation with a Lilly clinical pharmacologist 
or CRP.  Any additional medication used during the course of the study must be documented.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 41
LY3303560
8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Subjects/patients will be discontinued from the IP in the following circumstances:

AE
o
if a CSE occurs, the IP is to be discontinued and appropriate measures taken.  
Lilly or its designee should be alerted immediately.  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 wellbeing of the subject/patient  
o
a clinically significant systemic hypersensitivity reaction occurs following 
administration of the IP (for example, drug-related symptomatic bronchospasm, 
allergy-related edema/angioedema, 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 edema or cerebral 
microhemorrhage
Subjects/patients who discontinue the study early should complete all remaining scheduled visits 
if feasible or, at a minimum, the early termination procedures as shown in the Schedule of 
Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Subject/Patients
The criteria for enrollment must be followed explicitly.  If the Sponsor or investigator identifies a 
patient who did not meet enrollment criteria and was inadvertently enrolled, a discussion must 
occur between the Lilly clinical pharmacologist and the investigator to determine if the patient 
may continue in the study.  If both agree it is medically appropriate to continue, the investigator 
must obtain documented approval from the Lilly clinical pharmacologist to allow the 
inadvertently enrolled patient to continue in the study without continued treatment with IP.
8.2.
Discontinuation from the Study
Subjects/patients will be discontinued in the following circumstances:

Enrollment in any other clinical trial involving an IP or enrollment 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)


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 42
LY3303560

Investigator Decision
o
the investigator decides that the subject/patient should be discontinued from the 
study
o
if the subject/patient, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study occurs prior to introduction of the new 
agent

Subject/Patient Decision
o
the subject/patient, or designee, for example, parents, legal guardian or caregiver 
(for patients with AD), requests to be withdrawn from the study
Subjects/patients who discontinue the study early will have end-of-study procedures performed 
as shown in the Schedule of Activities (Section 2).
8.3.
Patients/Subjects Lost to Follow-up
A subject/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 subjects/patients who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 43
LY3303560
9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the 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 subjects/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 subject/patient.
The investigator is responsible for the appropriate medical care of subjects/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 IP or the study, 
or that caused the subject/patient to discontinue the IP before completing the study.  The 
subject/patient should be followed until the event resolves, stabilizes 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 subject’s/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 cause and effect relationship between the IP, 
study device and/or study procedure and the AE.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 44
LY3303560
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s/patient’s IP 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 hospitalization

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.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject/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 IP) 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 investigational product or procedure.  
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 
require the reporting of SUSARs.  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.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 45
LY3303560
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.
Subjects/patients should be instructed to contact the investigator as soon as possible if he or she 
has a complaint or problem with the IP [or drug delivery system] so that the situation can be 
assessed.
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 randomization.
Refer to the IB for LY3303560.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject/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 subject/patient, vital signs measurements should be conducted according to the 
Schedule of Activities (Section 2).  
Screening vital signs will be obtained in the sitting position (after at least 5 minutes sitting).  In 
Cohorts 8 and 9 (patients with AD), for Visits 1 to 3, vital signs will be measured in the supine 
position only. For all other vital signs after study entry, subjects will rest in the supine position 
for at least 5 minutes and undergo supine blood pressure and pulse rate measurements.  Subjects 
will sit for approximately 2 minutes then stand for approximately 2 minutes and undergo 
standing blood pressure and pulse rate measurements. If subjects are unable to stand, supine 
vital signs only will be recorded.  If the subject is unable to stand or sit, omission of the standing 
or sitting vital signs will not be considered a protocol violation.
Subjects/patients who are unable to stand for 2 minutes because of adverse symptoms should be 
placed immediately in a supine position with their legs elevated above the level of their chest.  
An unscheduled measurement of blood pressure and pulse rate should be obtained as soon as 
possible without causing delay in the resumption of recumbency.
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.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 46
LY3303560
9.4.3. Electrocardiograms
For each subject/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 
subject/patient receives the first dose of the IP, 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.  
Subjects/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 deemed clinically necessary.  Collection of additional ECGs at a 
particular time point is allowed to ensure high quality records.  All screening ECGs recorded 
should be stored at the investigational site.
At screening and at all timepoints post-Day 7, 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 subject/patient meets entry criteria.
At all other timepoints, ECGs will be obtained in triplicate at approximately 1-minute intervals at 
each ECG time point and will be transmitted 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 subject/patient for symptoms (for example, 
palpitations, near syncope, syncope) to determine whether the subject/patient can continue in the 
study.  The investigator or qualified designee is responsible for determining if any change in 
subject/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 centralized ECG laboratory
designated by Lilly.  The central ECG laboratory will perform a basic quality control check (for 
example, 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).


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 47
LY3303560
9.4.4. Other Tests
9.4.4.1.
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 sign.  
Table LMDA.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.
Table LMDA.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 to 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 sign
Absent
Present
9.4.4.2. Alertness and Attention Assessments (Cohorts 10 and 11)
The Bond and Lader Visual Analog Scale (VAS), and Digit Span Forward and Backward 
Test will be performed according to the Schedule of Activities (Section 2).
9.4.4.2.1. Bond and Lader VAS
The Bond and Lader VAS (Bond et al. 1974) consists of 16 mood self-rating 100-mm lines 
between 2 opposite adjectives.  The subject has to indicate on the line how he or she is feeling at 
the time of evaluation.  The response is scored by measuring the distance in millimeters between 
the left end of the line and the subject’s mark.  This questionnaire derives 3 factors that assess 
self-rated alertness, self-rated calmness, and self-rated contentment.  Approximately 5 minutes is 
needed to complete the questionnaire.  Subjects will complete a training session for the VAS as 
indicated in the Schedule of Activities (Section 2).  This test will be completed approximately 5 
minutes before all other assessments at the same time point.
9.4.4.2.2. Digit Span Forward and Backward Test
The Digit Span Forward and Backward subtest (Wechsler 2009) of the Wechsler Adult 
Intelligence Scale-IV (Wechsler 2008) is a brief test of attention.  Digit Span is a series of orally 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 48
LY3303560
presented number sequences that the examinee repeats verbatim for Digits Forward and in 
reverse for Digits Backward (Wechsler 2009).
9.4.4.3.
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 edema (ARIA-E) and microhemorrhage (ARIA-H).  A 1.5T scanner is preferred but a 
3T scanner may be used if a 1.5T scanner is not available.  Patients in Cohorts 8 and 9 with 
>4 microhemorrhages in their screening MRI will be excluded from the study.  
Microhemorrhages might indicate a higher risk for macrohemorrhage as well as the presence of 
significant amyloid angiopathy, and there appears to be a risk of microhemorrhage with some 
antiamyloid treatments in preclinical models and possibly in humans as well.
The determination of the number of microhemorrhages will be required to be assessed on a MRI 
using T2*-weighted gradient-echo sequence.  Additional fluid attenuation inversion recovery
(FLAIR) images will be performed to evaluate for the presence of vasogenic edema.  All 
baseline and safety imaging will be analyzed by a central reader blinded to treatment.
9.4.4.4.
Injection-Site Assessments (Cohort 5)
Injection sites will be observed and evaluated for injection-site reactions after SC dose 
administration, as specified in the Schedule of Activities (Section 2). If an injection-site reaction
is present, it will be fully characterized (including erythema, induration, pain, itching, etc.) and 
will be closely monitored until resolution.
Investigational site staff will be provided with separate instructions/training in how to 
consistently evaluate injection-site reactions and their severity.  Photographs of injection-site 
reactions will be taken in a standardized fashion for record-keeping purposes; however, the 
photographs will not be used to evaluate injection-site reaction severity.
9.4.4.5.
Columbia Suicide Severity Rating Scale (Cohorts 8 and 9)
By industry guidance regarding suicidality (US Food and Drug Administration; FDA), any 
assessment of suicide-related thoughts and behaviors 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 behaviors in this study.
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicide-related 
thoughts and behaviors during the assessment period.  The scale includes suggested questions to 
solicit the type of information needed to determine whether a suicide-related thought or behavior 
has occurred.  The C-SSRS will be administered as specified in the Study Schedule 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 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 49
LY3303560
impaired population may be unable to give an accurate response.  The child version of the C-
SSRS has condensed this section into 1 question.  This reason, and also the suggested wording 
for the scale questions having been simplified, resulted in the child version being chosen for this 
study.  There is cognitive impairment in this population and inability of the caregiver/informant 
to have direct knowledge of the patient’s thoughts; therefore, Lilly will assess the investigator’s 
confidence in the responses to the child C-SSRS with a rater question in the CRF.
The child version of the C-SSRS should be administered to the patient with the caregiver/study 
informant present or available by phone.  Responses from both the caregiver/study informant and 
patient should be considered when administering the scale.  The response from the 
caregiver/study informant may be provided over the phone.  If a suicide-related thought or 
behavior 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.
If the investigator determines that suicide-related behaviors have occurred, a Lilly SHSF will be 
used to collect additional information to allow for a more complete assessment of these 
behaviors.  Patients with any clinically significant changes as determined by the investigator will 
be referred to a mental health professional.
9.4.4.6.
Imaging (Cohorts 8 and 9)
A florbetapir scan will be performed at screening.  At the florbetapir PET scanning visit, patients 
will receive a single IV administration of approximately 370 MBq (10 mCi) of florbetapir F 18, 
followed 50 minutes later by a 20 minute continuous imaging session.  The injection of the 
imaging agent will be followed by a saline flush according to the injection procedure described 
in the imaging operations manual. The image should be reviewed immediately following the 
acquisition session.  If the image is not interpretable because of technical artifact (scanner 
failure, patient motion), the patient can be rescanned. However, in order to maximize image 
quality, it is strongly recommended that this second imaging session begin as soon as possible, 
ideally within 80 minutes of the florbetapir administration. 
A total of two 18F-AV-1451 PET scans will be performed, approximately 12 weeks apart.  At
each 18F-AV-1451 PET imaging visit, patients will receive a single IV administration of 
approximately 370 MBq (10 mCi) of 18F-AV-1451.  At approximately 75 minutes following 
injection, a continuous 30 minute brain scan (6 acquisitions, each of 5 minutes in duration) will 
be performed.  
9.4.4.6.1. Radiation Doses Associated with PET Imaging
The estimated exposure to ionizing radiation per patient enrolled in this study (effective dose) is 
summarized in Table LMDA.5.  This includes contributions from florbetapir and 18-AV-1451 
scans, along with low-dose CT scans required for attenuation correction.  The injected doses for 
florbetapir and 18F-AV-1451 are lower than typically used, in order to minimize the overall 
radiation exposure to the patients.  However, the duration of each PET scan will be longer than 
typically performed in order to preserve the final image quality and ensure robust image 
quantification.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 50
LY3303560
For the screening florbetapir PET scan, if the image is not interpretable because of technical 
artifact (scanner failure, patient motion), the patient may be asked to schedule an additional scan 
and have a second scan performed.  Each patient will only undergo up to 1 additional PET scan 
beyond those scheduled in this protocol. In this case, the patient would be exposed to an 
additional 3.92 mSv of ionizing radiation.
Table LMDA.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) 
Florbetapir scan
10
370
7.43
1
  7.43
18F-AV-1451 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 nonclinical CT scan is 
obtained (estimated at 0.4 mSv) as part of the PET scan attenuation correction process when the scan is done on a 
PET/CT scanner.
9.4.5. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist 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
If a study subject/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 subject/patient safety and compliance with regulatory guidance, 
the investigator is to consult with the Lilly designated 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.  


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 51
LY3303560
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 Blinding/Unblinding Plan.
9.4.6. Immunogenicity Assessments
As detailed in the Schedule of Activities (Section 2), blood samples for immunogenicity testing 
will be collected for both healthy subjects and patients with AD to determine antibody 
production against the LY3303560. Additional samples may be collected if there is a possibility 
that an AE is immunologically mediated.  Immunogenicity will be assessed by a validated assay 
designed to detect anti-drug antibodies in the presence of LY3303560.  Antibodies may be 
further characterized and/or evaluated for their ability to neutralize the activity of the 
LY3303560.  
Samples will be retained for a maximum of 15 years after the last subject/patient visit, or for a 
shorter period if local regulations and 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 of 
approximately 3 mL each 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.  Time points for 
PK sampling may be modified based on any available interim PK results obtained during the 
study. 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.
9.5.1. Cerebrospinal Fluid Sampling (Cohorts 8 and 9)
A lumbar x-ray may be conducted to rule out potential contraindication to a lumbar puncture, 
such as significant osteoarthritic disease and bone overgrowth. If an x-ray was conducted within 
12 months of screening, this may be used.
A licensed anesthesiologist or other specially trained physician will insert a flexible, indwelling 
subarachnoid lumbar catheter designed for serial sampling of CSF.  Serial CSF samples will be 
collected from each patient at times specified in the Schedule of Activities (Section 2).  
At each designated time point, CSF will be collected (5 mL at the -4-hour predose time point 
when sample is collected for safety [red blood cell (RBC) count, glucose, and protein], PK, and 
PD biomarkers; 4 mL at the -2-hour predose time point when sample is collected for PK/PD 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 52
LY3303560
biomarkers only; 4 mL at 0-hour time point when sample is collected for safety, and PK/PD 
biomarkers; 4 mL at each postdose time point when sample is collected for measurement of 
PK/PD biomarkers).  Because 4 to 5 mL cannot be collected instantaneously, 8 to 10 minutes is 
needed to collect 4 to 5 mL at a rate of 0.5 mL/min.  Postdose CSF collections are therefore 
started as close to the designated time as possible.  
The residual volume “dead space” that remains in the sterilized tubing needs to be withdrawn 
and separately retained prior to subsequent samples being collected using the same rate of 
0.5 mL/min.  The tubing set-up used by the site retains approximately 1.7 mL of fluid.  
Therefore, before each collection period, 2 mL over a 4-minute period needs to be collected and 
stored.  These samples may be stored and used for assay validation or exploratory work.  
Patients who cannot complete the entire CSF sampling period but who complete CSF collections 
for a minimum of 24 hours postdose will not be replaced.  
The safety of draining 6 mL of CSF in a given hour has been documented (Jhee and Zarotsky 
2003).  This volume is considerably less than the normal rate of CSF production, which is 
approximately 20 to 24 mL/hour (White et al. 1969; Baker et al. 1999).  Removal of up to 
12 mL/hour is tolerated based on previous clinical experience; therefore, no more than 12 mL of 
CSF will be taken during a given hour including that withdrawn from the “dead space”.
Red blood cell counts will be measured in CSF at catheter placement and at least once before 
dosing with study drug and may be measured at other times as deemed necessary by the 
investigator.  Red blood cell counts are to be measured using a clinical laboratory method 
available to the study site.  In addition, each CSF sample collected will be visually inspected for 
evidence of gross blood contamination.  The results of CSF RBC counts are to be documented in 
the CRF.  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 PD and statistical analyses if the level of contamination 
is estimated to be sufficient to produce misleading results.  This calculation will be based on the 
number of RBCs present in the samples, the estimated amount of blood/plasma that would 
correlate to that number of RBCs, and the estimated concentration of LY3303560 that would 
potentially be from blood contamination given the Cmax of the drug at that dose.  
Patients will be carefully monitored for post lumbar catheter headaches.  The investigator may 
use hydration, analgesics, and a blood patch to treat the headache as clinically indicated. 
9.5.2. Bioanalysis
Plasma and CSF samples will be analyzed 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.  Analyses of samples 
collected from placebo-treated subjects and patients are not planned.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject or patient visit for the study.  


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 53
LY3303560
9.6.
Exploratory Pharmacodynamics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 10 mL will be collected for measurement of plasma tau concentrations if a 
suitable assay exists.  A maximum of 5 additional time points per subject/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 if a suitable assay exists.  The samples will 
be identified by the subject/patient number and stored for a maximum of 15 years after the last 
subject/patient visit for the study at a facility selected by the sponsor.  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 subject/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, the mechanism of action of 
LY3303560. Time points for PD samples may be modified based on any available interim 
results obtained during the study. 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, PD samples should be collected from the arm that did not receive the IV 
infusion of study drug.
The sample(s) will be stored for up to a maximum of 15 years after the last subject/patient visit 
for the study at a facility selected by the sponsor.  
9.6.1. Exploratory Cognitive and Functional Scales (Cohorts 8 and 9)
The test of cognitive function, MMSE, Clinical Dementia Rating - Sum of Boxes (CDR-SB), 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 and single dose 
nature of the study. Cognitive and functional tests that are performed on the same day should be 
done in a specific order. Cognitive and functional tests should be completed in this order:  1) 
FCSRT-IR, 2) CDR, and 3) MMSE.
9.6.1.1.
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).


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 54
LY3303560
9.6.1.2.
Clinical Dementia Rating–Sum of Boxes
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.
9.6.1.3.
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).  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.
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 edema 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 program.  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 subject/patient number.  These samples and any data 
generated can be linked back to the subject/patient only by the investigative site personnel.  


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 55
LY3303560
Samples will be retained for a maximum of 15 years after the last subject/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.  
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 utilized, 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, PD, 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, blood ribonucleic acid 
(RNA), proteins, lipids, and other cellular elements.
Serum, plasma, CSF, whole 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 AD, mechanism of action of LY3303560, and/or research 
method, or for validating diagnostic tools or assay(s) related to neurodegenerative diseases.
All samples will be coded with the subject/patient number.  These samples and any data 
generated can be linked back to the subject/patient only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject/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.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 56
LY3303560
10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The sample size is customary for Phase 1 studies evaluating safety, PK, and/or PD parameters, 
and at the conclusion of the trial confidence intervals for PK, PD, and cognition endpoints may 
be computed in order to evaluate the precision of the estimates where appropriate.  
Up to 90 healthy subjects may be enrolled to ensure that approximately 70 subjects (8 subjects 
per cohort, except for Cohort 5 [n=6]) reach at least Day 29 of the study.  
For each of the IV healthy subject cohorts, the intention is to include 4 Japanese subjects and 4 
non-Japanese subjects (preferred non-Asian) to support the development of LY3303560 in Japan.  
The target minimum requirement is to include 4 Japanese subjects in at least 3 of these cohorts 
(12 Japanese subjects total), including the highest dose level cohort.  It is not anticipated that 
there will be differences in LY3303560 exposure/safety/PD response between Japanese and non-
Japanese subjects, therefore the enrollment is not contingent upon fulfilling this requirement.  If 
4 Japanese subjects are not included in a cohort initially, the cohort will complete with non-
Japanese subjects and additional Japanese subjects may subsequently be enrolled to achieve the
intended 4 Japanese subjects, at the discretion of the sponsor. 
Up to 20 patients with AD may be enrolled to ensure that 16 patients (8 patients in each cohort)
complete Cohorts 8 and 9. 
See Section 5.2 for replacement of subjects/patients.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of healthy subject and patient disposition will be provided at the end of the 
study. 
All patients/healthy subjects 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/healthy subject’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 summarized at 
baseline, with the exception of weight which will also be summarized over time.  
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or designee.
Pharmacokinetic and PD analyses will be conducted on the full analysis set.  This set includes all 
data from all randomized healthy subjects and patients receiving a dose of the IP according to the 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 57
LY3303560
treatment the subjects/patients actually received.  Safety analyses will be conducted for all 
enrolled patients/healthy subjects, whether or not they completed all protocol requirements.
Summary statistics, data tabulations, and data graphs by ethnicity (Japanese and non-Japanese, 
and combined) will be provided as appropriate.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Analyses 
will be fully detailed in the statistical analysis plan (SAP).  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP 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 
symptom will be classified by the most suitable term from the medical regulatory dictionary.
The number of IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters.  The parameters will be listed and summarized using standard descriptive 
statistics for values at each time point as well as changes from baseline.  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.
Magnetic resonance imaging changes in volume over the course of the study will be explored 
and exploratory evaluation of vMRI changes for whole brain, ventricle, whole brain boundary 
shift integral and hippocampus will be summarized; further analyses may be conducted and will 
be outlined in the SAP.  A shift table for each dose group will be constructed to assess the MRI 
measurement predose and postdose for changes and additions of ARIA-E and ARIA-H.
For Cohorts 8 and 9, suicide-related thoughts and behaviors based on the C-SSRS will be listed 
by patient.  Only time points and patients that show ideation/behavior of suicide will be 
displayed, that is, all ‘no’s will not be displayed.
An assessment of potential prolongation will be performed using plots of PK data versus QTc 
values.  The frequency of subjects with a maximum increase from baseline in QTcF interval will 
be summarized for each treatment according to the following categories:  >30 ms and >60 ms.  
In addition, the frequency of subjects with QTcF postdose values, according to the following 
categories:  >450 ms, >480 ms and >500 ms, will be summarized by treatment.
Analyses of QTc using QTcF from ECG monitoring in a Phase 1 trial will be performed to judge 
the extent and/or risk of QT prolongation. Scatter plots will be created of QTcF versus 
LY3303560 concentration and change from baseline QTcF versus LY3303560 concentration. 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 58
LY3303560
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.  Separate analysis may be 
conducted for healthy subjects and patients with AD as required.
For Cohorts 10 and 11, results from the Bond and Lader VAS, and Digit Span Forward and 
Backward tests will be summarized by parameter and time point, including change from 
baseline.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
It is intended that PK parameter estimates for LY3303560 in serum and CSF will be calculated 
by standard noncompartmental methods of analysis.  The primary serum and CSF parameters for 
analysis will be maximum drug concentration (Cmax), area under the concentration versus time 
curve from time 0 to infinity (AUC0-∞) and AUC from time 0 to the last measurable 
concentration (AUC0-tlast) of LY3303560.  Other serum PK parameters, such as half-life, 
clearance, and volume of distribution may be reported after IV administration of LY3303560.  
Serum PK parameters such as bioavailability, apparent clearance, apparent volume of 
distribution and half-life may be reported after SC administration. 
A model-based approach may also be implemented using nonlinear mixed effects modeling 
(NONMEM) or other appropriate software to estimate serum and/or CSF PK parameters.
Exploratory analyses of the effect of dose, route of administration, concentration or demographic 
factors, including healthy subjects versus patients, on the PK parameters may be conducted, and 
modeling analyses may be performed for characterization purposes.  Exploratory analyses 
relating LY3303560 serum exposure versus LY3303560 CSF concentrations may be conducted.
10.3.2.2. Pharmacokinetic Statistical Inference
The serum PK parameters, Cmax and AUC0-∞or AUC0-tlast, for LY3303560 obtained for 
healthy subjects (IV only) will be evaluated to estimate the dose-exposure proportionality of 
LY3303560 using a linear-effects power model (Smith et al. 2000).  In this model, log-
transformed dose will be the independent variable, and subject will be a random effect.  Both 
Cmax and AUC will be log-transformed prior to analysis.  The least-square means for each 
treatment together with the treatment differences and associated 90% confidence intervals (CIs) 
will be estimated from the model.  These estimates will be back-transformed to present 
geometric means, the ratios of geometric means, and the corresponding 90% CIs. Dose-exposure 
analysis will be conducted using the healthy subject IV cohorts (Cohorts 1, 2, 3, 4, 6, 7, 10, and 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 59
LY3303560
11). Exploratory analyses of Japanese and non-Japanese subjects may be conducted.  Additional 
dose-exposure analyses may be conducted using patient data. 
10.3.3. Exploratory Pharmacodynamic Analyses 
10.3.3.1. Pharmacodynamic Parameter Estimation
For the healthy subjects, plasma tau will be summarized and/or illustrated graphically by time 
and dose/formulation.
For the patient cohorts (Cohorts 8 and 9), the concentration of the CSF biomarkers, including 
tau, p-tau, Aβ, and neurograinin, will be summarized and/or illustrated graphically based on 
availability of data.  The mean change in concentration of the biomarkers from predose will be 
evaluated.  
10.3.3.2. Pharmacodynamic Statistical Inference
No statistical analysis of PD parameters are planned.
10.3.4. Pharmacokinetic/Pharmacodynamic Analyses (Cohorts 8 and 
9)
Model-based approaches may be used to characterize the relationship between changes in CSF 
biomarkers and exposure of LY3303560.
10.3.5. 18F-AV-1451 Imaging and Cognition Analyses (Cohorts 8 and 
9)
Cognition endpoints collected at screening and Day 85 may be summarized and correlated with 
imaging and CSF endpoints. The data are collected to provide information on cognition changes 
in a 2 to 3 month timeframe will not be used to assess efficacy of the molecule.
Amyloid status at baseline will be summarized and may be used as a factor in plots of other 
endpoints.
18F-AV-1451 SUVR data will be summarized and/or plotted by region of interest as appropriate, 
further details will be given in the statistical analysis plan.  Change from baseline of tau burden 
within regions of interested will be calculated, however, no formal analyses is planned to be 
conducted due to single dose nature of the study.
Additionally, the relationship between LY3303560 serum exposure and imaging endpoints may 
be explored graphically or by a modeling approach.  
10.3.6. Evaluation of Immunogenicity
Antibody formation will be listed and summarized as well as presented graphically over time by 
subject/patient and treatment.  If trends following the dosing of LY3303560 are observed, then a 
mixed effect model will be used, fitting dose and day and the interaction between day and dose 
as a fixed effects and the dependent variable as the log transformed change from baseline in 
antibody formulation following dosing of LY3303560.  If a neutralization assay is performed, 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 60
LY3303560
the frequency of neutralizing antibodies will be determined.  The relationship between the 
presence (or absence) of antidrug antibodies and clinical parameters (e.g., AEs and changes in 
blood pressure) may be assessed.  Likewise, the relationship between the presence of antidrug 
antibodies and the PK parameters and PD response to LY3303560 may be assessed.
10.3.7. Interim Analyses
Select individuals may gain access to unblinded data, prior to the interim or final database lock, 
in order to initiate the final population PK/PD model development processes for interim or final 
analyses.  The individuals and unblinded data are as specified in the unblinding plan.  
Information that may unblind the study during the analyses will not be reported to study sites or 
blinded study team until the study has been unblinded.
Safety and/or PK interim access to data (IAD) is scheduled to occur throughout the study.  The 
purpose of these IAD reviews is to examine the safety data and guide dose selections.  The 
investigator and the Lilly study team will make the determination regarding dose escalation 
based on their review of the safety and tolerability data, along with PK data, as applicable.
An interim review of safety and PK data is planned after healthy subjects in Cohort 3 complete 
the 28-day postdose PK blood draw.  Additional interim PK data reviews may be performed as 
required during study conduct.  The PK data obtained during the study may be used to assist in 
dose-escalation decisions, but such data are not required for dose escalation.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 61
LY3303560
11.
References
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 
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270-279.
Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, Bruce AB, Orth DN, 
Geracioti TD Jr. Serial CSF corticotropin-releasing hormone levels and adrenocortical activity 
in combat veterans with posttraumatic stress disorder. Am J Psychiatry. 1999;156(4):585-588.
Bond AJ, James DC, Lader MH. Physiological and psychological measures in anxious patients. 
Psychol Med. 1974;4(4):364-373.
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.
Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol. 1987;3:13-36.
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.
Jhee SS, Zarotsky V. Safety and tolerability of serial cerebrospinal fluid (CSF) collections during 
pharmacokinetic/pharmacodynamic studies: 5 years experience. Clin Res Reg Affairs.
2003;20(3):357-363.
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. 
2011;7(3):263-269.
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.
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.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 62
LY3303560
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.
Wechsler D. WAIS-IV administration and scoring manual. 4th ed. San Antonio, TX: Pearson;
2008.
Wechsler D. Wechsler Memory Scale (WMS–IV) technical and interpretive manual. 4th ed.
San Antonio, TX: Pearson; 2009.
White RJ, Dakters JG, Yashon D, Albin MS. Temporary control of cerebrospinal fluid volume 
and pressure by means of an externalized valve-drainage system. J Neurosurg.
1969;30(3):264-269.
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.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 63
LY3303560
Appendix 1.
Abbreviations and Definitions


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 64
LY3303560
Term
Definition
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale-Cognitive Subscale
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 unfavorable 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
ARIA-E
amyloid related imaging abnormality-edema
ARIA-H
amyloid related imaging abnormality-microhemorrhage
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]). 
AUC
area under the concentration versus time curve
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 subject/patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the subject/patient are not.  A double-blind 
study is one in which neither the subject/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-SB
Clinical Dementia Rating-Sum of boxes
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CL
Total clearance
Cmax
maximum drug concentration
CNS
central nervous system
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.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 65
LY3303560
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
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.
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.
CRU
clinical research unit
CSE
clinically significant event
CSF
cerebrospinal fluid
C-SSRS
Columbia Suicide Severity Rating Scale
ECG
electrocardiogram
ELISA
enzyme-linked immunosorbent assay
enroll
The act of assigning a subject/patient to a treatment.  Subjects/patients who are enrolled in 
the trial are those who have been assigned to a treatment.
enter
Subjects/patients entered into a trial are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERB/IRB
ethical review board/institutional review board
FCSRT-IR
free and cued selective reminding test with immediate recall
FDA
Food and Drug Administration
GCP
good clinical practice
HIV
human immunodeficiency virus
IAD
interim access to data
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
IgG
gamma globulin


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 66
LY3303560
informed consent
A process by which a subject/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 subject’s/patient’s decision to participate.  Informed consent is documented 
by means of a written, signed and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked.
Investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
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
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical trial.
MCI
mild cognitive impairment
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NOAEL
no-observed-adverse-effect level
NFT
neurofibrillary tangles
Non-
investigational 
product (non-IP)
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.
NONMEM
nonlinear mixed effects modeling
PD
pharmacodynamic
PET
positron emission tomography
PK
pharmacokinetic
QTcF
Fridericia's corrected QT
RBC
Red blood cell
RNA
ribonucleic acid


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 67
LY3303560
SAD
single-ascending dose
SAE
serious adverse event
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.  
SHSF
Self-Harm Supplemental Form
SUSARs
suspected unexpected serious adverse reactions 
TPO
third-party organizations
VAS
Visual Analog Scale


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 68
LY3303560
Appendix 2.
Clinical Laboratory Tests
Laboratory Testsa
Hematology
Clinical Chemistry
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (red blood cell [RBC])
Bicarbonate
Mean cell volume (MCV)
Chloride
Mean cell hemoglobin (MCH)
Calcium
Mean cell hemoglobin concentration (MCHC)
Phosphorous
Leukocytes (white blood cell [WBC])
Magnesium
Cell morphology (absolute or relative % counts):
Glucose (random)
Neutrophils
Blood urea nitrogen (BUN)
Lymphocytes
Uric acid
Monocytes
Total cholesterolb
Eosinophils
Total protein
Basophils
Creatinine
Platelets
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Urinalysis
Alkaline phosphatase
Specific gravity
Gammaglutamyl transferaseb
pH
Total bilirubin
Protein
Albumin
Glucose
Ketones
Pregnancy testc
Bilirubin
Follicle-stimulating hormoneb,d
Urobilinogen
Ethanol testinge
Blood
Urine drug screene
Nitrite
Microscopic examination of sediment
Viral serologyb,f
Hepatitis B surface antigen
Coagulation (Cohorts 8 and 9)b,g
Hepatitis C antibody
Prothrombin time (PT)
Human immunodeficiency virus (HIV)
International normalized ratio (INR)
Partial thromboplastin time (PTT)
a
Safety laboratory tests performed at screening will be validated by the local laboratory.  All other safety 
laboratory tests performed during the study will be validated by the central laboratory at the time of initial 
testing.
b Performed only at screening.
c
Per the investigator’s discretion, females only.  To be completed by the clinical research unit.  A serum 
pregnancy test will be performed at screening; a urine pregnancy test will be performed prior to PET scans 
(Cohorts 8 and 9) and dosing.
d To be done for women only when needed to confirm postmenopausal status.
e
To be completed by clinical research unit at each clinical research unit admission.
f
Each of these tests will be completed unless results have been obtained from the subjects/patients within the last 
6 months.
g
Performed at local laboratory.  Results will be validated by local lab at the time of initial testing.  


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 69
LY3303560
Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject/patient/patient’s caregiver understands the potential risks and 
benefits of participating in the study.

ensuring that informed consent is given by each subject/patient/patient’s caregiver or 
legal representative.  This includes obtaining the appropriate signatures and dates on the 
ICF prior to the performance of any protocol procedures and prior to the administration 
of IP.

answering any questions the subject/patient/patient’s caregiver may have throughout the 
study and sharing in a timely manner any new information that may be relevant to the 
subject’s/patient’s willingness to continue his or her participation in the trial.
Ethical Review
The investigator must give assurance that the 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 ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current 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 TPO.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 70
LY3303560
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 investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
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 subject/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.
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.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 71
LY3303560
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, 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 judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 72
LY3303560
Appendix 4.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
Protocol I8G-MC-LMDA Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
25
1
25
Clinical laboratory testsa
12
10
120
LY3303560 serum PKb
3
21 (+5)
63 (+15)
Blood discard for cannula patency
1
7
7
Plasma tau PD samplesb
0.5
19 (+5)
9.5 (+2.5)
Plasma PD samples for storageb
10
16 (+5)
160 (+50)
Serum PD samples for storageb
2
6 (+5)
12 (+10)
Immunogenicity
7.5
7
52.5
Stored serum sample for possible 
exploratory immune safety
14
3
42
Sample for genetic testing
10
1
10
RNA testing
10
2
20
Total
521 (598.5)
Total for clinical purposes [rounded up to nearest 10 mL] 
530 (600)
a
Additional samples may be drawn if needed for safety purposes.
b
A maximum of 5 additional time points per subject 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.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 73
LY3303560
Appendix 5.
Management of Infusion Reactions
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


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 74
LY3303560
Appendix 6.
Protocol Amendment I8G-MC-LMDA(b) 
Summary [Single-Dose, Dose-Escalation Study with 
LY3303560 to Evaluate the Safety, Tolerability, and 
Pharmacokinetics in Healthy Subjects and Patients with 
Mild Cognitive Impairment due to Alzheimer’s Disease 
or Mild to Moderate Alzheimer’s Disease]
Overview
Protocol I8G-MC-LMDA [Single-Dose, Dose-Escalation Study with LY3303560 to Evaluate the 
Safety, Tolerability, and Pharmacokinetics in Healthy Subjects and 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 (b) and will be used to conduct the 
study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

The single dose escalation in Study LMDA will be extended from the current maximum 
achieved dose of 1400 to 5600 mg. Higher doses of LY3303560 will be administered to 
healthy volunteers as 2 single dose cohorts of 2800 and 5600 mg. The mechanistic 
PK/PD model, which was used to predict an efficacious dose of 385-mg LY3303560 by 
estimating the steady-state reduction in aggregated tau in CSF, was updated based on 
recent nonclinical findings in monkey. The updated model now suggests that the 
predicted clinical dose of LY3303560 may be higher than what was previously predicted. 
The administration of higher doses of LY3303560 is also supported by preliminary safety 
and PK data from the preceding single-dose cohorts. LY3303560 is well tolerated when 
administered as a single dose up to 1400 mg. There were no dose-limiting AEs and no 
clinically significant changes in MRIs, ECGs, vital signs, neurological examinations, and 
safety laboratory tests. The PK of LY3303560 following single oral doses was 
approximately linear up to 1400 mg, supporting continued increasing exposure with 
LY3303560 dosing.  The projected mean exposure at the highest dose of 5600 mg is 
expected to approximate the mean exposure observed in the 6-month toxicology studies 
in cynomolgus monkeys.

The Bond and Lader, and Digit Span Forward and Backward tests have been added as 
additional safety measures in Cohorts 10 and 11 in order to assess potential CNS effects 
when high doses of LY3303560 are administered.

Per request from the CRU, the screening visit window in Cohorts 8 and 9 has been 
increased from 42 to 70 days to allow greater flexibility for the patients.

In Cohorts 8 and 9, per request from the CRU, the time point for the Visit 3 CSF 
sampling, vital signs, and ECG measurements has been amended from 48 to 36 hours.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 75
LY3303560

In Cohorts 8 and 9, orthostatic vital signs will not be measured during the first 36 hours; 
Sections 2 (Schedule of Activities) and 9.4.2 (Vital Signs) have been updated to clarify 
this. This is due to the feasibility of measuring orthostatic vital signs when the patient is 
in a supine position during serial CSF sampling.

Appendix 5 (Management of Infusion Reactions) has been amended to correct an error in 
the flow diagram for the management of infusion reactions.

Minor editorial changes and formatting corrections were made but not necessarily 
documented below.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 76
LY3303560
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Synopsis
Treatment Arms and Duration:  
For all cohorts (except Cohort 5), subjects or patients will receive either LY3303560 or placebo as an IV single 
dose; the planned doses are 7, 21, 70, 210, 700, and 1400 mg, 2800, and 5600 mg.  In Cohort 5, it is intended that
subjects will receive a single SC dose of 210 mg LY3303560, dependent on the observed safety profile from 
previous cohorts.
Number of Subject/Patients:
Cohorts 1 to 7, 10, and 11 (Healthy subjects):  Up to 7090 subjects may be enrolled so that approximately 5470
subjects (8 subjects per cohort, except for Cohort 5 [n=6]), reach at least Day 29 of the study.
2. Schedule of Activities


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 77
LY3303560
Study Schedule Protocol I8G-MC-LMDA (Cohorts 1 to 7, 10, and 11, Healthy Subjects)
Screen
ED
Study Day
-28 to -1
-1
1
2
3
4
5
6
7
15
22
29
43
57
71
85
113
141
Visit Window (days)
±1 ±2 ±2 ±3 ±3 ±3 ±3 ±3
±3
Prior/concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Xl
X
Preexisting conditions/AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xl
Xl
X
Alertness and attention assessments 
(Cohorts 10 and 11 only)
X
0
72j
X
X
X
X
X
Vitals (hours)c,d
X
X
0e, 0.5k, 
3, 12
24
48
72
X
X
X
X
X
X
X
X
X
X
Xl
Xl
X
LY3303560 serum PK (hours)i
0e, 0.5k, 
2, 4, 12
24
48
72
96
120 144
X
X
X
X
X
X
X
Xl
Xl
X
Plasma tau PD samples (hours)i
X
0e,0.5k, 2, 
4, 12
24
48
72
96
120 144
X
X
X
X
X
Xl
Xl
a
Subjects in Cohorts 1 to 4, and 6, 7, 10, and 11 will receive an IV single dose; subjects in Cohort 5 will receive a single SC dose.
l
Cohorts 10 and 11 only.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 78
LY3303560
Study Schedule Protocol I8G-MC-LMDA (Cohorts 8 and 9, Patients with AD)
Screen
ED
Study Day
-42 70 to 
-1
-1
1
2
3
4
5
6
7
15
22
29
43
57
71
85
Visit Window (days)
±1 ±2 ±2 ±3 ±3 ±3 ±3
Vitals (hours)d,e
X
X
0f, 0.5o, 3, 12
24, 
36
48
72
X
X
X
X
X
X
X
X
X
X
X
12-lead electrocardiogram (hours)e,g
X
X
0f, 0.5o, 3, 12
24, 
36
48
72
X
X
X
X
X
CSF sampling for PK and PD evaluations 
(hours)m
0f, 2, 4, 12
24, 
36
48
d
Screening vital signs will be obtained in the sitting position (after at least 5 minutes sitting).  For Visits 1 to 3, vital signs will be taken in the supine position 
only.  For all other vital signs after study entry, subjects will rest in the supine position for at least 5 minutes and undergo supine blood pressure and pulse rate 
measurements.  Subjects will sit for approximately 2 minutes then stand for approximately 2 minutes and undergo standing blood pressure and pulse rate 
measurements.  If subjects are unable to stand, supine vital signs only will be recorded. 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 79
LY3303560
3.1.
Study Rationale
[…]
Prior to this study, LY3303560 has had not been administered to humans.  This first-in-human 
study will investigate the safety, tolerability, and pharmacokinetics (PK) of LY3303560 in 
healthy subjects and patients with AD.  Safety and tolerability evaluations will be conducted 
over a wide range of single doses and dose escalation will not proceed until safety data from 
previous doses have been reviewed.  This study will aim to assess whether a maximum-tolerated 
dose (MTD) can be established or to demonstrate the tolerability of a dose greater than the 
expected therapeutic dose.  The data generated in this study will be used to help design 
subsequent clinical studies.  The inclusion of Japanese subjects in this study will facilitate the 
inclusion of Japanese subjects in subsequent clinical trials.
3.2.
Background
3.2.1. Preliminary Data from Cohorts 1 through 7
As of 07 February 2017, the single-dose escalation up to 1400 mg has been completed (Cohorts 
1 to 7). A single subcutaneous (SC) cohort of 210 mg has also been completed (Cohort 5). No 
serious adverse events (SAEs) have been reported, and no subject has withdrawn from the study 
because of an adverse event (AE).  A total of 27 AEs have been reported by a total of 16 
subjects, irrespective of causality. The most common AEs reported were headache (4), upper 
respiratory infection (2), contact dermatitis (2), back pain (2), and influenza (2).  A total of 7 
AEs were deemed related to study drug by the investigator:  headache (2) and hot flashes, feeling 
swollen, upper respiratory infection, vomiting, and cloudy mind (1 each).  There have been no 
infusion reactions reported to date, and there have been no clinically significant findings in 
magnetic resonance imaging (MRI) scans. In addition, there have been no clinically significant 
changes in vital signs, electrocardiograms (ECGs), neurological examinations, and safety 
laboratory tests. 
Preliminary PK data following single intravenous (IV) doses indicated that the exposure of 
LY3303560 was approximately linear up to 1400 mg. The observed clearance was 
approximately 180 mL/day, with a half-life of 2 to 3 weeks. A relative bioavailability of 
approximately 60% was calculated based on PK data from the 210-mg SC cohort.  The observed 
PK profile of LY3303560 is consistent with the PK properties of an immunoglobulin (Ig) G 
antibody.
3.3.
Benefit/Risk Assessment
The nonclinical safety information for LY3303560 detailed in the Investigator’s Brochure (IB) 
adequately supports the transition from preclinical status to a clinical, single-dose study.  On the 
basis of the nonclinical data, LY3303560 is not considered to be a high-risk compound.  This 
protocol reflects the fact that LY3303560 hads not been administered to humans prior to this 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 80
LY3303560
studystarting Study LMDApreviously, and to mitigate this risk, the study has been designed to be 
conducted in accordance with principles outlined in the Guideline on Strategies to Identify and 
Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products.  It is 
intended that sentinel dosing will be conducted for the first dose cohort to minimize risk to 
subjects.  Sentinel dosing will also be conducted for Cohorts 10 and 11 (2800 and 5600 mg), the 
additional cohorts introduced in Amendment (b).  Based on preliminary PK data from Cohorts 1
to 7, the mean exposure of LY3303560 at a dose of 5600 mg in Cohort 11 is predicted to 
approximate the no-observed-adverse-effect level (NOAEL) exposure observed in the monkey 
(see Section 5.5).  Accordingly, in addition to review of safety data, the PK data from the 
2800 mg dose will be analyzed and the projected exposure of 5600 mg will be reviewed prior to 
dose escalation.  In addition, for Cohorts 10 and 11, alertness and attention assessments will be 
administered to assess potential central nervous system (CNS) effects.
Risks around immunogenicity and infusion reactions are considered to be monitorable and 
manageable at the planned dose range of 7 to 14005600 mg for LY3303560 in healthy subjects
and patients with AD.
More information about the known and expected benefits, risks, serious adverse events (SAEs)
and reasonably anticipated adverse events (AEs) of LY3303560 areis to be found in the IB.
5.
Study Design
5.1.
Overall Design
This is a Phase I, subject-/patient- and investigator-blind, placebo-controlled, randomized, 
parallel, single-ascending dose (SAD) study in healthy subjects and patients with mild cognitive 
impairment (MCI) due to AD or mild to moderate AD.  The study has been designed to assess 
the safety, tolerability, and PK of single intravenous (IV) and subcutaneous (SC) doses of 
LY3303560.  The planned doses to be explored are 7, 21, 70, 210, 700, and 1400, 2800, and 
5600 mg.
Cohorts 1 to 7, 10, and 11 will consist of healthy subjects.  The planned number of subjects per 
cohort will be 8 (6:2, LY3303560:  placebo), except for Cohort 5 (6 subjects on LY3303560).  
For each IV cohort, the intention is to enroll 4 subjects of Japanese origin (first generation) and 4 
subjects of non-Japanese origin, but enrollment to a cohort will not be contingent upon fulfilling 
these requirements.  The minimum requirement is to enroll 4 Japanese subjects to at least 3 of the 
IV cohorts, including the highest dose level cohort (a minimum of 12 Japanese subjects in total).  
However, if enrollment of Japanese subjects is slower than anticipated, cohorts may complete 
enrollment with non-Japanese subjects and proceed to dose escalation without waiting for the 
desired number of Japanese subjects to be enrolled.  If 4 subjects of Japanese origin are not 
included in a cohort initially, additional subjects may subsequently be enrolled to achieve a 
maximum of 4 subjects of Japanese origin, if agreed between the sponsor and investigator.  
Although not required, it is preferred that the non-Japanese subjects are not Asian.  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.  Cohorts 8 and 9 will 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 81
LY3303560
consist of patients with MCI due to AD or mild to moderate AD.  The number of patients 
(LY3303560:  placebo) in each cohort will be 6:2 patients.  
Subjects/patients will be admitted to the clinical research unit (CRU) on Day -1 and eligibility 
will be confirmed.  Safety will be monitored by AEs, electrocardiograms (ECGs), vital signs 
(blood pressure and heart rate), physical examinations, neurological examinations and safety 
laboratory tests; and additionally for Cohorts 10 and 11, the Bond and Lader, and the Digit Span 
Forward and Backward test. Cohorts 8 and 9The Columbia Suicide Severity Rating Scale 
(C-SSRS) will be assessed in Cohorts 8 and 9.  Subjects/patients will remain resident in the CRU 
and safety will be monitored daily until discharge from the CRU on Day 4 at the earliest, then at 
regular intervals thereafter (see the Schedule of Activities in Section 2).  In addition, each 
subject/patient will have 1 baseline magnetic resonance imaging (MRI) scan prior to dosing with 
LY3303560 or placebo, then approximately 2 weeks and 3 months after dosing, primarily for the 
assessment of any potential imaging abnormalities.  In Cohorts 8 and 9, cerebrospinal fluid 
(CSF) will be obtained by an indwelling lumbar catheter prior to dosing with LY3303560 or 
placebo, and up to 48 hours after dosing with LY3303560 or placebo to measure CSF levels of 
LY3303560 and tau related pharmacodynamic (PD) biomarkers.
[…]
Sentinel dosing will be performed for Cohorts 1, 10, and 11.  Two subjects will be dosed initially 
(1 assigned to LY3303560 and 1 to placebo) and followed to 48 hours postdose before the 
remaining subjects in that cohort are dosed.  The remaining 6 subjects may be dosed on the same 
day, at appropriate intervals.  If there are no issues with the first cohort, subjects in subsequent 
cCohorts 12 to 9 may be dosed on the same day at appropriate intervals, or on separate days, as 
practical, however, the timing of dosing will be staggered such that subjects will not be dosed 
simultaneously.
The highest dose may be adjusted based on emerging data, but it is intended that the magnitude 
of the escalation between dose levels will not exceed a half-log interval (approximately 3-fold) 
and a maximum dose of 1400 5600 mg LY3303560 will not be exceeded.  All subjects in a 
particular cohort must have been dosed and safety data for 2 weeks after dosing must be 
reviewed from at least 4 subjects on LY3303560 and 1 subject on placebo, prior to dose 
escalation. Additionally, PK data from Cohort 10 will be reviewed prior to escalation to Cohort 
11. If criteria for stopping rules are not met (see Section7.4.1), then the next dose cohort will be 
enrolled with next planned dose increases until 1400 5600 mg or stopping criteria are met.  If a 
termination dose is reached, a dose reduction of at least one-half of the termination dose may be 
tested in one of the remaining dose cohorts, if deemed appropriate.
The PK data for LY3303560 obtained during the study may be used to assist in dose escalation 
decisions, but such data are not required for dose escalation, except for dose escalation from 
Cohorts 10 and 11.  If the PK data reveal that the current sampling schedule does not allow for 
an adequate characterization of the PK profile, the blood sampling schedule for subsequent dose 
administrations may be adjusted.  A maximum of 5 additional PK samples per subject may be 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 82
LY3303560
allowed if indicated by emerging data.  See Section 10.3.7 for further information about PK 
reviews.
Previous diagram:
SAD 1 (HS)
7 mg IV
6 LY: 2 PL
(sentinel dosing)
SAD 2 (HS)
21 mg IV
6 LY: 2 PL
SAD 3 (HS)
70 mg IV
6 LY: 2 PL
SAD 5 (HS)
210 mg SC
6 LY
SAD 8 (AD)
IV Dose TBD 
6 LY: 2 PL
SAD 4 (HS)
210 mg IV
6 LY: 2 PL
SAD 6 (HS)
700 mg IV
6 LY: 2 PL
SAD 7 (HS)
1400 mg IV
6 LY: 2 PL
SAD 9 (AD)
IV Dose TBD
6 LY: 2 PL
2 wk
safety
2 wk
safety
2 wk safety
2 wk safety
2 wk safety
2 wk safety
2 wk safety/PK
2 wk safety


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 83
LY3303560
New diagram:
5.2.
Number of Participants
For Cohorts 1 to 7, 10, and 11, up to 7090 healthy subjects may be enrolled so that 
approximately 54 70 subjects (8 subjects per cohort, except for Cohort 5 [n=6]) reach at least 
Day 29 of the study.  
5.4.
Scientific Rationale for Study Design
[…]
Given planned doses for Cohorts 10 and 11 will approximate the NOAEL exposure in monkeys, 
sentinel dosing will also be conducted in these cohorts. In addition, the Bond and Lader, and 
Digit Span Forward and Backward test will be measured in these cohorts to assess potential CNS 
effects.
SAD 1 (HS)
7 mg IV
6 LY: 2 PL
(sentinel dosing)
SAD 2 (HS)
21 mg IV
6 LY: 2 PL
SAD 3 (HS)
70 mg IV
6 LY: 2 PL
SAD 5 (HS)
210 mg SC
6 LY
SAD 8 (AD)
IV Dose TBD 
6 LY: 2 PL
SAD 4 (HS)
210 mg IV
6 LY: 2 PL
SAD 6 (HS)
700 mg IV
6 LY: 2 PL
SAD 7 (HS)
1400 mg IV
6 LY: 2 PL
SAD 9 (AD)
IV Dose TBD
6 LY: 2 PL
2 wk
safety
2 wk
safety
2 wksafety
2 wk safety
2 wk safety
2 wk safety
2 wk safety/PK
2 wk safety
SAD 10 (HS)
2800 mg IV
6 LY: 2 PL 
(sentinel dosing)
2 wk safety
SAD 11 (HS)
5600 mg IV
6 LY: 2 PL 
(sentinel dosing)
2 wk safety 
and PK


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 84
LY3303560
5.5.
Justification for Dose
The proposed dose range is 7 to 1400 5600 mg LY3303560.  The doses were selected based 
upon the analysis of nonclinical PK, efficacy and toxicology data from studies conducted in 
Tg4510 tau transgenic mice expressing human four-repeat tau with the P301L mutation that is 
linked to hereditary tauopathy and cynomolgus monkeys. 
A mechanistic PK/PD model was used to predict a clinically relevant LY3303560 dose range by 
estimating the steady-state reduction in aggregated tau in CSF at various doses.  The CSF was 
used as a surrogate matrix to understand the disposition of aggregated tau in the central nervous 
system CNS.  Model predictions suggested a clinical dose of 10.5 mg LY3303560 administered 
every 4 weeks (Q4W) and 385 mg LY3303560 Q4W will decrease CSF aggregated tau by 
approximately 20% and 90%, respectively.  However, an update to the PK/PD model based on 
recent nonclinical findings in monkey suggest that the predicted clinical dose of LY3303560 
may be higher than what was previously predicted.  As such, the maximum dose to be evaluated 
in this study has been increased from 1400 to 5600 mg.  A dose of 10.5 mg (20% decrease in 
CSF aggregated tau) is defined as the minimally anticipated biological effect level (MABEL).  
Therefore, a starting dose of 7 mg LY3303560 (approximately 0.1 mg/kg for a 70-kg person) is 
below the MABEL and thus considered an appropriate starting dose.
The safety of LY3303560 was assessed in a 5-week and 6-month toxicology studiesy in 
cynomolgus monkeys which included evaluation of safety pharmacology and toxicokinetics.  
The cynomolgus monkey is an appropriate large animal species to evaluate the safety of 
LY3303560 with respect to monomeric tau.  The administration of LY3303560 in monkeys up to 
a maximum dose of 200 mg/kg/week (bolus IV) for 5 weeks or 6 months resulted in no 
compound-related adverse findings.  It is anticipated that the mean exposure resulting from doses 
of LY3303560 to be administered in Cohorts 10 and 11 will approximate the mean exposure in 
monkeys dosed 200 mg/kg LY3303560 (the NOAEL), see Table LMDA.2.  The safety and PK 
data from doses up to 1400 mg LY3303560 also support dosing in Cohorts 10 and 11.  The 
safety of LY3303560 was also assessed in a 5-week and 6-month toxicology studiesy in a 
Tg4510 mouse model.  The Tg4510 transgenic mouse is an appropriate species to evaluate the 
safety of LY3303560 with respect to binding aggregated tau and small tau fibrils.  The 
administration of LY3303560 to Tg4510 mice up to a maximum SC dose of 200 mg/kg resulted 
in no compound-related adverse findings.
The nonclinical safety profile of LY3303560 in monkeys and Tg4510 mice supports clinical 
development dosing up to the planned dose of 20 mg/kg (1400 mg for a 70 kg person) based on 
ICH S6 guidelines (Table LMDA.2).


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 85
LY3303560
Table LMDA.6.
Margin of Safety for Subcutaneous/Intravenous Administration of 
LY3303560 Based on Administered Dose and Predicted Exposure
Dose
Dose
Multiplea
(Starting dose/
Maximum dose)
AUC0-168hr
(µg•dayhr/mL)
Exposure
Multiplea
(Starting dose/
Maximum dose)
Humanb
Starting Dose
Maximum Dose
7 mg (0.1 mg/kg)
1400 5600 mg (820 
mg/kg)
–
–
79936.1c
159,81735,400
–
–
Tg4510 mouse 
NOAELcd
200 mg/kg
2000/2.510
509,00015,458e
428637/0.43.2
Monkey NOAELdf
200 mg/kg
2000/2.510
995,50047,083e
13041,246/1.3
Abbreviations:  AUC0-168hr = area under the serum concentration time curve from time zero through 168 hours 
postdose; NOAEL = no-observed-adverse-effect level; NOEL = no-observed-effect level.
a
Dose multiple is the dose in animals divided by the dose in humans based on mg/kg basis.  Exposure multiple is 
the calculated AUC in animals divided by the predicted AUC in humans.
b
Clinical dose assumes a 70 kg subject; 7 mg = 0.1 mg/kg, 1400 5600 mg = 20 80 mg/kg.
c
Observed data from Study LMDA (preliminary).
cd NOAEL determined in a 5-week6-month repeat dose toxicity study (Study 83215066195).
e
AUC is mean of male and female.
df NOAEL determined in a 5-week6-month repeat dose toxicity study (Study 83215056196).
Overall, the proposed starting dose of 7 mg LY3303560 is considered appropriate as it is below 
the calculated MABEL.  , and tThe proposed projected mean exposure at the highest planned 
dose of 56001400 mg is expected to approximate the NOAEL exposure observed in the
supported by the top dose of 200 mg/kg in the 1-month monkey 6-month toxicology study in 
cynomolgus monkeys.  Prior to dosing Cohort 11 (5600 mg), LY3303560 PK data from Cohort 
10 (2800 mg) will be reviewed and the exposure for Cohort 11 (5600 mg) will be predicted.  The 
dose to be administered in Cohort 11 may be adjusted if necessary to ensure the projected mean 
exposure does not exceed the mean monkey NOAEL exposure of 47,083 µg•day/mL.
6.
Study Population
[…]
Screening may occur up to 28 days before enrollment for Cohorts 1 to 7, 10, and 11 (healthy 
subjects).  Subjects who are not enrolled within 28 days of screening may be subjected to an 
additional medical assessment and/or clinical measurements to confirm their eligibility.
Screening may occur up to 4270 days before enrollment for Cohorts 8 and 9 (patients with AD).  
Patients who are not enrolled within 4270 days of screening may be subjected to an additional 
medical assessment and/or clinical measurements to confirm their eligibility and exceptions to 
the 4270-day screening window may be granted as follows:

MRI:  56 days


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 86
LY3303560

free and cued selective reminding test with immediate recall (FCSRT-IR), Mini 
Mental State Examination (MMSE), and Clinical Dementia Rating (CDR):  90 days

florbetapir imaging:  120 days
6.1.
Inclusion Criteria
[1a]
For Cohorts 1 to 7, 10, and 11, are overtly healthy, as determined by medical 
history and physical examination
[3]
are at least 30 years old at the time of screening for Cohorts 1 to 7, 10, and 11.  
For Cohorts 8 and 9, are at least 50 years old at the time of screening
[8]
for healthy subjects (Cohorts 1 to 7, 10, and 11):  are able and willing to give 
signed informed consent.  For Cohorts 8 and 9, patients not capable of 
providing consent must provide assent; informed consent must be provided by 
a legally authorized representative
6.2.
Exclusion Criteria
[28]
for healthy subjects (Cohorts 1 to 7, 10, and 11):  have used or intend to use 
over-the-counter or prescription medication (including herbal medications) 
within 7 days prior to dosing or during the study with the exception of 
vitamins and mineral supplements (not providing >100% of the recommended 
dietary allowance); thyroid replacement and/or estrogen hormone 
replacement; and occasional paracetamol/acetaminophen.  If this situation 
arises, inclusion of an otherwise suitable subject may be at the discretion of 
the sponsor.  
7.1.
Treatment Administered
This study involves a comparison of LY3303560 and placebo, over a planned dose range of 7 to 
1400 5600 mg.  Table LMDA.3 shows the treatment regimens.
For all cohorts except Cohorts 5, and 7, 10, and 11, the IP will be administered as a slow IV 
infusion over at least 30 minutes.  Every attempt should be made to complete the infusion within 
60 minutes.  The infusion time for Cohorts 7 and 10 should be at least 6090 minutes, and for 
Cohort 11, at least 90 minutes.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 87
LY3303560
7.4.1. Dose Decision/Escalation
[…]
Safety data will be the primary criteria for the dose escalation.  In addition, if available at the 
time of dose escalation decision, PK (Cmax, AUC, and total clearance [CL]) results will be used 
as supporting data for dose escalation, but such data are not required, aside from dose escalation 
from Cohort 10 to 11 (see below).  No dose escalation can occur without prior discussion and 
agreement between the investigator and the Lilly clinical pharmacologist/CRP.
[…]
For dose escalation from Cohort 10 to 11, LY3303560 PK data from Cohort 10 will be analyzed 
and the exposure at 5600 mg LY3303560 re-projected based on the observed PK at 2800 mg 
LY3303560.  The PK projection will be reviewed before escalation to Cohort 11 and the dose to 
be administered in Cohort 11 may be adjusted if necessary to ensure the projected mean 
exposure does not exceed the mean monkey NOAEL exposure of 47,083 µg•day/mL.
9.4.2. Vital Signs
[…]
Screening vital signs will be obtained in the sitting position (after at least 5 minutes sitting).  In 
Cohorts 8 and 9 (patients with AD), for Visits 1 to 3, vital signs will be measured in the supine 
position only. For all other vital signs after study entry, subjects will rest in the supine position 
for at least 5 minutes and undergo supine blood pressure and pulse rate measurements.  Subjects 
will sit for approximately 2 minutes then stand for approximately 2 minutes and undergo 
standing blood pressure and pulse rate measurements. If subjects are unable to stand, supine 
vital signs only will be recorded.  If the subject is unable to stand or sit, omission of the standing 
or sitting vital signs will not be considered a protocol violation.
9.4.4.2.  Alertness and Attention Assessments (Cohorts 10 and 11)
The Bond and Lader Visual Analog Scale (VAS), and Digit Span Forward and Backward Test 
will be performed according to the Schedule of Activities (Section 2).
9.4.4.2.1.  Bond and Lader VAS
The Bond and Lader VAS (Bond et al. 1974) consists of 16 mood self-rating 100-mm lines 
between 2 opposite adjectives.  The subject has to indicate on the line how he or she is feeling at 
the time of evaluation.  The response is scored by measuring the distance in millimeters between 
the left end of the line and the subject’s mark.  This questionnaire derives 3 factors that assess 
self-rated alertness, self-rated calmness, and self-rated contentment.  Approximately 5 minutes is
needed to complete the questionnaire.  Subjects will complete a training session for the VAS as 


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 88
LY3303560
indicated in the Schedule of Activities (Section 2).  This test will be completed approximately 5 
minutes before all other assessments at the same time point.
9.4.4.2.2.  Digit Span Forward and Backward Test
The Digit Span Forward and Backward subtest (Wechsler 2009) of the Wechsler Adult 
Intelligence Scale-IV (Wechsler 2008) is a brief test of attention.  Digit Span is a series of orally 
presented number sequences that the examinee repeats verbatim for Digits Forward and in 
reverse for Digits Backward (Wechsler 2009).
Note:  Subsequent heading numbering for the Magnetic Resonance Imaging, Injection-Site 
Assessments (Cohort 5), Columbia Suicide Severity Rating Scale (Cohorts 8 and 9), Imaging 
(Cohorts 8 and 9), Radiation Doses Associated with PET Imaging sections has been updated 
with the addition of the Alertness and Attention Assessments section.
10.1.
Sample Size Determination
[…]
Up to 7090 healthy subjects may be enrolled to ensure that approximately 5470 subjects (8 
subjects per cohort, except for Cohort 5 [n=6]) reach at least Day 29 of the study.
10.3.1.2.  Statistical Evaluation of Safety
[…]
For Cohorts 10 and 11, results from the Bond and Lader VAS, and Digit Span Forward and 
Backward tests will be summarized by parameter and time point, including change from 
baseline.
10.3.2.2.  Pharmacokinetic Statistical Inference
The serum PK parameters, Cmax and AUC0-∞or AUC0-tlast, for LY3303560 obtained for 
healthy subjects (IV only) will be evaluated to estimate the dose-exposure proportionality of 
LY3303560 using a linear-effects power model (Smith et al. 2000).  In this model, log-
transformed dose will be the independent variable, and subject will be a random effect.  Both 
Cmax and AUC will be log-transformed prior to analysis.  The least-square means for each 
treatment together with the treatment differences and associated 90% confidence intervals (CIs) 
will be estimated from the model.  These estimates will be back-transformed to present 
geometric means, the ratios of geometric means, and the corresponding 90% CIs.  Dose-exposure 
analysis will be conducted using the healthy subject IV cohorts (Cohorts 1, 2, 3, 4, 6, and 7, 10, 
and 11). Exploratory analyses of Japanese and non-Japanese subjects may be conducted.  
Additional dose-exposure analyses may be conducted using patient data.


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 89
LY3303560
11.
References
Bond AJ, James DC, Lader MH. Physiological and psychological measures in anxious 
patients. Psychol Med. 1974;4(4):364-373.
Wechsler D. WAIS-IV administration and scoring manual. 4th ed. San Antonio, TX: Pearson;
2008.
Wechsler D. Wechsler Memory Scale (WMS–IV) technical and interpretive manual. 4th ed. 
San Antonio, TX: Pearson; 2009.
Appendix 4.
Blood Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
25
1
25
Clinical laboratory testsa
12
10
120
LY3303560 serum PKb
3
19 21 (+5)
57 63 (+15)
Blood discard for cannula patency
1
7
7
Plasma tau PD samplesb
0.5
17 19 (+5)
89.5 (+2.5)
Plasma PD samples for storageb
10
16 (+5)
160 (+50)
Serum PD samples for storageb
2
6 (+5)
12 (+10)
Immunogenicity
7.5
7
52.5
Stored serum sample for possible 
exploratory immune safety
14
3
42
Sample for genetic testing
10
1
10
RNA testing
10
2
20
Total
514 521 (573598.5)
Total for clinical purposes [rounded up to nearest 10 mL] 
520 530 (580600)


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 90
LY3303560
Appendix 5. Management of Infusion Reactions
Previous diagram:


I8G-MC-LMDA(b) Clinical Pharmacology Protocol
Page 91
LY3303560
New diagram:
Abbreviations:  BP = blood pressure; IM = intramuscular; IV = intravenous; NSAID = nonsteroidal anti-
inflammatory drug; PO = by mouth.
a
Continue supportive care in accordance with the symptoms/signs (Section 7.4.2.2).
Source:  Adapted from Lichtenstein et al. 2015


Leo Document ID = a1a0517f-5e18-4c25-a89c-94f38ff135da
Approver: 
Approval Date & Time: 31-Jul-2017 08:30:58 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 31-Jul-2017 12:03:12 GMT
Signature meaning: Approved
PPD
PPD