Clinical trial NCT04014361
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2019-08-09; Completion date: 2020-02-09
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to learn more about the safety and side effects of LY3154885 when given by mouth to healthy participants. The study will have up to four parts. Each participant will enroll in only one part. The study will last up to 70 days for each participant, including screening and follow-up.

Detailed description:

Arms: arm 1: 15, 45, 100, 200, 300 or 375 milligrams (mg) LY3154885 administered orally in two of three study periods. arm 2: Placebo administered orally in one of three study periods. arm 3: 45 mg LY3154885 administered orally in period 1 followed by 200 mg Itraconazole administered orally on 10 consecutive days and then 45 mg LY3154885 co-administered with 200 mg itraconazole orally during period 2. arm 4: Placebo administered orally during period 1 followed by 200 mg Itraconazole administered orally on 10 consecutive days and then placebo co-administered with 200 mg itraconazole orally during period 2. arm 5: Part C was not initiated. arm 6: Part C was not initiated. arm 7: Part D was not initiated.
Interventions: intervention 1: LY3154885 - Capsule intervention 2: Placebo - Capsule intervention 3: Itraconazole intervention 4: LY3154885 - Tablet
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally. intervention 3: Administered orally. intervention 4: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol J1Z-MC-HUAA (b)  
Single- and Multiple-Ascending Dose, Safety, Tolerability, and Pharmacokinetic Study with 
LY3154885 in Healthy Subjects 
NCT04014361 
Approval Date: 16-Aug-2019 


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1
L Y 3 1 5 4 8 8 5
Pr ot o c ol J 1 Z -M C -H U A A ( b)
Si n gl e - a n d M ulti pl e -A s c e n di n g D o s e, S af et y , T ol er a bilit y, 
a n d P h ar m a c o ki n eti c St u d y  wit h L Y 3 1 5 4 8 8 5 i n H e alt h y 
S u bj e ct s
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s pr ot o c ol i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c a l i n v e sti g ati o n of 
L Y 3 1 5 4 8 8 5, u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s .
L Y 3 1 5 4 8 8 5
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Cli ni c al P h ar m a c ol o g y Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y :  
0 7 M a y
2 0 1 9
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y :  2 1 J u n e 2 0 1 9
A m e n d m e nt ( b ) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e pr o vi d e d b el o w.
A p pr o v al D at e: 1 6- A u g- 2 0 1 9 G M T


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
Table of Contents
Single- and Multiple-Ascending Dose, Safety, Tolerability, 
and Pharmacokinetic Study with LY3154885 in Healthy 
Subjects
Section
Page
Protocol J1Z-MC-HUAA(b) Single- and Multiple-Ascending Dose, 
Safety, Tolerability, and Pharmacokinetic Study with LY3154885 in 
Healthy Subjects .................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................24
3.1.
Study Rationale............................................................................................................25
3.2.
Background..................................................................................................................25
3.3.
Benefit/Risk Assessment..............................................................................................26
4.
Objectives and Endpoints..................................................................................................27
5.
Study Design.....................................................................................................................28
5.1.
Overall Design .............................................................................................................28
5.1.1.
Part A (Single-Ascending Dose)...........................................................................28
5.1.2.
Part B (CYP3A4 Inhibition).................................................................................29
5.1.3.
Part C (Multiple-Ascending Dose) .......................................................................30
5.1.4.
Optional Part D (Pharmacokinetics of Capsule and Tablet 
Formulations and Food Effect).............................................................................31
5.2.
Number of Participants.................................................................................................32
5.3.
End of Study Definition ...............................................................................................33
5.4.
Scientific Rationale for Study Design...........................................................................33
5.5.
Justification for Dose ...................................................................................................33
6.
Study Population...............................................................................................................37
6.1.
Inclusion Criteria..........................................................................................................37
6.2.
Exclusion Criteria ........................................................................................................38
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................40
6.3.
Lifestyle and/or Dietary Requirements .........................................................................41
6.3.1.
Meals and Dietary Restrictions.............................................................................41
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................42
6.3.3.
Activity................................................................................................................42
6.3.4.
Blood and Plasma Donations................................................................................42


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
6.4.
Screen Failures.............................................................................................................42
7.
Treatment..........................................................................................................................43
7.1.
Treatment Administered...............................................................................................43
7.1.1.
Packaging and Labeling .......................................................................................43
7.2.
Method of Treatment Assignment ................................................................................44
7.2.1.
Selection and Timing of Doses.............................................................................44
7.3.
Blinding .......................................................................................................................44
7.4.
Dose Modification........................................................................................................45
7.4.1.
Dose Decision/Escalation.....................................................................................45
7.5.
Preparation/Handling/Storage/Accountability...............................................................45
7.6.
Treatment Compliance .................................................................................................46
7.7.
Concomitant Therapy...................................................................................................46
7.8.
Treatment after the End of the Study............................................................................46
8.
Discontinuation Criteria ....................................................................................................47
8.1.
Discontinuation from Study Treatment.........................................................................47
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................47
8.2.
Discontinuation from the Study....................................................................................47
8.3.
Subjects Lost to Follow-up...........................................................................................49
9.
Study Assessments and Procedures ...................................................................................50
9.1.
Efficacy Assessments...................................................................................................50
9.2.
Adverse Events ............................................................................................................50
9.2.1.
Serious Adverse Events........................................................................................51
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................52
9.2.2.
Complaint Handling.............................................................................................52
9.3.
Treatment of Overdose.................................................................................................52
9.4.
Safety...........................................................................................................................52
9.4.1.
Laboratory Tests ..................................................................................................52
9.4.2.
Vital Signs ...........................................................................................................52
9.4.3.
Electrocardiograms ..............................................................................................53
9.4.4.
Ambulatory Blood Pressure Monitoring ...............................................................54
9.4.5.
Neurological Examination....................................................................................54
9.4.6.
Columbia-Suicide Severity Rating Scale (Part C Only) ........................................54
9.4.7.
Exploratory Scales and Questionnaire (Part C Only) ............................................55
9.4.7.1.
Profile of Mood States Second Edition ...........................................................55
9.4.7.2.
Physician Withdrawal Checklist .....................................................................55
9.4.8.
Safety Monitoring ................................................................................................55
9.4.8.1.
Hepatic Safety................................................................................................55
9.5.
Pharmacokinetics .........................................................................................................56


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
9.5.1.
Bioanalysis...........................................................................................................56
9.6.
Exploratory Pharmacodynamics ...................................................................................57
9.6.1.
Exploratory Cognition Assessments (Part C Only) ...............................................57
9.7.
Genetics .......................................................................................................................57
9.8.
Biomarkers...................................................................................................................58
9.9.
Health Economics ........................................................................................................58
10.
Statistical Considerations and Data Analysis.....................................................................59
10.1. Sample Size Determination ..........................................................................................59
10.2. Populations for Analyses..............................................................................................59
10.2.1.
Study Participant Disposition ...............................................................................59
10.2.2.
Study Participant Characteristics ..........................................................................59
10.3. Statistical Analyses ......................................................................................................59
10.3.1.
Safety Analyses....................................................................................................59
10.3.1.1.
Clinical Evaluation of Safety..........................................................................59
10.3.1.2.
Statistical Evaluation of Safety.......................................................................60
10.3.2.
Pharmacokinetic Analyses....................................................................................60
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................60
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................60
10.3.3.
Exploratory Pharmacodynamic Analyses .............................................................61
10.3.4.
Exploratory Pharmacokinetic/Pharmacodynamic Analyses...................................61
10.3.5.
Data Review During the Study.............................................................................62
10.3.6.
Interim Analyses..................................................................................................62
11.
References ........................................................................................................................63
12.
Appendices .......................................................................................................................65


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
List of Tables
Table
Page
Table HUAA.4.1.
Objectives and Endpoints .......................................................................27
Table HUAA.5.1.
Relevant Margins of Safety from Toxicology Studies for 
Administration of LY3154885 Based on Administered Dose and 
Predicted Human Exposure.....................................................................35
Table HUAA.7.1.
Treatments Administered........................................................................43
Table HUAA.8.1.
Potentially Clinically Significant Vital Sign Criteria...............................48
Table HUAA.9.1.
Scoring of Neurological Examination Findings.......................................54


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
List of Figures
Figure
Page
Figure HUAA.5.1.
Illustration of study design for Part A. ....................................................29
Figure HUAA.5.2.
Illustration of study design for Part B. ....................................................30
Figure HUAA.5.3.
Illustration of study design for Part C. ....................................................31
Figure HUAA.5.4.
Illustration of study design for Part D. ....................................................32


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................66
Appendix 2.
Clinical Laboratory Tests........................................................................71
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................72
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............75
Appendix 5.
Blood Sampling Summary......................................................................76
Appendix 6.
Protocol Amendment J1Z-MC-HUAA(b) Summary
Single- and Multiple-Ascending Dose, Safety, Tolerability, and 
Pharmacokinetic Study with LY3154885 in Healthy Subjects.................78


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
1. Protocol Synopsis
Title of Study:
Single- and Multiple-Ascending Dose, Safety, Tolerability, and Pharmacokinetic Study with LY3154885 in 
Healthy Subjects
Rationale: 
LY3154885 is a positive allosteric modulator (also called “potentiator”) of the dopamine D1 receptor (D1 PAM)
being developed for the potential treatment of Alzheimer’s dementia and Lewy body dementia, including dementia 
with Lewy bodies and Parkinson’s disease dementia.
LY3154885 has not been administered to humans.  This first-in-human study will investigate the safety, tolerability, 
and pharmacokinetics (PK) of single and multiple doses of LY3154885 in healthy subjects.  The study will also 
investigate the impact of cytochrome P450 (CYP) 3A4 inhibition on the safety, tolerability, and PK of LY3154885, 
and the PK of LY3154885 after a single dose via a tablet or capsule formulation.  The data generated in this study 
will be used to help design subsequent clinical studies.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To explore the safety and tolerability of single and multiple 
doses of LY3154885 in healthy subjects
Incidence of treatment-emergent adverse events 
(TEAEs)
Secondary

To determine the pharmacokinetics (PK) of LY3154885 
following administration of single and multiple oral doses 
of LY3154885

To determine the PK of LY3154885 when administered 
with itraconazole (Part B only)

To assess safety and tolerability of LY3154885 when 
administered with itraconazole (Part B only)

To compare the PK of LY3154885 when administered with 
a capsule or tablet formulation (Part D only)

To evaluate the effect of a high-fat diet on the PK of 
LY3154885 (Part D only)
Maximum observed drug concentration (Cmax), 
time to Cmax (tmax), and area under the 
concentration versus time curve (AUC) of 
LY3154885
Cmax and AUC for LY3154885 alone and in the 
presence of itraconazole
TEAEs
Cmax, tmax, and AUC of LY3154885 for capsule 
and tablet formulations
Cmax, tmax, and AUC of LY3154885 with and 
without a high-fat diet


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
Summary of Study Design:
Study J1Z-MC-HUAA is a Phase 1, single-center study in healthy subjects to be conducted in 4 parts:

Part A will be a subject- and investigator-blind, placebo-controlled, randomized, single-ascending dose, 
3-period crossover study to evaluate safety, tolerability, and PK of LY3154885 in 2 alternating cohorts.

Part B will be a subject- and investigator-blind to LY3154885/placebo, single period, drug-drug interaction 
study with itraconazole.

Part C will be a subject- and investigator-blind, placebo-controlled, randomized, 14-day multiple-ascending 
dose, parallel-group, 3-cohort, single-period study to evaluate safety, tolerability, and PK of LY3154885.

Optional Part D will be an open-label, 3-period, 3-sequence PK study of LY3154885 administered using a 
capsule or tablet formulation.  Part D will also include a pilot food effect evaluation.
Treatment Arms and Planned Duration for an Individual Subject:
Part A:  Subjects will attend a screening visit up to 28 days prior to dosing in Period 1.  Admission to the clinical 
research unit (CRU) will be in the afternoon of Day -2 of the first period and on Day -1 for Periods 2 and 3.  After 
an overnight fast, subjects will receive either LY3154885 or placebo as a single oral dose on Day 1 and will remain 
inpatient for at least 48 hours after dosing (until Day 3), after which they may be discharged at the discretion of the 
investigator.  The washout time between doses for a given subject will be at least 7 days.  A poststudy follow-up 
visit will be conducted at least 7 days after the final dose.
Part B:  Subjects will attend a screening visit up to 28 days before dosing.  Subjects will be admitted to the CRU in 
the afternoon of Day -2 and will receive a single oral dose of LY3154885 or placebo on Day 1 after an overnight 
fast.  There will be a 7-day washout period followed by 10 days of dosing with 200 mg itraconazole (twice daily on 
Day 8 [dose separated by 12 hours], then once daily on Days 9 through 17).  Subjects will receive LY3154885 or 
placebo on Day 14, approximately 1 hour after the dose of itraconazole.
Part C:  Subjects will receive either LY3154885 or placebo as a single oral once-daily dose from Days 1 through 14.  
Study drug will be administered as a single oral dose in the morning under fasted conditions.  Subjects will attend a 
screening visit up to 28 days prior to dosing and will be admitted to the CRU in the afternoon of Day -2.  After the 
initial dose (Day 1), subjects will be required to remain in-house for at least 48 hours after dosing (Day 3) and at the 
discretion of the investigator. Subjects will attend the CRU on Days 4, 5, 6, 9, and 10 on an outpatient basis for 
daily dosing and will be permitted to leave the CRU at the discretion of the investigator.  A poststudy follow-up visit 
will be conducted approximately 7 days after discharge.
Optional Part D:  Subjects will attend a screening visit up to 28 days prior to dosing in Period 1; admission to the 
CRU will be in the afternoon of Day -2 (Periods 1 and 2) and on Day -1 (Period 3).  In Period 1, subjects will 
undergo an overnight fast before receiving a single oral dose of LY3154885 (capsule formulation) on Day 1.  
Subjects will remain inpatient for at least 48 hours after dosing, after which they may be discharged at the discretion 
of the investigator.  Subjects will be re-admitted to the CRU on Day 6, and will undergo an overnight fast before 
receiving a subsequent single oral dose of LY3154885 on Day 8 with the same formulation.  Subjects will be 
discharged on Day 10, at least 48 hours after dosing.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
Period 2 will be conducted as described for Period 1; however, LY3154885 will be administered as a tablet 
formulation.  Period 3 will be conducted as described for Period 1; however, subjects will receive a single oral dose 
of LY3154885 (tablet formulation) after administration of a high-fat diet.
Number of Subjects:
For Part A, up to 30 subjects may be enrolled into Cohorts 1 and 2 in order to ensure that approximately 12 subjects 
per cohort (8 LY3154885; 4 placebo) complete this part of the study.
For Part B, up to 15 subjects may be enrolled in order to ensure that approximately 12 subjects (9 LY3154885; 
3 placebo) complete this part of the study.
For Part C, up to 45 subjects may be enrolled in order to ensure that approximately 36 subjects complete this part of 
the study (with approximately 12 subjects [9 LY3154885; 3 placebo] completing each dose level).
For optional Part D, up to 12 subjects may be enrolled in order to ensure that approximately 9 subjects complete this 
part of the study.
Statistical Analysis:
Safety:  Safety parameters that will be assessed include adverse events, clinical laboratory parameters, vital signs, 
and electrocardiogram parameters.  The parameters will be listed and summarized using standard descriptive 
statistics.  Additional analysis will be performed if warranted upon review of the data.
Pharmacokinetics:  Pharmacokinetic parameters including maximum observed drug concentration (Cmax), time to 
Cmax (tmax), and area under the concentration versus time curve (AUC) following single and multiple doses of 
LY3154885 will be calculated using standard noncompartmental methods of analysis.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
2. Schedule of Activities


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part A: Single-Ascending Dose – 3 Study Periods)
Screening
Periods 1, 2, and 3
ED
Follow-
up
Comments
Procedure
-28 to -3 
days prior to 
dosing in 
Period 1
Day -2
Day -1
Day 1
Day 2
Day 3
At least 
7 days 
after final 
dose
Informed consent
X
Admission to CRU
X (Period 
1)
X (Periods 
2&3)
Discharge from CRU
X
Medical history
X
AE/medication review
X
X
X
X
X
X
Height/weight
X
X
X
Height at screening only.
Neurological exam
(hours)
X
Predose, 
4, 8
24
48
X
X
LY3154885/Placebo 
administration (hours)
0
Vital signs (BP, PR 
[supine], temperature) 
(hours)
X
X
Predose, 
2, 4, 8, 
12
24, 36
48
X
X
Time points may be added for each 
study period, if clinically indicated.  
On Day 1, temperature will be 
measured at predose only.
ABPM
X  
X
X
The ABPM on Day -1 is a 24-hour 
collection in Period 1 only (baseline 
measurement).  See Section 9.4.4.
Clinical laboratory tests
X
X
Predose
X
X
X
See Appendix 2, Clinical Laboratory 
Tests, for details. PI must review the 
result of Day-2 results prior to Day 1 
dose in Period 1 only.
Pregnancy test
X
X
X
X
Serum test at screening and admission
of Period 1 only; urine test at all 
other time points.  
PE/MA
X
Predose
X
X
Full PE/MA at screening and prior to 
final discharge from the study.  
Symptom-directed PE/MA at all other 
time points and as deemed necessary 
by the investigator.
continued


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part A: Single-Ascending Dose – 3 Study Periods) (concluded)
Screening
Periods 1, 2, and 3
ED
Follow-up
Comments
Procedure
-28 to -3 
days prior 
to Period 1
Day -2
Day -1
Day 1
Day 
2
Day 
3
At least 
7 days after 
final dose
Single safety 12-lead ECG 
(hours)
X
Predose, 2, 
4
24
48
X
X
PK sampling (hours)
Predose, 
0.5, 1, 2, 3, 
4, 5, 6, 8, 12
24, 
36
48
Sampling times are relative to 
the time of study treatment 
administration (0 hour).
Stored non-PGx plasma 
sample (hours)
Predose, 8
24
Stored sample for biomarker 
research. Sampling times are 
relative to the time of study 
treatment administration (0 
hour).
PGx sample
X
Single sample for 
pharmacogenetic analysis taken 
prior to/on Day 1 of Period 1.
Urine collection (hours)
0-12, 12-24 
24-36
Urine collection time starts from 
actual dosing time on Day 1 and 
finishes within ±30 minutes of 
the 36-hour time point.
Serum creatinine 
Predose
To be collected at predose and 
sent to central laboratory. 
Note:  Site should schedule activities as appropriate. In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures: ECG, vital signs, PK samples, clinical laboratory tests, urine samples, biomarkers, and storage samples.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CRU = clinical research unit; 
ECG = electrocardiogram; ED = early discontinuation; MA = medical assessment; PE = physical examination; PGx = pharmacogenetic; PI = principal 
investigator; PK = pharmacokinetic; PR = pulse rate.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part B: Drug-Drug Interaction with CYP3A4 Inhibition – Single Period)
Screening
Days
Procedure
-28 to -3
-2
-1
1
2
3
4-6
7
8
9
10-11
12
13
14
15
Informed consent
X
Admission to CRU
X
X
X
Discharge from CRU
X
X
PE/MA
X
Directed MA
X
Predose
Predose
Predose
AE/medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight/height
X
X
Pregnancy test
X
X
Neurological exam (hours)a
X
Predose, 4,
(8)
24
48
Predose, 4,
(8)
24
Clinical laboratory tests
X
X
Predose
Predose
Predose
ABPM
X
X
X
X
X
X
LY3154885/Placebo 
administration
X
X 
Administration of 
itraconazole
X
X
Outpatient 
dosing
X
X
X
Vital signs (BP, PR 
[supine], temperature) 
(hours)a
X
Predose 2, 4, 
8, 12
24
48
Predose,
2, 4, 12
24
Predose 2, 4, 
8, 12
24, 36
12-lead ECG
X
Predose
Predose
Predose
PGx sample
X
LY3154885 PK sampling 
(hours)a
Predose, 0.5, 
1, 2, 3, 4, 5, 
6, 8, 12
24, 36
48
Predose, 0.5, 
1, 2, 3, 4, 5, 
6, 8, 12
24, 36 
Itraconazole and 
metabolite(s) PK sampling 
(hours)
-1, 0, 1, 2, 
5, 8, 12
continued


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part B: Drug-Drug Interaction with CYP3A4 Inhibition – Single Period) (concluded)
Days
ED
Follow-up
Comments
Procedure
16
17
18
Approx 7 days 
after discharge
Discharge from CRU
X
PE/MA
X
X
X
Full PE/MA at screening and prior to final discharge from the study.  
Symptom-directed PE/MA at all other time points and as deemed 
necessary by the investigator.
Directed MA
X
X
AE/medication review
X
X
X
X
X
Weight/height
X
X
Height at screening only.
Pregnancy test
X
X
Serum test at screening and admission; urine test at all other time points.  
Women with confirmed nonchildbearing potential status can be 
exempted from further pregnancy tests during the study after screening.
Neurological exam (hours)a
48
The 8-hour time point is optional.
Clinical laboratory tests
X
X
X
See Appendix 2, Clinical Laboratory Tests, for details. PI must review 
the Day -2 laboratory result before dosing on Day 1
ABPM
X
The ABPM on Day -1 is a 24-hour collection for baseline measurement. 
On dosing days, the ABPM recording will be initiated approximately 2 
hours prior to dosing for measurement of predose baseline.
Administration of itraconazole
X
X
Itraconazole 200 mg will be administered twice daily on Day 8 (dose 
separated by 12 hours) and once daily on Days 9 through 17.
Itraconazole should be administered at approximately the same time 
every morning.  For the outpatient dosing days, subjects will record the 
actual time of dose administration on a diary card.
On Day 14, itraconazole should be administered 1 hour before 
LY3154885 administration (see Section 5.1.2).
Vital signs (BP, PR [supine], 
temperature) (hours)a
48, 60
72
96
X
X
Time points may be added for each study period, if clinically indicated.  
On Day 1, temperature will be measured at predose only.
12-lead ECG
X
X
X
Single safety ECGs.
PGx Sample
Single sample for pharmacogenetic analysis.
LY3154885 PK sampling (hours)a
48, 60
72
96
Sampling times are relative to the time of LY3154885 administration 
(0 hour).


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 16
LY3154885
Note: Site should schedule activities as appropriate. In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures: ECG, vital signs, PK samples, and clinical laboratory tests.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CRU = clinical research unit; CYP = cytochrome 
P450; ECG = electrocardiogram; ED = early discontinuation; MA = medical assessment; PE = physical examination; PI = principal investigator; 
PK = pharmacokinetic; PR = pulse rate.
a
Predose time points refer to dosing before itraconazole and LY3154885.  All postdose time points are relative to the LY3154885 dose.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 17
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part C: Multiple-Ascending Dose – Single Period)
Screening
Days
ED
Follow-up
Comments
Procedure
-28 to 
-3
-2
-1
1
2
3-6
7
8-13
14
15
Approx 
7 days 
after 
discharge
Informed consent
X
Admission to 
CRU
X
D6
D10
Afternoon admission.
Discharge from 
CRU
D3
D8
X
Medical history
X
AE/medication 
review
X
X
X
X
X
X
X
X
X
X
Height/weight
X
X
X
Height at screening only.
Neurological 
exam (hours)
X
Predose, 
4, (8)
24
48
Predose, 
4, (8)
24, 48
X
X
The 8-hour time point is 
optional.
LY3154885/
Placebo
administration
X
X
X
X
X
X
On Days 4, 5, 6, 9, and 10, 
subjects will receive their dose 
of LY3154885/placebo at the 
CRU and then may be 
discharged at the discretion of 
the investigator.
Vital signs (BP, 
PR [supine], 
temperature) 
(hours)
X
X
Predose,  
2, 4, 8, 
12
Predose,
2, 4, 8, 
12
Predose, 
2
Predose, 
2, 4, 8, 
12
Predose, 
2
Predose, 
2, 4, 8, 
12
X
X
X
Time points on outpatient 
dosing days (Days 4, 5, 6, 9, 
and 10) may be adjusted based 
on emerging data from Part A 
and/or if clinically indicated.
On Days 1 to 14, temperature 
will be measured at predose
only.
continued


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 18
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part C:  Multiple-Ascending Dose – Single Period) (continued)
Screening
Days
ED
Follow-up
Comments
Procedure
-28 to 
-3 
-2
-1
1
2
3-6
7
8-13
14
15
Approx
7 days 
after 
discharge
ABPM
X
X
X
X
D11& 
12
X
The ABPM on Day -1 is a 24-
hour collection for baseline 
measurement. On dosing days, 
the ABPM recording will be 
initiated approximately 2 hours 
prior to dosing for 
measurement of predose 
baseline.
Clinical
laboratory tests
X
X
Predose
Predose
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
PI must review Day -2 result 
prior to dose on Day 1.
Pregnancy test
X
X
Predose
X
X
X
Serum test at screening and 
admission; urine test at all 
other time points per 
investigator discretion.  
Women with confirmed 
nonchildbearing potential 
status can be exempted from 
further pregnancy tests during 
the study after screening.
PE/MA
X
Predose
X
X
X
Full PE/MA at screening and 
prior to final discharge from 
the study.  Symptom-directed 
PE/MA at all other time points 
and as deemed necessary by 
the investigator.
  continued


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 19
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part C:  Multiple-Ascending Dose – Single Period) (concluded)
Screening
Days
ED
Follow-up
Comments
Procedure
-28 to 
-3 
-2
-1
1
2
3-6
7
8-13
14
15
Approx 
7 days 
after 
discharge
12-lead ECG 
(hours)
X
Predose
(-45 
min, -30 
min, -15 
min)
Predose 
Predose
Predose, 
(-45 
min, -30 
min, -15 
min), 2, 
3, 4, 6, 
8, 12
24
X
X
Single safety ECGs at 
screening and ED/follow-up;
triplicate ECGs at all other 
times.  ECGs coinciding with 
PK sample time points are to 
be conducted as close as 
possible prior to PK sampling.
PGx sample
X
Single sample for 
pharmacogenetic analysis 
taken prior to/on Day 1.
Stored non-PGx
plasma sample
(hours)
Predose, 
8
Predose
Predose, 
8
PK sampling 
(hours)
Predose, 
0.5, 1, 2, 
3, 4, 5, 
6, 8, 12
Predose
Predose, 
0.5, 1, 2, 
3, 4, 5, 
6, 8, 12
Predose 
(D8 
only)
Predose, 
0.5, 1, 2, 
3, 4, 5, 
6, 8, 12
24 
Sampling times are relative to 
the time of LY3154885 
administration (0 hour).
POMS-2®
X
D6 only
D13 
only
Exploratory 
cognition 
assessments 
(HVLT, DSST)
X
D6 only
D13 
only
PWC-20
Predose
X
X
X
C-SSRS and Lilly 
Self-Harm 
Supplement Form
X
X
D3 &
D6 only
D8 & 
D10
only
X
X
X
Administer at screening, each
admission, and each discharge 
from the CRU.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 20
LY3154885
Note: Site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures: ECG, vital signs, PK samples, clinical laboratory tests, biomarkers, and storage samples.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CRU = clinical research unit; C-SSRS = Columbia-
Suicide Severity Rating Scale; D = day; DSST = Digital Symbol Substitution Test; ECG = electrocardiogram; ED = early discontinuation; HVLT = Hopkins 
Verbal Learning Test; MA = medical assessment; PE = physical examination; PGx = pharmacogenetic; PI = principal investigator; PK = pharmacokinetic; 
POMS-2 = Profile of Mood States Second Edition; PR = pulse rate; PWC-20 = Penn Physician Withdrawal Checklist.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 21
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part D: Formulations/Food Effect – 3 Study Periods)
Periods 1, 2, and 3
Screening
Days
ED
Follow-up
Comments
Procedure
-28 to 
-3
-2
-1
1
2
3
4-6
7
8
9
10
11-13
14
15
16
Approx 7 
days after 
discharge
Informed 
consent
X
Admission to 
CRU
X
X
X 
D6
X
D13
Admission on Day -2 is 
for Periods 1 and 2.
Admission on Day -1 is 
for Period 3.
Discharge from 
CRU
X
X
X
Medical history
X
AE/medication 
review
X
X
X
X
X
X
X
X
X
X
X
X
Height/weight
X
X
X
X
X
Height at screening 
only
Neurological 
exam
X
Predose, 
4, (8)
24
48
X
Predose, 
4, (8)
24
48
Predose, 
4, (8)
24
48
The 8-hour time point 
is optional.
LY3154885
Administration
X
X
X
Period 1 (capsule) and 
2 (tablet) will be under 
fasting conditions; 
Period 3 (tablet) will be 
under fed conditions 
(see Section 6.3.1).
Vital signs (BP, 
PR [supine], 
temperature) 
(hours)
X
X
Predose, 
2, 4, 8, 
12
24
48
Predose, 
2, 4, 8, 
12
24
48
Predose, 
2, 4, 8, 
12
24
48
X
X
Time points may be 
added for each study 
period, if clinically 
indicated.  On Days 1,
8, and 14, temperature 
will be measured at 
predose only.
  continued
Study Schedule Protocol J1Z-MC-HUAA (Part D: Formulations/Food Effect – 3 Study Periods) (continued)


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 22
LY3154885
Periods 1, 2, and 3
Screening
Days
ED
Follow-
up
Comments
Procedure
-28 to 
-3
-2
-1
1
2
3
4-6
7
8
9
10
11-
13
14
15
16
Approx 7 
days after 
discharge
ABPM
X
X
X
X
X
X
X
X
For Periods 1 and 2 only.  
The ABPM on Day -1 is 
a 24-hour collection for 
baseline measurement. 
On dosing days, the 
ABPM recording will be 
initiated approximately 2 
hours prior to dosing for 
measurement of baseline.
Clinical 
laboratory
tests
X
Pre-
dose
Pre-
dose
X
Pre-
dose
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for 
details.
Pregnancy 
test
X
X
Pred
ose
Pred
ose
X
X
Serum test at screening 
and admission of Period 
1 only; urine test at all 
other times.  
Women with confirmed 
nonchildbearing potential 
status can be exempted 
from further pregnancy 
tests during the study 
after screening.
  continued


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 23
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part D:  Formulations/Food Effect – 3 Study Periods) (concluded)
Periods 1, 2, and 3
Screening
Days
ED
Follow-
up
Comments
Procedure
-28 to 
-3
-2
-1
1
2
3
4-6
7
8
9
10
11-13
14
15
16
Approx 7 
days after 
discharge
PE/MA
X
X
X
Full PE/MA at 
screening and prior 
to final discharge 
from the study.  
Symptom-directed 
PE/MA at all other 
time points and as 
deemed necessary 
by the investigator.
12-lead ECG
X
Predose
Predose
Predose
X
X
Single safety ECGs.  
ECGs coinciding 
with PK sample 
time points are to be 
conducted as close 
as possible prior to 
PK sampling.
PK sampling
(hours)
Predose, 
0.5, 1, 2, 
3, 4, 5, 6, 
8, 12
24, 
36
48
Predose, 
0.5, 1, 2, 
3, 4, 5, 6, 
8, 12
24, 
36
48
Predose, 
0.5, 1, 2, 
3, 4, 5, 6, 
8, 12
24,
36
48
PGx sample
Predose
Period 1 only
Note:  Site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures:  ECG, vital signs, PK samples, clinical laboratory tests, biomarkers, and storage samples.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CRU = clinical research unit; D = day; 
ECG = electrocardiogram; ED = early discontinuation; MA = medical assessment; PE = physical examination; PGx = pharmacogenetic; PK = 
pharmacokinetic; PR = pulse rate. 


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 24
LY3154885
3. Introduction
Eli Lilly and Company (Lilly) is developing the small molecule, LY3154885, for the potential 
treatment of Alzheimer’s dementia and Lewy body dementia (LBD), including dementia with 
Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).
Lewy body dementia is an umbrella term for a continuum of progressive neurodegenerative 
cognitive disorders that include DLB and PDD.  Parkinson’s disease dementia and DLB are 
pathologically indistinguishable with substantial overlap in clinical phenotype.  Prominent 
clinical features of both include progressive cognitive impairment, recurrent visual 
hallucinations, fluctuations in attention and wakefulness, and parkinsonism (Lippa et al. 2007; 
Thomas et al. 2018).  Diagnostic features of PDD and DLB are also similar, the key distinction 
being timing of dementia onset relative to parkinsonism, if present (McKeith et al. 2005; Emre et 
al. 2007).  Per consensus criteria, PDD is diagnosed when onset of parkinsonism precedes 
dementia, whereas for DLB the onset of dementia should begin no later than 1 year after, and 
often preceding, parkinsonism that is variably present (McKeith et al. 2005).  It is the arbitrarily 
defined sequencing of symptom onset that historically differentiated the 2 conditions.
Lewy body dementias are pathologically characterized by intraneuronal inclusions of Lewy 
bodies throughout subcortical and cortical brain regions, a major component of which is 
misfolded aggregated -synuclein (Beyer et al. 2009).  Lewy body formation and propagation is 
accompanied by progressive neurodegenerative processes, particularly affecting the 
dopaminergic and cholinergic neurons (Harding and Halliday 2001; Klein et al. 2010; 
Colloby et al. 2012).  These neuropathological findings in both PDD and DLB are largely 
indistinguishable and characterized by subcortical, cortical, and limbic Lewy bodies and 
alpha-synuclein pathology.
The cognitive impairments overlap with progressive executive dysfunction, visual-spatial 
abnormalities, and relatively preserved memory early in the course of disease (Lippa et al. 2007).  
Cognitive impairments have the same genetic risk mutations with alpha-synuclein duplications 
and glucocerebrosidase mutations being associated with the development of either PDD or DLB.  
Prodromal features (ie, rapid eye movement sleep behavior disorder and hyposmia) are risk 
factors for both conditions.  The conditions have similar nonmotor features with prominent 
visual hallucinations, fluctuations in arousal, autonomic dysfunction, depression/anxiety, and 
sleep disturbances and share neuroimaging characteristics with overlapping patterns of atrophy, 
glucose utilization, and neurotransmitter changes (cortical cholinergic deficits [Colloby et al. 
2016] and striatal/cortical dopaminergic deficits [Klein et al. 2010]).  Treatment approaches are 
similar, with avoidance of neuroleptics.  Acetylcholine esterase inhibitors are used for the 
treatment of cognitive impairments in both conditions.  Although PDD and DLB have 
traditionally been considered 2 distinct clinical entities, the constellation of supportive 
pathological, clinical, genetic, imaging, and neurochemical data suggest that they fall within a 
spectrum of the same disease (Berg et al. 2014; Gomperts 2016; Friedman 2018; Jellinger 2018; 
Jellinger and Korczyn 2018).  The 2 diseases share similar and overlapping pathologies in 
monoaminergic and acetylcholinergic neurotransmitter deficits that a positive allosteric 


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 25
LY3154885
modulator (also called “potentiator”) of the dopamine D1 receptor (D1 PAM) may help 
ameliorate.  Critical clinical components of LBDs are also found in Alzheimer’s disease.  For 
example, dopamine insufficiency has been observed in patients with Alzheimer’s disease 
(Mitchell et al. 2011); thus, a meaningful number of patients with Alzheimer’s disease exhibit 
parkinsonian symptoms.  Alzheimer’s disease is an age-related neurodegenerative disease that
results in the slow decline of cognitive and behavioral functions with the characteristic symptom 
of memory loss in patients (Takizawa et al. 2015).  Currently available treatments for 
Alzheimer’s disease have modest benefits for treating cognitive impairment and limited or no 
benefit for other symptoms such as vigilance, depressive symptoms, daytime alertness, and 
apathy.  By potentiating the response to the remaining brain dopamine (or administered 
levodopa), a D1 PAM should improve cognitive performance by enhancing frontal dopaminergic 
neurotransmission, and it is therefore proposed for the treatment of dementia in LBDs (PDD and 
DLB).  In addition to facilitating dopamine neurotransmission, a D1 PAM may be effective in 
improving cognitive dysfunctions in Alzheimer’s disease through activation of cortical neurons, 
markers of synaptic plasticity, and enhanced release of the acetylcholine neurotransmitter.  Other 
effects such as reduced daytime sleepiness, improved mood, and goal-directed behaviors leading 
to reduced apathy (via activation of cortical and striatal D1 receptors) would also be beneficial in 
the LBD and Alzheimer’s disease population.
3.1.
Study Rationale
LY3154885 has not been administered to humans.  This first-in-human study will investigate the 
safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of LY3154885 in 
healthy subjects.  The study will also investigate the impact of cytochrome P450 (CYP) 3A4 
inhibition on the safety, tolerability, and PK of LY3154885 after a single dose via a tablet or 
capsule formulation.  The data generated in this study will be used to help design subsequent 
clinical studies.
3.2.
Background
LY3154885 is a D1 PAM.  By increasing the affinity of the D1 receptor for dopamine, a D1 
PAM should amplify the response to endogenous dopamine, increasing D1 tone when and where 
dopamine is released.  By increasing the affinity of the D1 receptor for dopamine, D1 PAMs 
amplify the response to endogenous dopamine, increasing D1 tone when and where dopamine is 
released (Svensson et al. 2017; Bruns et al. 2018).
This mode of activity is in contrast to direct acting D1 agonists, which activate all D1 receptors 
to which they have access for as long as they are present.  Some D1 agonists also show rapid 
development of tolerance due to constant activation of the D1 receptor.  In contrast, because the 
mechanism of action of a D1 PAM is dependent on endogenous dopamine tone and thus subject 
to normal feedback control, a D1 PAM should have a much lower propensity for overstimulation 
and desensitization.
LY3154885 has demonstrated a favorable safety profile in good laboratory practice (GLP)-
compliant toxicology and safety pharmacology studies to support clinical trials, with 
cardiovascular (CV) and central nervous system (CNS) effects that are transient, monitorable, 


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 2 6
L Y 3 1 5 4 8 8 5
a n d v o i d of c orrelati n g a d verse pat h ol o gic c ha n ges.  
 
L Y 3 1 5 4 8 8 5 has de m o nstrate d s uita ble a bs or pti o n, distri b ut i on, meta b o lis m, a n d e xcreti o n 
pr o perties i n i n vitr o e x peri me nts a n d i n n o nc li nical i n vi v o st u dies t o warra nt cli nical 
i n vesti gati on.  T he c o m p o u n d is li p o p hilic a n d ne utral, wit h acce pta ble s o l ubilit y a n d hi g h 
p er m ea bilit y.  It is eli mi nate d mai nl y via he patic meta b olis m b y C Y P 3 A 4 a n d U D P -
gl uc ur o n os yltra nsferase ( U G T).  I n h u ma n s, L Y 3 1 5 4 8 8 5 is pr ojecte d t o ha ve l o w oral cleara nce 
a n d a half-life of a p pr o xi matel y 1 2 h o urs.  T he dr u g-dr u g i nteracti o n ris k wit h L Y 3 1 5 4 8 8 5 is 
c o nsi dere d l o w base d o n i n vitr o data a n d pr ojecte d h u ma n d ose a n d e x p os ures.  H o we ver, si nce 
t here is s o me u n certai nt y a b o ut t he e xte nt t hat C Y P 3 A 4 meta b olis m c o ntri b utes t o t he o verall 
cleara nce of L Y 3 1 5 4 8 8 5, t his will be e val uate d as part of t his st u d y  b y c oa d mi nisteri n g 
L Y 3 1 5 4 8 8 5 wit h itrac o naz ole, a str o n g C Y P 3 A 4 i n hi bit or. Itrac o naz ole is pre dicte d t o res ult i n 
a L Y 3 1 5 4 8 8 5 area u n der t he c o nce ntrati o n vers us ti me c ur ve ( A U C ) t hat is 2. 6-ti mes t he A U C 
w he n L Y 3 1 5 4 8 8 5 is a d mi nistere d al o ne.
3. 3.
B e n efit/ Ri s k A s s e s s m e nt
T he n o ncli nical safet y i nf or mati on f or L Y 3 1 5 4 8 8 5 a de q uatel y s u p p orts t he tra nsiti on fr om 
precli nic al stat us t o cli nical de vel o p me nt .  O n t he basis of t he n o ncli nical data, L Y 3 1 5 4 8 8 5 
is n ot c o nsi dere d t o be a hi g h -ris k c o mp o u n d.  T his pr ot oc ol  reflects t he fact t hat L Y 3 1 5 4 8 8 5
has n ot bee n a d mi nistere d t o h u ma ns pre vi o usl y , a n d t o mitigate t hi s ris k, t he st u d y will be 
c o n d ucte d i n acc or da nce wit h pri nci ples o utli ne d i n t he G ui deli ne o n Strate gi es t o I de ntif y a n d 
Mi tigate Ris ks f or Fi rst-i n-H u m a n Cli nical Trials wit h I n vestig ati o n al  Me dici nal Pr o d ucts. A n y 
p ote nti al ris k c o uld b e i de nt ifie d earl y t hr o u g h clos e m o ni t ori n g a n d s ur veilla nce, s uc h as 
electr ocar dio gr a m s (E C G s) a n d assess me nt of vit al sig ns .
T here i s n o a nticipate d t hera pe uti c be nefit for t he s u bjects.
M ore i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, seri o us a d verse e ve nts ( S A Es) ,
a n d reas o na bl y a nt ici pate d a d verse e ve nts ( A Es) of L Y 3 1 5 4 8 8 5 are t o be f o u n d i n t he
I n vesti gat or’s Br oc h ure (I B).
C CI
C CI


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 27
LY3154885
4. Objectives and Endpoints
Table HUAA.4.1 shows the objectives and endpoints of the study.
Table HUAA.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To explore the safety and tolerability of single and multiple 
doses of LY3154885 in healthy subjects
Incidence of treatment-emergent adverse events 
(TEAEs)
Secondary

To determine the pharmacokinetics (PK) of LY3154885 
following administration of single and multiple oral doses 
of LY3154885

To determine the PK of LY3154885 when administered 
with itraconazole (Part B only)

To assess safety and tolerability of LY3154885 when 
administered with itraconazole (Part B only)

To compare the PK of LY3154885 when administered with 
a capsule or tablet formulation (Part D only)

To evaluate the effect of a high-fat diet on the PK of 
LY3154885 (Part D only)
Maximum observed drug concentration (Cmax), 
time to Cmax (tmax) and, area under the 
concentration versus time curve (AUC) of 
LY3154885
Cmax and AUC for LY3154885 alone and in the 
presence of itraconazole
TEAEs
Cmax, tmax, and AUC of LY3154885 for capsule 
and tablet formulations
Cmax, tmax, and AUC of LY3154885 with and 
without a high-fat diet 
Exploratory (Part C Only)

To explore any procognitive effects of LY3154885 in 
healthy subjects using the Hopkins Verbal Learning Test 
(HVLT) and Digital Symbol Substitution Test (DSST)

To explore the effect of LY3154885 on subjective mood 
using the Profile of Mood States Second Edition (POMS-2)

To evaluate any potential withdrawal symptoms following 
multiple once-daily dosing of LY3154885
HVLT and DSST
Effect on mood profile
Responses to Penn Physician Withdrawal 
Checklist (PWC-20)


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
5. Study Design
5.1.
Overall Design
This is a Phase 1, single-center study in healthy subjects to be conducted in 4 parts:

Part A will be a subject- and investigator-blind, placebo-controlled, randomized, single-
ascending dose (SAD), 3-period crossover study to evaluate safety, tolerability, and PK 
of LY3154885 in 2 alternating cohorts.

Part B will be a subject- and investigator-blind to LY3154885/placebo, single-period, 
drug-drug interaction study with itraconazole.

Part C will be a subject- and investigator-blind, placebo-controlled, randomized, 14-day 
multiple-ascending dose (MAD), parallel-group, 3-cohort, single-period study to evaluate 
safety, tolerability, and PK of LY3154885.

Optional Part D will be an open-label, 3-period 3-sequence PK study of LY3154885 
administered using a capsule or tablet formulation.  Part D will also include a pilot food 
effect evaluation.
Study governance considerations are described in detail in Appendix 3.
5.1.1. Part A (Single-Ascending Dose)
Part A will be conducted in 2 alternating cohorts (Cohorts 1 and 2), each consisting of 
approximately 12 subjects who will participate in up to 3 study periods. The planned doses of 
LY3154885 to be tested are 15, 45, 100, 200, 400, and 500 mg (see Section 5.5 for details).
Sentinel dosing will be used in Part A of the study.  For all dose levels, LY3154885 and placebo 
will be administered first to 2 subjects (1:1 LY3154885:Placebo) in a blinded manner. These 
subjects will be followed up for 24 hours postdose; if the dose is well tolerated, dosing of the 
remaining 10 subjects in the cohort at the same dose level may begin. 
Each subject in Cohorts 1 and 2 will be randomized to receive 2 single oral doses of LY3154885 
and 1 oral dose of placebo as a capsule formulation over 3 study periods in a crossover fashion.  
For each study period, it is intended that 8 subjects will receive LY3154885 and 4 subjects will 
receive placebo.  
In Period 1, subjects will be admitted to the clinical research unit (CRU) on the afternoon of 
Day -2 for set up of baseline ambulatory blood pressure monitoring (ABPM) (see Section 9.4.4)
and on Day -1 for Periods 2 and 3.  Subjects will undergo an overnight fast (Section 6.3.1) before 
dosing with LY3154885 or placebo as a single oral dose on Day 1 and will remain inpatient for 
at least 48 hours after dosing (until Day 3), after which they may be discharged at the discretion 
of the investigator.  The washout time between doses for a given subject will be at least 7 days.  
A poststudy follow-up visit will be conducted at least 7 days after the final dose.
All available safety data, including AEs, vital signs (blood pressure [BP] and pulse rate [PR]), 
ECGs, and clinical laboratory tests, from all subjects dosed will be assessed prior to escalating to 


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 29
LY3154885
the next dose level (see Section 10.3.5).  Safety data must include data from at least 2 days from 
a minimum of 6 subjects who received LY3154885. The investigator and sponsor will review 
the data, with the investigator remaining blinded.  If dose escalation is terminated prior to 
reaching Dose 6 because of tolerability issues, previous dose levels may be repeated or 
lower/intermediate dose levels may be tested.
Subjects will provide total urine collections for the 36 hours postdose in each period for 
exploratory metabolism and potential assessment of drug absorption and renal elimination; an 
additional blood sample will be collected to determine serum creatinine measurements.
Figure HUAA.5.1 illustrates the study design for Part A.
Abbreviations:  LY = LY3154885; n = number of subjects; PL = placebo.
Each subject will receive 2 doses of LY3154885 and 1 placebo dose.
Figure HUAA.5.1.
Illustration of study design for Part A.
5.1.2. Part B (CYP3A4 Inhibition)
Part B will consist of approximately 12 subjects [9 LY3154885; 3 placebo] and will assess the 
effect of itraconazole, a CYP3A4 inhibitor, on the safety, tolerability, and PK of LY3154885.  
The LY3154885 dose to be studied in Part B will be determined based on safety, tolerability, and 
PK data from Part A and will be administered as a capsule formulation.  See Section 5.5 for 
further LY3154885 dose justification.
As detailed in the Schedule of Activities (Section 2), subjects will be admitted to the CRU in the 
afternoon of Day -2 for set up of baseline ABPM (see Section 9.4.4) and will undergo an 
overnight fast (see Section 6.3.1) before receiving a single oral dose of LY3154885 or placebo 
on Day 1.  Subjects may be discharged from the CRU on Day 3 and will be re-admitted on Day 
7.  There will be a 7-day washout period followed by 10 days of dosing with 200 mg 
itraconazole (twice daily on Day 8 [dose separated by 12 hours], then once daily on Days 9
through 17).  See Section 6.3.1 for the fasting requirements for the itraconazole dosing.  Subjects 
will be discharged from the CRU on Day 9 after receiving their dose of itraconazole and will be 
self-dosing on an outpatient basis from Days 10 through 12.  Subjects will be asked to complete 
a diary card to document the actual date and time of dose administration.
Safety review completed after each 
dose level prior to escalation
Period 1
Period 2
Period 3
Cohort 1
(n=12; 
8LY:4PL)
Dose 1 
LY or PL 
≥7 day 
washout
Dose 3 
LY or PL 
≥7 day 
washout
Dose 5 
LY or PL 
≥7 day 
washout
Cohort 2
(n=12; 
8LY:4PL)
Dose 2 
LY or PL 
≥7 day 
washout
Dose 4 
LY or PL 
≥7 day 
washout
Dose 6 
LY or PL 


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 30
LY3154885
Subjects will be re-admitted to the CRU in the evening of Day 12 and will undergo an overnight 
fast (see Section 6.3.1) before receiving a single oral dose of LY3154885 or placebo on Day 14, 
approximately 1 hour after the dose of itraconazole.  Blood sampling for PK purposes 
(LY3154885 and itraconazole) will occur according to the Schedule of Activities in Section 2.  
Subjects will remain in the CRU until discharge on the morning of Day 18, approximately 
24 hours after the final dose of itraconazole.
Figure HUAA.5.2 illustrates the study design for Part B.
Abbreviations: BID = twice daily; CRU = clinical research unit; LY = LY3154885; 
PK = pharmacokinetic; PL = placebo; QD = once daily.
Figure HUAA.5.2.
Illustration of study design for Part B.
5.1.3. Part C (Multiple-Ascending Dose)
The decision to conduct Part C will be made after review of safety, tolerability, and PK data 
from Parts A (SAD) and B (CYP3A4 Inhibition).  
Part C will explore up to 3 dose levels in 3 separate cohorts (Cohorts 4 to 6) of healthy subjects.  
Each cohort will consist of approximately 12 subjects (9 LY3154885; 3 placebo) dosed daily for 
14 days with a capsule formulation.
Subjects will participate in a single study period consisting of 14 days of once-daily dosing with 
LY3154885 or placebo; study drug will be administered as a single oral dose in the morning 
under fasted conditions (see Section 6.3.1).  Subjects will be admitted to the CRU on the 
afternoon of Day -2 for set up of baseline ABPM (see Section 9.4.4) and will be required to 
remain in-house for at least 48 hours after dosing (Day 3), and at the discretion of the 
investigator.  As detailed in the Schedule of Activities (Section 2), subjects will attend the CRU 
on Days 4, 5, 6, 9, and 10 on an outpatient basis for daily dosing and will be permitted to leave 
the CRU at the discretion of the investigator.  Pharmacokinetic sampling will be conducted as 
detailed in Section 2.  To assess CV effects and potential accommodation over time, ABPM will 
Study Day
-1
1
15
16
17
Single dose of 
LY3154885 or 
placebo 
(9 LY: 3 PL)
Daily dosing of 200 mg itraconazole(BID 
on Day 8; QD on Days 9 through 17)
Subjects will self-dose on an outpatient 
basis on Days 10 to 12.
PK sampling of LY3154885
PK sampling of itraconazole and metabolites
8
14
Single dose of 
LY3154885 or 
placebo 
(9 LY: 3 PL)
2
3
7-day washout
18
Admission to CRU
Discharge from CRU
-2
7
9
12


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 31
LY3154885
be included on Day -1 (baseline) and on Days 1, 2, 7, 11 and 12, and 14.  A poststudy follow-up 
visit will be conducted approximately 7 days after discharge.
The doses evaluated will be selected based on emerging data from Parts A and B and from the 
lower doses from Part C (see Section 5.5 for details).  If the safety data do not support increasing 
the dose in subsequent cohorts, then a dose may be repeated or lower/intermediate doses may be 
explored.  The PK data obtained during the study may be used to assist in dose-escalation 
decisions, but such data are not required for dose-escalation purposes.  For the safety review 
prior to dose decisions between cohorts, all available safety data (AEs, vital signs, ECGs, and 
laboratory results) to Day 14 from at least 6 subjects taking LY3154885 must be reviewed by the 
sponsor and investigator.  In addition, each cohort (including at least 6 subjects treated with 
LY3154885) will complete dosing to Day 14 prior to the next cohort being admitted to the CRU 
for dosing.
Figure HUAA.5.3 illustrates the study design for Part C.
Abbreviations:  LY = LY3154885; PL = placebo; QD = once daily.
Figure HUAA.5.3.
Illustration of study design for Part C.
5.1.4. Optional Part D (Pharmacokinetics of Capsule and Tablet 
Formulations and Food Effect)
The decision to conduct Part D will be made after review of safety, tolerability, and PK data 
from Parts A (SAD) and B (CYP3A4 Inhibition).  Part D may be conducted in parallel with 
Part C.
Part D is optional and will assess the PK of single oral doses of LY3154885 in approximately 
9 healthy subjects when administered as a capsule (Period 1), as a tablet (Period 2), and as a 
tablet with a high-fat diet (Period 3).  The dose for Part D will not exceed the highest dose tested 
in Part A (SAD) that was deemed safe and well tolerated.
In Periods 1 and 2, subjects will be admitted to the CRU the afternoon of Day -2 for set up of 
baseline ABPM (see Section 9.4.4); admission for Period 3 will be on Day -1.  In Period 1, 
subjects will undergo an overnight fast (see Section 6.3.1) before receiving a single oral dose of 
Cohort 4 
(LY=9; PL=3)
Cohort 5 
(LY=9; PL=3)
Cohort 6
(LY=9; PL=3)
LY or placebo
Low Dose
(QD for 14 days)
LY or placebo
Medium Dose
(QD for 14 days)
LY or placebo
High Dose
(QD for 14 days)
Safety data to 
at least Day 6
Safety data to 
at least Day 6


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
LY3154885 (capsule formulation) on Day 1.  Subjects will remain inpatient for at least 48 hours 
after dosing, after which they may be discharged at the discretion of the investigator.  Subjects 
will be re-admitted to the CRU on Day 6 and will undergo an overnight fast before receiving a 
subsequent single oral dose of LY3154885 on Day 8 with the same formulation. Subjects will be 
discharged on Day 10, at least 48 hours after dosing.  Re-admission to the CRU will be on 
Day 13, and following an overnight fast, subjects will receive a single oral dose of LY3154885 
on Day 14 with the same formulation.  Final discharge from the CRU will occur on Day 16.  
Pharmacokinetic sampling will be conducted as detailed in the Schedule of Activities 
(Section 2).
Period 2 will be conducted as described for Period 1; however, LY3154885 will be administered 
as a tablet formulation.
Period 3 will be conducted as described for Period 1; however, subjects will receive a single 
oral dose of LY3154885 (tablet formulation) after administration of a high-fat diet (see 
Section 6.3.1). 
The follow-up visit will occur approximately 7 days after final discharge.
Figure HUAA.5.4 illustrates the study design for Part D.
Abbreviation:  n = number of subjects; PK = pharmacokinetic.
Figure HUAA.5.4.
Illustration of study design for Part D.
5.2.
Number of Participants
For Part A, up to 30 subjects may be enrolled into Cohorts 1 and 2 in order to ensure that 
approximately 12 subjects per cohort (8 LY3154885; 4 placebo) complete this part of the study.
For Part B, up to 15 subjects may be enrolled in order to ensure that approximately12 subjects 
(9 LY3154885; 3 placebo) complete this part of the study.
For Part C, up to 45 subjects may be enrolled in order to ensure that approximately 36 subjects 
complete this part of the study (with approximately 12 subjects [9 LY3154885; 3 placebo] 
completing each dose level).
For optional Part D, up to 12 subjects may be enrolled in order to ensure that approximately
9 subjects complete this part of the study.
Period 1
Period 2
Period 3
LY3154885
n=9
LY3154885
capsule
(Days 1, 8 and 
14)
≥7 day 
washout
LY3154885 
tablet
(Days 1, 8 and 
14)
≥7 day 
washout
LY3154885 
tablet after high 
fat meal
(Days 1, 8 and 
14)
≥7 day 
washout
Intensive PK sampling on Days 1, 8, and 14


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 3
L Y 3 1 5 4 8 8 5
5. 3.
E n d of St u d y D efi niti o n
E n d of t he st u d y  is t he date of t he last visit or last sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule o f 
Act i vities ( Sectio n 2 ) for t he last s u bject.
5. 4.
S c i e ntifi c R ati o n al e f or St u d y D e si g n
T his st u d y  will be c o n d ucte d t o e val uate t he safet y, t olera bility, a n d P K of si n gle a n d mul tiple 
d oses of L Y 3 1 5 4 8 8 5 i n healt h y s u bjects.
I n Parts A, B, a n d C, t he s u bjects a n d site staff (e xce pt p har mac y staff) will be b li n de d t o 
treat me nt all ocati o n t o all o w a n u n biase d assess me nt of t he safet y  a n d t olera bilit y data, w hi c h 
will all o w a m ore r o b ust c o m paris o n bet wee n L Y 3 1 5 4 8 8 5 a n d place b o data .
I n Part A, B, a n d D, a was h o ut peri o d of at least 7 da ys has bee n selecte d t o mi ni mize carr y o ver 
effects bet wee n d oses base d o n t he pre dicte d h u ma n P K o f L Y 3 1 5 4 8 8 5 fr o m n o ncli nical st u dies .
A ta blet f or m ulat i on is bei n g de vel o pe d f or u pc o mi n g st u dies a n d t he effect of f o o d o n t he P K of 
L Y 3 1 5 4 8 8 5 is u n k n o w n ; t heref ore, Part D will c o m pare t he P K pr ofile o f a ta blet for m ulat i on 
vers us ca ps ule f or mulat i on a n d t he effect of f o o d o n t he P K of L Y 3 1 5 4 8 8 5 gi ve n wit h t he 
ta blet f or mulat i on.
5. 5.
J u stifi c ati o n f or D o s e
I n Part A, the pla n ne d cli nical d ose s t o be teste d are 1 5 , 4 5, 1 0 0, 20 0, 4 0 0 , a n d 5 0 0 m g base d o n 
a ni mal t o xic o l og y /t o xic o ki net ics, precli nical p har mac ol og y , a n d P K i nf or mat i on.  I n Part B 
(C Y P 3 A 4 I nteractio n), t he L Y 3 1 5 4 8 8 5 d ose selecti o n will be base d o n e mer gi n g data fr o m 
Part A b ut is c urre ntl y pla n ne d t o be ≤2 0 0 m g.  I n Pa rt C (M A D ), d ose selecti on will be base d o n 
e mer gi n g safet y,  t olera bilit y, a n d P K data fr o m Part A a n d Part B, b ut Part C is c urre ntl y pla n ne d 
t o start at 3 5 m g a n d n ot e xcee d t he hi g hest d ose i n Part A or t he ma xi m u m e x p os ure ac hie ve d i n 
Part A or B t hat are f ou n d t o be well t olerate d.  I n Part D, t he d ose f or t he ca ps ule a n d ta blet is 
pl a n ne d t o be ≤4 0 0 m g b ut will ult i matel y be base d o n e mer gi n g safety,  t olera bilit y,  a n d P K data 
fr om Part A.
T he t o xi cit y pr ofile of L Y 3 1 5 4 8 8 5 has bee n c haracterize d i n rats a n d m o n ke ys t hr o u g h a 
pac ka ge of G L P c o m plia nt, re peat -d ose t o xic o l og y, safet y p har mac o l og y , a n d ge netic t o xic ol og y  
st u dies; n o n-G L P t o xi cit y st u dies were c o n d ucte d wit h L Y 3 1 5 4 8 8 5 as well a n d are disc usse d i n 
t he I B.  T hese st u dies wit h L Y 3 1 5 4 8 8 5 de m o nstrate a n acce pta ble safety pr ofile f or h u ma n 
testi n g with C V a n d C N S effects t hat are tra nsie nt a n d m o nit ora bl e.
C CI


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 4
L Y 3 1 5 4 8 8 5
(Ta ble H U A A. 5. 1 ).
T he m a xi m u m d os e for t his st u d y  is e x pecte d t o be 5 0 0 m g base d o n a ni mal t o xic ol og y  st u dies 
a n d h u ma n P K pre dicti o ns f or L Y 3 1 5 4 8 8 5 , 
 
  A 5 0 0 -m g d ose i n h u ma ns is pre dicte d t o res ult i n a 
mea n plas ma A U C o f 
µ g × hr/ m L a n d C m a x of   
 µ g/ mL; t hese val ues are e q ui vale nt t o 
1/ 1 0t h t he A U C at t he N O A E L i n m o n ke ys a n d 1/ 1 0t h t he C m a x at t he N O A E L i n rats .  T he 
C m a x a n d A U C-base d m ult i ples ass ociate d wit h 
 fr om t he 
n o n- G L P st u d y  in rats, w hi c h were n ot o bser ve d at si milar e x p os ures i n t he G L P st u d y , are als o 
prese nte d i n Ta ble H U A A. 5 . 1.  T o n ote, t he pre dicte d h u ma n C m a x at 5 0 0 m g is 
 bel o w 
t he C m a x at  t he N O E L f or
 i n b ot h rats a n d m o n ke ys .  P har mac o ki netic data will be 
re vie we d d uri n g t he st u d y t o s u p p ort d ose escalati o ns (see Secti o n 1 0. 3. 5 f or details) a n d 
mai ntai n pre dicte d dr u g e x p os ures bel o w 1/ 1 0t h t he A U C at t he N O A E L i n m o n ke ys a n d 1/ 1 0t h 
t he C m a x at  t he N O A E L i n rats. A d ose hi g her t ha n 5 0 0 m g ma y be st u die d if h u ma n P K data 
fr om pre vi o us c o h orts s u g gests t he pre dicte d e x p os ure will be bel o w 1/ 1 0t h t he A U C at t he 
N O A E L i n m o n ke ys a n d 1/ 1 0t h t he C m a x at  t he N O A E L i n rats.
I n Part B (C Y P 3 A 4 I nteracti o n ), t he L Y 3 1 5 4 8 8 5 d ose select i on will be base d o n e mer gi n g data 
fr om P art A b ut i s c urre ntl y pla n ne d t o be ≤2 0 0 m g . It is pre dicte d t hat t he ma xi m u m e x p os ure 
i ncrease i n L Y 3 1 5 4 8 8 5 w he n a d mi nistere d wit h itrac o naz ole, a str o n g C Y P 3 A 4 i n hi bit or, is 
C CI
C CI
C CI
C CI
C C
I
C CI
C CI
P P D


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 5
L Y 3 1 5 4 8 8 5
a p pr o xi matel y 2. 6-f ol d.  T heref ore, t he L Y 3 1 5 4 8 8 5 d ose selecte d will be bel o w t he hi g hest d ose 
dee m e d well t olerate d t hat has a plas ma e x p os ure t o all o w f or u p t o a 2. 6 -f ol d i ncrease i n 
e x p os ure t hat ma y res ult fr o m c oa d mi nistrati o n wit h itrac o naz ole, a n d t he pre di cte d L Y 3 1 5 4 8 8 5 
pl as ma e x p os ure at t his d ose w he n c oa d mi nistere d wit h itrac o naz ole will be bel o w 1/ 1 0t h t he 
A U C at t he N O A E L i n m o n ke ys a n d 1/ 1 0t h t he C m a x at  t he N O A E L i n rats.  T he d ose re gi me n 
f or itrac o naz ole will be 2 0 0 m g t wic e dail y o n Da y 8 ( d ose se parate d b y 1 2 h o urs ) a n d o nce dail y  
o n Da y s 9 t hr o u g h 1 7.
I n Part C (M A D ), the d ose s will be base d o n e mer gi n g safet y,  t olera bilit y , a n d P K data fr o m  
Part A ( S A D ) a n d Part B.  E mer gi n g safet y a n d t olera bilit y data fr o m Part C will als o be 
c o nsi dere d f or d ose escalati on .  T he hig hest d ose teste d i n Part C will n ot e xcee d t he hi g hest 
d ose i n Part A (c urre ntl y pla n ne d t o be 5 0 0 m g) t hat was well t olerate d or t he ma xi m u m 
e x p os ure ac hie ve d i n Part A or B f o u n d t o be well t olerate d.
I n Part D, t he pla n ne d d ose f or t he ca ps ule a n d ta blet will be ≤4 0 0 m g b ut will  ulti matel y be 
base d o n e mer gi n g safet y , t olera bilit y, a n d P K data fr o m Part A .
C CI


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 3 6
L Y 3 1 5 4 8 8 5
C CI


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG.  The nature of any 
conditions present at the time of the physical examination and any preexisting conditions will be 
documented.
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, are 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:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination  
[1a] male subjects:
Men, regardless of their fertility status, with partners who are nonpregnant 
women of childbearing potential, must agree to either remain abstinent (if 
this is their preferred and usual lifestyle) or use condoms with spermicide as 
well as 1 additional highly effective (<1% failure rate) method of 
contraception (such as combination oral contraceptives, implanted 
contraceptives, or intrauterine devices) or effective method of contraception 
(such as diaphragms with spermicide) for 3 months following dosing.
Men with pregnant partners should use condoms with spermicide during 
intercourse for the duration of the study or for 3 months following dosing, 
whichever is longer.
Men who are in exclusively same-sex relationships (as their preferred and 
usual lifestyle) or with female partners of nonchildbearing potential are not 
required to use contraception.
Men should refrain from sperm donation for the duration of the study or for 
3 months following the last dose of study drug, whichever is longer.
[1b] female subjects of nonchildbearing potential, including those who are:
A. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy,
bilateral salpingectomy, confirmed tubal ligation, or tubal occlusion) or 
congenital anomaly such as Müllerian agenesis; or
B. postmenopausal, defined as 1 of the following:


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
i.
a woman at least 50 years of age with an intact uterus, not on hormone 
replacement therapy, who has had either:
a.
cessation of menses for at least 1 year; or 
b.
at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone level ≥40 mIU/mL at screening
ii.
a woman at least 55 years of age, not on hormone replacement therapy, 
who has had at least 6 months of spontaneous amenorrhea; or
iii.
a woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy
[2]
are between 21 and 65 years of age, inclusive, at the time of screening
[3]
have a body mass index (BMI) of 18.0 to 35.0 kg/m2, inclusive
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[5]
have venous access sufficient to allow for blood sampling 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
[7]
are able and willing to give signed 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, biological or 
legal guardian, child, or sibling
[9]
are Lilly employees
[10] are currently enrolled in a clinical study 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 study involving an 
investigational product. If the previous investigational product has a long 
half-life, 5 half-lives or 30 days (whichever is longer) should have passed
[12]
have previously completed or withdrawn from this study or any other study 
investigating LY3154885, and have previously received LY3154885
[13]
have known allergies to LY3154885, related compounds or any components 
of the formulation, itraconazole, or history of significant atopy


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 39
LY3154885
[14]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[15]
have a marked baseline prolongation of corrected QT (QTc) interval (for 
example, repeated demonstration of a QTcB interval >450 msec for males or 
>470 msec for females); 
A history of additional risk factors for Torsades de Pointes (for example, heart 
failure, hypokalemia, family history of Long QT Syndrome); 
The use of concomitant medications that prolong the QT/QTc interval
[16]
have an abnormal BP (taken after the subject has been in a supine position for 
at least 5 minutes) for the population, as determined by a systolic BP 
>140 mm Hg or a diastolic BP >90 mm Hg at screening or a preexisting 
history of hypertension. Up to 2 additional measurements may be taken after 
an appropriate resting interval at screening to confirm eligibility
[17]
have a significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine (such as Cushing syndrome, 
hyperthyroidism, hyperaldosteronism), hematological, or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs; of constituting a risk when taking the investigational 
medicinal product (IMP); or of interfering with the interpretation of data
[18]
have a history of or current significant psychiatric disorders 
[19]
have a history of head injury (eg, skull fracture, cerebral contusion, trauma 
resulting in prolonged unconsciousness), intracranial neoplasm or 
hemorrhage, prior seizure (other than remote history of childhood febrile
seizure), or other condition that would place the subject at increased risk 
of seizure
[20]
regularly use known drugs of abuse and/or show positive findings on drug 
screening
[21]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[22]
show evidence of hepatitis B and/or positive hepatitis B surface antigen 
[23]
show evidence of hepatitis C and/or positive hepatitis C antibody
[24]
are women who are lactating


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
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LY3154885
[25]
have used or intend to use over-the-counter/herbal supplements (eg, St. John’s 
wort) or prescription medication within 14 days or 5 half-lives, whichever is 
longer, before initial dosing or during the study (vitamin/mineral supplements 
and occasional paracetamol/acetaminophen up to 3-g dose in a 24-hour period
are allowed).  If this situation arises, inclusion of an otherwise suitable subject 
may be at the discretion of the investigator and sponsor.  Medications that 
inhibit or induce CYP3A4 are specifically excluded within 14 days prior to 
dosing and during the study
[26]
have donated blood of more than 450 mL or have participated in a 
clinical study that required similar blood volume drawn within the past 
3 calendar months
[27]
have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (males >65 years and females) or are 
unwilling to stop alcohol consumption for 24 hours prior to CRU admissions 
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)
[28]
have tobacco consumption of more than 10 cigarettes per day (or the 
equivalent) or are unable or unwilling to refrain from nicotine use while 
resident at the CRU
[29]
consume Seville oranges or Seville orange–containing products, grapefruit or 
grapefruit-containing products, star fruits or star fruit-containing products, 
pomegranates, and/or pomelos within 14 days prior to dosing or during 
the study
[30]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in
the study
In addition, for Part B only:
[31]
have impaired hearing or a history of hearing problems
In addition, for Part C only:
[32]
Presence of significant uncontrolled neuropsychiatric disorder; have recent 
history (within 30 days prior to the screening visit and any time between 
screening and admission) of a suicide attempt; or develops active suicidal 
ideation with some intent to act with or without a specific plan (yes to 
question 4 or 5 on the “Suicidal Ideation” portion of the Columbia Suicide-
Severity Rating Scale [C-SSRS]) or develops suicide-related behaviors as 
recorded on the C-SSRS at screening or admission; or are clinically judged by 
the investigator to be at risk for suicide
6.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria [8] and [9] prevent conflict of interest in study participants.  Exclusion 
Criteria [10] through [29] and [32] exclude medical conditions, medication intolerance, and 
concomitant medication use that may constitute a risk for the subject and/or may confound the 


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assessment of study endpoints.  Exclusion Criterion [31] excludes subjects with hearing 
problems in Part B because itraconazole has been associated with transient or permanent 
hearing loss.
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
Part A:  Subjects will be required to fast overnight (at least 8 hours) prior to dosing on Day 1 and 
for at least 4 hours after dosing with LY3154885/placebo, with the exception of water, which
will be freely available after dosing.
Part B:  Subjects will be required to fast overnight (at least 8 hours) prior to each dosing day 
(including itraconazole dosing) and for at least 4 hours after dosing with LY3154885, and 
coadministration of LY3154885 and itraconazole, with the exception of water that will be freely 
available after dosing.  Subjects will also need to fast for approximately 2 hours prior to the 
evening dose of itraconazole on Day 8 and at least 1 hour after dosing, with the exception of 
water, which will be freely available after dosing.
Part C:  Subjects will be required to fast overnight (at least 8 hours) on all dosing days and for at 
least 4 hours after dosing on Days 1, 7, and 14 (intensive PK days), with the exception of water,
which will be freely available after dosing.  On nonintensive PK days, subjects may receive a 
light breakfast approximately 1 hour after dosing.
Part D:  In Periods 1 and 2, subjects will be required to fast overnight (at least 8 hours) prior to 
dosing on Days 1, 8, and 14 and for at least 4 hours after dosing with LY3154885, with the 
exception of water, which will be freely available after dosing.  All other meals will be provided 
according to CRU procedures. In Period 3, following an overnight fast of at least 8 hours, 
subjects will start the high-fat diet (see below) 30 minutes prior to administration of the study 
drug on Days 1, 8, and 14.  Subjects will consume this entire meal in 30 minutes or less; 
however, the study drug will be administered 30 minutes after the start of the meal.  The study 
drug should be administered with approximately 240 mL of room temperature water.  No further 
food will be allowed for at least 4 hours postdose.  Fluids will be restricted from 1 hour prior to 
and until 1 hour after dosing, except for fluid provided with the meal and water required for dose 
administration.
The standardized high-fat, high-calorie meal (fat comprises approximately 50% of total caloric 
content of the meal) should consist of approximately 1000 calories.  No additional food or 
substitute is allowed.  A typical test meal is 2 eggs fried or scrambled in butter, 2 strips of bacon, 
2 slices of toast with butter, 4 ounces of hash brown potatoes, and 8 ounces of whole milk.  This 
test meal derives approximately 150, 250, and 500 to 600 calories from protein, carbohydrates, 
and fat, respectively.


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6.3.2. Caffeine, Alcohol, and Tobacco 
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.
Subjects will not be permitted to consume alcohol from 48 hours prior to CRU admissions and 
while resident at the CRU. During the study, while not resident at the CRU, the maximum daily 
alcohol intake should not exceed 2 units (see Exclusion Criterion [27], Section 6.2, for 
unit definition).
Smoking, tobacco consumption, or use of any nicotine-replacement therapy is not permitted 
while resident at the CRU. While not resident in the CRU, smoking should not exceed
10 cigarettes per day or equivalent in nicotine use or nicotine substitutes.
6.3.3. Activity
Subjects should avoid strenuous exercise and/or activity for at least 48 hours prior to CRU 
admission and while resident at the CRU.
Subjects should remain upright for at least 2 hours after dosing, with the exception of any 
requirements for protocol procedures (eg, supine for ECGs).
6.3.4. Blood and Plasma Donations
Subjects are not permitted to make blood or plasma donations while participating in the study.
6.4.
Screen Failures
As this study will be conducted in healthy subjects only, individuals who do not meet the criteria 
for participation (ie, screen failure) may not be re-screened, although specific tests such as 
clinical laboratory tests and vital signs/ECGs may be repeated at the discretion of the investigator 
to confirm study eligibility.
Subjects who were eligible for inclusion in previous cohorts but were not randomized for 
nonmedical reasons may be reassessed for eligibility/inclusion in a subsequent cohort.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of LY3154885 or matching placebo administered orally.  
Table HUAA.7.1 shows the treatment regimens.
Capsules (or tablets for optional Part D) of LY3154885 and/or placebo will be administered 
orally with approximately 240 mL of room temperature water in the morning of each dosing day 
with subjects in a sitting position.  Subjects will not be allowed to lie supine for approximately
2 hours after dosing, unless clinically indicated or for study procedures.
Table HUAA.7.1.
Treatments Administered
Treatment Name
LY3154885
LY3154885
Placebo
Itraconazole
Dosage Formulation
Capsule
Tablet
Capsule
Solution
Unit Dose Strength(s)/
Dosage Level(s)
Extemporaneous 
preparation 
15 to 500 mg
Extemporaneous 
preparation
Dose to be determined
Matching 
placebo
10 mg/mL
Route of Administration
Oral
Oral
Oral
Oral
The investigator or designee is responsible for:

explaining the correct use of the investigational product(s) to the subject

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials. 
7.1.1. Packaging and Labeling
The LY3154885 capsules or tablets will be prepared extemporaneously.  The proposed range of 
strengths to be prepared is listed in Table HUAA.7.1.
In Parts A, B and C, for any specific cohort/dosing period, the total number of capsules 
administered will be the same for all subjects, regardless of whether assigned to placebo or 
LY3154885. However, the number of capsules may vary between dosing periods and cohorts to 
maintain the blind.
Instructions for extemporaneous preparation of the study drug will be provided by the sponsor.  
This will be performed by trained personnel (eg, pharmacist) within a facility at the CRU who 
are qualified to perform these types of operations.


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For LY3154885 capsules, the LY3154885 pure compound with no inactive ingredients will be 
filled into capsules. 
For LY3154885 tablets, the LY3154885 pure compound will be combined with other common 
excipients and compressed into tablets for use in Part D. 
Matching placebo for the LY3154885 capsules will be sourced centrally.  Itraconazole will be 
sourced locally by the site.
The investigational product will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
In Parts A, B, and C, the randomization table will be prepared by the statistician (or appropriate 
delegate) for the study and provided to the CRU pharmacists or pharmacy staff involved in dose 
preparation.  The allocation and dispensing of the study drug will be fully documented and 
verified by a second person.  Detailed records of the amounts of the study drug received, 
prepared, dispensed, and remaining at the end of the study will be maintained by the 
CRU pharmacist.
7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the subject’s case report form (CRF).  In Part B, for 
the outpatient dosing days for itraconazole, subjects will record the actual time of dose 
administration on a diary card.
Dosing with itraconazole should occur approximately 1 hour before dosing with LY3154885 (or 
placebo) when the 2 drugs are coadministered.
7.3.
Blinding
Parts A, B, and C will be investigator- and subject-blind; Part D will be open-label.  The 
sponsors and site monitors are not blinded.
To preserve the blind, only a minimum number of personnel at the CRU (namely, CRU 
pharmacy staff) will see the randomization table before the study is complete.  Individuals 
involved with study drug preparation will not be involved in any of the clinical aspects of the 
study, including study drug administration and AE assessments.  Blinding will be maintained 
throughout the conduct of the study until after all data are cleaned to an acceptable level of 
quality and the CRF is entry locked.
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.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.


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7.4.
Dose Modification
Dose levels, sampling schedule, timing of procedures (eg, PK and ECG assessments), and length 
of CRU stay may be adjusted in view of emerging safety or PK data during the study.  Dose 
increments may be changed, a dose level may be repeated, or a lower dose may be administered.  
If a dose reduction is required, the dose level for the following cohort (ie, the cohort following 
the one that received a lower than planned dose) cannot exceed ½ log.  The timing of blood 
samplings may be adjusted, but the number of samples will not exceed what has been planned, 
plus the additional samples.  The duration of the CRU stay or the duration of safety follow-up 
may be increased (eg, if the half-life of LY3154885 is longer than anticipated) but not decreased.  
These changes must be appropriately documented and communicated by the sponsor to the 
investigator.  Because these adjustments to timings or dose levels are allowable changes 
permitted by the protocol, they would not require a protocol amendment.
7.4.1. Dose Decision/Escalation
By nature of being a dose-escalation study, data will be evaluated on an ongoing basis until the 
maximum tolerated dose (MTD) is determined or the highest planned dose is administered.  The 
highest dose level that is tolerated will be designated as the MTD.
Safety data will be the primary criteria for the dose escalation.  In addition, if available at the 
time of the dose-escalation decision, PK results will be used as supporting data.  No dose 
escalation can occur without prior discussion and agreement between the investigator and the 
Lilly study team. See Sections 5.1.1 and 5.1.3 for further details.
Safety data, in particular AEs, SAEs, BP, PR, and adverse laboratory abnormalities, will be 
independently assessed by the investigator and will be considered related to the investigational 
medicinal product, unless there is clear evidence that the event is not related.  
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 related to LY3154885 administration
2) 2 subjects experience a clinically significant event of persistent tremors that is
deemed to be related to LY3154885 administration 
3) 2 subjects experience clinically significant increases in scheduled vital signs that 
are deemed to be related to LY3154885 administration
4) 2 or more subjects at 1 dose level experience other moderate or severe treatment-
related AEs that impair normal activities and are deemed to be related to 
LY3154885 administration
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all investigational product 
received and that any discrepancies are reported and resolved before use of the study treatment.


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Only participants enrolled in the study may receive IMP or study materials, and only authorized 
site staff may supply or administer IMP.  All IMP should be stored in an environmentally 
controlled and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as 
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The IMP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
Subjects on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  These permitted medications have been described 
in Exclusion Criterion [25].
In general, concomitant medication should be avoided; however, paracetamol/acetaminophen 
(1g, maximum 3g/24 hours) may be administered at the discretion of the investigator for 
treatment of headaches, etc.  If the need for concomitant medication (other than acetaminophen) 
arises, inclusion or continuation of the subject in the study may be at the discretion of the 
investigator after consultation with a Lilly clinical pharmacologist.  Drugs that are known 
inducers or inhibitors of CYP3A4 are specifically excluded.  Any medication used during the 
course of the study must be documented.
7.8.
Treatment after the End of the Study
This section is not applicable for this study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
A subject will be discontinued from receiving further doses of IMP if the investigator assesses 
that continuation on IMP may pose a risk to the well-being of the subject in question.  Subjects 
may also be discontinued from the IMP if a clinically significant event (CSE) occurs in the 
opinion of the investigator.  Following the investigator’s determination that CSE criteria have 
been met and the investigator’s judgment of relatedness to the IMP is documented, a decision 
will be made between the investigator and Lilly or its designee regarding subject discontinuation.
Discontinuation of the IMP for abnormal liver tests should be considered by the investigator 
when a subject meets 1 of the following conditions after consultation with the Lilly designated 
medical monitor:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>5upper limit of normal (ULN)

ALT or AST >3ULN and total bilirubin level (TBL) >2ULN or 
international normalized ratio >1.5 or

ALT or AST >3ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase (ALP) >3ULN

ALP >2.5ULN and TBL >2ULN

ALP >2.5ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Subjects discontinuing from the treatment prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 of this protocol.
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 study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study


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
Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Subject Decision
o
the subject requests to be withdrawn from the study

If any of the potentially clinically significant vital sign criteria (Table HUAA.8.1) are met 
at 3 consecutive scheduled time points using in-clinic vital sign monitoring on Day 1 
and following study drug dosing, the subject should be discontinued from the study drug.  
The relative value of the potentially clinically significant vital sign criteria is calculated 
by comparing the mean of the 3 supine BP and PR measurements at Time 0 on that day.
Table HUAA.8.1.
Potentially Clinically Significant Vital Sign Criteria
o
For vital sign measurements that meet the criteria for potentially clinically 
significant vital signs (Table HUAA.8.1), action will be left to the discretion of 
the investigator and may include discontinuation of study drug or subject.  Prior to 
subject being discontinued from the study, the investigator should consult with the 
Lilly clinical pharmacologist (CP) or designee.

Subjects will be discontinued from the study if the mean QT interval corrected for 
heart rate using Fridericia’s formula (QTcF) on the ECG is >500 milliseconds or 
there is an absolute change of >60 milliseconds when compared with baseline


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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 subjects 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).  
The specifications in this protocol for the timing of safety and sample collection are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual procedure time has to be correctly recorded in the CRF, 
including samples that are collected outside of the allowable time window.  Failure or being late 
(ie, outside stipulated time allowances) to perform procedures or obtain samples due to 
legitimate clinical issues (eg, equipment technical problems, venous access difficulty, or subject 
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will still be required to notify the sponsor in writing via a 
file note.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in the 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.
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.
Investigators must document their review of each laboratory safety report.
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.
The investigator will record all relevant AE and SAE information in the CRF.  After the 
informed consent form is signed, study site personnel will record, via CRF, the occurrence and 


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nature of each subject’s preexisting conditions, including clinically significant signs and 
symptoms of the disease under treatment in the study.  Additionally, site personnel will record 
any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product and/or study procedure and the AE.
Planned surgeries should not be reported as AEs, unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s IMP is discontinued as a result of an AE, study site personnel must report this to 
Lilly or its designee via CRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above
Study site personnel must alert the Lilly CP/clinical research physician (CRP), or designee, of 
any SAE as soon as practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, 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. 


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Pregnancy (maternal or paternal exposure to IMP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  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.
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 they have 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 LY3154885 is considered any dose higher than the 
dose assigned through randomization.  General supportive medical management will be provided 
at the investigator’s discretion.
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). 
With the exception of safety laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor, if a central vendor is used for the study.
9.4.2. Vital Signs
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2). Vital signs will comprise BP, PR, and body temperature.
For supine measurements of BP and PR, subjects should be in the supine position for at least 
5 minutes before the procedure.
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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For orthostatic measurements of BP and PR, subjects should be supine for at least 5 minutes and 
stand for at least 2 minutes for supine and standing measurements, respectively.  If the subject 
feels unable to stand, supine vital signs only will be recorded.
9.4.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the investigational product should be reported to Lilly or its 
designee as an AE via the CRF.
At screening, early discontinuation, and follow-up, 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.  
In Parts A, B and D, single ECGs will be collected at all time points.
In Part C, at all time points other than screening, early discontinuation, and follow-up, ECGs will 
be collected in triplicate.
Electrocardiograms should preferably be recorded before collecting any blood samples.  Subjects 
must be supine for approximately 5 minutes before ECG collection and remain supine but awake 
during ECG collection.  Consecutive replicate ECGs will be obtained at approximately 1-minute 
intervals.  Electrocardiograms may be obtained at additional times, when deemed clinically 
necessary.  Collection of more ECG replicates than expected at a particular time point will be 
permitted to ensure high-quality records.
Electrocardiograms will be interpreted by a qualified investigator (physician  or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings 
be identified.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (eg, palpitations, near syncope, 
syncope) to determine whether the subject can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in subject management is needed 
and must document his/her review of the ECG printed at the time of evaluation from at least 1 of 
the triplicate ECGs from each time point.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (eg, demographics and 
study details), then store the ECGs in a database.  At a future time, the stored ECG data may be 
overread at the central ECG laboratory for further evaluation of machine-read measurements or 
to meet regulatory requirements. 


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The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes, unless a cardiologist overread of the ECGs is conducted prior to completion of the 
final study report (in which case, the overread data would be used).
9.4.4. Ambulatory Blood Pressure Monitoring
Ambulatory blood pressure monitoring will be performed in all parts of the study.  The ABPM 
device will be fitted to the subject’s nondominant arm and will record ambulatory BP and PR 
every 30 minutes during awake hours (0700 hours to 2200 hours) and every 60 minutes 
throughout the night (2200 hours to 0700 hours).  All Day -1 recordings are 24 hours and will 
serve as baseline. The recording on dosing days will be initiated approximately 2 hours prior to 
the planned dosing time (baseline value) and will continue according to the Schedule of 
Activities (Section 2).  Subjects will be encouraged to maintain light activity (e.g, walking) and 
keep the same routine during the ABPM study days.  Ambulatory blood pressure monitoring data 
may not be used for subject management or dose escalation decisions.
9.4.5. Neurological Examination 
A directed neurological examination will be performed by the investigator (or designee) at the 
time points specified in the Schedule of Activities (Section 2).  If clinically significant 
abnormalities are noted at these time points, additional examinations should be performed as 
clinically necessary.  Examination procedures may include inspection for tremor, extraocular 
movements, brachial and patellar deep tendon reflexes, finger-nose pointing, and Romberg sign.
Table HUAA.9.1 presents the scoring of neurological examination findings.  
Table HUAA.9.1.
Scoring of Neurological Examination Findings
Score
0
1
2
3
4
Tremor
Absent
Visible with limb 
extension and/or 
careful inspection
Visible without 
limb extension
Interferes with 
motor function
Nystagmus
Absent
1 to 3 beats on 
lateral gaze
>3 beats on 
lateral gaze
Present on 
forward gaze
Reflexes (brachial or patellar)
Absent
Trace
Normal
Increased
Clonic
Finger-nose
Normal
Abnormal
Romberg sign
Absent
Present
9.4.6. Columbia-Suicide Severity Rating Scale (Part C Only)
The C-SSRS (Columbia Lighthouse Project [WWW]) captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviors during the assessment period.  The scale 
includes suggested questions to solicit the type of information needed to determine if a suicide-
related thought or behavior has occurred.  The C-SSRS will be administered by appropriately 
trained site personnel at the time points specified in the Schedule of Activities (Section 2).  
Subjects with any significant change must be referred to a psychiatrist.


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If the investigator determines that suicide-related behaviors have occurred, the Lilly Self-Harm 
Supplement Form will be used to collect additional information to allow for a more complete 
assessment of these behaviors.  As noted above, subjects with any clinically significant change, 
as determined by the investigator, must be referred to a psychiatrist.
9.4.7. Exploratory Scales and Questionnaire (Part C Only)
9.4.7.1.
Profile of Mood States Second Edition
The Profile of Mood States Second Edition (POMS-2) (Heuchert and McNair 2012) is a 35-item, 
adjective rating scale and is considered to be a standardized mood-state inventory.  Subjects will 
be instructed to rate each adjective on the basis of how they feel at the present time on a scale 
with 5 response options (scored numerically from 0 to 4, respectively):  “Not at all,” “A little,” 
“Moderately,” “Quite a bit,” and “Extremely.”  The POMS-2 will be completed at the time 
points stipulated in the Schedule of Activities (Section 2).
9.4.7.2.
Physician Withdrawal Checklist
The Penn Physician Withdrawal Checklist (PWC-20) is a 20-item checklist that will be used to 
assess the presence and severity of withdrawal symptoms.  The scale was originally developed to 
assess the severity of withdrawal symptoms in anxiolytic medication discontinuation (Rickels et 
al. 2008).  The PWC-20 is a validated, shortened version of the original 35-item checklist, where 
the 20-items were selected based on their statistical ability to differentiate between placebo and 
LY3154885 (Rickels et al. 1990; Schweizer et al. 1990).  The 20 items assess the subject’s level 
of symptoms on a variety of withdrawal symptoms since last visit.  Each of the 20 items are 
scored as 0 (not present), 1 (mild), 2 (moderate), or 3 (severe).
9.4.8. Safety Monitoring
The Lilly CP and principal investigator (PI) will monitor safety data throughout the course of the 
study. In the event of safety concerns, the Lilly clinical pharmacologist and PI will recommend a 
protocol amendment or termination of the trial and will report to the investigational review board 
(IRB) accordingly. 
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data, such as BP, PR, ECGs, and ABPM

laboratory analytes

adverse events
When appropriate, the Lilly CP will consult with the functionally independent Global Patient 
Safety therapeutic area physician or CRP.
9.4.8.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3ULN, ALP ≥2ULN, or elevated TBL ≥2
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatinine kinase to confirm the 


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abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator based on 
consultation with the Lilly CP or CRP.  Monitoring should continue until levels normalize and/or 
are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2ULN on 2 or more consecutive blood tests 

subject discontinued from treatment due to a hepatic event or abnormality of 
liver tests

hepatic event considered to be an SAE
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL and approximately 2 mL will be collected to determine the plasma 
concentrations of LY3154885 and itraconazole, respectively.  If indicated by emerging data, a
maximum of 3 blood samples per subject may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and time (24-hour clock time) of each sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Urine samples will be collected for the characterization of renal clearance of LY3154885.  Urine 
samples will be used to determine creatinine and LY3154885 concentration.  Total urine output 
for the appropriate period post LY3154885 administration will be collected, pooled, and 
refrigerated.  At the end of the collection period, the total urine volume will be recorded.  Any 
special instructions for the collection and handling of urine samples will be provided by the 
sponsor.  Exploratory metabolite identification of LY3154885 may be conducted using urine 
samples.  In Part A only, venous blood samples of approximately 3.5 mL each will be collected 
to determine serum creatinine measurements. 
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 LY3154885 and itraconazole and metabolites will be assayed using a validated 
liquid chromatography with tandem mass spectrometry (LC/MS/MS) method.  Samples collected 
from subjects receiving placebo will be retained and only analyzed for LY3154885 if required to 
confirm subject dosing records.


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Bioanalytical samples collected to measure investigational product concentrations (including 
placebo samples) 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, such as metabolism and/or protein binding work.
9.6.
Exploratory Pharmacodynamics
9.6.1. Exploratory Cognition Assessments (Part C Only)
The Digital Symbol Substitution Test (DSST) and Hopkins Verbal Learning Test (HVLT) will 
be included in Part C to assess relevant aspects of cognition, vigilance, and working memory that 
may provide a pharmacodynamic signal in healthy volunteers.  The tests will be completed at the 
time points stipulated in the Schedule of Activities (Section 2).

DSST:  The DSST is an assessment of complex scanning and visual tracking.  The screen 
shows a series of 9 numbered symbols that represent a “key.”  The participant is then 
presented with a series of parallel boxes that contain a symbol in the top half of the box 
and must provide a “number” response for the bottom half by referring to the key.  
Numbers are selected using the touch screen.  The participant is given 90 seconds to 
respond to as many symbols as possible.

HVLT:  The HVLT is an easily administered 12-item, 3 learning trial, verbal learning test 
with delayed recall and recognition memory testing.  The test requires recall of a series of 
12 words over 3 learning trials, free recall after a delay, and a recognition trial.
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 exposure or response to 
LY3154885 and to investigate genetic variants thought to play a role in neurodegenerative 
diseases or neurological disorders.  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/IRBs impose shorter time limits, for the study at a 
facility selected by Lilly.  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 LY3154885 or after LY3154885 is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  Regardless of technology utilized, data generated will be used 
only for the specific research scope described in this section. 


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9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, 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.
Blood samples for non-pharmacogenetic biomarker research will be collected at the times
specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3154885, mechanism of action of LY3154885, and/or research method, or for validating 
diagnostic tools or assay(s).
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.  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 
LY3154885 or after LY3154885 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 is customary for Phase 1 studies evaluating safety and PK, and is not powered 
on the basis of statistical hypothesis testing.
Subjects who are randomized but not administered treatment or do not complete all treatment 
periods/doses may be replaced to ensure that enough subjects complete all parts of the study.  
Replacement subjects will be allocated the same treatment/sequence as the dropout subjects.  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.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The subject’s age, sex, weight, BMI, height, race, or other demographic characteristics will be 
recorded and may be used in the PK and safety analyses as quantitative or classification 
variables.  These data will be summarized using standard descriptive statistics.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least 1 dose 
of the investigational product and have evaluable PK data.  
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.  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 enrollment 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.


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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 AEs, clinical laboratory parameters, vital signs, 
and ECG parameters.  The parameters will be listed and summarized using standard descriptive 
statistics.  Additional analysis will be performed if warranted upon review of the data. All 
planned safety analyses will be detailed in the statistical analysis plan (SAP). 
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3154885 will be calculated by standard 
noncompartmental analysis methods. Parameters for analysis will be maximum observed drug 
concentration (Cmax), time to Cmax (tmax), and area under the concentration versus time curve 
(AUC) of  LY3154885 following single and multiple doses of LY3154885.  Following multiple 
dosing, accumulation ratios based on LY3154885 AUC will be calculated as follows:  AUC 
Day 14 / AUC Day 1 and AUC Day 7 / AUC Day 1.  Other PK parameters such as half-life, 
apparent clearance, and apparent volume of distribution may be reported using 
noncompartmental analysis methods.  
If appropriate data are obtained, renal clearance of LY3154885 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 clearance.
If available, plasma concentration data for itraconazole and its metabolites (if applicable) will be 
summarized or listed in the clinical study report, and the data may subsequently be used for 
exploratory model development. A noncompartmental PK analysis of itraconazole and its 
metabolites may be conducted if deemed valuable to the interpretation of the study results but is 
not required to complete the clinical study report.
10.3.2.2. Pharmacokinetic Statistical Inference
Descriptive statistics of the PK parameters calculated from Parts A, B, C, and D will be 
presented by treatment.  The following details are noted for the respective sections.
Part A:  The PK parameters Cmax and AUC for LY3154885 will be evaluated to estimate the 
dose-exposure proportionality of LY3154885 using a linear-mixed-effect power model.  In this 
model, log-transformed dose will be the independent variable and subject will be a random 
effect.  Both Cmax and AUC will be log-transformed prior to analysis.  The least-squares (LS) 
means for each treatment together with the treatment differences and associated 90% confidence 
intervals (CIs) will be estimated from the model.  These estimates will be back-transformed to 
present geometric means, the ratios of geometric means, and the corresponding 90% CIs.
Part B:  The PK parameters Cmax and AUC for LY3154885 when administered alone and with 
itraconazole will be compared using an analysis of variance (ANOVA) model.  The parameters 
will be log-transformed prior to analysis.  The model will include a fixed-effect for the treatment 
(LY + itraconazole : LY) and a random effect for subject.  The LS means for each treatment, the 


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difference between the treatment LS means (LY3154885 + itraconazole – LY3154885), and the 
associated 90% CIs will be estimated from the ANOVA model and back-transformed from the 
log scale to provide estimates of the geometric means, geometric mean ratio, and corresponding 
90% CIs.  The tmax of LY3154885 for both treatments will be analyzed using a Wilcoxon 
signed-rank test.  An estimate of the median difference and 90% CI will be calculated.
Part C:  The plasma PK parameters Cmax and AUC for LY3154885 obtained on Day 14 will be 
evaluated to estimate the dose-exposure proportionality of LY3154885 using a linear-mixed-
effect power model.  For details of the model, see Part A above.
Plasma concentrations of LY3154885 will be evaluated graphically and/or descriptively to assess 
the achievement of steady-state, but no formal analysis will be performed for attainment 
of steady-state.
Part D:
Effect of formulation:  The AUC and Cmax for LY3154885 following administration with a 
capsule and tablet formulation in a fasted state will be log transformed and analyzed using a 
mixed effects ANOVA model.  The model will include fixed effects for formulation (capsule :
tablet).  The LS means for each formulation 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 means.  The tmax of LY3154885
between formulations will be analyzed using a Wilcoxon signed-rank test.  An estimate of the 
median difference and 90% CI will be calculated.
Effect of high-fat diet: The AUC and Cmax for LY3154885 following administration with a 
tablet formulation in the fed state and fasted state will be log transformed and analyzed using a 
mixed-effects ANOVA model.  The model will include fixed effects for food (fed : fasted).  The 
LS means for fed and fasted 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 means.  The tmax of LY3154885 between fed 
and fasted will be analyzed using a Wilcoxon signed-rank test.  An estimate of the median 
difference and 90% CI will be calculated.
10.3.3. Exploratory Pharmacodynamic Analyses
Endpoints from the DSST and HVLT will be summarized by domain (as appropriate), time, and 
treatment.  Change from baseline may be displayed as appropriate.  
Further details of analyses will be provided in the SAP.
10.3.4. Exploratory Pharmacokinetic/Pharmacodynamic Analyses 
No LY3154885 exposure–response analyses are planned; however, analyses may be conducted 
for exploratory purposes based on review of the data.


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10.3.5. Data Review During the Study
Access to safety and tolerability data is scheduled to occur after every dosing session (see 
Sections 5.1.1, 5.1.2, 5.1.3, and 5.1.4 [study design], and 5.5 [dose justification] for further 
details).  Pharmacokinetic data will be reviewed to guide implementation of this study (such 
as adjustment to blood sampling time) and to support dose escalations at the following 
decision points: 

In Part A, LY3154885 PK data (up to 48 hours postdose) from Doses 1 to 3 will be 
reviewed prior to administration of Dose 5

In Part A, LY3154885 PK data (up to 48 hours postdose) from Dose 5 will be reviewed 
prior to administration of Dose 6

In Part B, LY3154885 PK data (up to 96 hours postdose) will be reviewed to inform a 
decision on the conduct of Part C and D

In Part C, LY3154885 PK data (up to 24 hours postdose on Day 15) from the low dose 
(Cohort 4) will be reviewed prior to administration of the high dose (Cohort 6)
The investigator and the Lilly sponsor team will make the determination regarding dose 
escalation based upon their review of the safety and tolerability data and any available PK 
data. Data reviews may be added as deemed appropriate by the sponsor without a 
protocol amendment.
10.3.6. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP/CRP/investigator or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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Beyer K, Domingo-Sàbat M, Ariza A. Molecular pathology of Lewy body diseases. Int J Mol
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Heuchert JP, McNair DM. POMS 2® Profile of Mood States. 2nd ed. North Tonawanda, NY: 
MHS Inc; 2012.
Jellinger KA. Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts 
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Jellinger KA, Korczyn AD. Are dementia with Lewy bodies and Parkinson’s disease dementia
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Klein JC, Eggers C, Kalbe E, Weisenbach S, Hohmann C, Vollmar S, Baudrexel S, 
Diederich NJ, Heiss WD, Hilker R. Neurotransmitter changes in dementia with Lewy bodies 
and Parkinson disease dementia in vivo. Neurology. 2010;74(11):885-892.
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Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, 
Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, 
Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, 
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Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, 
Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, 
Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, 
Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, 
Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M;
Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report 
of the DLB Consortium. Neurology. 2005;65(12):1863-1872.
Mitchell RA, Herrmann N, Lanctôt KL. The role of dopamine in symptoms and treatment of 
apathy in Alzheimer’s disease. CNS Neurosci Ther. 2011;17(5):411-427.
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J Clin Psychopharmacol. 2008;28(4):447-451.
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benzodiazepines. I. Effects of abrupt discontinuation. Arch Gen Psychiatry. 
1990;47(10):899-907.
Schweizer E, Rickels K, Case WG, Greenblatt DJ. Long-term therapeutic use of 
benzodiazepines. II Effects of gradual taper. Arch Gen Psychiatry. 1990;47(10):908-915.
Svensson KA, Heinz BA, Schaus JM, Beck JP, Hao J, Krushinski JH, Reinhard MR, Cohen MP, 
Hellman SL, Getman BG, Wang X, Menezes MM, Maren DL, Falcone JF, Anderson WH, 
Wright RA, Morin SM, Knopp KL, Adams BL, Rogovoy B, Okun I, Suter TM, Statnick MA, 
Gehlert DR, Nelson DL, Lucaites VL, Emkey R, DeLapp NW, Wiernicki TR, Cramer JW, 
Yang CR, Bruns RF. An allosteric potentiator of the dopamine D1 receptor increases 
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Takizawa C, Thompson PL, van Walsem A, Faure C, Maier WC. Epidemiological and economic 
burden of Alzheimer’s disease: a systematic literature review of data across Europe and the 
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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ABPM
ambulatory blood pressure monitoring
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
blinding
A procedure in which one or more parties to the study 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/her 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/or his/her 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
BP
blood pressure
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed drug concentration
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-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.


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CP
clinical pharmacologist
CRF
case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
cardiovascular
CYP
cytochrome P450
D1 PAM
positive allosteric modulator (also called “potentiator”) of the dopamine D1 receptor
DSST
Digital Symbol Substitution Test
ECG
electrocardiogram
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
GLP
good laboratory practice
hERG
human ether-a-go-go-related gene
HIV
human immunodeficiency virus
HR
heart rate
HVLT
Hopkins Verbal Learning Test
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  


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Investigational 
medicinal product 
(IMP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, 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 study at a study site.  If a study is 
conducted by a team of individuals at a study 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
LS
least squares
MAD
multiple-ascending dose
MTD
maximum tolerated dose
NOAEL
no-observed-adverse-effect level
NOEL
no-observed-effect level
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.
PD
Parkinson’s disease
PI
principal investigator
PK
pharmacokinetic(s)
POMS-2
Profile of Mood States Second Edition
PR
pulse rate
PWC-20
Penn Physician Withdrawal Checklist
QTc
QT interval corrected for heart rate
QTCF
QT interval corrected for heart rate using Fridericia’s formula
randomize
the process of assigning subjects/patients to an experimental group on a random basis
SAD
single-ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  


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SRP
safety review panel
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin level
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
tmax
time to Cmax
UGT
UDP-glucuronosyltransferase
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology\:
Clinical Chemistry:
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate 
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Glucose (random)
Leukocytes (WBC)
Total cholesterol 
Platelets
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase (ALP)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Alanine aminotransferase (ALT)
Basophils
Creatinine
Gamma-glutamyl transferase (GGT)a
Urinalysisb:
Urea
Specific gravity
pH
Protein
Hepatitis B surface antigena,c
Glucose
Hepatitis C antibody
Ketones
HIVa,c
Bilirubin
Urobilinogen
Pregnancy test (if applicable)d
Blood
FSH (if applicable)a,e
Nitrite
Thyroid stimulating hormone (TSH)a
Leukocytes
Microscopic examination of sediment (if dipstick abnormal)b
Note:  Results of these assays will be validated by the local laboratory at the time of testing.  Additional tests may be 
performed or autocalculated by the laboratory as part of its standard panel that cannot be removed.  Some of the 
above parameters are calculated from measured values.  Inclusion or omission of calculated values will not be 
considered a protocol deviation.
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood 
cells; WBC = white blood cells.
a
Performed at screening only.
b
If clinically indicated, per investigator’s discretion.
c
Tests may be waived if they have been performed within 6 months before screening with reports available 
for review.
d
Serum test at screening and admission; urine test at all other times.  Women with confirmed nonchildbearing 
potential status can be exempted from further pregnancy tests during the study after screening.
e
To be performed only at screening for assessment of menopause status, if necessary.


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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 nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

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 study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure and updates during the course of the study

ICF

relevant curricula vitae


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party 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, the 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 case report forms (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.


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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.
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.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject/patient personal information collected will be provided in a 
written document to the subject by the Sponsor.
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 patients in consultation with Lilly or its designee clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time, INR
WBC
Neutrophils
Hepatic Serologiesa,b
Lymphocytes
Hepatitis A antibody, IgG
Monocytes
Hepatitis A antibody, IgM
Eosinophils
Hepatitis B surface antigen
Basophils
Hepatitis B surface antibody
Platelets
Hepatitis B core antibody, total or hepatitis B core antibody, IgM
Hepatitis C antibody
Hepatic Chemistrya
Hepatitis E antibody, IgG
Total bilirubin
Hepatitis E antibody, IgM
Conjugated bilirubin
Alkaline phosphatase
Anti-nuclear antibodya
ALT
Alkaline phosphatase isoenzymesa
AST
Anti-smooth muscle antibody (or anti-actin antibody)a
GGT
Creatine kinase
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyl 
transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood cells; WBC = white 
blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol J1Z-MC-HUAA Sampling Summary (Part A: Ascending Dose—3 Study Periods)
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume (mL)
Screening testsa
18
1
18
Clinical laboratory testsa
8
7
56
PK samplingb
2
39 (+3)
78 (+6)
Blood discard for cannula patency
1
30
30
Stored non-PGx plasma sample
10
9
90
PGx sample
10
1
10
Serum creatinine
3.5
3
10.5
Total
292.5 (298.5)
Total for clinical purposes (rounded up to nearest 10 mL)
300 (300)
Abbreviations:  PGx = pharmacogenetic; PK = pharmacokinetic.
a
Additional samples may be drawn if needed for safety purposes.
b
If indicated by emerging data, a maximum of 3 blood samples may be collected at additional time points during 
the study if warranted and agreed upon between both the investigator and sponsor (as shown in parentheses).
Protocol J1Z-MC-HUAA Sampling Summary (Part B: CYP3A4 Inhibition—Single Study Period)
Purpose
Blood Volume 
per Sample (mL)
Number of 
Blood Samples
Total Volume 
(mL)
Screening testsa
18
1
18
Clinical laboratory testsa
8
5
40
PK sampling for LY3154885b
2
29 (+3)
58 (+6)
PK sampling for itraconazole and metabolite(s)
2
7
14
Blood discard for cannula patency
1
20
20
Total
150 (156)
Total for clinical purposes (rounded up to nearest 10 mL)
150 (160)
Abbreviation:  PK = pharmacokinetic.
a
Additional samples may be drawn if needed for safety purposes.
b
If indicated by emerging data, a maximum of 3 blood samples may be collected at additional time points during 
the study if warranted and agreed upon between both the investigator and sponsor (as shown in parentheses).


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Protocol J1Z-MC-HUAA Sampling Summary (Part C: Multiple-Ascending Dose—Single Study Period)
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
18
1
18
Clinical laboratory testsa
8
4
32
PK samplingb
2
33 (+3)
66 (+6)
Blood discard for cannula patency
1
30
30
Stored non-PGx plasma sample
10
5
50
PGx sample
10
1
10
Total
206 (212)
Total for clinical purposes (rounded up to nearest 10 mL)
210 (220)
Abbreviations:  PGx = pharmacogenetic; PK = pharmacokinetic.
a
Additional samples may be drawn if needed for safety purposes.
b
If indicated by emerging data, a maximum of 3 blood samples may be collected at additional time points during 
the study if warranted and agreed upon between both the investigator and sponsor (as shown in parentheses).
Protocol J1Z-MC-HUAA Sampling Summary (Part D: Formulations/Food Effect—3 Study Periods)
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
18
1
18
Clinical laboratory testsa
8
16
128
PK samplingb
2
117 (+3)
234 (+6)
Blood discard for cannula patency
1
90
90
PGx sample
10
1
10
Total
480 (486)
Total for clinical purposes (rounded up to nearest 10 mL)
480 (490)
Abbreviations:  PGx = pharmacogenetic; PK = pharmacokinetic.
a
Additional samples may be drawn if needed for safety purposes.
b
If indicated by emerging data, a maximum of 3 blood samples may be collected at additional time points during 
the study if warranted and agreed upon between both the investigator and sponsor (as shown in parentheses).


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 7 8
L Y 3 1 5 4 8 8 5
A p p e n di x 6.
Pr ot o c ol A m e n d m e nt J 1 Z -M C -H U A A( b ) 
S u m m ar y
Si n gl e - a n d M ulti pl e -A s c e n di n g D o s e, S af et y , 
T ol er a bilit y , a n d P h ar m a c o ki n eti c St u d y wit h L Y 3 1 5 4 8 8 5 
i n H e alt h y S u bj e ct s
O v er vi e w
Pr ot oc ol  J 1 Z-M C -H U A A “ Si n gle - a n d M ult i ple-Asce n di n g D ose, Safet y,  T olera bilit y, a n d 
P har mac o ki net ic St u d y wit h L Y 3 1 5 4 8 8 5 i n Healt hy S u bjects” has bee n a me n de d.  T he ne w 
pr ot oc ol  is i n dicate d b y A me n d me nt (b ) a n d will be use d t o c o n d uct t he st u d y in place of a n y 
prece di n g versi o n of t he pr ot oc ol.
After recei pt of fee d bac k fr o m t he U S F o o d a n d Dr u g A d mi nistrati o n, t he f oll owi n g c ha n ge s
ha ve bee n ma de t o t his pr ot oc ol:

Secti o n 5. 1. 3. Part C ( M ult i ple-Asce n di n g D ose) has bee n m o difie d t o e xte n d t he re vie w 
p eri o d f or safet y data fr o m 6 t o 1 4 da y s prior t o ma ki n g a fi nal decisi o n a b o ut t he d ose 
le vel t o be a d mi nistere d t o t he ne xt c o h ort.
o
Te xt wi t hi n secti on 5. 5 (J ustificati o n f or D ose) has bee n m o difie d t o reflect t he 
i ncl usi on of t he m o n ke y  N O E L data.
Ot her c ha n ges ma de t o t he pr ot oc ol are as f o ll ows:

Secti o n 1 ( Pr ot oc ol  S y n o psis): 
o
T he l a n g ua ge has bee n u p date d t o state t hat f or parts A, B, C, a n d D, s u bjects will 
be a d mitte d t o t he C R U ( Da y  -2, first peri o d) i n t he after n o o n.  
o
E ve ni n g a d missi o n has bee n delete d.

Secti o n 2 ( Sc he d ule of Act i vities – Parts A – D): 
o
T he c o m me nt secti o n i n t he p h ysical e xa mi nati on/ me dical assess me nt ( P E/ M A)
r o w has bee n u p date d t o state t hat a f ull P E/ M A will be c o n d ucte d pri or t o fi nal 
di sc har ge fr o m t he st u d y.  
C CI


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
Section 2 (Schedule of Activities – Part A): 
o
“Single safety” has been added to the description within the 12-lead ECG row.
o
Also on this row, ECG measurements at hours 2 and 4 (Day 1) have been added, 
and 
o
measurements at hours 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 (Day 1) and 36 (Day 2) have 
been deleted.  
o
The comments previously contained within the comment section in this row have 
been deleted.

Section 2 (Schedule of Activities – Parts B and C): 
o
A requirement to conduct clinical laboratory tests on Day -2 has been added.  A 
comment has been added to state that the PI must review the Day -2 laboratory
results before dosing on Day 1.

Section 2 (Schedule of Activities – Parts B and C): 
o
The comment associated with the ABPM row has been updated to include the 
term “predose”.

Section 2 (Schedule of Activities – Part C): 
o
The comments have been updated within the admission to CRU row to reflect that 
admission will occur in the afternoon rather than the evening.
o
The Day -1 ECG measurement has been deleted.  
o
Additional ECG measurements have been added at -45 min, -30 min, and -15 min 
(Days 1 and 14).  
o
ECG measurements have been deleted at 1, 2, 3, 4, 5, 6, 8, and 12 hours (Days 1 
and 7), and
o
the predose measurement (Day 8 only) has been deleted from the D8-13 column.

Sections 5.1.1, 5.1.2, 5.1.3, 5.1.4 (Parts A – D):
o
Admission to the CRU on Day -2 has been changed from the evening to the 
afternoon.

Section 8.1 (Discontinuation from Study Treatment): 
o
The discontinuation criterion “ALT or AST >3ULN sustained for more 
than 2 weeks or” has been removed.  The MAD study is 14 days long and 
this is not applicable. 

Section 8.4.3 (Electrocardiograms):  
o
Language has been added to specify that single ECGs will be collected at all time 
points in Part A.  
o
The requirement to perform triplicate ECG measurements in Part A for all time 
points other than screening, early discontinuation, and follow-up has been deleted.


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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 (Treatment Arms and Planned Duration for an Individual Subject)
Part A:  Subjects will attend a screening visit up to 28 days prior to dosing in Period 1.  
Admission to the clinical research unit (CRU) will be on in the evening afternoon of Day -2 of 
the first period and on Day -1 for Periods 2 and 3.  After an overnight fast, subjects will receive 
either LY3154885 or placebo as a single oral dose on Day 1 and will remain inpatient for at least 
48 hours after dosing (until Day 3), after which they may be discharged at the discretion of the 
investigator.  The washout time between doses for a given subject will be at least 7 days.  A 
poststudy follow-up visit will be conducted at least 7 days after the final dose.
Part B:  Subjects will attend a screening visit up to 28 days before dosing.  Subjects will be 
admitted to the CRU ion the evening afternoon of Day -2 and will receive a single oral dose of 
LY3154885 or placebo on Day 1 after an overnight fast.  There will be a 7-day washout period 
followed by 10 days of dosing with 200 mg itraconazole (twice daily on Day 8 [dose separated 
by 12 hours], then once daily on Days 9 through 17).  Subjects will receive LY3154885 or 
placebo on Day 14, approximately 1 hour after the dose of itraconazole.
Part C:  Subjects will receive either LY3154885 or placebo as a single oral once-daily dose from 
Days 1 through 14.  Study drug will be administered as a single oral dose in the morning under 
fasted conditions.  Subjects will attend a screening visit up to 28 days prior to dosing and will be 
admitted to the CRU ion the evening afternoon of Day -2.  After the initial dose (Day 1), subjects 
will be required to remain in-house for at least 48 hours after dosing (Day 3) and at the discretion 
of the investigator.  Subjects will attend the CRU on Days 4, 5, 6, 9, and 10 on an outpatient 
basis for daily dosing and will be permitted to leave the CRU at the discretion of the investigator.  
A poststudy follow-up visit will be conducted approximately 7 days after discharge.
Optional Part D:  Subjects will attend a screening visit up to 28 days prior to dosing in Period 1; 
admission to the CRU will be ion the evening afternoon of Day -2 (Periods 1 and 2) and on Day -
1 (Period 3).  In Period 1, subjects will undergo an overnight fast before receiving a single oral 
dose of LY3154885 (capsule formulation) on Day 1.  Subjects will remain inpatient for at least 
48 hours after dosing, after which they may be discharged at the discretion of the investigator.  
Subjects will be re-admitted to the CRU on Day 6, and will undergo an overnight fast before 
receiving a subsequent single oral dose of LY3154885 on Day 8 with the same formulation.  
Subjects will be discharged on Day 10, at least 48 hours after dosing.
Period 2 will be conducted as described for Period 1; however, LY3154885 will be administered 
as a tablet formulation.  Period 3 will be conducted as described for Period 1; however, subjects 
will receive a single oral dose of LY3154885 (tablet formulation) after administration of a high-
fat diet.


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2. Schedule of Activities


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Study Schedule Protocol J1Z-MC-HUAA (Part A:  Single-Ascending Dose – 3 Study Periods)
Screening
Periods 1, 2, and 3
ED
Follow-up
Comments
Procedure
-28 to -3 
days prior to 
dosing in 
Period 1
Day -2
Day -1
Day 1
Day 2
Day 3
At least 
7 days 
after final 
dose
Informed consent
X
Admission to CRU
X (Period 
1)
X (Periods 
2&3)
Discharge from CRU
X
Medical history
X
AE/medication review
X
X
X
X
X
X
Height/weight
X
X
X
Height at screening only.
Neurological exam 
(hours)
X
Predose, 
4, 8
24
48
X
X
LY3154885/Placebo 
administration (hours)
0
Vital signs (BP, PR 
[supine], temperature) 
(hours)
X
X
Predose, 
2, 4, 8, 
12
24, 36
48
X
X
Time points may be added for each 
study period, if clinically indicated.  
On Day 1, temperature will be 
measured at predose only.
ABPM
X  
X
X
The ABPM on Day -1 is a 24-hour 
collection in Period 1 only (baseline 
measurement).  See Section 9.4.4.
Clinical laboratory tests
X
X
Predose
X
X
X
See Appendix 2, Clinical Laboratory 
Tests, for details. PI must review the 
result of Day-2 results prior to Day 1 
dose in Period 1 only.
Pregnancy test
X
X
X
X
Serum test at screening and 
admission of Period 1 only; urine test 
at all other time points.  
PE/MA
X
Predose
X
X
Full PE/MA at screening and prior to 
final discharge from the CRUstudy.  
Symptom-directed PE/MA at all 
other time points and as deemed 
necessary by the investigator.
continued


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Study Schedule Protocol J1Z-MC-HUAA (Part A:  Single-Ascending Dose – 3 Study Periods) (concluded)
Screening
Periods 1, 2, and 3
ED
Follow-up
Comments
Procedure
-28 to -3 
days prior 
to 
Period 1
Day -2
Day -1
Day 1
Day 
2
Day 
3
At least 
7 days after 
final dose
Single safety 12-lead ECG 
(hours)
X
Predose, 2, 4 0.5, 
1, 2, 3, 4, 5, 6, 8, 
12
24, 
36
48
X
X
Single safety ECGs at screening 
and ED/follow-up; triplicate 
ECGs at all other times.  ECGs 
coinciding with PK sample time 
points are to be conducted as 
close as possible to PK 
sampling.
PK sampling (hours)
Predose, 0.5, 1, 
2, 3, 4, 5, 6, 8, 12
24, 
36
48
Sampling times are relative to 
the time of study treatment 
administration (0 hour).
Stored non-PGx plasma 
sample (hours)
Predose, 8
24
Stored sample for biomarker 
research.  Sampling times are 
relative to the time of study 
treatment administration (0 
hour).
PGx sample
X
Single sample for 
pharmacogenetic analysis taken 
prior to/on Day 1 of Period 1.
Urine collection (hours)
0-12, 12-24 
24-
36
Urine collection time starts from 
actual dosing time on Day 1 and 
finishes within ±30 minutes of 
the 36-hour time point.
Serum creatinine 
Predose
To be collected at predose and 
sent to central laboratory. 


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 84
LY3154885
Note:  Site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures:  ECG, vital signs, PK samples, clinical laboratory tests, urine samples, biomarkers, and storage samples.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CRU = clinical research unit; 
ECG = electrocardiogram; ED = early discontinuation; MA = medical assessment; PE = physical examination; PGx = pharmacogenetic; PI = principal 
investigator; PK = pharmacokinetic; PR = pulse rate.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 85
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part B:  Drug-Drug Interaction with CYP3A4 Inhibition – Single Period)
Screening
Days
Procedure
-28 to -3
-2
-1
1
2
3
4-6
7
8
9
10-11
12
13
14
15
Informed consent
X
Admission to CRU
X
X
X
Discharge from CRU
X
X
PE/MA
X
Directed MA
X
Predose
Predose
Predose
AE/medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight/height
X
X
Pregnancy test
X
X
Neurological exam (hours)a
X
Predose, 4, 
(8)
24
48
Predose, 4, 
(8)
24
Clinical laboratory tests
X
X
Predose
Predose
Predose
ABPM
X
X
X
X
X
X
LY3154885/Placebo 
administration
X
X 
Administration of 
itraconazole 
X
X
Outpatient 
dosing
X
X
X
Vital signs (BP, PR 
[supine], temperature) 
(hours)a
X
Predose 2, 4, 
8, 12
24
48
Predose, 
2, 4, 12
24
Predose 2, 4, 
8, 12
24, 36
12-lead ECG
X
Predose
Predose
Predose
PGx sample
X
LY3154885 PK sampling 
(hours)a
Predose, 0.5, 
1, 2, 3, 4, 5,
6, 8, 12
24, 36
48
Predose, 0.5, 
1, 2, 3, 4, 5, 
6, 8, 12
24, 36 
Itraconazole and 
metabolite(s) PK sampling 
(hours)
-1, 0, 1, 2, 
5, 8, 12
continued


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 86
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part B:  Drug-Drug Interaction with CYP3A4 Inhibition – Single Period) (concluded)
Days
ED
Follow-up
Comments
Procedure
16
17
18
Approx 7 days 
after discharge
Discharge from CRU
X
PE/MA
X
X
X
Full PE/MA at screening and prior to final discharge from the CRU
study.  Symptom-directed PE/MA at all other time points and as deemed 
necessary by the investigator.
Directed MA
X
X
AE/medication review
X
X
X
X
X
Weight/height
X
X
Height at screening only.
Pregnancy test
X
X
Serum test at screening and admission; urine test at all other time points.  
Women with confirmed nonchildbearing potential status can be 
exempted from further pregnancy tests during the study after screening.
Neurological exam (hours)a
48
The 8-hour time point is optional.
Clinical laboratory tests
X
X
X
See Appendix 2, Clinical Laboratory Tests, for details. PI must review 
the Day -2 laboratory result before dosing on Day 1.
ABPM
X
The ABPM on Day -1 is a 24-hour collection for baseline measurement.  
On dosing days, the ABPM recording will be initiated approximately 2 
hours prior to dosing for measurement of predose baseline. 
Administration of itraconazole
X
X
Itraconazole 200 mg will be administered twice daily on Day 8 (dose 
separated by 12 hours) and once daily on Days 9 through 17.
Itraconazole should be administered at approximately the same time 
every morning.  For the outpatient dosing days, subjects will record the 
actual time of dose administration on a diary card.
On Day 14, itraconazole should be administered 1 hour before 
LY3154885 administration (see Section 5.1.2).
Vital signs (BP, PR [supine], 
temperature) (hours)a
48, 60
72
96
X
X
Time points may be added for each study period, if clinically indicated.  
On Day 1, temperature will be measured at predose only.
12-lead ECG
X
X
X
Single safety ECGs.
PGx Sample
Single sample for pharmacogenetic analysis. 
LY3154885 PK sampling (hours)a
48, 60
72
96
Sampling times are relative to the time of LY3154885 administration 
(0 hour).


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 87
LY3154885
Note:  Site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures:  ECG, vital signs, PK samples, and clinical laboratory tests.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CRU = clinical research unit; CYP = cytochrome 
P450; ECG = electrocardiogram; ED = early discontinuation; MA = medical assessment; PE = physical examination; PI = principal investigator;
PK = pharmacokinetic; PR = pulse rate.
a
Predose time points refer to dosing before itraconazole and LY3154885.  All postdose time points are relative to the LY3154885 dose.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 88
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part C:  Multiple-Ascending Dose – Single Period)
Screening
Days
ED
Follow-up
Comments
Procedure
-28 to 
-3
-2
-1
1
2
3-6
7
8-13
14
15
Approx 
7 days 
after 
discharge
Informed consent
X
Admission to 
CRU
X
D6
D10 
Evening Afternoon admission.
Discharge from 
CRU
D3
D8
X
Medical history
X
AE/medication 
review
X
X
X
X
X
X
X
X
X
X
Height/weight
X
X
X
Height at screening only.
Neurological 
exam (hours)
X
Predose, 
4, (8)
24
48
Predose, 
4, (8)
24, 48
X
X
The 8-hour time point is 
optional.
LY3154885/
Placebo
administration
X
X
X
X
X
X
On Days 4, 5, 6, 9, and 10, 
subjects will receive their dose 
of LY3154885/placebo at the 
CRU and then may be 
discharged at the discretion of 
the investigator.
Vital signs (BP, 
PR [supine], 
temperature) 
(hours)
X
X
Predose,  
2, 4, 8, 
12
Predose, 
2, 4, 8, 
12
Predose, 
2
Predose, 
2, 4, 8, 
12
Predose, 
2
Predose, 
2, 4, 8, 
12
X
X
X
Time points on outpatient 
dosing days (Days 4, 5, 6, 9, 
and 10) may be adjusted based 
on emerging data from Part A 
and/or if clinically indicated.
On Days 1 to 14, temperature 
will be measured at predose 
only.
continued


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 89
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part C:  Multiple-Ascending Dose – Single Period) (continued)
Screening
Days
ED
Follow-up
Comments
Procedure
-28 to 
-3 
-2
-1
1
2
3-6
7
8-13
14
15
Approx 
7 days 
after 
discharge
ABPM
X
X
X
X
D11& 
12
X
The ABPM on Day -1 is a 24-
hour collection for baseline 
measurement.  On dosing days, 
the ABPM recording will be 
initiated approximately 2 hours 
prior to dosing for 
measurement of predose
baseline.
Clinical
laboratory tests
X
X
Predose
Predose
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
PI must review Day -2 result 
prior to dose on Day 1.
Pregnancy test
X
X
Predose
X
X
X
Serum test at screening and 
admission; urine test at all 
other time points per 
investigator discretion.  
Women with confirmed 
nonchildbearing potential 
status can be exempted from 
further pregnancy tests during 
the study after screening.
PE/MA
X
Predose
X
X
X
Full PE/MA at screening and 
prior to final discharge from 
the CRU study.  Symptom-
directed PE/MA at all other 
time points and as deemed 
necessary by the investigator.
continued


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 90
LY3154885
Study Schedule Protocol J1Z-MC-HUAA (Part C:  Multiple-Ascending Dose – Single Period) (concluded)
Screening
Days
ED
Follow-up
Comments
Procedure
-28 to 
-3 
-2
-1
1
2
3-6
7
8-13
14
15
Approx 
7 days 
after 
discharge
12-lead ECG 
(hours)
X
X
Predose
(-45 
min, -30 
min, -15 
min) 1, 
2, 3, 4, 
5, 6, 8, 
12
Predose 
Predose
1, 2, 3, 
4, 5, 6, 
8, 12
Predose 
(D8 
only) 
Predose,
(-45 
min, -30 
min, -15 
min), 2, 
3, 4, 6, 
8, 12
24
X
X
Single safety ECGs at 
screening and ED/follow-up; 
triplicate ECGs at all other 
times.  ECGs coinciding with 
PK sample time points are to 
be conducted as close as 
possible prior to PK sampling.
PGx sample
X
Single sample for 
pharmacogenetic analysis 
taken prior to/on Day 1.
Stored non-PGx
plasma sample
(hours)
Predose, 
8
Predose
Predose, 
8
PK sampling 
(hours)
Predose, 
0.5, 1, 2, 
3, 4, 5, 
6, 8, 12
Predose
Predose, 
0.5, 1, 2, 
3, 4, 5, 
6, 8, 12
Predose 
(D8 
only)
Predose, 
0.5, 1, 2, 
3, 4, 5, 
6, 8, 12
24 
Sampling times are relative to 
the time of LY3154885 
administration (0 hour).
POMS-2®
X
D6 only
D13 
only
Exploratory 
cognition 
assessments 
(HVLT, DSST)
X
D6 only
D13 
only
PWC-20
Predose
X
X
X
C-SSRS and Lilly 
Self-Harm 
Supplement Form
X
X
D3 & 
D6 only
D8 & 
D10 
only
X
X
X
Administer at screening, each 
admission, and each discharge 
from the CRU.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 91
LY3154885
Note:  Site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures:  ECG, vital signs, PK samples, clinical laboratory tests, biomarkers, and storage samples.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CRU = clinical research unit; C-SSRS = Columbia-
Suicide Severity Rating Scale; D = day; DSST = Digital Symbol Substitution Test; ECG = electrocardiogram; ED = early discontinuation; HVLT = Hopkins 
Verbal Learning Test; MA = medical assessment; PE = physical examination; PGx = pharmacogenetic; PI = principal investigator; PK = pharmacokinetic; 
POMS-2 = Profile of Mood States Second Edition; PR = pulse rate; PWC-20 = Penn Physician Withdrawal Checklist.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 92
LY3154885
[…]
Study Schedule Protocol J1Z-MC-HUAA (Part D:  Formulations/Food Effect – 3 Study Periods) (concluded)
Periods 1, 2, and 3
Screening
Days
ED
Follow-
up
Comments
Procedure
-28 to 
-3
-2
-1
1
2
3
4-6
7
8
9
10
11-13
14
15
16
Approx 7 
days after 
discharge
PE/MA
X
X
X
Full PE/MA at 
screening and prior 
to final discharge 
from the CRU
study.  Symptom-
directed PE/MA at 
all other time points 
and as deemed 
necessary by the 
investigator.
12-lead ECG
X
Predose
Predose
Predose
X
X
Single safety ECGs.  
ECGs coinciding 
with PK sample 
time points are to be 
conducted as close 
as possible prior to 
PK sampling.
PK sampling 
(hours)
Predose, 
0.5, 1, 2, 
3, 4, 5, 6, 
8, 12
24, 
36
48
Predose, 
0.5, 1, 2, 
3, 4, 5, 6, 
8, 12
24, 
36
48
Predose, 
0.5, 1, 2, 
3, 4, 5, 6, 
8, 12
24,
36
48
PGx sample
Predose
Period 1 only


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 93
LY3154885
Note:  Site should schedule activities as appropriate.  In cases where several study procedures are scheduled at the same time, follow this order of priority for 
procedures:  ECG, vital signs, PK samples, clinical laboratory tests, biomarkers, and storage samples.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; BP = blood pressure; CRU = clinical research unit; D = day; 
ECG = electrocardiogram; ED = early discontinuation; MA = medical assessment; PE = physical examination; PGx = pharmacogenetic; PK = 
pharmacokinetic; PR = pulse rate. 


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 94
LY3154885
5.1.1. Part A (Single-Ascending Dose)
[…]
In Period 1, subjects will be admitted to the clinical research unit (CRU) on the evening
afternoon of Day -2 for set up of baseline ambulatory blood pressure monitoring (ABPM) (see 
Section 9.4.4) and on Day -1 for Periods 2 and 3.  Subjects will undergo an overnight fast 
(Section 6.3.1) before dosing with LY3154885 or placebo as a single oral dose on Day 1 and will 
remain inpatient for at least 48 hours after dosing (until Day 3), after which they may be 
discharged at the discretion of the investigator.  The washout time between doses for a given 
subject will be at least 7 days.  A poststudy follow-up visit will be conducted at least 7 days after 
the final dose.
5.1.2. Part B (CYP3A4 Inhibition)
[…]
As detailed in the Schedule of Activities (Section 2), subjects will be admitted to the CRU in the
evening afternoon of Day -2 for set up of baseline ABPM (see Section 9.4.4) and will undergo an 
overnight fast (see Section 6.3.1) before receiving a single oral dose of LY3154885 or placebo 
on Day 1.  Subjects may be discharged from the CRU on Day 3 and will be re-admitted on Day 
7.  There will be a 7-day washout period followed by 10 days of dosing with 200 mg 
itraconazole (twice daily on Day 8 [dose separated by 12 hours], then once daily on Days 9 
through 17).  See Section 6.3.1 for the fasting requirements for the itraconazole dosing.  Subjects 
will be discharged from the CRU on Day 9 after receiving their dose of itraconazole and will be 
self-dosing on an outpatient basis from Days 10 through 12.  Subjects will be asked to complete 
a diary card to document the actual date and time of dose administration.
5.1.3. Part C (Multiple-Ascending Dose)
[…]
Subjects will participate in a single study period consisting of 14 days of once-daily dosing with 
LY3154885 or placebo; study drug will be administered as a single oral dose in the morning 
under fasted conditions (see Section 6.3.1).  Subjects will be admitted to the CRU on the evening
afternoon of Day -2 for set up of baseline ABPM (see Section 9.4.4) and will be required to 
remain in-house for at least 48 hours after dosing (Day 3), and at the discretion of the 
investigator.  As detailed in the Schedule of Activities (Section 2), subjects will attend the CRU 
on Days 4, 5, 6, 9, and 10 on an outpatient basis for daily dosing and will be permitted to leave 
the CRU at the discretion of the investigator.  Pharmacokinetic sampling will be conducted as 
detailed in Section 2.  To assess CV effects and potential accommodation over time, ABPM will 
be included on Day -1 (baseline) and on Days 1, 2, 7, 11 and 12, and 14.  A poststudy follow-up 
visit will be conducted approximately 7 days after discharge.


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 95
LY3154885
The doses evaluated will be selected based on emerging data from Parts A and B and from the 
lower doses from Part C (see Section 5.5 for details).  If the safety data do not support increasing 
the dose in subsequent cohorts, then a dose may be repeated or lower/intermediate doses may be 
explored.  The PK data obtained during the study may be used to assist in dose-escalation 
decisions, but such data are not required for dose-escalation purposes.  For the safety review 
prior to dose decisions between cohorts, all available safety data (AEs, vital signs, ECGs, and 
laboratory results) to at leastDay 614 from at least 6 subjects taking LY3154885 must be 
reviewed by the sponsor and investigator.  In addition, each cohort (including at least 6 subjects 
treated with LY3154885) will complete dosing to Day 14 prior to the next cohort being admitted 
to the CRU for dosing.
5.1.4. Optional Part D (Pharmacokinetics of Capsule and Tablet Formulations and Food 
Effect)
[…]
In Periods 1 and 2, subjects will be admitted to the CRU the evening afternoon of Day -2 for set 
up of baseline ABPM (see Section 9.4.4); admission for Period 3 will be on Day -1.  In Period 1, 
subjects will undergo an overnight fast (see Section 6.3.1) before receiving a single oral dose of 
LY3154885 (capsule formulation) on Day 1.  Subjects will remain inpatient for at least 48 hours 
after dosing, after which they may be discharged at the discretion of the investigator.  Subjects 
will be re-admitted to the CRU on Day 6 and will undergo an overnight fast before receiving a 
subsequent single oral dose of LY3154885 on Day 8 with the same formulation.  Subjects will be 
discharged on Day 10, at least 48 hours after dosing.  Re-admission to the CRU will be on 
Day 13, and following an overnight fast, subjects will receive a single oral dose of LY3154885 
on Day 14 with the same formulation.  Final discharge from the CRU will occur on Day 16.  
Pharmacokinetic sampling will be conducted as detailed in the Schedule of Activities 
(Section 2).


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 9 6
L Y 3 1 5 4 8 8 5
5. 5 J u stifi c ati o n f or D o s e
[ …]
T he m a xi m u m d os e for t his st u d y  is e x pecte d t o be 5 0 0 m g base d o n a ni mal t o xic ol og y  st u dies 
a n d h u ma n P K pre dicti o ns f or L Y 3 1 5 4 8 8 5, 
 
 5 0 0- m g d ose i n h u ma ns is pre dicte d t o res ult i n a 
mea n plas ma A U C o f
µ g × hr/ m L a n d C m a x of
 µ g/ mL; t hese val ues are e q ui vale nt t o 
1/ 1 0t h t he A U C at t he N O A E L i n m o n ke ys a n d 1/ 1 0t h t he C m a x at t he N O A E L i n rats.  T he 
C m a x a n d A U C-base d m ult i ples ass ociate d wit h 
 fr om t he 
n o n -G L P st u d y  in rats, w hi c h were n ot o bser ve d at si milar e x p os ures i n t he G L P st u d y , are als o 
prese nte d i n Ta ble H U A A. 5. 1 .  T o n ote, t he pre dicte d h u ma n C m a x at 5 0 0 m g is
-f ol d 
bel o w t he C m a x at t he N O E L f or 
 effects i n b ot h rats a n d m o n ke ys.  P har mac o ki netic data 
will be re vie we d d uri n g t he st u d y  t o s u p p ort d ose escalat i ons (see Sect i on 1 0. 3. 5 f or details) a n d 
mai ntai n pre dicte d dr u g e x p os ures bel o w 1/ 1 0t h t he A U C at t he N O A E L i n m o n ke ys a n d 1/ 1 0t h 
t he C m a x at  t he N O A E L i n rats.  A d ose hi g her t ha n 5 0 0 m g ma y be st u die d if h u ma n P K data 
fr om pre vi o us c o h orts s u g gests t he pre dicte d e x p os ure will be bel o w 1/ 1 0t h t he A U C at t he 
N O A E L i n m o n ke ys a n d 1/ 1 0t h t he C m a x at  t he N O A E L i n rats.
C CI
C CI
C CI
C CI
C CI
C CI


J 1 Z- M C -H U A A ( b) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 9 7
L Y 3 1 5 4 8 8 5
[ …]
C CI


J1Z-MC-HUAA(b) Clinical Pharmacology Protocol
Page 98
LY3154885
8.1. Discontinuation from Study Treatment
[…]

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>5upper limit of normal (ULN)

ALT or AST >3ULN sustained for more than 2 weeks or

ALT or AST >3ULN and total bilirubin level (TBL) >2ULN or 
international normalized ratio >1.5 or

ALT or AST >3ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase (ALP) >3ULN

ALP >2.5ULN and TBL >2ULN

ALP >2.5ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
8.4.3. Electrocardiograms
[…]
At screening, early discontinuation, and follow-up, 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.  
In Parts A, B and D, single ECGs will be collected at all time points.
In Parts A and C, at all time points other than screening, early discontinuation, and follow-up, 
ECGs will be collected in triplicate. 


L e o  D o c u m e n t  I D  =  e d 9 f 6 5 5 f - 5 2 9 1 - 4 1 f 7 - a a 3 e - 4 c c 1 5 9 c 1 d d 1 5
A p p r o v e r :
A p p r o v a l  D a t e  &  T i m e :  1 6 - A u g - 2 0 1 9  1 9 : 5 2 : 3 3  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 6 - A u g - 2 0 1 9  1 9 : 5 4 : 0 4  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
Statistical Analysis Plan J1Z-MC-HUAA  
Single- and Multiple-Ascending Dose, Safety, Tolerability, and Pharmacokinetic Study with 
LY3154885 in Healthy Subjects 
NCT04014361 
Approval Date: 18-Jul-2019 


Final, 11 July 2019
             Page 1 of 20
STATISTICAL ANALYSIS PLAN
Single- and Multiple-Ascending Dose, Safety, Tolerability, and Pharmacokinetic Study 
with LY3154885 in Healthy Subjects
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 11-July-2019
Study Drug: LY3154885
Sponsor Reference: J1Z-MC-HUAA
Covance CRU Study: 1001215-8404743
Clinical Phase I
Approval Date: 18-Jul-2019 GMT


Final, 11 July 2019
             Page 2 of 20
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  8404743
Sponsor Reference J1Z-MC-HUAA
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Primary Objective.................................................................................................... 6
4.2
Secondary Objectives .............................................................................................. 6
4.3
Exploratory Objectives (Part C Only) ...................................................................... 7
5.
STUDY DESIGN........................................................................................................... 7
5.1
Part A (Single-Ascending Dose).............................................................................. 7
5.2
Part B [Cytochrome P450 (CYP) 3A4 inhibition Inhibition].................................... 8
5.3
Part C (Multiple-Ascending Dose)........................................................................... 9
5.4
Optional Part D (Pharmacokinetics of Capsule and Tablet Formulations and Food 
Effect) ................................................................................................................... 10
6.
TREATMENTS........................................................................................................... 11
7.
SAMPLE SIZE JUSTIFICATION ............................................................................... 12
8.
DEFINITION OF ANALYSIS POPULATIONS.......................................................... 12
9.
STATISTICAL METHODOLOGY ............................................................................. 13
9.1
General.................................................................................................................. 13
9.2
Demographics and Subject Disposition.................................................................. 13
9.3
Pharmacokinetic Assessment................................................................................. 13
9.3.1
Pharmacokinetic Analysis............................................................................. 13
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 14
9.4
Pharmacodynamic Assessment .............................................................................. 15
9.4.1
Exploratory Pharmacodynamic Analysis ...................................................... 15
9.5
Safety and Tolerability Assessments...................................................................... 16
9.5.1
Adverse events ............................................................................................. 16
9.5.2
Concomitant medication............................................................................... 16
9.5.3
Clinical laboratory parameters...................................................................... 16
9.5.4
Vital signs .................................................................................................... 16
9.5.5
Electrocardiogram ........................................................................................ 16
9.5.5.1 Electrocardiogram analysis (Part A) ............................................................. 17
9.5.5.2 Electrocardiogram analysis (Part C).............................................................. 17
9.5.6
Ambulatory Blood Pressure Monitoring ....................................................... 17
9.5.7
Neurological Examination ............................................................................ 18
9.5.8
Columbia-Suicide Severity Rating Scale (Part C Only)................................. 18
9.5.9
Exploratory Scales and Questionnaire (Part C Only)..................................... 18
9.5.10
Hepatic Monitoring ...................................................................................... 18


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9.5.11
Other assessments......................................................................................... 19
9.5.12
Safety and Tolerability Statistical Methodology............................................ 19
10. INTERIM ANALYSES ............................................................................................... 19
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 19
12. REFERENCES ............................................................................................................ 19
13. DATA PRESENTATION ............................................................................................ 19
13.1 Derived Parameters ............................................................................................... 19
13.2 Missing Data ......................................................................................................... 20
13.3 Insufficient Data for Presentation .......................................................................... 20


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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
ABPM
Ambulatory blood pressure monitoring
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AUC
Area under the concentration versus time curve
BP
Blood pressure
CI
Confidence interval
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Coefficient of variation
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DSST
Digital Symbol Substitution Test
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
HVLT
Hopkins Verbal Learning Test
ICH
International Conference on Harmonisation
LS
Least square
MAD
Multiple ascending dose
MAP
Mean arterial pressure
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
PD
Pharmacodynamic
PK
Pharmacokinetic


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POMS-2
Profile of Mood States Second Edition
PR
Pulse rate
PWC-20
Penn Physician Withdrawal Checklist
SAD
Single ascending dose
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SD
Standard deviation 
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal


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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
07 May 2019) and amendment (a) (dated 21 June 2019).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
of study drug for this study. When the SAP and TFL shells are agreed upon and finalized, they 
will serve as the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective

To explore the safety and tolerability of single and multiple doses of LY3154885 in 
healthy subjects
4.2
Secondary Objectives

To determine the PK of LY3154885 following administration of single and multiple oral 
doses of LY3154885

To determine the PK of LY3154885 when administered with itraconazole (Part B only)

To assess safety and tolerability of LY3154885 when administered with itraconazole 
(Part B only)

To compare the PK of LY3154885 when administered with a capsule or tablet 
formulation (Part D only)

To evaluate the effect of a high-fat diet on the PK of LY3154885 (Part D only)


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4.3
Exploratory Objectives (Part C Only)

To explore any procognitive effects of LY3154885 in healthy subjects using the Hopkins 
Verbal Learning Test (HVLT) and Digital Symbol Substitution Test (DSST)

To explore the effect of LY3154885 on subjective mood using the Profile of Mood States 
Second Edition (POMS-2)

To evaluate any potential withdrawal symptoms following multiple once-daily dosing of 
LY3154885
5. STUDY DESIGN
This is a Phase 1, single-center study in healthy subjects to be conducted in 4 parts:

Part A will be a subject- and investigator-blind, placebo-controlled, randomized, single
ascending dose (SAD), 3-period crossover study to evaluate safety, tolerability, and PK 
of LY3154885 in 2 alternating cohorts.

Part B will be a subject- and investigator-blind to LY3154885/placebo, single-period, 
drug-drug interaction study with itraconazole.

Part C will be a subject- and investigator-blind, placebo-controlled, randomized, 14-day 
multiple-ascending dose (MAD), parallel-group, 3-cohort, single-period study to evaluate 
safety, tolerability, and PK of LY3154885.

Optional Part D will be an open-label, 3-period 3-sequence PK study of LY3154885 
administered using a capsule or tablet formulation. Part D will also include a pilot food 
effect evaluation.
5.1
Part A (Single-Ascending Dose)
Part A will be conducted in 2 alternating cohorts (Cohorts 1 and 2), each consisting of 
approximately 12 subjects who will participate in up to 3 study periods. The planned doses of 
LY3154885 to be tested are 15, 45, 100, 200, 400, and 500 mg.
Sentinel dosing will be used in Part A of the study. For all dose levels, LY3154885 and placebo 
will be administered first to 2 subjects (1:1 LY3154885:Placebo) in a blinded manner. These 
subjects will be followed up for 24 hours postdose; if the dose is well tolerated, dosing of the 
remaining 10 subjects in the cohort at the same dose level may begin.
Each subject in Cohorts 1 and 2 will be randomized to receive 2 single oral doses of LY3154885 
and 1 oral dose of placebo as a capsule formulation over 3 study periods in a crossover fashion. 
For each study period, it is intended that 8 subjects will receive LY3154885 and 4 subjects will 
receive placebo.
In Period 1, subjects will be admitted to the clinical research unit (CRU) on the evening of 
Day -2. A 24 hour baseline ambulatory blood pressure monitoring (ABPM) recording on Day -1 
of Period 1. ABPM recording on dosing days will be initiated 2 hours prior to dose for Periods 1,
2 and 3. Subjects will undergo an overnight fast before dosing with LY3154885 or placebo as a 
single oral dose on Day 1 and will remain inpatient for at least 48 hours after dosing (until Day 
3), after which they may be discharged at the discretion of the investigator. The washout time 


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between doses for a given subject will be at least 7 days. A post study follow-up visit will be 
conducted at least 7 days after the final dose.
All available safety data, including adverse events (AEs), vital signs (blood pressure [BP] and 
pulse rate [PR]), electrocardiogram (ECGs), and clinical laboratory tests, from all subjects dosed 
will be assessed prior to escalating to the next dose level. Safety data must include data from at 
least 2 days from a minimum of 6 subjects who received LY3154885. The investigator and 
sponsor will review the data, with the investigator remaining blinded. If dose escalation is 
terminated prior to reaching Dose 6 because of tolerability issues, previous dose levels may be 
repeated or lower/intermediate dose levels may be tested.
Subjects will provide total urine collections for the 36 hours postdose in each period for 
exploratory metabolism and potential assessment of drug absorption and renal elimination; an 
additional blood sample will be collected to determine serum creatinine measurements. The 
figure below illustrates the study design for Part A.
5.2
Part B [Cytochrome P450 (CYP) 3A4 inhibition Inhibition]
Part B will consist of approximately 12 subjects [9 LY3154885; 3 placebo] and will assess the 
effect of itraconazole, a CYP3A4 inhibitor, on the safety, tolerability, and PK of LY3154885. 
The LY3154885 dose to be studied in Part B will be determined based on safety, tolerability, and 
PK data from Part A and will be administered as a capsule formulation.
Subjects will be admitted to the CRU on the evening of Day -2. A 24 hours baseline ABPM will 
be recorded on Day -1. A 2 hrs ABPM measure will be initiated prior to dose time. Subjects will 
undergo an overnight fast before receiving a single oral dose of LY3154885 or placebo on Day 
1. Subjects may be discharged from the CRU on Day 3 and will be re-admitted on Day 7. There 
will be a 7-day washout period followed by 10 days of dosing with 200 mg itraconazole (twice 
daily on Day 8 [dose separated by 12 hours], then once daily on Days 9 through 17). Subjects 


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will be discharged from the CRU on Day 9 after receiving their dose of itraconazole and will be 
self-dosing on an outpatient basis from Days 10 through 12. Subjects will be asked to complete a 
diary card to document the actual date and time of dose administration.
Subjects will be re-admitted to the CRU in the evening of Day 12 and will undergo an overnight 
fast before receiving a single oral dose of LY3154885 or placebo on Day 14, approximately 
1 hour after the dose of itraconazole. Blood sampling for PK purposes (LY3154885 and 
itraconazole) will occur according to the scheduled timepoints. Subjects will remain in the CRU 
until discharge on the morning of Day 18, approximately 24 hours after the final dose of 
itraconazole. The figure below illustrates the study design for Part B.
5.3
Part C (Multiple-Ascending Dose)
The decision to conduct Part C will be made after review of safety, tolerability, and PK data 
from Parts A (SAD) and B (CYP3A4 Inhibition). 
Part C will explore up to 3 dose levels in 3 separate cohorts (Cohorts 4 to 6) of healthy subjects. 
Each cohort will consist of approximately 12 subjects (9 LY3154885; 3 placebo) dosed daily for 
14 days with a capsule formulation.
Subjects will participate in a single study period consisting of 14 days of once-daily dosing with 
LY3154885 or placebo; study drug will be administered as a single oral dose in the morning 
under fasted conditions. Subjects will be admitted to the CRU on the evening of Day -2. A 24 
hour baseline ABPM will be recorded on Day -1. and a 2 hours ABPM will be initiated on Day 1 
prior to dose. Subject will be required to remain inhouse for at least 48 hours after dosing (Day 
3), and at the discretion of the investigator. Subjects will attend the CRU on Days 4, 5, 6, 9, and 
10 on an outpatient basis for daily dosing and will be permitted to leave the CRU at the 


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discretion of the investigator. PK sampling will be conducted. To assess cardiovascular effects 
and potential accommodation over time, ABPM will be included on Day -1 (baseline) and on 
Days 1, 2, 7, 11, 12, and 14. A poststudy follow-up visit will be conducted approximately 7 days 
after discharge.
The doses evaluated will be selected based on emerging data from Parts A and B and from the 
lower doses from Part C. If the safety data do not support increasing the dose in subsequent 
cohorts, then a dose may be repeated or lower/intermediate doses may be explored. The PK data 
obtained during the study may be used to assist in dose-escalation decisions, but such data are 
not required for dose-escalation purposes. For the safety review prior to dose decisions between 
cohorts, all available safety data (AEs, vital signs, ECGs, and laboratory results) to at least Day 6 
from at least 6 subjects taking LY3154885 must be reviewed by the sponsor and investigator. In 
addition, each cohort (including at least 6 subjects treated with LY3154885) will complete 
dosing to Day 14 prior to the next cohort being admitted to the CRU for dosing. The figure 
below illustrates the study design for Part C.
5.4
Optional Part D (Pharmacokinetics of Capsule and Tablet Formulations and 
Food Effect)
The decision to conduct Part D will be made after review of safety, tolerability, and PK data 
from Parts A (SAD) and B (CYP3A4 Inhibition). Part D may be conducted in parallel with 
Part C.
Part D is optional and will assess the PK of single oral doses of LY3154885 in approximately 9 
healthy subjects when administered as a capsule (Period 1), as a tablet (Period 2), and as a tablet 
with a high-fat diet (Period 3). The dose for Part D will not exceed the highest dose tested in 
Part A (SAD) that was deemed safe and well tolerated.
In Periods 1 and 2, subjects will be admitted to the CRU the evening of Day -2. A 24 hours
baseline ABPM will be recorded on Day -1. A 2 hours ABPM will be initiated prior to dose in 


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each Period. Subject’s admission for Period 3 will be on Day -1. In Period 1, subjects will 
undergo an overnight fast before receiving a single oral dose of LY3154885 (capsule 
formulation) on Day 1. Subjects will remain inpatient for at least 48 hours after dosing, after 
which they may be discharged at the discretion of the investigator. Subjects will be re-admitted 
to the CRU on Day 6 and will undergo an overnight fast before receiving a subsequent single 
oral dose of LY3154885 on Day 8 with the same formulation. Subjects will be discharged on 
Day 10, at least 48 hours after dosing. Re-admission to the CRU will be on Day 13, and 
following an overnight fast, subjects will receive a single oral dose of LY3154885 on Day 14 
with the same formulation.
Final discharge from the CRU will occur on Day 16. 
Period 2 will be conducted as described for Period 1; however, LY3154885 will be administered 
as a tablet formulation. Period 3 will be conducted as described for Period 1; however, subjects 
will receive a single oral dose of LY3154885 (tablet formulation) after administration of a high-
fat diet.
The follow-up visit will occur approximately 7 days after final discharge. The figure below 
illustrates the study design for Part C.
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Part
Study Treatment Name
Treatment order in TFL
Part A
Placebo
1
15 mg LY3154885
2
45 mg LY3154885
3
100 mg LY3154885
4
200 mg LY3154885
5
400 mg LY3154885
6
500 mg LY3154885
7
Part B
Placebo
1


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B mg LY3154885
2
200 mg itraconazole
3
Placebo + 200 mg itraconazole
4
B mg LY3154885 + 200 mg itraconazole
5
Part C
Placebo
1
C1 mg LY3154885
2
C2 mg LY3154885
3
C3 mg LY3154885
4
Part D
D mg LY3154885 capsule
1
D mg LY3154885 tablet
2
D mg LY3154885 tablet (fed)
3
7. SAMPLE SIZE JUSTIFICATION
For Part A, up to 30 subjects may be enrolled into Cohorts 1 and 2 in order to ensure that 
approximately 12 subjects per cohort (8 LY3154885; 4 placebo) complete this part of the study.
For Part B, up to 15 subjects may be enrolled in order to ensure that approximately 12 subjects 
(9 LY3154885, 3 placebo) complete this part of the study.
For Part C, up to 45 subjects may be enrolled in order to ensure that approximately 36 subjects 
complete this part of the study (with approximately 12 subjects [9 LY3154885; 3 placebo] 
completing each dose level).
For Part D, up to 12 subjects may be enrolled in order to ensure that approximately 9 subjects 
complete this part of the study.
The sample size is customary for Phase 1 studies evaluating safety and PK, and is not powered 
on the basis of statistical hypothesis testing. 
Subjects who are randomized but not administered treatment or do not complete all treatment 
periods/doses may be replaced to ensure that enough subjects complete all parts of the study. 
Replacement subjects will be allocated the same treatment/sequence as the dropout subjects. 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.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of 
LY3154885 or placebo.
The “PK” population will consist of all subjects who received at least one dose of LY3154885
and have evaluable PK data.


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All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters) the geometric mean and geometric 
coefficient of variation (CV%) will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height and body mass index will be summarized by part and listed. All other 
demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
The PK parameter estimates for LY3154885 will be calculated by standard noncompartmental 
analysis methods. Parameters for analysis will be maximum observed drug concentration (Cmax), 
time to Cmax (tmax), and area under the concentration versus time curve (AUC) of LY3154885 
following single and multiple doses of LY3154885. Following multiple dosing, accumulation 
ratios based on LY3154885 AUC will be calculated as follows: AUC Day 14 / AUC Day 1 and 
AUC Day 7 / AUC Day 1. Other PK parameters such as half-life, apparent clearance, and 
apparent volume of distribution may be reported using noncompartmental analysis methods. 
If appropriate data are obtained, renal clearance of LY3154885 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 clearance. 


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If available, plasma concentration data for itraconazole and its metabolites (if applicable) will be 
summarized or listed in the CSR, and the data may subsequently be used for exploratory model 
development. A noncompartmental PK analysis of itraconazole and its metabolites may be 
conducted if deemed valuable to the interpretation of the study results but is not required to 
complete the CSR.
9.3.2
Pharmacokinetic Statistical Methodology
Statistical analysis of the PK parameters will be produced by Covance. All summary outputs will 
be produced by Lilly.
Part A: The PK parameters Cmax and AUC for LY3154885 will be evaluated to estimate the 
dose-exposure proportionality of LY3154885 using a linear-mixed-effect power model. In this 
model, log-transformed dose will be the independent variable and subject will be a random 
effect. Both Cmax and AUC will be log-transformed prior to analysis. The least-squares (LS) 
means for each treatment together with the treatment differences and associated 90% confidence 
intervals (CIs) will be estimated from the model. These estimates will be back-transformed to 
present geometric means, the ratios of geometric means, and the corresponding 90% CIs.
Example SAS code for the analysis:
proc mixed data=xxx;
class subject;
model log_pk = log_dose / alpha=0.1 cl solution outpred=resids ddfm=kr;
random subject;
estimate 'xx mg' intercept 1 log_dose yy / alpha=0.1 cl; /*Log value of xx*/
estimate 'zz mg - xx mg' log_dose pp / alpha=0.1 cl; /*Difference in log 
values of zz and xx*/
ods output solutionf=est estimates=estims;
run;
Part B: The PK parameters Cmax and AUC for LY3154885 when administered alone and with 
itraconazole will be compared using an analysis of variance (ANOVA) model. The parameters 
will be log-transformed prior to analysis. The model will include a fixed-effect for the treatment 
(LY + itraconazole : LY) and a random effect for subject. The LS means for each treatment, the 
difference between the treatment LS means (LY3154885 + itraconazole – LY3154885), and the 
associated 90% CIs will be estimated from the ANOVA model and back-transformed from the 
log scale to provide estimates of the geometric means, geometric mean ratio, and corresponding 
90% CIs. 
Example SAS code for the analysis:
proc mixed data=xxx;
class treatment subject;
model log_pk = treatment /residual ddfm=kr;
random subject;
lsmeans treatment / cl pdiff alpha=0.1;
ods output lsmeans=lsm diffs=estims;
run;


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The tmax of LY3154885 for both treatments will be analyzed using a Wilcoxon signed-rank test. 
An estimate of the median difference and 90% CI will be calculated.
Part C: The plasma PK parameters Cmax and AUC for LY3154885 obtained on Day 14 will be 
evaluated to estimate the dose-exposure proportionality of LY3154885 using a linear-mixed-
effect power model. The model used will be the same as Part A above but without subject as a 
random effect. 
Part D:
Effect of formulation: The AUC and Cmax for LY3154885 following administration of a capsule 
and tablet formulation in a fasted state will be log transformed and analyzed using a mixed 
effects ANOVA model. The model will include fixed effects for formulation (capsule : tablet)
and a random effect for subject. The LS means for each formulation 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 means. 
The tmax of LY3154885 between formulations will be analyzed using a Wilcoxon signed-rank 
test. An estimate of the median difference and 90% CI will be calculated.
Effect of high-fat diet: The AUC and Cmax for LY3154885 following administration of a tablet 
formulation in the fed state and fasted state will be log transformed and analyzed using a mixed-
effects ANOVA model. The model will include fixed effects for food (fed : fasted) and a random 
effect for subject. The LS means for fed and fasted 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 means. 
The tmax of LY3154885 between fed and fasted will be analyzed using a Wilcoxon signed-rank 
test. An estimate of the median difference and 90% CI will be calculated.
The SAS code for both analyses will be similar to the Part B analysis.
9.4
Pharmacodynamic Assessment
9.4.1
Exploratory Pharmacodynamic Analysis
The DSST and HVLT will be included in Part C to assess relevant aspects of cognition, 
vigilance, and working memory that may provide a PD signal in healthy volunteers. 
Endpoints from the DSST and HVLT will be summarized by domain (as appropriate), time, and 
treatment. Change from baseline (predose) will also be presented.
POMS-2: a profile of mood states is also included in Part C to assess subject transient, 
fluctuation feelings and enduring affect states. POMS-2 is a 35-item, adjective rating scale and is 
considered to be a standardized mood-state inventory. The change from baseline (predose) may 
be presented as applicable. 


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9.5
Safety and Tolerability Assessments
9.5.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose. 
All AEs will be listed. Treatment-emergent AEs will be summarized by part, treatment, severity 
and relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by part, treatment, Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.1 system organ class and preferred term. The summary and frequency AE
tables will be presented for all causalities and those considered related to the study drug. Any 
serious AEs will be listed. For Part B only, AEs by day of onset will be presented.
9.5.2
Concomitant medication
Concomitant medication will be coded using the World Health Organization drug dictionary 
(Version September 2018). Concomitant medication will be listed.
9.5.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by part, parameter and treatment, 
and listed. Where postdose data is available, changes from baseline, where baseline is defined as 
Day 1 predose will also be presented. Urinalysis data will be listed. Additionally, clinical 
chemistry, hematology and urinalysis data outside the reference ranges will be listed and flagged 
on individual subject data listings.
9.5.4
Vital signs
Vital signs data will be summarized by part, treatment and timepoint, together with changes from 
baseline, where baseline is defined as the Day 1 predose assessment. Figures of mean vital signs 
and mean changes from baseline profiles will be presented by part and treatment. 
Values for individual subjects will be listed.
9.5.5
Electrocardiogram
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the PR, 
QT, QRS duration and heart rate. In addition, QTcF (the QT interval corrected using Fridericia’s 
formula) will be calculated as follows:


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  8404743
Sponsor Reference J1Z-MC-HUAA


3 60HR
QT
QTcF 
The ECG data will be summarized by part, treatment and timepoint, together with changes from 
baseline, where baseline is defined as the mean of the triplicate assessment. Figures of mean 
ECG data and mean changes from baseline will be presented by treatment. The frequency of 
subjects with a maximum increase from baseline in QTcF interval will be summarized for each 
treatment according to the following categories: >30 ms and >60 ms. In addition, the frequency 
of subjects with QTcF postdose values, according to the following categories: >450 ms, >480 ms 
and >500 ms, will be summarized by treatment. 
9.5.5.1
Electrocardiogram analysis (Part A)
The relationship between the time-matched LY3154885 concentrations and changes from 
baseline and time-matched placebo in QTcF interval will be explored graphically using a scatter 
plot. A regression analysis using a linear mixed-effects model will be performed. A plasma 
LY3154885 concentration-QT analysis will be performed to assess the changes from baseline 
(Day 1 predose) and time-matched mean placebo in the QTcF interval relative to plasma 
LY3154885 concentrations across all dose levels. The change from baseline adjustment will be 
based on individual subject’s Day 1 predose value, and an additional placebo adjustment will be 
based on individual subject’s time-matched placebo values. The analysis will be performed by 
plotting double delta QTcF against LY3154885 concentrations, including all post dosing 
timepoints. A linear mixed-effects model will be performed on the double delta QTcF values and 
will include LY3154885 concentration as a covariate. The estimated regression line and 
associated 90% confidence interval (CI) will be fitted on the plot and the p-value for the slope 
reported. Estimated delta QTcF and 90% CI at the geometric mean Cmax (estimated from the 
highest given dose in the study) will also be presented.
9.5.5.2
Electrocardiogram analysis (Part C)
The same analysis to Part A will be performed in Part C, but the change from baseline 
adjustment will be based on individual subject’s Day 1 predose value, and an additional placebo 
adjustment will be based on mean time-matched placebo values.
9.5.6
Ambulatory Blood Pressure Monitoring
Ambulatory blood pressure monitoring (ABPM) will be performed in all parts of the study. A 
24 hours baseline (off study drug) will be measure in all subjects and at least a 2 hour measure 
prior to dose will be also be measured on selected dosing days. The ABPM device will record 
ambulatory BP and PR every 30 minutes during awake hours (e. g. 0700 hours to 2200 hours) 
and every 60 minutes throughout the night (e.g. 2200 hours to 0700 hours).
The primary parameters for the ABPM data will be peak hourly mean values of systolic blood 
pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), and nadir 
hourly mean values for PR. These data will be listed and summarized by part and treatment.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  8404743
Sponsor Reference J1Z-MC-HUAA
Mean hourly SBP, DBP, MAP, and PR values will be calculated, summarized by part and 
treatment, and plotted, together with changes from baseline. Baseline value will be defined as the 
mean value during the 2 hours prior to the planned dosing time.
9.5.7
Neurological Examination
Elements of the neurological examination may include inspection for tremor, extraocular 
movements, brachial and patellar deep tendon reflexes, finger-nose pointing, and Romberg sign.
The below table presents the scoring of the neurological examination findings. 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 to 
baseline.
Score
0
1
2
3
4
Tremor
Absent
Visible with limb 
extension and/or 
careful inspection
Visible without 
limb extension.
Interferes with 
motor function
Nystagmus
Absent
1 to 3 beats on 
lateral gaze
>3 beats on 
lateral gaze
Present on 
forward gaze
Reflexes (brachial or patellar)
Normal
Trace
Absent
Increased
Clonic
Finger-nose
Normal
Abnormal
Romberg sign
Absent
Present
The frequency of neurological survey data will be summarized by part, treatment and timepoint, 
and listed.
9.5.8
Columbia-Suicide Severity Rating Scale (Part C Only)
The Columbia Suicide Severity Rating Scale (C-SSRS) captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviours during the assessment period. The C-SSRS
and Lilly Self-Harm Supplement Form data will be listed.
9.5.9
Exploratory Scales and Questionnaire (Part C Only)
The Penn Physician Withdrawal Checklist (PWC-20) is a 20-item checklist that will be used to 
assess the presence and severity of withdrawal symptoms. The PWC-20 data will be summarized 
by treatment and timepoint and listed.
9.5.10 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality. Additional safety data may be collected if 
required, as defined in the protocol. Where applicable, the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be 
listed. Any concomitant medication of acetaminophen/paracetamol will be listed. Results from 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  8404743
Sponsor Reference J1Z-MC-HUAA
any hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan, and 
a biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.5.11
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.5.12
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
Access to safety and tolerability data is scheduled to occur after every dosing session. 
Pharmacokinetic data will be reviewed to guide implementation of this study and to support dose 
escalations. Data reviews may be added as deemed appropriate by the sponsor without a protocol 
amendment. 
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.  8404743
Sponsor Reference J1Z-MC-HUAA
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 563c5820-336a-45c5-b10a-5be1c73cad89
Approver: 
Approval Date & Time: 16-Jul-2019 10:35:33 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Jul-2019 19:42:59 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 18-Jul-2019 12:49:53 GMT
Signature meaning: Approved
PPD
PPD
PPD