Clinical trial NCT02989389
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2016-12-12; Completion date: 2017-07-21
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to investigate the safety of LY3323795 and the effects it has on the body. The study drug or placebo (sugar pill) will be given by mouth to healthy participants. The study has three parts. Each participant may only enroll in one part. The study will last 14 to 43 days, depending on the part. Screening must be completed prior to study start.

Detailed description:

Arms: arm 1: Participants received escalating doses of 0.3 mg (milligrams), 1 mg, 3 mg, 10 mg, 30 mg and 100 mg of LY3323795 orally. arm 2: Participants received placebo identical to LY3323795 orally. arm 3: Participants received 6 mg, 20 mg and 80 mg of LY3323795 orally. arm 4: Participants received placebo identical to LY3323795 orally. arm 5: Part C was not initiated due to a Lilly internal strategy decision. arm 6: Part C was not initiated due to a Lilly internal strategy decision.
Interventions: intervention 1: LY3323795 intervention 2: Itraconazole intervention 3: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally

Protocol documents:
Prot_000.pdf: 
 
 
Protocol I9F-MC-SCAA(a) 
 
 
Single-Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of LY3323795 in Healthy Subjects 
 
 
NCT02989389 
 
 
Approval Date: 02-Dec-2016 


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
Page 1
LY3323795
ProtocolI9F-MC-SCAA(a)
Single-Ascending Dose Study to Assess the Safety, 
Tolerability, Pharmacokinetics,and Pharmacodynamics of 
LY3323795 in Healthy Subjects
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 
LY3323795, 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. 
Approval Date: 02-Dec-2016 GMT
LY3323795
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:27October 
2016
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.


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LY3323795
Table of Contents
Single-Ascending Dose Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3323795 in Healthy Subjects
Section
Page
Protocol I9F-MC-SCAA(a) Single-Ascending Dose Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3323795 in Healthy Subjects..........................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................21
3.2.
Background..................................................................................................................21
3.3.
Benefit/Risk Assessment..............................................................................................22
4.
Objectives and Endpoints..................................................................................................24
5.
Study Design.....................................................................................................................25
5.1.
Overall Design .............................................................................................................25
5.1.1.
Part A:  Dose-Escalation Study ............................................................................27
5.1.1.1.
Dose Escalation and Interim Access to Data in Part A ....................................27
5.1.2.
Part B:  CSF Sampling Study ...............................................................................28
5.1.2.1.
Dose Selection and Pharmacokinetic Analysis in Part B .................................28
5.1.3.
Part C:  Itraconazole Interaction Study .................................................................29
5.2.
Number of Participants.................................................................................................30
5.3.
End of Study Definition ...............................................................................................30
5.4.
Scientific Rationale for Study Design...........................................................................30
5.5.
Justification for Dose ...................................................................................................31
6.
Study Population...............................................................................................................34
6.1.
Inclusion Criteria..........................................................................................................34
6.2.
Exclusion Criteria ........................................................................................................35
6.3.
Lifestyle and/or Dietary Requirements .........................................................................37
6.3.1.
Meals and Dietary Restrictions.............................................................................37
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................38
6.3.3.
Activity/Other Requirements................................................................................38
6.4.
Screen Failures.............................................................................................................38
7.
Treatment..........................................................................................................................39


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LY3323795
7.1.
Treatment Administered...............................................................................................39
7.1.1.
Packaging and Labeling .......................................................................................40
7.2.
Method of Treatment Assignment ................................................................................40
7.2.1.
Selection and Timing of Doses.............................................................................40
7.3.
Blinding .......................................................................................................................40
7.4.
Dose Modification........................................................................................................41
7.4.1.
Dose Decision/Escalation.....................................................................................41
7.5.
Preparation/Handling/Storage/Accountability...............................................................42
7.6.
Treatment Compliance .................................................................................................42
7.7.
Concomitant Therapy...................................................................................................43
8.
Discontinuation Criteria ....................................................................................................44
8.1.
Discontinuation from Study Treatment.........................................................................44
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................44
8.2.
Discontinuation from the Study....................................................................................44
8.3.
Subjects Lost to Follow-up...........................................................................................44
9.
Study Assessments and Procedures ...................................................................................45
9.1.
Efficacy Assessments...................................................................................................45
9.2.
Adverse Events ............................................................................................................45
9.2.1.
Serious Adverse Events........................................................................................46
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................46
9.2.2.
Complaint Handling.............................................................................................47
9.3.
Treatment of Overdose.................................................................................................47
9.4.
Safety...........................................................................................................................47
9.4.1.
Laboratory Tests ..................................................................................................47
9.4.2.
Vital Signs ...........................................................................................................47
9.4.3.
Electrocardiograms ..............................................................................................48
9.4.4.
Other Tests...........................................................................................................49
9.4.4.1.
Neurological Survey.......................................................................................49
9.4.4.2.
Ophthalmic Examinations...............................................................................49
9.4.5.
Safety Monitoring ................................................................................................50
9.4.5.1.
Hepatic Safety Monitoring..............................................................................50
9.5.
Pharmacokinetics .........................................................................................................50
9.5.1.
Bioanalysis...........................................................................................................51
9.6.
Pharmacodynamics ......................................................................................................51
9.7.
Genetics .......................................................................................................................52
9.8.
Biomarkers...................................................................................................................52
9.9.
Health Economics ........................................................................................................53
10.
Statistical Considerations and Data Analysis.....................................................................54


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LY3323795
10.1. Sample Size Determination ..........................................................................................54
10.2. Populations for Analyses..............................................................................................54
10.2.1.
Study Participant Disposition ...............................................................................54
10.2.2.
Study Participant Characteristics ..........................................................................55
10.3. Statistical Analyses ......................................................................................................55
10.3.1.
Safety Analyses....................................................................................................55
10.3.1.1.
Clinical Evaluation of Safety..........................................................................55
10.3.1.2.
Statistical Evaluation of Safety.......................................................................55
10.3.2.
Pharmacokinetic Analyses....................................................................................56
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................56
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................56
10.3.3.
Pharmacodynamic Analyses.................................................................................57
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................57
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................57
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................57
10.3.5.
Interim Analyses..................................................................................................58
11.
References ........................................................................................................................59


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LY3323795
List of Tables
Table
Page
Table SCAA.1.
Objectives and Endpoints .......................................................................24
Table SCAA.2.
Margin of Safety for Oral Administration of LY3323795 Based on 
Administered Dose and Predicted Exposure............................................33
Table SCAA.3.
Treatments Administered........................................................................39
Table SCAA.4.
Scoring of Neurological Surveys ............................................................49


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List of Figures
Figure
Page
Figure SCAA.1.
Illustration of study design for Protocol I9F-MC-SCAA. ........................26


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................61
Appendix 2.
Clinical Laboratory Tests........................................................................66
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................67
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............70
Appendix 5.
Blood and CSF Sampling Summary........................................................71
Appendix 6.
Protocol Amendment I9F-MC-SCAA(a) Summary 
Single-Ascending Dose Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of LY3323795 in 
Healthy Subjects.....................................................................................73


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LY3323795
1. Protocol Synopsis
Title of Study:
Single-Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3323795 in Healthy Subjects
Rationale:
Lilly is developing LY3323795 for the treatment of Alzheimer’s disease (AD). It is believed that inhibiting β-site 
amyloid precursor protein-cleaving enzyme-1 activity will prevent β-amyloid (Aβ) plaque formation and subsequent 
deposition, which is an early and necessary event in the pathogenesis of AD.
LY3323795 has not been administered to humans. This first-in-human dose study will investigate the safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of LY3323795 in healthy subjects. Safety and 
tolerability evaluations will be conducted over a range of single doses, and dose escalation will not proceed until 
safety data from previous doses have been reviewed. The data generated in this study will be used to help design 
and identify doses for subsequent clinical trials.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To explore the safety and tolerability of single doses of 
LY3323795 in healthy subjects.
Incidence of treatment-emergent adverse 
events.
Secondary

To explore the plasma and cerebrospinal fluid (CSF) 
PK of single doses of LY3323795.

To explore the plasma and CSF PD of single doses of 
LY3323795.
Maximum drug concentration (Cmax) and the 
area under the concentration-versus-time curve 
(AUC) in plasma; and Cmax and AUC in CSF 
for various time frames.
Minimum Aβ1-40 or Aβ1-42 concentration 
observed following administration of study 
drug, expressed as the percentage change in 
concentration from baseline.
Summary of Study Design:
Study I9F-MC-SCAA is a Phase 1 study of LY3323795 in healthy subjects that will be conducted in 3 parts. Part A 
(Doses 1 to 6) will be a subject- and investigator-blind, placebo-controlled, randomized, single-ascending dose, 3-
period, 2-cohort (6:3 subjects, LY3323795:placebo per cohort), dose-escalation study to evaluate safety, tolerability,
and plasma PK/PD of LY3323795.  Part B will be a subject- and investigator-blind, placebo-controlled, randomized, 
single-dose, 3-cohort (5:2 subjects, LY3323795:placebo per cohort), single-period, lumbar catheter study to evaluate 
the central and plasma PK/PD of LY3323795.  Doses in Part B will not be administered until equal or greater doses 
have been administered in Part A and shown to be well tolerated. Part C will be an open-label, 2-period, fixed-
sequence, single-cohort design with 8 subjects to evaluate a potential CYP3A4 interaction when LY3323795 is 
coadministered with itraconazole.


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
Treatment Arms and Duration:
For Part A (Cohorts 1 and 2), subjects will receive oral doses of either LY3323795 or placebo; the anticipated doses
are 0.3mg, 1mg, 3mg, 10mg, 30mg,and100mg.  
For Part B (Cohorts 3, 4,and 5), subjects will receivea single oral dose ofplacebo orLY3323795less than or equal 
to doses previously administered and found to be well tolerated in Part A.
For Part C (Cohort 6), Period 1, subjects will be administered an oral dose of LY3323795at a dose level that was 
welltolerated in Part A.For Period 2, subjects will be coadministered an oral dose of LY3323795 (same dose as 
Period 1)in the presenceof itraconazole(on Day 16).Itraconazole 200 mg will be administered twice on Day 10
and oncedaily on Days 11to 21.
Number of Subjects:
For Cohorts 1 and 2 in Part A, up to approximately 24subjects may be enrolled so that approximately 18 subjects (9 
subjects per cohort[6:3, LY3323975:placebo])complete the study.
For Cohorts 3 to 5 in Part B, up to approximately 30 subjects may be enrolled so that approximately 21 subjects (7 
subjects percohort[5:2, LY3323975:placebo])complete the study.
For Cohort 6 in Part C, up to 12 subjects may be enrolled so that approximately 8 subjects complete the study.
Statistical Analysis:
The sample size for Part A is customary for Phase 1 studies evaluating safety, PK,and/or PDparameters, and is not 
based on statistical mean estimation. Parts B and C are not formally powered to detect a prespecified anticipated 
effect;however, precision intervals have been calculated to show what may be observed for changes in 
cerebrospinal fluid (CSF)Aβ and effect of itraconazole on LY3323795 given the sample sizes.
Noformalinterim analyses are planned for this study. Interim access to data (IAD) is scheduled to occur throughout 
the study. The purpose of these IAD reviews is to examine the safety and orPK/PD data and guide dose selections.
All investigational product and protocol procedure adverse eventswill be listed, and if the frequency of events
allows, safety data will be summarized using descriptive methodology. Safety laboratory parameters, vital signs,
and electrocardiogramparameters will be listed and summarized using standard descriptive statistics for values at 
eachtime point as well as changes from baseline.
PKparameter estimates for LY3323795 will be calculated usingstandard noncompartmental methods of analysis.
The primary parameters for analysis will be Cmaxand AUC of LY3323795.  Other noncompartmental parameters, 
such as half-life, apparent clearance, and apparent volume of distribution may be reported.
For Parts A and B, plasma concentrations of Aβ
1-40and Aβ1-42will be summarized for each dose group based on the 
nadir concentration (C
nadir) and the time to reach C
nadir(t
nadir).
In Part B, CSF concentrations of Aβ
1-40, Aβ
1-42, and
 will be 
summarized for each dose group based on the C
nadir, t
nadir, and the 24-hour average values, expressed as a percentage 
change from baseline. Statisticalanalysis of CSF Aβ
1-40and Aβ
1-42
CCI
concentrations obtained over the fixed-scheduled 
sampling period will be analyzed using a repeated-measures analysis with the primary statistical estimation of the 
overall mean percentagechange from baselineand 90% confidence interval among the LY3323795 doses and 
placebo at each post dose time point.


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
For Part C, the area under the curve from time 0 extrapolated to infinity and Cmax for LY3323795 administered alone 
and in the presence of itraconazole will be compared with an analysis of variance model. 


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
2. Schedule of Activities


I9F-MC-SCAA(a) Clinical Pharmacology Protocol 
Page 12 
LY3323795 
Study Schedule Protocol I9F-MC-SCAA:  Part A, Periods 1 through 3 
 
Screen 
Periods 1 to 3 
 
FDC
a ED
Notes 
Study Day 
-28 to -2 
-1 
1
b 
2 
3 
4 
5 
6 
7 
Admit to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
Discharge from CRU 
 
 
 
 
X 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
Ethanol and urine drug 
screens 
X 
 
 
 
 
 
 
 
 
 
 
An additional ethanol and urine drug screen 
may be done at the discretion of the 
investigator at readmission to the CRU. 
Ophthalmic examination 
X 
 
 
 
X 
 
 
 
 
X 
X See Section 9.4.4.2 for details. 
12-Lead ECG (hours) 
X 
 
0, 1, 2, 4, 
6, 8, 12 
24 
48 
 
 
 
X 
X 
X ECGs coinciding with PK sample time points 
are to be conducted as close as possible to PK 
sampling.  See Section 9.4.3 for other details. 
Vital signs (hours) 
X 
 
0, 1, 2, 4, 
6, 8, 12 
24 
X 
X 
X 
X 
X 
X 
X See Section 9.4.2 for details. 
Clinical laboratory 
values (hours) 
X 
X 
 
 
48 
 
 
 
X 
X 
X Screening tests will occur at local laboratories 
and other analyses will be at central 
laboratory.  Blood will be collected on Day -1 
for both local and central labs.  Investigator 
will review local lab results before dosing in 
each period.  
LY3323795 study drug 
 
 
X 
 
 
 
 
 
 
 
 
Subjects are required to fast before and after 
drug administration.  See Section 6.3.1 for 
details. 
LY3323795 plasma PK 
samples (hours) 
 
 
0, 0.5, 1, 
2, 3, 4, 6, 
8, 12 
24 
48 
72 
96 
120 
144 
 
 
A maximum of 5 additional plasma samples 
per subject may be drawn during the study at 
the discretion of the investigator or sponsor.  
These additional samples may be drawn to 
measure LY3323795 or Aβ concentrations. 
PD plasma samples 
(hours) 
 
 
0, 0.5, 1, 
2, 3, 4, 6, 
8, 12 
24 
48 
72 
96 
120 
144 
 
 
A maximum of 5 additional plasma samples 
per subject may be drawn during the study at 
the discretion of the investigator or sponsor. 


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
Screen
Periods 1 to 3
FDC
a
ED
Notes
Study Day
-28 to -2
-1
1
b
2
3
4
5
6
7
Storage plasma samples 
(hours)
0, 0.5, 1, 
2, 3, 4, 6, 
8, 12
24
48
72
96
120
144
This is not an additional draw; sample will be 
taken from PD blood sample and stored 
separately. Stored samples will be used for
other assays yet to be determined.
Weight/height
X
X
X
X
Height measured at screening only.  
Urine collection (hours)
0-24
24-
48
Urine to be collected continuously during the 
2 separate collection periods (0-24 and 24-48 
hours).
Neurological survey 
(hours)
X
X
24
48
X
X
X
Neurological surveys on PK sampling days 
are to be conducted as close as possible to PK 
sampling.  If abnormalities are noted, refer to 
Section 9.4.4.1.
Sample for genetic 
testing
X 
Period 1 only.
Abbreviations:  Aβ = β-amyloid; CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FDC = final discharge; PD = 
pharmacodynamics; PK = pharmacokinetics.
a
Study final discharge procedures should be completed 14-21 days after the last dose.
b
Time 0 is predose.


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LY3323795
Study Schedule Protocol I9F-MC-SCAA:  Part B
Study Day
Screen
-28 to -1
-1
1
a
2
3
4
5
6
7
FDC
b
ED
Notes
Admit to CRU
X
Discharge from CRU
X
Discharge to be approximately
24 hours after CSF catheter is 
removed, at investigator’s
discretion.
Physical examination
X
X
X
X
Ethanol and urine 
drug screens
X
An additional ethanol and urine 
drug screen may be done at the 
discretion of the investigator.
Ophthalmic
examination
X
X
X
X
X
See Section 9.4.4.2 for details.
12-Lead ECG 
(hours)
X
0
48
±2
X
X
X
These will be single ECGs. 
ECGs coinciding with PK 
sample time points are to be 
conducted as close as possible 
to PK sampling. Time of Day 3 
ECG can vary depending on 
when the CSF catheter is 
removed. Other ECGs may be 
obtained – see Section 9.4.3.
Vital signs (hours)
X
0, 1, 2, 4, 6
24
X
X
X
X
X
X
X
Timing of vital sign collections
may be adjusted. See Section 
9.4.2 for details.
Clinical laboratory
values (hours)
X
X
48
X
X
X
Blood will be collected on Day 
-1 for both local and central 
labs.  Investigator will review 
local lab results before dosing.
LY3323795 study 
drug
X
Subjects are required to fast 
before and after drug 
administration.  See Section 
6.3.1 for details.


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
Study Day
Screen
-28 to -1
-1
1
a
2
3
4
5
6
7
FDC
b
ED
Notes
LY3323795 plasma 
PK samples (hours)
0, 0.5, 1, 2, 3, 4, 6, 
8, 12
24, 
36
48
72
96
120
144
A maximum of 5 additional 
plasma samples per subject 
may be drawn during the study 
at the discretion of the 
investigator or sponsor.  These 
additional samples may be 
drawn to measure LY3323795
or Aβ concentrations.
Plasma PD samples 
(hours)
0, 0.5, 1, 2, 3, 4, 6, 
8, 12
24, 
36
48
72
96
120
144
Additional samples possible as 
per LY3323795 plasma PK
sample note above.
Storage PD plasma 
samples (hours)
0, 0.5, 1, 2, 3, 4, 6, 
8, 12
24, 
36
48
72
96
120
144
Additional samples possible as 
per LY3323795 plasma PK
sample note above.
X-ray
X
Subjects who agree to have 
lumbar punctures may have a 
lumbar x-ray conducted at 
screening, at site’s discretion.  
If an x-ray was done within 12 
months of screening, this may 
be used.
Weight/height
X
X
X
X
Height measured at screening 
only.
CSF, continuous
(hours)
-4, -2, 0, 1, 2, 3, 4, 
5, 6, 7, 8, 9, 10, 12, 
14, 16, 18, 20
24, 
28, 
32, 
36
CSF samples will be collected 
during the stabilization period. 
See Section 5.1.2 for details of 
how CSF samples at different 
time points will be processed.
Neurological survey 
(hours)
X
X
24
48
X
X
Neurological surveys on PK 
sampling days are to be 
conducted as close as possible 
to PK sampling.  For Day 3, 
time can vary depending on 


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
Page 16
LY3323795
when the CSF catheter is 
removed.  If abnormalities are 
noted, refer to Section 9.4.4.1.
Sample for genetic 
testing
X
Abbreviations:  Aβ = β-amyloid; CRU = clinical research unit; CSF = cerebrospinal fluid; ECG = electrocardiogram; ED = early discontinuation; FDC = final 
discharge; PD = pharmacodynamics; PK = pharmacokinetics.
a
Time 0 is predose.
b
Study final discharge procedures should be completed 14-21 days after the last dose.


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
Page 17
LY3323795
Study Schedule Protocol I9F-MC-SCAA:  Part C
Screen
Period 1
7-Day 
Wash-
out
Period 2
FDC
a
ED
Notes
Study Day
-28 to 
-2
-1
1
2
3-9
10
11 to 
14
15
16
b
17
18
19 20
21
22
23
Admit to CRU
X
X
X
Subjects will be admitted on 
Days -1, 9, and 15.
Discharge from 
CRU
X
X
X
Subjects will be discharged 
on Days 3, 11, and 18.
Physical 
examination
X
X
X
X
Ethanol and urine 
drug screens
X
An additional ethanol and 
urine drug screen may be 
done at the discretion of the 
investigator at readmission 
to the CRU.
Ophthalmic
examination
X
48
X
X
X
See Section 9.4.4.2 for 
details of eye tests to be 
conducted.
12-Lead ECG 
(hours)
X
0, 1, 2, 
4, 6, 8, 
12
24
48
0, 1, 2, 
4, 6, 8, 
12
24
48
X
X
X
See Section 9.4.3 for details. 
At predose (time 0), 3 sets 
of triplicate ECGs will be 
obtained approximately 10 
minutes apart. ECGs 
coinciding with PK sample 
time points are to be 
conducted as close as 
possible to PK sampling.  
See Section 9.4.3 for more 
details. 


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
Page 18
LY3323795
Screen
Period 1
7-Day 
Wash-
out
Period 2
FDC
a
ED
Notes
Study Day
-28 to 
-2
-1
1
2
3-9
10
11 to 
14
15
16
b
17
18
19 20
21
22
23
Vitals (hours)
X
0, 1, 2, 
4, 6, 8, 
12
24
X
X
X
X
0, 1, 2, 
4, 6, 8, 
12
24
X
X
X
X
X
X
X
X
See Section 9.4.2 for details.
Clinical 
laboratory values 
(hours)
X
X
48, 
Day 9
0
48
X
X
X
Screening tests will take 
place at local laboratories
and other analyses will be at 
central laboratory. Blood 
will be collected on Day -1 
for both local and central 
labs.  Investigator will 
review local lab results
before dosing in Period 1.
LY3323795
study drug
X
X
Subjects are required to fast 
before and after drug 
administration.  See Section
6.3.1 for details.
Itraconazole 
study drug
BID
QD
X
X
X
X
X
X
X
Subjects will be dosed as 
inpatients on Days 10 and 
15-17, and as outpatients on 
Days 11-14 and 18-21.
Itraconazole will be dosed 
twice on Day 10, 12 hours 
apart.  Additional daily 
doses may be added 
depending on the PK results
of LY3323795.  See Section 
5.1.3 for further details.


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
Screen
Period 1
7-Day 
Wash-
out
Period 2
FDC
a
ED
Notes
Study Day
-28 to 
-2
-1
1
2
3-9
10
11 to 
14
15
16
b
17
18
19 20
21
22
23
LY3323795
plasma PK 
samples (hours)
0, 0.5, 
1, 2, 3, 
4, 6, 8, 
12
24
48, 72, 
96, 
120, 
144
0, 0.5, 
1, 2, 3, 
4, 6, 8, 
12
24
48
72 96 120 144 168
A maximum of 5 additional 
plasma samples per subject 
may be drawn during the 
study at the discretion of the 
investigator or sponsor.  
These additional samples 
may be drawn to measure 
LY3323795 or Aβ 
concentrations.
Itraconazole 
plasma PK 
samples (hours)
0, 1, 2, 
3, 4, 6, 
8, 12
24
Times are relative to the 
itraconazole dose 
administered on Day 16.  
See Section 9.5 for details.
Weight/height
X
X
X
X
Height measured at 
screening only.
Neurological 
survey (hours)
X
X
24
48, 
144
X
24
48
144
X
X
Neurological surveys on PK 
sampling days are to be 
conducted as close as 
possible to PK sampling.  If 
abnormalities are noted, 
refer to Section 9.4.4.1.
Sample for 
genetic testing
X
Abbreviations: Aβ = β-amyloid; BID = twice a day; CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; FDC = final discharge; 
PK = pharmacokinetics; QD = once a day.
a
Study final discharge procedures should be completed 14-21 days after the last dose.
b
Time 0 is predose.


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LY3323795
3.Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive 
decline, loss of independent function,and ultimately death.  While symptomatic treatments are 
available, their effects are temporary and do not affect the progression of disease pathology
. 
Disease-modifying agents that target the underlying disease pathology are currently unavailable
andrepresenta significant unmet medical need for patients, their families,and caregivers.  The 
primary pathological hallmarks of AD identified at autopsy include neuritic-amyloid (Aβ) 
plaques and neurofibrillary tangles composed of tau aggregates (Hyman et al. 2012).  Mounting 
evidence indicates that, while both Aplaques and tau tangles may be drivers of neuronal 
degeneration and disease progression, Ais likely an early initiator of the AD neurodegenerative 
cascade.  As such, progression of AD may beslowed down by inhibiting thegeneration ofAin 
the brain.
Aβ is part of the amyloid precursor protein (APP), which is a transmembrane proteinwidely 
expressed on the cell surface, particularly in neurons. APP iscleaved through 2 pathways 
involving 3 secretase enzymes: α-secretase, γ-secretase, and β-site APP-cleaving enzyme 
[BACE]1 (previously referred to as β-secretase). 
 
In the second pathway, BACE1 cleaves the APP molecule, 
generating membrane-associated C99 and releasing a larger secreted fragment called  
. 
γ-Secretase then cleaves C99 in a heterogeneous manner within the membrane releasing a variety 
of Aβ species that aggregate in protofibrils, then fibrils, which seem to comprise the mass of Aβ 
plaques in AD brain tissue (Turner et al. 2003). While both γ-secretase and BACE1 inhibition
represent effective means of precluding the formation of Aβ, BACE1 inhibition may provide 
improved safety and tolerability (Doody et al. 2013).
BACE1 shares approximately 64% amino acid similarity with BACE2.  Unlike BACE1, which is 
primarilyexpressed inneurons, BACE2 appears to be primarily expressed in the periphery, with 
highest expression in the colon, kidney, pancreas, prostate, stomach, and trachea,butminimal 
expression in the brain (Bennett et al. 2000).  While both enzymes appear to cleave APP,the 
cleavage site appears to be slightly different between the 2 enzymes, with BACE2 cleaving APP 
closer to the site associated with α-secretase. Based on the relative expression of these 2
enzymes, along with the differential cleavage sites for APP, BACE1 appears to be the primary 
enzyme responsible for the production of Aβ. This is further supported by studies in mice with a 
homozygousBACE1 knockout, where production of Aβ and C99 is effectively abolished 
(Vasser 2004).  The physiological role of BACE2 is less well studied than that of BACE1.
MultipleBACE2 substrateshave been reported,including pigment cell-specific melanocyte 
protein 17,whichplays a crucial role in eumelanin synthesis and melanogenesis(Rochinet al. 
2013),andtransmembrane protein 27 (TMEM27),whichregulates pancreatic beta cell mass 
and modulates glucose homeostasis
CCI
(Esterházy et al. 2011).Selectively targeting BACE1 with 
LY3323795 maymitigate any potential risks associated with BACE2 inhibition.
CCI


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
3.1.
Study Rationale
Eli Lilly and Company (Lilly) is currently developing LY3323795, a synthetic small molecule 
that selectively inhibits BACE1 enzyme over BACE2, for the treatment of AD.
The aim of this first-in-human study is to assess the safety, tolerability, pharmacokinetics(PK),
and pharmacodynamics (PD) of single doses of LY3323795 in healthy subjects, and to identify 
doses for subsequent studies.The reduction of cerebrospinal fluid (CSF)Aβ concentrations 
following LY3323795 administration is thought to be the most important biomarker for this 
study. Accordingly, serial CSF collection will be employed in Part B of this study to assess 
changes in CSF Aβ concentrations across 3 dose levels. It is intended that thesedata can be used 
to aid in selecting doses for future studies.
3.2.
Background
Results from preclinical in vivostudies have suggested that BACE2 inhibition causescutaneous
hypopigmentation.  The hypothesis is that a BACE1-selective inhibitor should mitigate this 
hypopigmentation risk and other unknown risks of chronic BACE2 inhibition, while slowing 
down the progression of AD through a reduction in Aβ plaque formation.
In preclinical in vitroand in vivostudies, LY3323795 was shown to potentlyinhibit BACE1 
activity with a35-fold selectivity for BACE1 over BACE2, and did not produce 
hypopigmentation in a 6-week study in beagle dogsat a dose of 0.1 mg/kg.In nonclinical 
pharmacologicalstudies in a transgenic mouse model of amyloid deposition, oral administration 
of 0.1mg/kgand 1mg/kg of LY3323795 resulted in a 38% and 67% decrease,respectively,in 
brain cortical Aβ after 3hours. A robust reduction in Aβ CSF levels out to72 hours was also 
observed in beagle dogs following oral administration of 0.2mg/kg of LY3323795.
The toxicity of LY3323795was characterized ingood laboratory practice (GLP),repeat-dose 
studies of up to 1-monthduration in rats and dogs and in single-dose safety pharmacology 
studies assessingcardiovascular, respiratory, and central nervous system (CNS) effects. Primary 
findingsin thesestudies are summarized below, and additional details are included in the 
Investigator’s Brochure(IB) for LY3323795(Section 5.2.1, Nonclinical Safety Pharmacology 
and Toxicology).
Overt toxicity in the 1-month toxicity studies occurred at the highest doses administered 
to dogs (200 mg/kg).
o
CCI
In dogs, excessive body weight loss was observedat 200 mg/kg, leading to a 
dosing holiday and dose reduction to 120 mg/kg. CNS activity was noted in 1
male dog at 200 mg/kg.


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795

At the 120-mg/kg dose level in dogs, increased liver weight was noted, while 2- to 4-fold 
increases in alanine aminotransferase (ALT) concentrations (as compared to baseline 
values) were noted at 30 mg/kg and 120 mg/kg. These changes were considered 
nonadverse.

Dose-dependent QT corrected for heart rate (QTc) prolongation occurred following 
repeated administration in dogs of doses at and above 5 mg/kg; peak changes at 5 mg/kg 
and 120 mg/kg were +7 msec and +31 msec, respectively. No qualitative 
electrocardiogram (ECG) abnormalities were observed. Decreases in heart rate also 
occurred following repeated administration in dogs of doses at and above 5 mg/kg; peak 
changes at 5 mg/kg and 120 mg/kg were -15 bpm and -39 bpm, respectively.

In a single-dose cardiovascular safety study in dogs, QTc prolongation was noted at doses 
of 5 mg/kg (≤+4 msec) and 30 mg/kg (≤+9 msec). At all dose levels, minor decreases in 
heart rate were observed; at the 30-mg/kg dose level, a 6-bpm reduction in heart rate was 
observed (maximally). Also at the 30-mg/kg dose, minimally decreased systolic pressure 
(-7 mmHg), mean arterial pressure (-5 mmHg), and dP/dtmax (-240 mmHg/sec) occurred
during the first 6 hours postdose.

In rats, minimal increases in autofluorescent granules in the retinal pigmented epithelium 
were noted at the 150-mg/kg dose level and were considered nonadverse.

The no-observed-adverse-effect level (NOAEL) of LY3323795 was 120 mg/kg in dogs 
and 150 mg/kg in rats.
Itraconazole, an antifungal agent, will be administered in Part C of this study as it is known to be 
a potent inhibitor of CYP3A, and is commonly used in drug interaction evaluations. Peak 
plasma concentrations of itraconazole are reached within 2 to 5 hours following oral 
administration. As a consequence of nonlinear PK, itraconazole accumulates in plasma during 
multiple dosing. Bioavailability is increased when itraconazole is administered with food. The 
terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and 
increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma 
concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending 
on the dose and duration of treatment. The primary metabolite of itraconazole is hydroxy-
itraconazole.  Additional information including possible side effects of itraconazole can be found 
in the product insert.
3.3.
Benefit/Risk Assessment
Nonclinical safety information for LY3323795 adequately supports the transition from 
preclinical status to a clinical, single-dose study.  On the basis of the nonclinical data, 
LY3323795 is not considered to be a high-risk compound.  This protocol reflects the fact that 
LY3323795 has not been administered to humans previously, 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 (EMEA 2007).  Any identified risks are considered to be monitorable and 


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
manageable at the anticipated dose range of 0.3 mg to 100 mg for LY3323795 in healthy 
subjects.
It is intended that sentinel dosing will be conducted at all dose levels in Part A to minimize risk 
to subjects (see Section 5.1.1 for details), in accordance with the clinical research unit’s (CRU) 
procedures.  Additionally, the PK of LY3323795 will be assessed at pre-specified time points 
during the study, to ensure that median exposures do not exceed the lowest NOAEL exposure in 
toxicology studies conducted under GLP (in male rats). In this study, there is no expected 
therapeutic benefit for the subjects.
The risks of CSF drainage via indwelling catheter are similar to those of lumbar puncture (LP)
and are well known (Jhee and Zarotsky 2003).  The most common side effect reported is 
headache.  However, a vast majority of these headaches are mild to moderate in severity and 
respond to such first-line therapies as analgesia and hydration.  Individuals with persistent 
headaches may respond to a single blood patch without sequelae.  The rare persistence of 
headaches is thought to result from continued leakage of CSF from the area surrounding the 
needle insertion point.  If a persistent severe headache occurs, a “blood patch” should be 
performed.  This is done by injecting a small amount of the subject’s blood into the region of the 
supposed leak to try to seal it.  The blood patch procedure is effective in 95% of the cases for 
stopping the headache.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY3323795 is to be found in the IB.  
Information on AEs expected to be related to the investigational product may be found in Section 
7 (Development Core Safety Information) of the IB.


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LY3323795
4.Objectivesand Endpoints
TableSCAA.1shows the objectives and endpoints of the study.
TableSCAA.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To explore the safety and tolerability of single 
doses of LY3323795 in healthy subjects.
Incidence of treatment-emergent adverse events.
Secondary
To explore the plasma and cerebrospinal fluid
(CSF)pharmacokinetics (PK) of single doses of 
LY3323795.
To explore the plasma and CSF
pharmacodynamics (PD) of single doses of 
LY3323795.
Maximum drug concentration (C
max) and the area under 
the concentration-versus-time curve (AUC)in plasma;
and Cmaxand AUC in CSF for various timeframes.
The measures for PD analysis will be the minimum Aβ1-
40or Aβ
1-42concentration observed following 
administration of study drug, expressed as the 
percentagechange in concentration from baseline.
CCI


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LY3323795
5. Study Design
5.1.
Overall Design
Study I9F-MC-SCAA (SCAA) is a Phase 1 study in healthy subjects that will be conducted in 3
parts, as follows:

Part A will be a subject- and investigator-blind, placebo-controlled, randomized, single-
ascending dose, 3-period, dose-escalation study to evaluate safety, tolerability, and 
plasma PK/PD of LY3323795. 

Part B will be a subject- and investigator-blind, placebo-controlled, randomized, single-
dose, single-period, lumbar catheter study with up to 3 cohorts/dose levels, to evaluate 
the central and plasma PK/PD of LY3323795.

Part C will be an open-label, 2-period, fixed-sequence, single-cohort study to evaluate a 
potential CYP3A4 interaction when LY3323795 is coadministered with itraconazole.
Figure SCAA.1 illustrates the study design.


I9F-MC-SCAA(a) Clinical Pharmacology Protocol
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LY3323795
Abbreviations: CSF = cerebrospinal fluid; d = day; Itra = itraconazole; LY = LY3323795; PD = pharmacodynamics; PK = 
pharmacokinetics; PL = placebo; TBD = to be determined.
Figure SCAA.1.
Illustration of study design for Protocol I9F-MC-SCAA.
Period 1
Period 2
Period 3
Cohort 1
(n=9)
(LY=6; 
PL=3)
Dose 1,
0.3 mg 
LY or PL
≥14 d 
washout
Dose 3,
3 mg
LY or PL
≥14 d 
washout
Dose 5, 
30 mg
LY or PL
≥14 d 
washout
Cohort 2
(n=9)
(LY=6; 
PL=3)
Dose 2,
1 mg 
LY or PL
≥14 d 
washout
Dose 4,
10 mg
LY or PL
≥14 d washout
Dose 6,
100 mg
LY or PL
Part A: Safety 
review to be 
completed after 
each dose level, 
prior to 
escalation.  
From Dose 4 
onwards, PK 
data review to be 
completed prior 
to dose 
escalation.
Part A: Dose Escalation 
Period 1
Cohort 3
(n=7)
(LY=5; PL=2)
Dose B1
or Placebo
Cohort 4
(n=7)
(LY=5; PL=2)
Dose B2
or Placebo
Cohort 5
(n=7)
(LY=5; PL=2)
Dose B3 
or Placebo
Part B: Serial CSF Sampling
Dose B1 will be determined 
by PK/PD data through Part 
A Dose 2, and safety data 
through Part A Dose 4.
Dose B2 will be determined by:
•
PK/PD data from Dose B1
•
PK/PD data from Part A Dose 4
•
Safety Data through Part A Dose 5.
Dose B3 will be determined by: 
•
Maximum tolerated dose from Part A
•
PK data from Part A.
•
PK/PD data from Doses B1 and B2.
Part C: Itraconazole Interaction
Period 1
Period 2
Cohort 6 (n=8)
(LY=8, Itra = 8)
LY
≥7 d washout
Itra (7 doses)
LY + Itra
Itra (5+ doses)


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LY3323795
5.1.1. Part A: Dose-Escalation Study
Part A is a dose-escalation study that will be conducted in 2 alternating cohorts (Cohorts 1 
and 2), each consisting of approximately 9 subjects (6:3 subjects, LY3323795:placebo at each 
dose level) who will participate in 3 study periods (total of 6 dose levels in the 2 cohorts). The 
number of subjects intended to be enrolled is detailed in Section 5.2. The first 4 dose levels of 
LY3323795 are anticipated to be 0.3 mg, 1 mg, 3 mg, and 10 mg.  Doses 5 and 6 are anticipated 
to be 30 and 100 mg, but will be confirmed following PK data reviews.  See Section 5.1.1.1 for 
details of dose-escalation decisions.
Sentinel dosing will be used in this study.  For all dose levels, LY3323795 and placebo will be 
administered first to a sentinel group of 2 subjects (1:1, LY3323795:placebo).  These subjects 
will be followed for 24 hours postdose; if the dose is well tolerated, dosing of the remaining 7 
subjects in the cohort may begin.
The proposed dose levels may be adjusted based on emerging safety and PK data (see Section 
7.4.1).
Subjects will be admitted to the CRU on Day -1 (see Part A Schedule of Activities, Section 2) 
and will remain as inpatients for at least 48 hours after dosing on Day 1, after which they may be 
discharged at the discretion of the investigator.  Subjects will then return for outpatient visits for 
up to 144 hours postdose (Day 7).  The washout time between doses for a given subject will be at 
least 14 days.
PK and PD (plasma Aβ) data, as well as safety assessments, including clinical laboratory tests, 
ECGs, AEs, vital signs, ophthalmic examinations, and neurological surveys, will be collected at 
various time points pre- and postdosing with LY3323795/placebo, as described in Part A 
Schedule of Activities (Section 2).  However, exact time points for PK/PD and safety 
assessments may be modified based on interim PK/PD results (see Section 5.1.1.1).
5.1.1.1.
Dose Escalation and Interim Access to Data in Part A
The decision to dose escalate will be based on safety reviews conducted after each dose (and PK 
reviews from Dose 4 [planned to be 10 mg] onwards).  Dose escalation will not occur until after 
a review of at least 3 days’ safety data from the preceding dose level has been carried out, and 
the dose shown to be safe.  Accordingly, safety data, including AEs, vital signs, neurological 
surveys, ophthalmic tests, ECGs, and clinical laboratory tests, will be assessed by both the 
investigator and the sponsor prior to each dose escalation.  Any available PK data may be 
reviewed but PK data are not required for the initial dose-escalation decisions.  However, from
Dose 4 onwards, LY3323795 PK data will be reviewed before escalation to the next subsequent 
dose level to verify that the projected median exposure does not exceed one tenth the NOAEL 
exposure established in rats (i.e. median area under the concentration-versus-time curve (AUC)
will not exceed 3,450 ng•hour/mL and median Cmax will not exceed 214 ng/mL) (see Section
7.4.1).  PK samples up to 96 hours postdose will be required to conduct the PK data reviews.  
The 96-hour PK sampling period may be adjusted based on emerging PK data.  Plasma Aβ data 
may also be reviewed to assess the PD profile.  Time points for PK and PD sampling and 
required safety assessments may be modified based on emerging PK and safety results.


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LY3323795
In addition to the reviews of PK data required after Dose 4 for the purposes of dose escalation, 
interim access to PKandPD (including plasma Aβ) data will occur aftertheanticipated1-mg 
dose (Dose2) and 10-mg dose (Dose 4) of Part A.  Data from thisinterim access to data (IAD) 
reviews, as well as results of thePK IADs following Doses 4,5,and6,willbe used at different 
points to selectdosesin Part B(see FigureSCAA.1).
5.1.2. Part B: CSF Sampling Study
Part B is a single-dose, 3-cohort (5:2subjects, LY3323795:placebo per cohort), single-period, 
lumbar catheter study to evaluate central PK/PD of LY3323795.  See Section 5.2for planned 
enrollment numbers.PartB may be conducted in parallel to Part A of the study, as long as the 
conditions have been met for each dose decision in Part B (see Section 5.1.2.1).
Subjects will be admitted to the CRU on Day -1 and will remain as inpatients until at least 
24hours after the CSF catheter is removed,after which they may be discharged at the discretion 
of the investigator.  CSF will be collected froman indwelling catheter usinga closed system.  
The catheter will be inserted approximately 4 hoursprior to study drug administration.CSF 
samples will be taken during this “stabilization”period approximately every 2 hours, as feasible.  
If some samplesduring the stabilization period are not collected for any reason, this will not be 
considered a protocol violation.
CSF PK and PD data will be collected by frequentsampling for 4hours predose and up to 36 
hours postdose (as described in the Part B Schedule of Activities,Section2). The minus 4-hour 
CSF sample will be collected for safety (red blood cell count, glucose, and protein, to be testedat 
the local laboratory) and PD biomarkers(which will be tested centrally).The minus 2-hour 
sample will be collected for PD biomarkers only; the 0-hour and subsequent postdose samples
will be collected for LY3323795 concentration and PD biomarkers.  An additional safety CSF 
sample will be collected at the removal of the catheter.  CSF PD samples will be split and stored 
Plasma PK and PD (plasma Aβ) data will be collected up to 144hours postdose (as described in 
the Part B Schedule of Activities,Section2).
Safety assessments including clinical laboratory tests, ECGs, AEs, vital signs, ophthalmic 
examinations, and neurological surveys will be collected(as described in the Part B Schedule of 
Activities, Section2).
Two IAD reviews are planned in Part B:  the first after the completion of dosing forCohort3and 
the second after dosing forCohort 4. All CSF PK/PD data will be included in these reviews, as 
well as plasma PK data through Day 4. See Section 5.1.2.1for details.
5.1.2.1. Dose Selection and Pharmacokinetic Analysis in Part B
CCI
Any dose selected for administration in Part B will be less than or equal to doses previously 
administered and found tobe well tolerated in Part A.  EmergingPKdata (and PD data, as 
available) from the first 2 dosesin Part A, and safety data through Dose 4 of Part A,will 
determine DoseB1 for Cohort 3.


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LY3323795
Cohort 3
Cohort 3 is intended to gauge the degree to which LY3323795 crosses the blood-brain barrier.  A 
3-mg dose is intended to be administered in Cohort 3, if supported by Part A data. Modeling of 
nonclinical data suggests that this dose would result in CSF LY3323795 concentrations 
exceeding the lower limit of quantification (approximately 0.1 ng/mL) for at least 12 hours. This 
dose may be modified if Part A data suggest that the plasma exposure of LY3323795 is 
meaningfully different from the nonclinical predictions.
Cohorts 4 and 5
The dose for Cohort 4 will be selected based on data from Cohort 3, specifically the plasma and 
CSF PK/PD data, alongside data from Part A.  The dose for Cohort 5 will also depend on these 
data from Cohort 3 and Part A, in addition to data from Cohort 4 (see Figure SCAA.1). Doses 
estimated to produce substantial reductions in CSF Aβ concentrations will be selected, with the 
goal that at least 1 of these doses will produce reductions in CSF Aβ of >50% (relative to 
baseline) for at least 4 hours. In no case will the doses selected exceed the maximum tolerated 
dose (MTD) found in Part A.
5.1.3. Part C: Itraconazole Interaction Study
Part C is an open-label, fixed-sequence, single-cohort study in 8 healthy subjects to evaluate 
potential CYP3A4 interaction when LY3323795 is coadministered with itraconazole.  Part C is 
divided into 2 periods.
In Period 1, subjects will be administered a dose of LY3323795 (intended to be 3 mg); the dose
will be at or below a level previously administered safely in Part A.  There will be a washout 
period of at least 7 days following this dose, with PK assessed up to 144 hours postdose.
In Period 2, subjects will be dosed with itraconazole for 6 consecutive days prior to 
coadministration with LY3323795.  On Day 10, subjects will receive itraconazole 200 mg twice, 
approximately 12 hours apart.  On Day 11, subjects will receive a morning dose of itraconazole 
200 mg prior to discharge.  On Days 12 to 14, subjects will attend the CRU on an outpatient 
basis and will receive doses of itraconazole 200 mg once daily in the morning.  On Day 15, 
subjects will be re-admitted to the CRU and will receive a single dose of itraconazole 200 mg.
On Day 16, subjects will be administered 200-mg itraconazole 1 hour prior to receiving 
LY3323795 (using the same LY3323795 dose administered in Period 1).  The timing may be 
adjusted based on available PK results from Part A.  All subjects in the cohort will receive 
LY3323795; there will be no placebo.  From Day 17 onwards, it is intended that subjects will 
receive daily doses of 200-mg itraconazole alone for 5 days; based on emerging PK data, this 
period of daily itraconazole dosing may be extended to ensure that CYP3A inhibition is 
maintained throughout the elimination of LY3323795.  Based on the projected half-life of 
LY3323795 (23 hours), 168 hours of sampling allows more than 3 half-lives of coverage in the 
event that clearance doubles; this would be sufficient to characterize a doubling in clearance.


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LY3323795
Samples will be collected to assess itraconazole PK on the day of dosing with LY3323795 (see 
Part C Schedule of Activities [Section 2]).  Exact time points for PK/PD and safety assessments 
may be modified based on emerging PK/PD results.
5.2.
Number of Participants
For Cohorts 1 and 2 in Part A, up to approximately 24 subjects may be enrolled so that 
approximately 18 subjects (9 subjects per cohort [6:3, LY3323795:placebo per dose level]) 
complete the study.
For Cohorts 3 to 5 in Part B, up to approximately 30 subjects may be enrolled so that 
approximately 21 subjects (7 subjects per cohort [5:2, LY3323795:placebo]) complete the study.
For Cohort 6 in Part C, up to 12 subjects may be enrolled so that approximately 8 subjects 
complete the study.
Subjects in 1 part of the study will not be allowed to participate in any other part of the study.
Subjects will be replaced as needed, rather than over-enrolled. See Section 10 for details on the 
replacement of subjects.
5.3.
End of Study Definition
The end of the study is the date of the last visit or last scheduled procedure for the last subject, as 
shown in the Schedule of Activities (Section 2).
5.4.
Scientific Rationale for Study Design
This study will be conducted to determine the safety and tolerability of LY3323795 in healthy 
subjects.
The crossover design in Part A of this study will allow each subject to act as their own control 
and allow for an assessment of within- and between-subject variability in evaluating tolerability 
and PK of different doses of LY3323795.  The placebo-controlled, dose-escalation strategy 
allows safety and PK/PD data to be obtained with a large degree of within-subject control data.
The collection times for PK samples and washout period between doses are based on the 
predicted PK and PD of LY3323795 from nonclinical studies. Based on the estimated half-life 
of approximately 23 hours, sample collection for up to 144 hours should be sufficient to fully 
assess the concentration-time profile, and a washout period of at least 14 days should be 
sufficient to ensure that there is no carryover between periods. Either or both may be revised 
based on reviews of preliminary PK data generated during the study.
It is intended that a range of 3 doses of LY3323795 be administered in Part B of the study based 
on the LY3323795 exposures and plasma PD response observed in Part A.  The aim is to 
determine a dose level that produces a substantial reduction in CSF Aβ.  The exact doses of 
LY3323795 administered in Part B will be determined after reviewing the emerging data from 
Part A, as well as available data from any previous doses carried out in Part B. However, doses 
in Part B will not exceed a dose that has been assessed in Part A as being safe and well tolerated.  


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To minimize confounding effects of the catheterization on Aβ concentrations, the indwelling 
catheter for CSF collection will be inserted approximately 4 hours prior to study drug 
administration to allow Aβ CSF measurements to stabilize.  Previous CSF catheter studies have 
shown large variability in CSF Aβ in the first few hours of collection after catheterization 
(Ereshefsky et al. 2007).
In healthy subjects, CSF indwelling catheter studies conducted by Lilly have shown increases in 
CSF Aβ concentration over 24 to 40 hours of sampling (Lucey et al. 2015).  In these CSF 
catheter studies, the initial 4-hour sampling interval following the catheter placement showed a 
10% to 15% increase in Aβ concentration.  Subjects receiving placebo following the catheter 
placement showed additional increases of 20% to 30% over a 36-hour CSF sampling period.  
Similar findings were shown by Bateman (2008).  Therefore, placebo will also be included in 
Part B of this study.  Previous studies have also shown that CSF Aβ concentrations slowly return 
to baseline following a treatment that disrupts Aβ synthesis; however, due to the large variability 
in CSF Aβ concentrations both within and between individuals, a long duration of sampling is 
required to fully characterize the PD time course.
An assessment of LY3323795 PK with concomitant itraconazole administration is planned in 
Part C.  In vitro recombinant CYP isoform phenotyping studies indicate CYP3A4 is the only 
tested CYP isoform that metabolizes LY3323795.  In vitro metabolism studies with human 
hepatocytes suggest that CYP-mediated metabolism accounts for approximately 70% of the 
overall metabolism in hepatocytes.  Taken together, these data result in a predicted LY3323795 
AUC increase of approximately 4-fold when LY3323795 is coadministered with the strong 
CYP3A inhibitor itraconazole. Accordingly, coadministration with itraconazole will help 
determine the clinical relevance of CYP3A inhibition on LY3323795 clearance.  The dosing 
regimen for itraconazole was optimized using a physiologically based PK model with the goal of 
reaching steady-state concentrations as rapidly as possible (Ke et al. 2014).  The use of the oral 
solution formulation of itraconazole is specified as it has higher bioavailability and less 
variability in absorption than solid dosage formulations.
5.5.
Justification for Dose
This study will evaluate plasma and CSF PK/PD of LY3323795 in an attempt to define a 
pharmaceutically relevant dose range for future studies. The initial proposed dose is 0.3 mg, 
which is anticipated to provide a maximum drug concentration (Cmax) of 0.625 ng/mL (90%
confidence interval [CI]: 0.36, 1.11), and an area under the curve from time 0 extrapolated to 
infinity (AUC[0-∞]) of 24.5 ng•hour/mL (90% CI: 9.09, 65.9). This dose (by body surface area) is
substantially lower than the dose levels identified as the NOAELs in 1-month GLP toxicology 
studies and is therefore appropriate for use (Table SCAA.2). The doses (based on body surface 
area) identified as the NOAELs in rats and dogs are 4,500- and 12,000-fold greater than the 
starting dose in humans. Margins calculated based on AUC exposure at the NOAELs relative to 
predicted human exposures at 0.3 mg are ≥1,408-fold (due to a gender difference in exposure) in 
rats and 2,214-fold higher in dogs.


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In a cardiovascular safety pharmacology study in dogs, no changes in QTc prolongation occurred 
at a dose of 0.5 mg/kg; this dose (based on body surface area) is 63-fold higher than the proposed 
starting dose in Study SCAA of 0.3 mg.
Part A
The doses studied in Part A will be selected to ensure that the exposures tested are anticipated to
produce significant CSF Aβ reductions at steady state. Based on nonclinical modeling, a plasma 
AUC of 1,800 ng•hour/mL (90% CI: 1240, 2600) is anticipated to produce a 90% time-averaged 
reduction in CSF Aβ at steady state. Based on allometric scaling of clearance, it is anticipated 
that a dose of 22 mg (90% CI: 7.5, 63) will achieve this exposure. Accordingly, it is intended 
that doses of at least 100 mg will be explored to ensure that the full range of pharmacologically 
relevant exposures is tested in Study SCAA.
The upper dose in SCAA is projected to be 100 mg.  However, assessments of PK at pre-
specified times are planned during the dose escalation, and the anticipated doses may be 
modified to ensure that median exposures do not exceed one tenth of the rat NOAEL determined 
in toxicology studies (i.e. median AUC will not exceed 3,450 ng•hour/mL and median Cmax will
not exceed 214 ng/mL).
Part B
Part B is an assessment of CSF PK/PD, with CSF collected over 36 hours following dose 
administration using a lumbar catheter. The initial dose in Part B is anticipated to be 3 mg, 
which is anticipated to produce measurable CSF LY3323795 concentrations. As described in 
Section 5.1.2.1, this dose may be increased if necessary, as long as the same dose level was well 
tolerated in Part A, to ensure that quantifiable LY3323795 concentrations are obtained.  The 
maximum dose administered in Part B is intended to be the MTD in Part A, although a lower 
dose may be selected if indicated by emerging PK/PD data from either Part A or Part B.
Part C
Part C will assess the interaction of LY3323795 with itraconazole, a CYP3A inhibitor.  The dose 
of LY3323795 administered in this part of the study will be the same as, or lower than, a dose 
that was safely administered in Part A.  The dose will be no greater than one-tenth of the MTD 
administered in Part A.  The planned itraconazole dose (200 mg) has been safely administered in 
previous drug interaction studies of this design.  


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Table SCAA.2.
Margin of Safety for Oral Administration of LY3323795 Based on 
Administered Dose and Predicted Exposure
Dose
(mg/kg)
Dose
(mg/m2)
Dose
Multiple
a
AUC (µg•hour/mL)
or Cmax (ng/mL)
Exposure 
Multiple
a
Human
b (0.3 mg)
0.2
-
0.0245 or 0.627
-
Rat NOAEL
c
150
900
4500
M=34.5 or 2140
F=91.5 or 4950
M=1408
F=3735
Dog NOAEL
d
120
2400
12,000
51.8 or 3095
2114
QTc LOEL 
(5 mg/kg)
Day 1 TK
NA
NA
NA
Cmax=1018
Cmax multiple=1623
-
Human
b (100 mg)
52.9
-
8.18 or 210
-
Rat NOAEL
c
150
900
17
M=34.5 or 2140
F=91.5 or 4950
M=4
F=11
Dog NOAEL
d
120
2400
45
51.8 or 3095
6
QTc LOEL 
(5 mg/kg)
Day 1 TK
NA
NA
NA
Cmax=1018
Cmax multiple=5
Abbreviations:  AUC = area under the plasma concentration-versus-time curve; Cmax = maximum drug 
concentration; F = female; LOEL = lowest-observed-effect-level; M = male; NA = not applicable; NOAEL = no-
observed-adverse-effect level; QTc = QT corrected for heart rate; TK = toxicokinetics.
a
Dose multiple is the dose in animals/dose in humans based on mg/m
2.  Exposure multiple is the calculated AUC 
in animals/projected AUC in humans (Projected human exposures located in Table 5.7 of the IB).
b
Day 28 AUC from the repeat-dose toxicity study in either rats or dogs (as indicated), unless otherwise specified.
c
NOAEL determined in a 1-month repeat-dose toxicity study in rats (Report 8339313).
d
NOAEL determined in a 1-month repeat-dose toxicity study in dogs (Report 8339298).


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6. Study Population
Eligibility of subjects for study enrollment will be based on the results of a screening medical 
history, physical examination, vital signs, clinical laboratory tests, ophthalmic examination, and 
ECGs.  The nature of any conditions present at the time of the physical examination and any 
preexisting conditions will be documented.
A generic screening informed consent may be used for screening procedures. Screening may 
occur up to 28 days prior to enrollment.  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.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination.
[1a] male subjects must agree to use an effective method of birth control 
during the study and for 3 months following the last dose of the 
investigational product. At least 1 effective method of contraception will 
be used (eg, condoms with spermicide, male sterilization, oral 
contraceptive pill, intrauterine device, 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 (ie, condom with spermicide, diaphragm with spermicide, 
female condom with spermicide).  However, 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.
[1b] female subjects are of nonchildbearing potential if they have undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy or tubal 
ligation) or are postmenopausal (defined as women aged at least 45 years 
with an intact uterus, who have not taken hormones or oral 
contraceptives for >1 year), and have either:
[i]
spontaneous amenorrhea for 6 to 12 months, not induced by a 
medical condition such as anorexia nervosa and not taking 
medications that induced the amenorrhea (eg, oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, 
selective estrogen receptor modulators, or chemotherapy);
[ii]
a follicle-stimulating hormone level >40 mIU/mL


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[2]
are aged at least 20 years at the time of screening 
[3]
have a body mass index (BMI) between 18.0 kg/m
2 and 32.0 kg/m2, inclusive
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations (with the 
exception of liver tests, which must be below the upper limit of normal
[ULN]) that are judged to be not clinically significant by the investigator
[5]
have venous access sufficient to allow for blood sampling as per the protocol
[6]
are reliable and willing to make themselves available for the duration of the
study and are willing to follow study procedures and research unit policies
[7]
have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, or biological or 
legal guardian, child, or sibling
[9]
are Lilly employees or employees of Parexel
[10] are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study
[11] have participated, within the last 30 days, in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed
[12] have previously completed or withdrawn from this study or any other study 
investigating LY3323795, and have previously received the investigational 
product
[13] have known allergies to LY3323795, related compounds, or any components 
of the formulation, itraconazole (if the subject is assigned to Part C), or 
history of significant atopy
[14] have a QTc (using Bazett’s formula) interval value of >450 msec (males) or 
>470 msec (females) or any abnormality in the 12-lead ECG that, in the 
opinion of the investigator, increases the risks associated with participating in 
the study
[15] have clinically significant abnormal blood pressure as determined by the 
investigator


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[16] 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 investigational product; or of interfering 
with the interpretation of data
[17] have known or ongoing psychiatric disorders, or active neuropsychiatric 
disease deemed clinically significant in the opinion of the investigator
[18] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening
[19] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[20] show evidence of hepatitis C and/or positive hepatitis C antibody 
[21] show evidence of hepatitis B and/or positive hepatitis B surface antigen 
[22] are women who are lactating
[23] have used or intend to use over-the-counter or prescription medication 
(including herbal medications) within 14 days prior to dosing or during the 
study, with the exception of vitamins and mineral supplements (not providing 
>100% of the recommended dietary allowance [RDA]), occasional 
paracetamol/acetaminophen up to 2-g dose in a 24-hour period, and/or 
hormone replacement therapy or thyroid replacement therapy.  If this situation 
arises, inclusion of an otherwise suitable subject may be at the discretion of 
the sponsor
[24] have donated blood >500 mL within the last month
[25] have an average weekly alcohol intake that exceeds 3 units per day or 21 units 
per week (males up to age 65 years) and 14 units per week (females, and 
males older than 65 years), or are unwilling to stop alcohol consumption 48 
hours prior to dosing until the completion of each study period (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)
[26] 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); have prior electroencephalogram with epileptiform 
activity; or surgery to the cerebral cortex
[27] have a history of clinically significant stroke that is deemed to be a risk to 
subject participation in the study, in the opinion of the investigator
[28] have a history of, or current, significant ophthalmic disease in the opinion of 
the investigator


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[29] are unwilling or unable to refrain from eating any food or drinking any 
beverage containing grapefruit or grapefruit juice (or other restricted foods as 
listed in Section 6.3.1) for at least 2 weeks prior to first dose until completion 
of the study
[30] consume more than 10 cigarettes per day or unable/unwilling to abide by CRU 
smoking restrictions before and during admissions
[31] in the opinion of the investigator and/or sponsor, are unsuitable for inclusion 
in the study
In addition, for Part B only:
[32] show clinically significant abnormalities in lumbar spine previously known or 
determined by screening lumbar x-ray (if conducted) that are considered
incompatible with LP by the investigator and/or the person conducting the LP 
(if not the investigator)
[33] have a history of clinically significant back pain, back pathology, and/or back 
injury (eg, degenerative disease, spinal deformity, or spinal surgery) that may 
predispose to complications or technical difficulty with LP
[34] have evidence or history of significant active bleeding or coagulation disorder 
or have taken nonsteroidal anti-inflammatory drugs or other drugs that affect 
coagulation or platelet function within 14 days prior to lumbar catheter 
insertion
[35] have an allergy to lidocaine (Xylocaine®) or its derivatives
[36] have medical or surgical conditions in which LP/lumbar catheterization is 
contraindicated
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Meals and Dietary Restrictions
Fasting – For all parts of the study, subjects will be required to fast overnight (at least 8 hours) 
prior to each dosing day and for at least 4 hours after LY3323795 or placebo dosing, with the 
exception of water that will be freely available before and after dosing.  However, no water is 
allowed 1 hour prior to ECG measurement.
For Part C, there will be no fasting required before or after dosing itraconazole alone. However, 
for coadministration of itraconazole with LY3323795, subjects will be required to fast overnight 
(at least 8 hours) prior to and for at least 4 hours after LY3323795 dosing.
Grapefruit – Subjects should refrain from eating any food or drinking any beverage containing 
grapefruit, pomelo, star fruit, Seville oranges, or juice from any of these fruits, from 2 weeks 
prior to dosing until completion of the study.


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Hydration – Subjects should be adequately hydrated throughout the study.  Therefore, subjects 
should be encouraged to drink several glasses of water each day.
6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine – Consumption of caffeine- and xanthine-containing products is allowed, provided that 
the subject’s consumption has been consistent for the last 30 days, and will remain consistent 
throughout the duration of the study.
Alcohol – Subjects will not be permitted to consume alcohol from 48 hours prior to CRU 
admissions until after the last PK sample is collected for each study period.  During outpatient 
periods, male subjects should be advised to limit alcohol consumption to no more than 21 units 
per week and female subjects to no more than 14 units per week, and all subjects should be 
advised to limit alcohol consumption to no more than 3 units in a day.
Tobacco – Subjects will not be permitted to smoke from 24 hours before visiting the CRU until 
discharge from the CRU.
6.3.3. Activity/Other Requirements
Subjects should avoid strenuous physical activity 48 hours prior to CRU visit and until final 
discharge from the study.
Subjects should avoid exposure to the sun, and not use sun lamps or tanning beds throughout the 
duration of the study.  High-factor sunscreen should be used if prolonged sun exposure is 
unavoidable.
Blood or plasma donations are not permitted while participating in the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
allowed to rescreen.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of LY3323795 and placebo over a planned dose range of 0.3 
mg to 100 mg in Parts A and B, and administration of LY3323795 alone and with itraconazole in 
Part C.  Table SCAA.3 shows the treatment regimens.
After an overnight fast (see Section 6.3.1), capsules of LY3323795 or placebo will be 
administered orally with approximately 240 mL of room-temperature water in the morning of 
each dosing day.
For Part A, subjects should remain upright (standing or sitting) for at least 4 hours after dosing, 
with the exception of any requirements for protocol procedures (eg, supine for ECGs).  For 
Part B, subjects will be encouraged to remain supine for the entire lumbar catheterization period.
In Part C, itraconazole will be administered as an oral solution with extra water if subjects prefer. 
No fast is required before or after dosing with itraconazole alone.
To ensure blinding is maintained in each cohort in Parts A and B, subjects assigned to 
LY3323795 and those assigned to placebo will receive the same number of capsules. In Part A,
the number of capsules between periods may vary based on dose-escalation decisions, but within 
a period, all subjects will receive the same number of capsules.
Table SCAA.3.
Treatments Administered
Treatment Name
LY3323795
Placebo
Itraconazole
Dosage Formulation
0.3-, 1-, and 10-mg capsules
Capsules to match
10 mg/mL solution
Planned Dosage 
Levels
0.3, 1, 3, 10, 30, and 100 
mg
-
200 mg
Route of 
Administration
Oral
Oral
Oral
The investigator’s designee is responsible for:

explaining the correct use of the investigational product(s) to the site personnel,

verifying that instructions are followed properly,

maintaining accurate records of investigational product dispensing and collection,

returning all unused medications to Lilly or its designee at the end of the study.


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In some cases, sites may destroy the material if, during the investigativesite selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.Subjects will be instructed to contact the 
investigator as soon as possible if he or she hasacomplaint or problem with the investigational 
product so that the situation can be assessed.  All clinical trial materialsprovided to the 
investigator will be stored in a secure place andallocated and dispensed by appropriately trained 
persons.The allocation and dispensing of theinvestigational products will be fully documented 
and verified by a second person. Detailedrecords of the amounts of the investigational product 
received, dispensed, and remaining at theend of the study will be maintained.
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled according to the country’s regulatory requirements.  Each 
capsule of LY3323795will be size 2, blue in color and will contain 0.3mg, 1mg,or 10 mg of 
active ingredient.  Placebo capsules will match LY3323795capsules in appearance.  LY3323795
and matching placebo capsules will be supplied to the investigator by Lilly for dispensing by 
unblinded pharmacy staff.
Clinical trial materials will be manufactured in accordance with good manufacturing practice. 
All drug supplies will be labeled according to applicable local regulatory requirements.
7.2.
Method of Treatment Assignment
Randomization tables for allocation of LY3323795and placebo will be prepared by the Lilly 
statistician.
7.2.1. Selection and Timing of Doses
Doses of LY3323795 will be administered at approximately the same time on each day.  The 
actual time of all dose administrations will be recorded in thesubject’scase report form (CRF).  
For LY3323795or placebo dosing, the dosing time is defined as the time when the first capsule 
is swallowed.
7.3.
Blinding
CCI
This study will be subject-and investigator-blindedexcept in Part C(itraconazole interaction), 
which will be open-label. 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. The randomization tables will be provided to the study site pharmacists or pharmacy 
staff involved in dose preparation.
As dosing occurs in the study, the pharmacy staff will document dosing at the site using an 
accountability log. Individuals involved with study drug preparation will not be involved in any 
clinical aspects of the study,including study drug administration and AE assessments. The 
sponsor team will not be blinded and may see the randomization tables and/or treatment table 
before the end of the study but this will be kept to a minimum. While the study blind is in effect, 


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individuals with access to the randomization tables and/or treatment table will not share the 
identifying information with investigative site staff involved with direct subject care or safety 
assessments. An exception is if sharing such information is required for emergency unblinding.
AEs and clinical safety abnormalities will be interpreted with the subject- and investigator-blind 
intact, on the assumption that active study drug was administered. If the AE is a clinically 
significant event (CSE), the investigator should judge whether the CSE is related to study drug 
administration while remaining blinded. 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.
Emergency codes will be available to the investigator. A code, which reveals the treatment 
group for a specific study subject, may be opened during the study only if the subject’s well-
being requires knowledge of his/her treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  Subject’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’s treatment assignment unless this could delay emergency treatment of the subject.  If a 
study subject’s treatment assignment is unblinded, Lilly must be notified immediately.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist or 
CRP for the study participant to continue in the study.
Upon completion of the study, all emergency codes must be returned to Lilly or its designee.
A detailed blinding/unblinding plan will be issued to the study site.
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 (that is lower than the MTD) 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.  As described in Sections 5.1.1.1
and 5.1.2.1, certain dose-escalation decisions will also be based on PK (Cmax, AUC, and 
clearance) data where available. No dose escalation can occur without prior discussion and 
agreement between the investigator and the Lilly clinical pharmacologist/CRP/study team.
Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator, and will be considered related to the investigational 
product unless there is clear evidence that the event is not related. See Section 10.3.1 for details.


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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 3.3 
times the original dose (a half-log increment).
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be discontinued:
1) a single subject experiences an SAE that is considered related to LY3323795
administration;
2) ≥2 subjects at the same dose level experience moderate or severe AEs that impair 
normal activities, and are considered related to LY3323795, but do not meet the 
CSE criteria;
3) ≥2 subjects at the same dose level experience similar CSEs considered related to 
LY3323795;
4) ≥2 subjects at the same dose level have an ophthalmic finding considered related 
to LY3323795;
5) ≥2 subjects, at any dose of LY3323795, have a QTc reading (mean of 3) that is
>500 msec or an increase of >60 msec above the mean QTc control value for at 
least 2 consecutive time points.  The mean QTc control value (mean of 3) is 
defined as the average of the Day 1, predose ECGs of the corresponding period.
Dosing may continue, if deemed appropriate by the investigator and sponsor, at doses lower than 
those that resulted in the dose escalation being stopped.
In the event of an SAE that is related to study drug, precautionary inpatient observation will be 
implemented, and dosing may be suspended. Dosing of a subject may resume only after the 
investigator and sponsor agree that it is appropriate to continue.
7.5.
Preparation/Handling/Storage/Accountability
Only participants enrolled in the study may receive investigational product 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 
accountable for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The investigational product, itraconazole, and placebo will be administered at the clinical site, 
and documentation of treatment administration will occur at the site.


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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 hormone 
replacement, and/or estrogen hormone replacement is allowed.  Occasional use of 
paracetamol/acetaminophen up to 2 g in a 24-period without prior consultation with a Lilly 
clinical pharmacologist will be allowed.  Drugs that are known substrates, inducers, or inhibitors 
of CYP3A are specifically excluded.  Additional drugs are to be avoided during the study unless 
required to treat an AE or for the treatment of an ongoing medical problem.
If the need for concomitant medication arises, inclusion or continuation of the subject 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 in the CRF.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Subjects who discontinue the investigational product early will have procedures performed as 
shown in the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject 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 subject 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 subject to continue in the study with or 
without continued treatment with investigational product.
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical trial involving an investigational product 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

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study

Subject Decision
o
the subject requests to be withdrawn from the study
Subjects who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
8.3.
Subjects Lost to Follow-up
A subject 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 subject who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 3 details the study governance, regulatory and ethical considerations.
Appendix 4 details the hepatic monitoring tests for treatment-emergent abnormalities.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects 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.
The investigator is responsible for the appropriate medical care of subjects 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 investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject 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 informed consent form is signed, study site personnel will record, via CRF, the 
occurrence and nature of each subject’s preexisting conditions.  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 
investigational product, study device, and/or study procedure and the AE.


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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 investigational product 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 1 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 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 investigational product) 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 Code of Federal Regulations 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.


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9.2.2. Complaint Handling
Lilly collects product complaints on investigational products 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 should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3323795 is considered any dose higher than the 
dose assigned through randomization.  General supportive medical management will be provided 
at the investigator’s discretion. 
Refer to the IB for LY3323795 for information on the clinical consequences of an overdose.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
9.4.2. Vital Signs
Vital signs will comprise blood pressure, pulse rate, and body temperature. 
For each subject, vital sign measurements should be performed according to the Schedule of 
Activities (Section 2). The timing of vital sign collections may be adjusted after a review of the 
PK data.
At screening, blood pressure and pulse rate will be obtained after subjects have been sitting for at 
least 5 minutes.
For vital signs after study entry, subjects will lie down for at least 5 minutes and undergo supine 
blood pressure and pulse rate measurements.  For Parts A and C only, subjects will then sit for 
approximately 2 minutes and stand for approximately 3 minutes and undergo standing blood 
pressure and pulse rate measurements.  If subjects are unable to stand, only supine vital signs 
will be recorded.  If subjects are unable to stand or sit, omission of the standing or sitting vital 
signs will not be considered a protocol violation.
Subjects who are unable to sit or stand for approximately 3 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.


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9.4.3. Electrocardiograms
For each subject, 12-lead ECGs will be obtained according to the Schedule of Activities (Section
2).  ECGs must be recorded before collecting any blood for safety or PK tests.  Subjects must be 
supine for at least 5 minutes before ECG collection and remain supine but awake during ECG 
collection.
ECGs 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 ECGs 
recorded should be stored at the investigational site. The timing of the ECG collections may be 
adjusted after a review of the PK data.
At screening and final discharge/early discontinuation, 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 meets entry criteria.
For the predose ECG measurement of each period in Parts A and C (but not Part B), 3 sets of 
triplicate ECGs will be obtained approximately 10 minutes apart.  For Part B, predose ECG 
measurements will be single.
For Parts A and C, after study entry, ECGs will be obtained in triplicate at approximately 1-
minute intervals at each ECG time point.  At least 1 ECG in each triplicate set will be interpreted 
by the investigator or qualified designee at the site as soon as possible after the time of ECG 
collection, and ideally while the subject is still present, for immediate subject management.
For Part B, at each time point, a single ECG will be collected and subsequently interpreted by the 
investigator or qualified designee in the same way as above.
If at any time a clinically significant increase in the QTc interval is present or the ECG shows a 
clinically important change, then the investigator should assess if the subject can continue in the 
study.  Any clinically significant findings that result in a diagnosis should be recorded on 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 obtained at appropriate intervals until readings return to within normal levels.  In 
addition, a 12-lead Holter recording may be initiated in an individual subject with a clinically
significant ECG abnormality. In these cases, digital recordings of continuous ECG recordings 
will be transferred to a central ECG laboratory designated by Lilly. The ECG laboratory will 
perform quality control checks for the time points of interest (eg, acquisition quality for ability to 
measure/interpret demographics and study details). The ECG laboratory will then store the 
recording and a cardiologist at the central ECG laboratory may conduct a full over-read on 
extracted ECG time points of interest. No reports will be issued from the central ECG laboratory 
back to the sites for any ECGs. All data from the ECG over-reads and measured intervals will be 
placed in a Lilly database for analytical and study report purposes. Any new clinically relevant 
finding should be reported as an AE.
The ECGs will subsequently be electronically transmitted to the centralized ECG vendor 
designated by Lilly for storage.  The automated ECG parameters will be used for data analysis 


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and report-writing purposes.  ECGs may be overread by a medically qualified professional 
(eg, cardiologist) to assess clinically significant findings on the automated ECG readings, should 
these occur.
9.4.4. Other Tests
9.4.4.1.
Neurological Survey
A directed neurological survey will be performed by a physician, nurse practitioner, or 
physician’s assistant according to the Schedule of Activities (Section 2).  If abnormalities are 
noted, additional examinations should be performed at daily intervals until the subject’s test 
scores have returned to baseline levels.  The examiner should be familiar with the subject’s 
baseline survey and may examine the subject prior to dosing as needed.  Mandated elements of 
the survey include inspection for tremor, extraocular movements, brachial and patellar deep 
tendon reflexes, finger-nose pointing, and Romberg sign.
Table SCAA.4 presents how the findings of the neurological survey will be scored.  For subjects 
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 with
baseline.  Other elements of the physical examination may be included on an optional or 
symptom-directed basis.
Table SCAA.4.
Scoring of Neurological Surveys
Score
0
1
2
3
4
Tremor, nonspecific 
location
Absent
Visible with limb 
extension and/or 
careful inspection
Visible without
limb extension
Interferes with 
motor function
Nystagmus, nonspecific 
location
Absent
1-3 beats on lateral 
gaze
>3 beats on lateral 
gaze
Present on forward 
gaze
Reflex test, nonspecific 
location
Absent
Trace
Normal
Increased
Clonic
Finger-nose
Normal
Abnormal
Romberg sign
Absent
Present
9.4.4.2. Ophthalmic Examinations
Ophthalmic assessments will be performed or supervised by a board-certified ophthalmologist or 
optometrist as specified in the Schedule of Activities (see Section 2) and/or as clinically 
indicated.
Eye testing will include distance and near visual acuity (best-corrected or pinhole using the 
Snellen chart and Near Reading Card), Humphrey visual field testing (using the 10-2 protocol 
with a red-on-white target), and ophthalmoscopy.
Only subjects who pass all other inclusion/exclusion criteria at screening should be sent for these 
eye examinations.  Results from subsequent eye tests during the study will be compared with the
screening results to track any changes in subjects’ vision.


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9.4.5. Safety Monitoring
The Lilly clinical pharmacologist 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 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

product complaints
9.4.5.1.
Hepatic Safety Monitoring
If a study subject experiences elevated ALT ≥3X ULN, alkaline phosphatase ≥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 safety and compliance with regulatory 
guidance, the investigator is to consult with the Lilly designated CRP/clinical pharmacologist
regarding collection of specific recommended clinical information and follow-up laboratory 
tests.
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 performed by the personnel 
included in the Unblinding/Blinding Plan.
9.5.
Pharmacokinetics
In Parts A and B, at the visits and times specified in the Schedule of Activities (Section 2), 
venous blood samples will be collected to determine the plasma concentrations of LY3323795.  
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.  For subjects participating 
in the itraconazole interaction (Part C), on the day of LY3323795 and itraconazole 
coadministration (Day 16), venous blood samples will be collected for measurement of 
itraconazole and its metabolites at the times specified in the Schedule of Activities for Part C. 
LY3323795 PK samples will also be drawn on Day 1 and on the day of coadministration (Day 
16).  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.
For Part B, CSF samples will be collected at the times specified in the applicable Schedule of 
Activities (Section 2) to determine the CSF LY3323795 and PD biomarker concentrations.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
In Part A, urine samples will be collected for the characterization of renal clearance.  Total urine 
output for 48 hours post investigational product administration will be collected, pooled, and 


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refrigerated.  The final urine sample will be collected at a time that coincides with a PKsample.  
At the end of the collection period, the total urine volume will be recorded.  Urine samples will 
be used to determine creatinine, quantification of LY3323795, and possible exploratory 
metabolite identification.
At the visits and times specified in the Schedule of Activities, venous blood samples will be 
collected to determine serum creatinine measurements. 
See Appendix 5for blood and CSF sampling details.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3323795in plasma and in CSF will be assayed using validated liquid 
chromatography with tandem mass spectrometry (LC/MS/MS) methods.  Plasma concentrations 
of itraconazolewill be assayed using LC/MS/MS methods.  If appropriate, plasma concentrations 
of itraconazole metabolites may also be quantified.  Analyses of samples collected from subjects 
who are given placebo are not planned.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses (eg,metabolism, 
protein binding).
9.6.
Pharmacodynamics
At the visits and times specified in the Scheduleof Activities(Section2), venous blood samples 
will be collected for measurement of plasma Aβ concentrations.
A maximum of 5 additional plasma samples per subject may be drawn during the study at the 
discretion of the investigator or sponsor.  These additional samples may be drawn to measure 
LY3323795or Aβ concentrations.
Plasma concentrations of Aβ1-40and Aβ1-42and CSF concentrations of Aβ1-40, Aβ
1-42CCI
,
 
will be determined using validated immunoassay methods.
.
Plasma and CSF samples collected for PD measurements will have aliquots stored for future 
exploratory work.The sample(s) will beidentified by the subject number (coded) andstored for 
upto a maximum of 15yearsafter the lastsubjectvisit for the study at a facility selected by the 
sponsor.  Any sample remaining after this period will be destroyed.  Research will be limited to 
investigation of the safety and disposition of LY3323795, PD biomarkers relevant to 
neurological disease, the mechanism of action of LY3323795, and/or identification of 
metabolites of LY3323795.
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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 used to investigate variable response to LY3323795. 
Assessment of variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs/institutional review boards [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 LY3323795 or after LY3323795 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, RNA, proteins, lipids, 
and other cellular elements.
Plasma and CSF samples for nonpharmacogenetic 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, variable response to LY3323795, pathways 
associated with AD and/or other neurological diseases, mechanism of action of LY3323795, 
and/or research method, or for validating diagnostic and research analytes, tools, or assay(s) 
related to AD and/or other neurological diseases.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel. 
Samples will be retained for a maximum of 15 years after the last subject 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 


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regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3323795 or after LY3323795 is commercially available.
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1.
Sample Size Determination
The sample size of 9 in each cohort of Part A is customary for Phase 1 studies evaluating safety,
PK, and/or PD parameters, and is not based on statistical mean estimation.
For Part B, given the CSF Aβ variability observed in prior studies that measured CSF Aβ, the 
sample size of 5 subjects per LY3323795 dose and 2 subjects per placebo in a parallel cohort, 
pooled placebo design is sufficient to detect a mean Aβ reduction of approximately 21% or more 
from baseline. Assuming a standard deviation of 22% for the CSF Aβ1-40, a sample size of 5 
subjects per dose would provide approximately 90% coverage probability that the half-width of 
the 80% CI for the mean of percentage change from baseline of CSF Aβ1-40 would be within 
21%. For example, if the estimate of the percentage change from baseline CSF Aβ1-40 at nadir 
concentration (Cnadir) is 50%, then the confidence limit for the percentage change from baseline 
would be (29%, 71%). 
For Part C, assuming a within-subject variability of 25% for the PK parameter (AUC or Cmax) of 
LY3323795, a sample size of 8 subjects would provide approximately 90% coverage probability 
that the half-width of the 90% CI for the geometric mean ratio of LY3323795 with itraconazole,
compared with LY3323795 alone, would be within 0.3 in log scale, or 1.35 in natural scale. For 
example, if the estimate of the ratio of LY3323795 with itraconazole over LY3323795 alone is 
1.2, then the confidence limit would be (88%, 162%).
Subjects who drop out may be replaced at the discretion of the sponsor and investigator to
achieve protocol-required completers. In Part A, a replacement subject’s treatment assignment
will follow that of the subject being replaced but may not require completion of all study periods.
In Part B, a replacement subject’s treatment assignment will follow that of the subject being 
replaced.  In Part C, all subjects, and any replacements, will be on the same treatment 
assignment.
Subjects who are randomized but not administered treatment may be replaced to ensure that a 
sufficient number of subjects complete the study, in accordance with the enrollment numbers 
given in Section 5.2.
10.2.
Populations for Analyses
10.2.1. Study Participant Disposition
All 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 
recorded.
A detailed description of subject disposition will be provided at the end of the study.


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10.2.2. Study Participant Characteristics
The subject’s age, sex, race, weight, BMI, height, smoking habits, or other demographic 
characteristics will be recorded and may be used in the PK, PD, and safety analyses as 
quantitative or classification variables.
10.3.
Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
PK/PD analyses will be performed on the full analysis set.  This set includes all data from all 
randomized subjects receiving at least 1 dose of the investigational product according to the 
treatment the subjects actually received.  Safety analyses will be performed for all enrolled
subjects, whether or not they completed all protocol requirements.
Additional exploratory analyses of the data will be performed as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post hoc analyses and incomplete disclosures of analyses.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to study entry 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 investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, CNS monitoring, 
eye assessments, vital signs, and ECG parameters. The parameters will be listed and 
summarized using standard descriptive statistics. Additional analyses will be performed if 
warranted upon review of the data. The statistical analysis plan will contain all details on the 
evaluation of safety measurements.
Analysis of QTc data from ECG monitoring in a Phase 1 trial is performed to judge the extent 
and/or risk of QT prolongation. A scatter plot will be generated to explore the relationship 
between QTc and drug exposure, and will assess the mean change in QTc using Fridericia’s 
formula as a function of plasma drug concentration. The QTc analysis will not include ECGs 
collected in Part C (itraconazole interaction), due to the potential for non-LY3323795-induced 
changes in QTc.


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Frequency tables of QTc changes from baseline and large QTc values may also be obtained in 
accordance with International Conference on Harmonisation guidance, and additional analyses 
may be conducted if required.
For each method of eye assessment, change from baseline (yes/no) and change from baseline 
clinically significant (yes/no) will be listed, and if there are sufficient changes they will be 
summarized by treatment group and compared with Fisher’s exact test.
Additional analyses may be performed for the purpose of fulfilling the Clinical Trial Registry 
requirements.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
PK parameter estimates for LY3323795 will be calculated using standard noncompartmental 
methods of analysis.
The primary parameters for analysis will be Cmax and AUC of LY3323795.  Other 
noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of 
distribution, may be reported.
Renal clearance of LY3323795 will be calculated as the ratio of amount excreted/AUC.  This
will be compared to the unbound glomerular filtration rate, which is estimated using creatinine
levels.
In Part C, PK parameter estimates for itraconazole samples collected on Day 16 will be 
calculated using standard noncompartmental methods of analysis. Cmax and AUC will be 
reported. Itraconazole concentrations collected as part of this study may be analyzed along with 
data collected in other studies as part of a larger assessment of itraconazole PK. If such an 
analysis is performed, the results of the analysis will be reported separately from the final report 
for this study.  Concentrations of itraconazole metabolites may be characterized on an 
exploratory basis.
10.3.2.2. Pharmacokinetic Statistical Inference
In Part C, the AUC(0-∞) and Cmax for LY3323795 administered alone and in the presence of
itraconazole will be compared using an analysis of variance (ANOVA) model. The parameters 
will be log-transformed prior to analysis. The model includes a fixed effect for the treatment and 
a random effect for subject. The following model will be built: ln(PK parameter) = treatment + 
subject + random error where treatment is a fixed effect with 2 levels: LY3323795 alone 
(reference) and LY3323795 with itraconazole (test).
The least square means for each treatment and the 90% CI for the difference in means will be
estimated from the ANOVA model and back-transformed from the log scale to provide estimates 
of the geometric means and 90% CIs for the ratio of the geometric means of LY3323795 + 
itraconazole versus LY3323795 alone.


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The time to Cmax(t
max) parameter will be analyzed using theWilcoxon-signed rank test. Median
differences and 90% CIs for the difference between LY3323795+itraconazole (test) and 
LY3323795 alone (reference) will be calculated.
10.3.3.Pharmacodynamic Analyses
10.3.3.1.PharmacodynamicParameter Estimation 
In Parts A and B, plasma concentrations of Aβ1-40and Aβ1-42will be summarized for each dose 
group based on the Cnadirand the time to reach Cnadir(t
nadir). 
In Part B, CSF concentrations of Aβ1-40, Aβ1-42, and  
 will be summarized for each dose 
group based on the Cnadir, t
nadir, and the 24-hour average values, expressed as a percentage change 
from baseline. 
 
Other parameters may 
be calculated, as appropriate.
10.3.3.2.Pharmacodynamic Statistical Inference
For Part B of this protocol, statistical analysis of CSF Aβ1-40and Aβ
1-42concentrations obtained 
over the fixed-scheduled sampling period will be analyzed using a repeated-measures analysis 
with the primary statistical inference of pairwise comparison of the overall mean difference 
among the LY3323795 doses and placebo using a90% CI.The statistical model may include the 
baseline CSF Aβ1-40and Aβ
1-42concentrations obtained during predose CSF collection period 
and fixed effects of dose groups (placebo and doses of LY3323795), scheduled CSF sampling 
time, and the interaction between dose groups and sampling times. A compound symmetric 
covariance structure may be used. From the statistical model, the primary statistical estimates 
will be the meanpercentagereduction from baseline in CSF Aβ1-40and Aβ
1-42concentrationsat 
each timepointwith LY3323795 over the 36-hour sampling interval. The above model will fit 
both the log-transformed and percentagechange from baseline in CSF Aβ1-40and Aβ
1-42
concentrations.
10.3.4.Pharmacokinetic/Pharmacodynamic Analyses
It is intended that a compartmental modeling approach will be used to describe the plasma and 
CSF PK and CSF PD of LY3323795.  Compartmental modeling will be performed using 
nonlinear mixed-effects modeling.  Although it is not intended that the model will assess the 
impact of patient-specific factors (such as age, body weight, or race/subrace) on LY3323795 PK, 
these may be included if appropriate.  Modeling may be performed sequentially by first 
modeling plasma PK and then fixing the values from that model when developing a model to 
describe CSF PK.  It is intended that an indirectresponse model will be used to characterize the 
PD effect of LY3323795 on CSF Aβ1-40formation, with PK parameters fixed to those values 
determined in previous steps.  Other PD endpoints (eg, Aβ1-42
CCI
) may be modeled, if warranted.  
CCI
CCI


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Other modeling approaches or graphical analyses may be used, as deemed appropriate.  The 
results of this modeling may not necessarily be included in the final study report.
10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.
Safety and/or PK IAD reviews are scheduled to occur throughout the study. The purpose of 
these IAD reviews is to examine the safety data and guide dose selections. 
In Part A, the investigator and the Lilly clinical pharmacologist/CRP/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 (Section 5.1.1).
In Part B, dose selection will be based on PK/PD data as described in Section 5.1.2.  
The investigator will remain blinded and the Lilly clinical pharmacologist/CRP/study team will 
be unblinded during these IAD reviews. 
The specifics about the timing of the IAD reviews and the procedures for selecting doses are 
described in the study design section of the protocol (Section 5).
Additional IAD reviews may be conducted at any time throughout the study as required to ensure
subjects’ safety or to help guide dosing. An assessment committee will not be formed.


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11.
References
Bateman RJ. Aβ turnover in human subjects. Alzheimer’s Dement. 2008;4(suppl 
1,4):T123-T124.
Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, Vassar R. Expression 
analysis of BACE2 in brain and peripheral tissues. J Biol Chem. 2000;275(27):20647-20651.
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, 
Thomas RG, Aisen PS; Alzheimer’s Disease Cooperative Study Steering Committee, 
Siemers E, Sethuraman G, Mohs R; Semagacestat Study Group. A phase 3 trial of 
semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369(4):341-350.
[EMEA] European Medicines Agency, Committee for Medicinal Products for Human Use 
(CHMP). Guideline on strategies to identify and mitigate risks for first-in-human clinical trials 
with investigational medicinal products. July 2007; London, UK. 
Ereshefsky L, Jhee SS, Leibowitz MT, Moran S, Yen M, Gertsik L. Demonstrating proof-of-
principle and finding the right dose: the role of CSF dynabridge studies. In: CPNP Annual 
Meeting; April 2007; Colorado Springs, CO.
Esterházy D, Stützer I, Wang H, Rechsteiner MP, Beauchamp J, Döbeli H, Hilpert H, Matile H, 
Prummer M, Schmidt A, Lieske N, Boehm B, Marselli L, Bosco D, Kerr-Conte J, Aebersold 
R, Spinas GA, Moch H, Migliorini C, Stoffel M. BACE2 is a β cell-enriched protease that 
regulates pancreatic β cell function and mass. Cell Metab. 2011;14(3):365-377.
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.
Ke AB, Zamek-Gliszczynski MJ, Higgins JW, Hall SD. Itraconazole and clarithromycin as 
ketoconazole alternatives for clinical CYP3A inhibition studies. Clin Pharmacol Ther.
2014;95(5):473-476.
Lucey BP, Gonzales C, Das U, Li J, Siemers ER, Slemmon JR, Bateman RJ, Huang Y, Fox GB, 
Claasen J, Slats D, Verbeek MM, Tong G, Soares H, Savage MJ, Kennedy M, Forman M, 
Sjögren M, Margolin R, Chen X, Farlow MR, Dean RA, Waring JF. An integrated multi-study 
analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected 
by lumbar puncture and indwelling lumbar catheter. Alzheimers Res Ther. 2015;7(1):53.
Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, Marks MS, De Strooper B, Raposo 
G, van Niel G. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment 
cells. Proc Natl Acad Sci USA. 2013;110(26):10658-10663.


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Turner PR, O’Connor K, Tate WP, Abraham WC. Roles of amyloid precursor protein and its 
fragments in regulating neural activity, plasticity and memory. Prog Neurobiol.
2003;70(1):1-32.
Vasser R. BACE1: the beta-secretase enzyme in Alzheimer’s disease. J Mol Neuroscience. 
2004;23(1-2):105-114.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
Aβ
-amyloid
AD
Alzheimer’s disease
AE
adverse event:  Any untoward medical occurrence in a subject 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.
ALT
alanine aminotransferase
ANOVA
analysis of variance
APP
amyloid precursor protein
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
AUC(0-∞)
area under the curve from time 0 extrapolated to infinity
BACE
β-site APP-cleaving enzyme
blinding
A procedure in which 1 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 is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not. A double-blind study is one in 
which neither the subject 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
CI
confidence interval
Cmax
maximum drug concentration
Cnadir
nadir 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.


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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
CYP
cytochrome P450
ECG
electrocardiogram
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are those 
who have been assigned to a treatment.
enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GLP
good laboratory practice
HIV
human immunodeficiency virus
IAD
interim access to data
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
informed consent
A process by which a subject 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 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.


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Investigational 
New Drug
An application to the FDA to allow testing of a new drug in humans.
investigational 
product
Apharmaceutical 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.
IRB
institutional review board
LC/MS/MS
liquid chromatography with tandem mass spectrometry 
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospectivesubject, to thesubject’s participation in the clinical trial.
LP
lumbar puncture
MTD
maximum tolerated dose
NOAEL
no-observed-adverse-effect level
non-
investigational 
product
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.
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PK/PD
pharmacokinetic(s)/pharmacodynamic(s)
QTc
QT correctedfor heart rate
RDA
recommended dietary allowance
SAE
serious adverse event
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.  
SUSAR
suspected unexpected serious adverse reaction
t
max
time to C
max
CCI
CCI


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tnadir
time to reach Cnadir
treatment-
emergent adverse 
event
Any untoward medical occurrence that emerges during a defined treatment period, having 
been absent pretreatment, or worsens relative to the pretreatment state, and does not 
necessarily have to have a causal relationship with this treatment 
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematologya
Clinical chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC)
Magnesium
Cell morphology
Glucose [random]
[Absolute counts of]:
Blood urea nitrogen
Neutrophils
Uric acid
Lymphocytes
Total cholesterol
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase
Aspartate aminotransferase
Urinalysisa
Alanine aminotransferase
Specific gravity
Creatinine
pH
Gamma-glutamyl transferase
Protein
Glucose
Ketones
Ethanol testingb,c
Bilirubin
Urine drug screenb,c
Urobilinogen
Hepatitis B surface antigenb
Blood
Hepatitis C antibodyb
Nitrite
HIVb
Pregnancy testd (if applicable)
FSHb
Coagulation (Part B only):
Prothrombin time
International normalized ratio
Partial thromboplastin time
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
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 at screening to confirm postmenopausal status.
c
Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit.
d
At investigator’s discretion.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the potential risks and benefits of participating in 
the study.

ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) prior to the performance of any protocol procedures and prior to the administration 
of investigational product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the trial.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Conference on Harmonization (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).  The ERB(s) will review the protocol as required.
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure (IB) and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH good clinical practice (GCP) Guidelines 
3) applicable laws and regulations


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Some of the obligations of the sponsor will be assigned to a third-party organization.
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 data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.


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Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, 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.


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Appendix 4. Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee clinical research 
physician.
Hepatic Monitoring Tests
Hepatic Hematology
a
Haptoglobin
a
Hemoglobin
Hematocrit
Hepatic Coagulation
a
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistry
a
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibody
a
AST
GGT
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)
a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Covance Central Laboratory Services (CCLS).
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood and CSF Sampling Summary
This table summarizes the approximatenumber of venipunctures and blood volumes forall 
blood sampling (screening, safety laboratories,and bioanalytical assays) during thestudy.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
ProtocolI9F-MC-SCAABlood Sampling Summary(Part A–3Periods)
Purpose
Maximum Blood Volume 
Per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening tests
a
25
1
25
Clinical laboratory tests(central)
a
5
12
60
Clinical laboratory tests(local lab)
12.5
3
37.5
LY3323795plasma PKb
2
45 (+5)
90 (10)
PD plasma samplesb
2
45 (+5)
90 (10)
2
45
90
Blood discard for cannula patency
1
33
33
Pharmacogenetics
10
1
10
Total
435.5 (455.5)
Total for clinical purposes [rounded up to nearest 10 mL] 
440 (460)
Abbreviations:  PD = pharmacodynamics; PK=pharmacokinetics.
a Additional samples may be drawn if needed for safety purposes.
b A maximum of 5 additional plasma samples per subject may be drawn during the study at the discretion of the 
investigator or sponsor.
ProtocolI9F-MC-SCAABlood Sampling Summary(Part B–1 Period)
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening tests
a
25
1
25
Clinical laboratory tests(central)
a
5
4
20
Clinical laboratory tests(local lab)
12.5
1
12.5
LY3323795plasma PKb
2
17(+5)
34(10)
PD plasma samplesb
2
17(+5)
34(10)
Storage plasma samples
2
17
34
Blood discard for cannula patency
1
12
12
Pharmacogenetics
10
1
10
Total
181.5 (201.5)
Total for clinical purposes [rounded up to nearest 10 mL] 
190 (210)
Abbreviations: PD = pharmacodynamics; PK=pharmacokinetics.
a Additional samples may be drawn if needed for safety purposes.
b
CCI
A maximum of 5 additional plasma samples per subject may be drawn during the study at the discretion of the 
investigator or sponsor.


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ProtocolI9F-MC-SCAACSF Sampling Summary(Part B –1 Period)
Purpose
Maximum CSF Volume 
Per Sample (mL)
Maximum Number 
of CSFSamples
Maximum Total 
Volume (mL)
CSF PK 
1
20
20
CSF PDand storage
3
22
66
RBC count(safety sample)
2
2
4
CSF flush
2
22
44
Total
134
Total for clinical purposes [rounded up to nearest 10 mL] 
140
Abbreviations:  CSF= cerebrospinal fluid; PD = pharmacodynamics; PK=pharmacokinetics; RBC = red blood cell.
1
22
22
Pharmacogenetics
10
1
10
Total
196
Total for clinical purposes [rounded up to nearest 10 mL] 
200
CCI
CCI
CCI


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Appendix 6.
Protocol Amendment I9F-MC-SCAA(a)
Summary 
Single-Ascending Dose Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics 
of LY3323795 in Healthy Subjects
Overview
Protocol I9F-MC-SCAA [Single-Ascending Dose Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of LY3323795 in Healthy Subjects] has been 
amended.  The new protocol is indicated by Amendment (a) 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:

Based on feedback received from the US Food and Drug Administration (FDA), the 
optional Dose 7 (Period 4) from Part A has been removed and the protocol has been 
updated to state that exposure must not exceed one tenth the NOAEL exposure 
established in male rats (i.e. median AUC will not exceed 3,450 ng•hour/mL and median 
Cmax will not exceed 214 ng/mL). In addition, for Part A, PK data reviews will be 
conducted before dose escalation from Dose 4 onwards, not Dose 5 onwards.
The following changes have been made based on feedback received from the site and errors 
noted in the original protocol:

For Parts A and B, ethanol and urine drug screens have been moved from Day -1 to 
screening, consistent with the original intent. For Part C, ethanol and urine drug screens 
were removed from the 7-Day Wash-out period. The investigator will discern the need 
for additional ethanol and urine drug screens based on each subject’s presentation on 
readmission to the CRU.

For Part B, the Day 3 ophthalmic examination has been moved to Day 4 to allow for at 
least a 24-hour recovery period following catheter removal.

A CSF safety sample has been added to Part B to reflect the site’s lumbar catheter 
standard operating procedure.

For Part C, additional vital sign measurements have been added to the schedule of 
activities to comply with the CRU standard operating procedures.

For Part C, a clinical laboratory assessment has been inserted on Day 9 prior to study 
drug dosing in Period 2. This is consistent with the original intent.

For Part C, weight measurements have been added to FDC and ED for consistency with 
Parts A and B of the study.


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
For Part B, Dose B1 will be determined by safety data through Part A Dose 4 instead of 
Dose 3 in order to collate additional data in the dose decision.

The capsule size has been corrected from Size 0 to Size 2, consistent with information in 
the IND.

The ECG recording information has been updated to reflect that ECGs will be recorded in 
triplicate for Part C and single in Part B, consistent with the original intent.

Several typographical updates and clarifications have been made to ensure consistency 
and accuracy.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1.
Protocol Synopsis
Summary of Study Design:
Study I9F-MC-SCAA is a Phase 1 study of LY3323795 in healthy subjects that will be conducted in 3 parts.  Part A 
(Doses 1 to 6) will be a subject- and investigator-blind, placebo-controlled, randomized, single-ascending dose, 3-
period, 2-cohort (6:3 subjects, LY3323795:placebo per cohort), dose-escalation study to evaluate safety, tolerability,
and plasma PK/PD of LY3323795.  An optional Period 4 may be implemented to evaluate Dose 7 depending on 
available PK data.  Part B will be a subject- and investigator-blind, placebo-controlled, randomized, single-dose, 3-
cohort (5:2 subjects, LY3323795:placebo per cohort), single-period, lumbar catheter study to evaluate the central 
and plasma PK/PD of LY3323795.  Doses in Part B will not be administered until equal or greater doses have been 
administered in Part A and shown to be well tolerated.  Part C will be an open-label, 2-period, fixed-sequence, 
single-cohort design with 8 subjects to evaluate a potential CYP3A4 interaction when LY3323795 is coadministered 
with itraconazole.
Treatment Arms and Duration:
For Part A (Cohorts 1 and 2), subjects will receive oral doses of either LY3323795 or placebo; the anticipated doses 
are 0.3 mg, 1 mg, 3 mg, 10 mg, 30 mg, and 100 mg.  An additional dose may be administered in Cohort 1, Period 4 
if required.


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2.
Schedule of Activities
Study Schedule Protocol I9F-MC-SCAA:  Part A, Periods 1 through 34
Screen
Periods 1 to 34
FDC
a
ED
Notes
Study Day
-28 to -2
-1
1
b
2
3
4
5
6
7
Ethanol and urine drug 
screens
X
X
An additional ethanol and urine drug screen 
may be done at the discretion of the 
investigator at readmission to the CRU.
Study Schedule Protocol I9F-MC-SCAA:  Part B
Study Day
Screen
-28 to -1
-1
1
a
2
3
4
5
6
7
FDC
b
ED
Notes
Ethanol and urine 
drug screens
X
X
An additional ethanol and urine 
drug screen may be done at the 
discretion of the investigator.
Ophthalmic
examination
X
X
X
X
X
X
See Section 9.4.4.2 for details.


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Study Schedule Protocol I9F-MC-SCAA:  Part C
Screen
Period 1
7-Day 
Wash-
out
Period 2
FDC
a
ED
Notes
Study Day
-28 to 
-2
-1
1
2
3-9
10
11 to 
14
15
16
b
17
18
19 20
21
22
23
Ethanol and urine 
drug screens
X
X
An additional ethanol and 
urine drug screen may be 
done at the discretion of the 
investigator at readmission 
to the CRU.
Vitals (hours)
X
0, 1, 2, 
4, 6, 8, 
12
24
X
X
X
X
0, 1, 2, 
4, 6, 8, 
12
24
X
X
X
X
X
X
X
X
See Section 9.4.2 for details.
Clinical 
laboratory values 
(hours)
X
X
48, 
Day 9
0
48
X
X
X
Screening tests will take 
place at local laboratories 
and other analyses will be at 
central laboratory.  Blood 
will be collected on Day -1 
for both local and central 
labs.  Investigator will 
review local lab results 
before dosing in Period 1.
Weight/height
X
X
X
X
Height measured at 
screening only.
5.1.
Overall Study Design

Part A will be a subject- and investigator-blind, placebo-controlled, randomized, single-ascending dose, 3-period (with an 
optional fourth period for Cohort 1), dose-escalation study to evaluate safety, tolerability, and plasma PK/PD of LY3323795. 


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LY3323795
Figure SCAA.1
Period 1
Period 2
Period 3
Optional Period 4
Cohort 1
(n=9)
(LY=6; 
PL=3)
Dose 1,
0.3 mg 
LY or PL
≥14 d 
washout
Dose 3,
3 mg
LY or PL
≥14 d 
washout
Dose 5, 
30 mg
LY or PL
≥14 d 
washout
Dose 7, 
TBD
LY or PL
Cohort 2
(n=9)
(LY=6; 
PL=3)
Dose 2,
1 mg 
LY or PL
≥14 d 
washout
Dose 4,
10 mg
LY or PL
≥14 d washout
Dose 6,
100 mg
LY or PL
Part A: Safety 
review to be 
completed after 
each dose level, 
prior to 
escalation.  
From Dose 5 
onwards, PK 
data review to be 
completed prior 
to dose 
escalation.
Part A: Dose Escalation 
Period 1
Cohort 3
(n=7)
(LY=5; PL=2)
Dose B1
or Placebo
Cohort 4
(n=7)
(LY=5; PL=2)
Dose B2
or Placebo
Cohort 5
(n=7)
(LY=5; PL=2)
Dose B3 
or Placebo
Part B: Serial CSF Sampling
Dose B1 will be determined 
by PK/PD data through Part 
A Dose 2, and safety data 
through Part A Dose 3.
Dose B2 will be determined by:
•
PK/PD data from Dose B1
•
PK/PD data from Part A Dose 4
•
Safety Data through Part A Dose 5.
Dose B3 will be determined by: 
•
Maximum tolerated dose from Part A 
(either Dose 6 or optional Dose 7)
•
PK data from Part A Dose 6.
•
PK/PD data from Doses B1 and B2.
Dose 7, if administered, 
to be determined 
by Dose 6 PK.
Part C: Itraconazole Interaction
Period 1
Period 2
Cohort 6 (n=8)
(LY=8, Itra = 8)
LY
≥7 d washout
Itra (7 doses)
LY + Itra
Itra (5+ doses)


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Period 1
Period 2
Period 3
Cohort 1
(n=9)
(LY=6; 
PL=3)
Dose 1,
0.3 mg 
LY or PL
≥14 d 
washout
Dose 3,
3 mg
LY or PL
≥14 d 
washout
Dose 5, 
30 mg
LY or PL
≥14 d 
washout
Cohort 2
(n=9)
(LY=6; 
PL=3)
Dose 2,
1 mg 
LY or PL
≥14 d 
washout
Dose 4,
10 mg
LY or PL
≥14 d washout
Dose 6,
100 mg
LY or PL
Part A: Safety 
review to be 
completed after 
each dose level, 
prior to 
escalation.  
From Dose 4 
onwards, PK 
data review to be 
completed prior 
to dose 
escalation.
Part A: Dose Escalation 
Period 1
Cohort 3
(n=7)
(LY=5; PL=2)
Dose B1
or Placebo
Cohort 4
(n=7)
(LY=5; PL=2)
Dose B2
or Placebo
Cohort 5
(n=7)
(LY=5; PL=2)
Dose B3 
or Placebo
Part B: Serial CSF Sampling
Dose B1 will be determined 
by PK/PD data through Part 
A Dose 2, and safety data 
through Part A Dose 4.
Dose B2 will be determined by:
•
PK/PD data from Dose B1
•
PK/PD data from Part A Dose 4
•
Safety Data through Part A Dose 5.
Dose B3 will be determined by: 
•
Maximum tolerated dose from Part A
•
PK data from Part A.
•
PK/PD data from Doses B1 and B2.
Part C: Itraconazole Interaction
Period 1
Period 2
Cohort 6 (n=8)
(LY=8, Itra = 8)
LY
≥7 d washout
Itra (7 doses)
LY + Itra
Itra (5+ doses)


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LY3323795
5.1.1. Part A: Dose-Escalation Study
Part A is a dose-escalation study that will be conducted in 2 alternating cohorts (Cohorts 1 
and 2), each consisting of approximately 9 subjects (6:3 subjects, LY3323795:placebo at each 
dose level) who will participate in 3 study periods (total of 6 dose levels in the 2 cohorts), with 
an optional fourth period for Cohort 1, if indicated by review of emerging data, comprising Dose 
7. The number of subjects intended to be enrolled is detailed in Section 5.2.  The first 54 dose 
levels of LY3323795 are anticipated to be 0.3 mg, 1 mg, 3 mg, and 10 mg, and 30 mg.  Doses 5 
and 6 areis anticipated to be 30 and 100 mg, but will be confirmed following pending PK data 
reviews from Dose 5.  See Section 5.1.1.1 for details of dose-escalation decisions.  The optional 
Dose 7 may be implemented based on review of emerging data as described in Section 5.5.
5.1.1.1.Dose Escalation and Interim Access to Data in Part A
The decision to dose escalate will be based on safety reviews conducted after each dose (and PK 
reviews from Dose 54 [planned to be 10 mg] onwards).  Dose escalation will not occur until after 
a review of at least 3 days’ safety data from the preceding dose level has been carried out, and 
the dose shown to be safe.  Accordingly, safety data, including AEs, vital signs, neurological 
surveys, ophthalmic tests, ECGs, and clinical laboratory tests, will be assessed by both the 
investigator and the sponsor prior to each dose escalation.  Any available PK data may be 
reviewed but PK data are not required for the initial dose-escalation decisions.  However, from 
Dose 54 onwards, LY3323795 PK data will be reviewed before escalation to the next subsequent 
dose level to verify that the projected median exposure does not exceed one tenth the NOAEL 
exposure established in rats (34,500ng.hour/mLi.e. median area under the concentration-versus-
time curve (AUC) will not exceed 3,450 ng•hour/mL and median Cmax will not exceed 214
ng/mL) (see Section 7.4.1).  PK samples up to 96 hours postdose will be required to conduct the 
PK data reviews.  The 96-hour PK sampling period may be adjusted based on emerging PK data.  
Plasma Aβ data may also be reviewed to assess the PD profile.  Time points for PK and PD 
sampling and required safety assessments may be modified based on emerging PK and safety 
results.
In addition to the reviews of PK data required after Dose 54 for the purposes of dose escalation, 
interim access to PK and PD (including plasma Aβ) data will occur after the anticipated 1-mg 
dose (Dose 2) and 10-mg dose (Dose 4) of Part A.  Data from this interim access to data (IAD) 
reviews, as well as results of the PK IADs following Doses 4, 5, and 6, and potentially 7, will be 
used at different points to select doses in Part B (see Figure SCAA.1).
5.1.2. Part B: CSF Sampling Study
Subjects will be admitted to the CRU on Day -1 and will remain as inpatients until at least 
24 hours after the CSF catheter is removed, after which they may be discharged at the discretion 
of the investigator.  CSF will be collected from an indwelling catheter using a closed system.  
The catheter will be inserted approximately 4 hours prior to study drug administration.  CSF 


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LY3323795
samples will be taken during this “stabilization” period approximately every 2 hours, as feasible.  
If some samples during the stabilization period are not collected for any reason, this will not be 
considered a protocol violation.
CSF PK and PD data will be collected by frequentsampling for 4hours predose and up to 36 
hours postdose (as described in the Part B Schedule of Activities,Section2). The minus 4-hour 
CSF sample will be collected for safety (red blood cell count, glucose, and protein, to be testedat 
the local laboratory) and PD biomarkers(which will be tested centrally).The minus 2-hour 
sample will be collected for PD biomarkers only; the 0-hour and subsequent postdose samples
will be collected for LY3323795 concentration and PD biomarkers.  An additional safety CSF 
sample will be collected at the removal of the catheter.  
 
5.1.2.1Dose Selection and Pharmacokinetic Analysis in Part B
Any dose selected for administration in Part B will be less than or equal to doses previously 
administered and found to be well tolerated in Part A.  EmergingPKdata (and PD data, as 
available) from the first 2 dosesin Part A, and safety data through Dose 34of Part A,will 
determine Dose B1 for Cohort 3.
5.5.
Justification for Dose
The upper dose in SCAA is projected to be 100 mg.  However, assessments of PK at pre-
specified times are planned during the dose escalation, and the anticipated dosesmay be 
modified to ensure that medianexposures do not exceed one tenth oftherat NOAEL determined 
in toxicology studies(i.e. median AUC will not exceed 3,450 ng•hour/mL and median Cmaxwill 
not exceed 214 ng/mL).
An optional Dose 7 may be administered in Cohort 1, Period 4 if safety data from previous doses 
are shown to be well tolerated and the maximum proposed exposure (ie, NOAEL established in 
rats AUC=34,500ng•hour/mL in males, the gender with the lowest exposure) has not been 
reached in the single-dose escalation.  If the maximum exposure is reached at any dose level, the 
additional planned dose period may be used to explore lower dose levels if warranted.  
Alternatively, Dose 7 may test a dose within the previously tested dose range, in order to better 
understand the safety, PK, or PD profile of LY3323795.
6.3.1. Meals and Dietary Restrictions
Fasting –For all partsof the study, subjects will be required to fast overnight (at least 8 hours) 
prior to each dosing day and for at least 4 hours after LY3323795or placebo dosing, with the 
exception of water that will be freely available before and after dosing.  However, no water is 
allowed 1 hourprior to pre-and post-ECG measurement.
CCI


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7.1.1. Packaging and Labelling
Clinical trial materials will be labeled according to the country’s regulatory requirements.  Each 
capsule of LY3323795 will be size zero2, blue in color and will contain 0.3 mg, 1 mg, or 10 mg 
of active ingredient.  Placebo capsules will match LY3323795 capsules in appearance.  
LY3323795 and matching placebo capsules will be supplied to the investigator by Lilly for 
dispensing by unblinded pharmacy staff.
9.4.3. Electrocardiograms
For Parts A and BC, after study entry, ECGs will be obtained in triplicate at approximately 1-
minute intervals at each ECG time point.  At least 1 ECG in each triplicate set will be interpreted 
by the investigator or qualified designee at the site as soon as possible after the time of ECG 
collection, and ideally while the subject is still present, for immediate subject management.
For Part C B (itraconazole interaction), at each time point, a single ECG will be collected and 
subsequently interpreted by the investigator or qualified designee in the same way as above.
Appendix 5. Blood and CSF Sampling Summary
Protocol I9F-MC-SCAA Blood Sampling Summary (Part A – 4 3 Periods)
Purpose
Maximum Blood Volume 
Per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
25
1
25
Clinical laboratory tests (central)a
5
1612
8060
Clinical laboratory tests (local lab)
12.5
43
5037.5
LY3323795 plasma PKb
2
60 45(+5)
120 90 (10)
PD plasma samplesb
2
60 45(+5)
120 90 (10)
Storage plasma samples
2
60 45
120 90
Blood discard for cannula patency
1
4433
4433
Pharmacogenetics
10
1
10
Total
569 (589)435.5
(455.5)
Total for clinical purposes [rounded up to nearest 10 mL] 
570 (590)440 (460)
Abbreviations:  PD = pharmacodynamics; PK = pharmacokinetics.
a
Additional samples may be drawn if needed for safety purposes.
b
A maximum of 5 additional plasma samples per subject may be drawn during the study at the discretion of the 
investigator or sponsor.


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LY3323795
Protocol I9F-MC-SCAA CSF Sampling Summary (Part B – 1 Period)
Purpose
Maximum CSF Volume 
Per Sample (mL)
Maximum Number 
of CSF Samples
Maximum Total 
Volume (mL)
CSF PK 
1
20
20
CSF PD and storage
3
22
66
RBC count (safety sample)
2
12
24
CSF flush
2
22
44
Total
1342
Total for clinical purposes [rounded up to nearest 10 mL] 
140
Abbreviations:  CSF = cerebrospinal fluid; PD = pharmacodynamics; PK = pharmacokinetics; RBC = red blood cell


PPD
Leo Document ID = bd9f95ad-d128-4024-8015-0b7fff968a0e
Approver: 
Approval Date & Time: 02-Dec-2016 14:04:10 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 02-Dec-2016 14:11:29 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
 
 
Statistical Analysis Plan: I9F-MC-SCAA 
 
 
Single-Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of LY3323795 in Healthy Subjects 
 
 
NCT02989389 
 
 
Approval Date: 20-Dec-2016 


I9F-MC-SCAAStatistical Analysis Plan Version 1
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LY3323795
1. Statistical Analysis Plan:  
I9F-MC-SCAA: SingleAscending Dose Study to Assess 
the Safety, Tolerability,Pharmacokinetics, and 
Pharmacodynamicsof LY3323795 in Healthy Subjects
Confidential Information
The information contained in this Statistical Analysis Plan (SAP)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 subsidia
ries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act (FOIA) 
Exemption 4.
LY3323795
A Phase 1 study of LY3323795 in healthy subjects that will be conducted in 3 parts.
PartsA and B aresubject-and investigator-blind, placebo-controlled, randomized studie
s.
Part A is a singleascending dose, 3-period, 2-cohort, crossover study to assess the safety, 
tolerability,and plasma pharmacokinetics (PK) and pharmacodynamics (PD) of LY3323795 
inhealthy volunteers.Part B is a single-dose, 3-cohort study to assess the safety, 
tolerability, and the plasma and cerebrospinal fluid (CSF) PK and PD of LY3323795.  
PartC is an open label, 2-period, fixed-sequence study in healthy volunteers to evaluate a 
potential cytochrome P450 (CYP) 3A4 interactionwhen LY3323795 is coadministeredwith 
itraconazole.
Approval Date: 20-Dec-2016 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Phase 1Statistical Analysis Plan electronically signed and approved by Lilly on date 
provided below.


I9F-MC-SCAA Statistical Analysis Plan Version 1
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LY3323795
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I9F-MC-SCAA:  Single Ascending Dose 
Study to Assess the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of LY3323795 in Healthy Subjects ......................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................4
4.
Objectives...........................................................................................................................5
4.1.
Primary Objective ..........................................................................................................5
4.2.
Secondary Objectives.....................................................................................................5
4.3.
Exploratory Objectives...................................................................................................5
5.
Summary of Study Design ..................................................................................................6
5.1.
Determination of Sample Size ........................................................................................6
5.2.
Method of Assignment to Treatment ..............................................................................7
6.
A Priori Statistical Methods ................................................................................................8
6.1.
General Considerations ..................................................................................................8
6.2.
Multicenter Studies ........................................................................................................8
6.3.
Multiple Comparisons/Multiplicity.................................................................................8
6.4.
Patient Disposition .........................................................................................................8
6.5.
Patient Characteristics ....................................................................................................8
6.5.1.
Subgroup Analyses ................................................................................................9
6.6.
Concomitant Therapy.....................................................................................................9
6.7.
Extent of Exposure.........................................................................................................9
6.8.
Safety Analyses..............................................................................................................9
6.8.1.
Clinical Evaluation of Safety..................................................................................9
6.8.2.
Statistical Evaluation of Safety...............................................................................9
6.8.2.1.
Adverse Events...............................................................................................10
6.8.2.2.
Eye Assessment..............................................................................................10
6.8.2.3.
Laboratory Tests.............................................................................................10
6.8.2.4.
Vital Signs and Weight...................................................................................10
6.8.2.5.
Electrocardiogram Intervals and Heart Rate....................................................10
6.9.
Pharmacokinetic Analyses............................................................................................11
6.9.1.
Pharmacokinetic Parameter Estimation ................................................................11
6.9.2.
Pharmacokinetic Statistical Inference...................................................................11
6.10. Pharmacodynamics Analyses .......................................................................................12
6.10.1.
Pharmacodynamics Parameter Estimation ............................................................12
6.10.2.
Pharmacodynamics Statistical Inference...............................................................12


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6.11. Pharmacokinetic/Pharmacodynamic Analyses..............................................................12
6.12. Interim Analyses and Data Monitoring.........................................................................13
6.13. Clinical Trial Registry Analyses...................................................................................13


I9F-MC-SCAA Statistical Analysis Plan Version 1
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3.
Revision History
Statistical Analysis Plan, Version 1 was approved prior to any data being received in-house and 
unblinding.


I9F-MC-SCAAStatistical Analysis Plan Version 1
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4. Objectives
4.1. Primary Objective
The primary objective of this study is to explore the safety and tolerability of single doses of 
LY3323795 in healthy subjects.
4.2. Secondary Objectives
The secondary objectives of this study are:
To explore the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of single 
doses of LY3323795.
To explore the plasma and CSF pharmacodynamics (PD) of single doses of LY3323795.
CCI
4.3. ExploratoryObjectives


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LY3323795
5.
Summary of Study Design
Study I9F-MC-SCAA (SCAA) is a Phase 1 study in healthy subjects that will be conducted in 
3 parts, as follows:

Part A will be a subject- and investigator-blind, placebo-controlled, randomized, single
ascending dose, 3-period, dose-escalation study to evaluate safety, tolerability, and 
plasma PK/PD of LY3323795. 

Part B will be a subject- and investigator-blind, placebo-controlled, randomized, single-
dose, single-period, lumbar catheter study with up to 3 cohorts/dose levels to evaluate the 
central and plasma PK/PD of LY3323795.

Part C will be an open-label, 2-period, fixed-sequence, single-cohort study to evaluate a 
potential cytochrome P450 (CYP) 3A4 interaction when LY3323795 is coadministered 
with itraconazole.
5.1.
Determination of Sample Size
The sample size of 9 in each cohort of Part A is customary for Phase 1 studies evaluating safety, 
PK, and/or PD parameters, and is not based on statistical mean estimation.
For Part B, given the CSF Aβ variability observed in prior studies that measured CSF Aβ, the 
sample size of 5 subjects per LY3323795 dose and 2 subjects per placebo in a parallel cohort, 
pooled placebo design is sufficient to detect a mean Aβ reduction of approximately 21% or more 
from baseline. Assuming a standard deviation of 22% for the CSF Aβ1-40, a sample size of 
5 subjects per dose would provide approximately 90% coverage probability that the half-width of 
the 80% confidence interval (CI) for the mean of percentage change from baseline of CSF Aβ1-40
would be within 21%. For example, if the estimate of the percentage change from baseline CSF 
Aβ1-40 at nadir concentration (Cnadir) is 50%, then the confidence limit for the percentage change 
from baseline would be (29%, 71%). 
For Part C, assuming a within-subject variability of 25% for the PK parameter (area under the 
drug plasma concentration versus time curve [AUC] or maximum concentration [Cmax]) of 
LY3323795, a sample size of 8 subjects would provide approximately 90% coverage probability 
that the half-width of the 90% CI for the geometric mean ratio of LY3323795 with itraconazole, 
compared with LY3323795 alone, would be within 0.3 in log scale, or 1.35 in natural scale. For 
example, if the estimate of the ratio of LY3323795 with itraconazole over LY3323795 alone is 
1.2, then the confidence limit would be (88%, 162%).
Subjects who drop out may be replaced at the discretion of the sponsor and investigator to
achieve protocol-required completers. In Part A, a replacement subject’s treatment assignment
will follow that of the subject being replaced but may not require completion of all study periods.  
In Part B, a replacement subject’s treatment assignment will follow that of the subject being 
replaced.  In Part C, all subjects, and any replacements, will be on the same treatment 
assignment.


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LY3323795
5.2.
Method of Assignment to Treatment
For Cohorts 1 and 2 in Part A, up to approximately 24 subjects may be enrolled so that 
approximately 18 subjects (9 subjects per cohort [6:3, LY3323795:placebo per dose level]) 
complete the study.
For Cohorts 3 to 5 in Part B, up to approximately 30 subjects may be enrolled so that 
approximately 21 subjects (7 subjects per cohort [5:2, LY3323795:placebo]) complete the study.
For Cohort 6 in Part C, up to 12 subjects may be enrolled so that approximately 8 subjects 
complete the study. Part C is open label study.
Randomization tables for allocation of LY3323795 and placebo will be prepared by the Lilly 
statistician.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or designee.
It is planned that all safety reporting including eye safety assessments will be conducted by 
Covance; with the exception of inferential analyses on safety, PK, PD, and biomarkers, which 
will be conducted by Eli Lilly and Company.
Pharmacokinetic and pharmacodynamic analyses will be conducted on the full analysis set. This 
set includes all data from all subjects receiving at least 1 dose of the investigational product. 
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.  
Additional exploratory analyses of the data will be conducted as deemed appropriate. As this is 
a Phase 1 study and there will be no formal statistical hypothesis testing, any changes to the
planned analysis will not necessitate a protocol amendment and will be detailed in the study
report.
Unless otherwise stated, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.10 (0.05 each side).  
6.2.
Multicenter Studies
Due to this being a primarily safety and tolerability study with as single investigation center and
low patient numbers per dose, there is no plan to fit center as a covariate in any of the models.
The demographic/disposition listings will make it clear as to which site each patient was 
attributed.
6.3.
Multiple Comparisons/Multiplicity
No adjustments for multiplicity will be made.
6.4.
Patient Disposition
All patients who discontinue from the study will be identified, and the extent of their
participation in the study will be reported. If known, a reason for their discontinuation will be 
given.
6.5.
Patient Characteristics
The patient’s age, sex, race, weight, body mass index (BMI), height, smoking habits, 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.


I9F-MC-SCAA Statistical Analysis Plan Version 1
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LY3323795
6.5.1. Subgroup Analyses
Any subgroup analyses will be exploratory (post hoc) in nature.  
6.6.
Concomitant Therapy
Concomitant therapy will be listed and summarized.
6.7.
Extent of Exposure
Dosing information for each individual subject will be listed.
6.8.
Safety Analyses
6.8.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association
with investigational product 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
Dictionary for Regulatory Activity (MedDRA).
The number of investigational product–related serious adverse events (SAEs) will be reported.
A listing of all patients’ laboratory values and a listing of abnormal laboratory values (for that 
parameter) during the treatment period will be provided, and results will be summarized.
6.8.2. Statistical Evaluation of Safety
The safety analyses will be conducted for Part A, B, and C separately.  The safety and 
tolerability of treatment will be assessed by summarizing the following:

Adverse Events
o
Treatment-emergent adverse events (TEAEs) by:

System Organ Class (SOC) and Preferred Term (PT)

Maximum severity

Considered to be related to investigational produce by investigator
o
Serious Adverse Events (SAEs)
o
Adverse events (AEs) leading to discontinuation

Vital signs and weight

Laboratory measurements

Electrocardiograms (ECGs)

Eye assessments
Safety parameters will be listed and summarized using standard descriptive statistics, where
appropriate. Additional analysis will be performed, if warranted, upon review of the data.


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6.8.2.1.
Adverse Events
Treatment-emergent adverse events are defined as the reported AEs that first occurred or 
worsened during the postbaseline phase, compared with baseline phase. For each TEAE, the 
severity level of the event (mild, moderate, or severe) will be determined by patient or physician 
opinion. The MedDRA Lowest Level Term (LLT) will be used in the treatment-emergent 
computation. For each LLT, the maximum severity at baseline will be used as the baseline 
severity.  If the maximum severity during postbaseline is greater than the maximum baseline 
severity, the event is considered to be treatment-emergent for the specific postbaseline period. 
For each patient and TE AE, the maximum severity for the MedDRA level being displayed (PT, 
High Level Term [HLT], or SOC) is the maximum postbaseline severity observed from all 
associated LLTs mapping to that MedDRA level.  For events that are gender-specific, the 
denominator and computation of the percentage will include only patients from the given gender.
6.8.2.2.
Eye Assessment
Eye testing will include distance and near visual acuity (best-corrected or pinhole using the 
Snellen Chart and Near Reading Card), Humphrey visual field testing (using the 10-2 protocol 
with a red-on-white target), and ophthalmoscopy.
Only subjects who pass all other inclusion/exclusion criteria at screening should be sent for these 
eye examinations.  Results from subsequent eye tests during the study will be compared with the 
screening results to track any changes in subjects’ vision.
For each method of eye assessment, change from baseline (Yes/No) and change from baseline 
clinically significant (Yes/No) will be listed, and if there are sufficient changes they will be 
summarized by treatment group and compared with Fisher’s exact test.
6.8.2.3.
Laboratory Tests
The listing of patients with abnormal high or low laboratory values, based on Covance reference 
ranges, at any time postbaseline will be created.
The listing of patients with elevations in hepatic laboratory tests as defined below will be 
created.  

An alanine aminotransferase (ALT) or aspartate aminotransferase (AST) measurement 
greater than or equal to 3 times (3) the Covance upper limit of normal (ULN) during the 
treatment period.  

A total bilirubin measurement greater than or equal to 2 times (2) ULN during the 
treatment period.
6.8.2.4.
Vital Signs and Weight
Plot of vital signs and weight over time will be created for each patient.
6.8.2.5.
Electrocardiogram Intervals and Heart Rate
Analysis of corrected QT (QTc) data from ECG monitoring in a Phase 1 trial is performed to 
judge the extent and/or risk of QT prolongation.  A scatter plot will be generated to explore the 
relationship between QTc and drug exposure, and will assess the mean change in QTc using 


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Fridericia’s formula as a function of plasma drug concentration.  The QTc analysis will not 
include ECGs collected in Part C (itraconazole interaction), due to the potential for non-
LY3323795-induced changes in QTc.  Frequency tables of QTc changes from baseline and large 
QTc values may also be obtained in accordance with International Conference on Harmonisation 
(ICH) guidance, and additional analyses may be conducted if required.
6.9.
Pharmacokinetic Analyses
6.9.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3323795 will be calculated using standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax and AUC of LY3323795.  Other 
noncompartmental parameters, such as half-life (t1/2), apparent clearance (CL/f), and apparent 
volume of distribution (VD), may be reported.
Renal clearance of LY3323795 will be calculated as the ratio of amount excreted/AUC.  This
will be compared to the unbound glomerular filtration rate (GFR), which is estimated using 
creatinine levels.
In Part C, PK parameter estimates for itraconazole samples collected on Day 16 will be 
calculated using standard noncompartmental methods of analysis. Maximum concentration and
AUC will be reported. Itraconazole concentrations collected as part of this study may be 
analyzed along with data collected in other studies as part of a larger assessment of itraconazole 
PK. If such an analysis is performed, the results of the analysis will be reported separately from 
the final report for this study.  Concentrations of itraconazole metabolites may be characterized 
on an exploratory basis.
6.9.2.
Pharmacokinetic Statistical Inference
In Part C, the area under the drug plasma concentration versus time from time zero to infinity 
(AUC[0-∞]) and Cmax for LY3323795 administered alone and in the presence of itraconazole will 
be compared using an analysis of variance (ANOVA) model. The parameters will be log-
transformed prior to analysis.  The model includes a fixed effect for the treatment and a random 
effect for subject.  The following model will be built:  ln (PK parameter) = treatment + subject + 
random error, where treatment is a fixed effect with 2 levels: LY3323795 alone (reference) and 
LY3323795 with itraconazole (test).
The least square (LS) mean for each treatment and the 90% CI for the difference in means will 
be estimated from the ANOVA model and back-transformed from the log scale to provide 
estimates of the geometric means and 90% CIs for the ratio of the geometric means of 
LY3323795 + itraconazole versus LY3323795 alone.
The time to Cmax (tmax) parameter will be analyzed using the Wilcoxon-signed rank test. 
Median differences and 90% CIs for the difference between LY3323795 + itraconazole (test) and 
the LY3323795 alone (reference) will be calculated.


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6.10.PharmacodynamicsAnalyses
6.10.1.Pharmacodynamics ParameterEstimation
In Parts A and B, plasma concentrations of Aβ1-40and Aβ
1-42will be summarized for each dose 
group based on the Cnadirand the time to reach C
nadir(t
nadir).  
In Part B, CSF concentrations of Aβ1-40, Aβ
1-42will be summarized for each dose group based on 
the C
nadir, t
nadir, and the 24-hour average values, expressed as a percentage change from baseline.  
 
 
 Other parameters may be 
calculated, as appropriate.
6.10.2.PharmacodynamicsStatistical Inference
For Part B of this protocol, statistical analysis of CSF Aβ1-40,Aβ1-42, 
concentrations obtained over the fixed-scheduled sampling period will be analyzed using a 
repeated-measures analysis with the primary statistical inference of pairwise comparison of the 
overall mean difference among the LY3323795 doses and placebo using a 90% CI.  The 
statistical model may include the baseline CSF Aβ1-40and Aβ
1-42concentrations obtained during 
predose CSF collection period and fixed effects of dose groups (placebo and doses of 
LY3323795), scheduled CSF sampling time, and the interaction between dose groups and 
sampling times.  A compound symmetric covariance structure may be used.  From the statistical 
model, the primary statistical estimates will be the mean percentage reduction from baseline in 
CSF Aβ1-40and Aβ
1-42concentrations at each time point with LY3323795 over the 36-hour 
sampling interval.  The above model will fit both the log-transformed and percentage change 
from baseline in CSF Aβ1-40and Aβ
1-42concentrations.
Additional exploratory analysis will be performed on plasma concentrations of TMEM27with a 
similar statistical model.  
6.11.Pharmacokinetic/Pharmacodynamic Analyses
It is intended that a compartmental modeling approach will be used to describe the plasma and 
CSF PK and CSF PD of LY3323795.  Compartmental modeling will be performed using 
nonlinear mixed-effects modeling.  Although it is not intended that the model will assess the 
impact of patient-specific factors (such as age, body weight, or race/subrace) on LY3323795 PK, 
these may be included,if appropriate.  Modeling may be performed sequentially by first 
modeling plasma PK and then fixing the values from that model when developing a model to 
describe CSF PK.  It is intended that an indirect response model will be used to characterize the 
PD effect of LY3323795 on CSF Aβ1-40formation, with PK parameters fixed to those values 
determined in previous steps.  Other PD endpoints (eg, Aβ1-42
CCI
) may be modeled, if warranted.  
Other modeling approaches or graphical analyses may be used, as deemed appropriate.  The 
results of this modeling may not necessarily be included in the final study report.
CCI


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Further details on the planned pharmacokinetic analyses can be found in the pharmacokinetic 
analysis plan.
6.12. Interim Analyses and Data Monitoring 
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, clinical research physician (CRP)/investigator, or 
designee will consult with the appropriate medical director or designee to determine if it is 
necessary to amend the protocol.
Safety and/or PK Interim Access to Data (IAD) reviews are scheduled to occur throughout the 
study. The purpose of these IAD reviews is to examine the safety data and guide dose selections. 
In Part A, the investigator and the Lilly clinical pharmacologist/CRP/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
In Part B, dose selection will be based on PK/PD data.  
The investigator will remain blinded and the Lilly clinical pharmacologist/CRP/study team will 
be unblinded during these IAD reviews. 
Additional IAD reviews may be conducted at any time throughout the study, as required, to 
ensure subjects’ safety or to help guide dosing. An assessment committee will not be formed.
6.13. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of AEs, 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 and 
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 SAE 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


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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).

Adverse event reporting is consistent with other document disclosures (for example, the 
clinical study report [CSR], manuscripts, and so forth)