A Safety, Tolerability, Pharmacokinetic, and Pilot Food Effect Study of Single- and Multiple-Ascending Doses of LY3526318 in Healthy Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol J2D-MC-CVAA (c) 
 
A Safety, Tolerability, Pharmacokinetic, and Pilot Food Effect Study of Single- and Multiple-
Ascending Doses of LY3526318 in Healthy Participants 
 
NCT03977974 
 
Approval Date: 16-Dec-2019 

J 2 D -M C -C V A A ( c) Cli ni c al Pr ot o c ol
P a g e 1
L Y 3 5 2 6 3 1 8
Pr ot o c ol J 2 D- M C -C V A A ( c)
A S af et y , T ol er a bilit y, P h ar m a c o ki n eti c, a n d Pil ot F o o d Eff e ct
St u d y  of Si n gl e- a n d M ulti pl e -A s c e n di n g D o s e s of L Y 3 5 2 6 3 1 8 
i n H e alt h y P arti ci p a nt s
E U D R A C T A : 2 0 1 9 -0 0 1 9 0 2 -8 0
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 st ri 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 al i n v e sti g ati o n of 
L Y 3 5 2 6 3 1 8 , 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 e r s on 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.
A p pr o v al D at e: 1 6- D e c- 2 0 1 9 G M T
L Y 3 5 2 6 3 1 8
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 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 o n d at e pr o vi d e d b el o w.

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Table of Contents
Protocol J2D-MC-CVAA(c)
A Safety, Tolerability, Pharmacokinetic, and Pilot Food Effect Study of Single- and 
Multiple-Ascending Doses of LY3526318 in Healthy Participants
Section
Page
1
Protocol Synopsis................................................................................................................8
2
Schedule of Activities .......................................................................................................11
3
Introduction ......................................................................................................................21
3.1
Study Rationale............................................................................................................21
3.2
Background..................................................................................................................21
3.3
Benefit/Risk Assessment..............................................................................................21
4
Objectives and Endpoints..................................................................................................23
5
Study Design.....................................................................................................................24
5.1
Overall Design .............................................................................................................24
5.2
Number of Participants.................................................................................................26
5.3
End of Study Definition ...............................................................................................27
5.4
Scientific Rationale for Study Design...........................................................................27
5.5
Justification for Dose ...................................................................................................28
6
Study Population...............................................................................................................30
6.1
Inclusion Criteria..........................................................................................................30
6.2
Exclusion Criteria ........................................................................................................31
6.3
Lifestyle and/or Dietary Requirements .........................................................................33
6.3.1
Meals and Dietary Restrictions.............................................................................33
6.3.2
Caffeine, Alcohol, and Tobacco ...........................................................................33
6.3.3
Activity................................................................................................................33
6.4
Screen Failures.............................................................................................................33
7
Treatment..........................................................................................................................34
7.1
Treatment Administered...............................................................................................34
7.1.1
Packaging and Labeling .......................................................................................35
7.2
Method of Treatment Assignment ................................................................................35
7.2.1
Selection and Timing of Doses.............................................................................35
7.3
Blinding .......................................................................................................................36
7.4
Dose Modification........................................................................................................36
7.4.1
Dose Escalation....................................................................................................36
7.4.1.1
Part A.............................................................................................................37
7.4.1.2
Part B .............................................................................................................37

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7.4.2
Stopping Rules.....................................................................................................37
7.5
Preparation/Handling/Storage/Accountability...............................................................37
7.6
Treatment Compliance .................................................................................................38
7.7
Concomitant Therapy...................................................................................................38
7.8
Treatment after the End of the Study............................................................................38
8
Discontinuation Criteria ....................................................................................................39
9
Study Assessments and Procedures ...................................................................................41
9.1
Efficacy Assessments...................................................................................................41
9.2
Adverse Events ............................................................................................................41
9.2.1
Serious Adverse Events........................................................................................42
9.2.1.1
Suspected Unexpected Serious Adverse Reactions..........................................42
9.2.2
Complaint Handling.............................................................................................43
9.3
Treatment of Overdose.................................................................................................43
9.4
Safety...........................................................................................................................43
9.4.1
Laboratory Tests ..................................................................................................43
9.4.2
Vital Signs ...........................................................................................................43
9.4.3
Electrocardiograms ..............................................................................................43
9.4.4
Physical Examination...........................................................................................44
9.4.5
Columbia-Suicide Severity Rating Scale ..............................................................44
9.4.6
Safety Monitoring ................................................................................................45
9.4.6.1
Hepatic Safety................................................................................................45
9.5
Pharmacokinetic Assessments......................................................................................45
9.5.1
Blood Sampling and Processing ...........................................................................45
9.5.2
Urine Sampling and Processing............................................................................46
9.5.3
Bioanalysis...........................................................................................................46
9.6
Pharmacodynamics ......................................................................................................46
9.7
Genetics .......................................................................................................................46
9.8
Biomarkers...................................................................................................................46
9.9
Health Economics ........................................................................................................46
10
Statistical Considerations and Data Analysis.....................................................................47
10.1
Sample Size Determination ..........................................................................................47
10.2
Populations for Analyses..............................................................................................47
10.2.1
Study Participant Disposition ...............................................................................47
10.2.2
Study Participant Characteristics ..........................................................................47
10.2.3
Concomitant Medications.....................................................................................47
10.3
Statistical Analyses ......................................................................................................47
10.3.1
Safety analysis .....................................................................................................47
10.3.2
Pharmacokinetic Analyses....................................................................................48

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10.3.2.1
Pharmacokinetic Population ...........................................................................48
10.3.2.1.1
Plasma Pharmacokinetic Parameter Estimation.........................................48
10.3.2.1.2
Urine Pharmacokinetic Parameter Estimation ...........................................48
10.3.2.2
Pharmacokinetic Statistical Inference .............................................................49
10.3.3
Data Review during the Study..............................................................................49
11
References ........................................................................................................................50
12
Appendices .......................................................................................................................52

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List of Tables
Table
Page
Table 2-1
Study Schedule Protocol J2D-MC-CVAA: Part A Cohorts 1-6 
(SAD).....................................................................................................11
Table 2-2
Study Schedule Protocol J2D-MC-CVAA: Part A-Cohort 10-(3 
Period Food Effect Cohort).....................................................................13
Table 2-3
Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 7.......15
Table 2-4
Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 8.......17
Table 2-5
Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 9.......19
Table 4-1
Objectives and Endpoints .......................................................................23
Table 5-1
Part A Stratification Based on Sex..........................................................24

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List of Figures
Figure
Page
Figure 5.1
Illustration of study design for Protocol J2D-MC-CVAA........................26

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................53
Appendix 2.
Clinical Laboratory Tests........................................................................56
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................57
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............60
Appendix 5.
Blood Sampling Summary......................................................................61
Appendix 6.
List of Excluded Concomitant Medications ............................................63
Appendix 7.
Protocol Amendment: J2D-MC-CVAA(a)..............................................68
Appendix 8.
Protocol Amendment: J2D-MC-CVAA(b)..............................................71
Appendix 9.
Protocol Amendment: J2D-MC-CVAA(c)..............................................79

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1 Protocol Synopsis
Title of Study:
A safety, tolerability, pharmacokinetic, and pilot food effect study of single- and multiple-ascending doses of 
LY3526318 in healthy participants
Rationale: 
LY3526318 is a small molecule that inhibits transient receptor protein ankyrin-1 (TRPA1), a calcium-permeable 
nonselective cation channel. There is strong clinical and preclinical evidence for TRPA1 antagonism in the 
alleviation of chronic pain. In humans, exogenous TRPA1 administration induces pain and nerve hyper-excitability. 
TRPA1 antagonists have been safe and well tolerated in healthy participants (ODM-108; NCT02432664) and in 
patients with diabetic neuropathy (GRC 17536; EU Clinical Trial Register 2012-002320-33). GRC 17536 has been 
efficacious for pain relief in a Phase 2a trial in patients with diabetic peripheral neuropathy. LY3526318 has been 
shown to be effective in preclinical pain models and will be further studied in patients with chronic pain after safety 
and pharmacodynamics have been characterized in healthy participants.
The first-in-human Phase 1 study will evaluate the safety, tolerability, and pharmacokinetic (PK) parameters of 
LY3526318 in healthy participants after oral administration. The study includes a single-ascending dose 
(SAD/Part A) and a multiple-ascending dose (MAD/Part B). 
Objectives/Endpoints:
Objectives
Endpoints
Primary (Part A)
To evaluate safety and tolerability of LY3526318 in healthy participants
following a single oral dose

AEs 

SAEs
Primary (Part B)
To evaluate safety and tolerability of LY3526318 in healthy participants
following multiple once-daily oral doses for 14 days

AEs 

SAEs
Secondary (Part A)
To evaluate the plasma pharmacokinetics of LY3526318 in healthy 
participants following a single oral dose

AUC

Cmax

tmax
Secondary (Part B)
To evaluate the plasma pharmacokinetics of LY3526318 in healthy 
participants following multiple once-daily oral doses for 14 days

AUC

Cmax

tmax
Abbreviations: AE = adverse event; AUC = area under the concentration versus time curve; Cmax = maximum
observed drug concentration; SAE = serious adverse event; tmax = time to Cmax.

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Summary of Study Design, Treatment Arms, and Planned Duration:
Study J2D-MC-CVAA is a single-center, randomized, double-blind, placebo-controlled, SAD (Part A) and MAD
(Part B) study of LY3526318 in healthy participants.
Part A - SAD
The single-ascending doses of LY3526318 or placebo will be administered, at planned dose levels of 10, 50, 100, 
400, 800, and 1000 mg, in 7 cohorts of 8 participants each, except the 100-mg cohort that will include 
12 participants. The dose levels may change subject to available safety and PK data review. 
Participants in the first cohort (10 mg, Cohort 1) will not be stratified by sex. A fixed number of females and males 
will be randomized in Cohorts 2 and 3 and the participants will be stratified to ensure equal distribution between 
females and males. Cohorts administered above LY3526318 100 mg are anticipated to exceed the approximate 10x 
margin to the projected no-observed-adverse-event-level (NOAEL)-equivalent exposure for males; for this reason, 
only female participants will be enrolled at dose levels higher than 100 mg. Additionally, males will only be dosed 
through 100 mg if exposure data from previous cohorts supports this. Randomization to LY3526318 or placebo will 
be 3:1 within each cohort or stratum, respectively, except for Cohort 10.
Following a screening period of up to 28 days, eligible participants will be confined to the clinical research unit 
(CRU) from Day -1 until all study assessments are completed on Day 3. A sentinel dosing strategy will be utilized 
for the first dose level (Cohort 1, 10 mg). Two participants will receive a sentinel dose (1 each with LY3526318 and 
placebo) and the remaining participants will be administered after review of safety data up to 48 hours postdose.
Dose escalation from the 10-mg to 50-mg cohort may occur after review of safety data from at least 6 participants in 
the 10-mg cohort. Dose escalations to subsequent cohorts may occur after review of safety data and available PK 
data through 48 hours postdose from at least 6 participants in the prior cohort.
The effect of food on LY3526318 PK will be explored in only female participants enrolled in the 100-mg cohort and 
in the 400-mg cohorts. The initial dose will be administered after an approximately 8-hour fast, followed by a 
washout period of at least 1 week, and a second dose administration following a standardized high-fat meal. To 
ensure a sufficient number of females for the food effect assessment at 100-mg dose level, the 100-mg cohort will be 
expanded to 12 participants (8 females and 4 males). An additional cohort (Cohort 10) will assess the effect of food 
on LY3526318 PK in 8 female participants. All participants in this cohort will receive 100 mg LY3526318 with 
standardized high fat meal in an open-label, 3-way crossover manner (meal administered prior to dose, at 30 minutes 
and at 1 hour post dose).
Except for the second dose in the food effect assessment cohorts, all other doses are planned to be administered after
an approximately 8-hour fast. However, following a review of the 100-mg and/or 400-mg fed and fasted data, 
subsequent cohorts may be administered with food.
Participants will return to the CRU for a final follow-up visit approximately 9 days after study drug administration 
or after the final fed-state dose for female participants in the 100- and 400-mg cohorts.
Part B - MAD
The multiple-ascending doses of LY3526318 or placebo will be administered, at planned dose levels of 100, 400, 
and 1000 mg, once daily for 14 days in 3 cohorts of 8 female participants each. It is likely that 1 or more dose levels 
in Part B may exceed the approximate 10x margin to the projected NOAEL-equivalent exposures for males; for this 

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reason, only female participants will be enrolled in Part B. The planned dose levels may be updated following a 
review of safety and PK data from Part A and they will not exceed those studied in Part A.
The first cohort of Part B will be administered LY3526318 following a review of Part A safety and PK data. Dose 
escalations to subsequent cohorts may occur after review of safety data and available PK data through 14 days from 
at least 6 participants in the prior cohort.
Following a screening period of up to 28 days, eligible participants will be confined to the CRU from Day -1, until 
all study assessments are completed on Days 15, 18, and 19 for Cohorts 7, 8, and 9, respectively. Within each 
cohort, participants will be randomly assigned to receive LY3526318 or placebo in a 6:2 ratio. 
LY3526318 or matching placebo is planned to be administered in an 8-hour fasting state once daily for 14 days. 
However, following a review of the food effect data from Part A, all doses may be administered with food.
Participants will return to the CRU for a final visit on Day 23.
Number of Participants:
Part A: Approximately 60 participants will be randomized to achieve 8 evaluable participants per cohort 
(6 LY3526318:2 placebo), except for the 100-mg cohort that will include 8 evaluable females and 4 evaluable males 
(females: 6 LY3526318:2 placebo; males: 3 LY3526318:1 placebo) and 100-mg food assessment cohort (Cohort 10) 
that will include 8 evaluate females and all will receive LY3526318 in an open-label manner.
Part B: Approximately 24 participants will be randomized to achieve 8 evaluable participants per cohort 
(6 LY3526318:2 placebo).
Additional cohorts of up to 8 participants each may be enrolled in either part of the study. Such additional cohorts 
may be enrolled in case intermediate or additional dose level(s) need to be studied or additional food effect need to 
be studied at other than planned dose levels. 
Statistical Analysis:
Safety: The primary safety endpoints are the numbers of treatment-emergent serious adverse events and adverse 
events. Summary statistics for each cohort will be provided by dose level and for all placebo participants combined.
Pharmacokinetic Parameters: Plasma PK parameters for LY3526318 and metabolite(s) of interest will be calculated 
using noncompartmental methods after single- and multiple-dose administration. Pharmacokinetic parameters will 
be summarized by dose level using descriptive statistics. Mean and individual plasma concentration versus time 
curves for LY3526318 will be represented graphically.

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2 Schedule of Activities
Table 2-1
Study Schedule Protocol J2D-MC-CVAA: Part A Cohorts 1-6 (SAD) 
S
Treatment/ In CRU
Posttreatment
EDa
Study Day
≤28
-1
1
2
3
10
Visit Window (days)
±2
Visits
1b
2c
3
CRU admission
X
CRU discharge
X
Participant information (including I/E 
criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination
(complete [C] or directed [D])
C
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
Vital signs including temperature
X
X
X (predose, 
2 h, 4 h, 8 h)
X
X
X
X
Hematology and clinical chemistry
X
X
Xd
Xd
X
X
Urinalysise
X
X
Pregnancy test (serum beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X (predose, 
2 h, 4 h, 8 h) 
X
X
C-SSRS
X
X
X
X
Randomization
X
Study drug administrationh
X
PK blood samplei
X
X
X
X
PK 24-hour urine collectionj
X 
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; 
h = hour; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; PK = pharmacokinetics; S = screening; 
SAD = single-ascending dose.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of the first dose being administered.
c
All participants will remain in the CRU until completion of Day 3 procedures.
d
Hematology and clinical chemistry sample to be taken in the morning.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest.

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h
All doses are planned to be administered in a fasting state (at least 8 hours predose and 4 hours postdose), with 
the exception of the 100- and 400-mg cohorts. In both cohorts, the initial dose will be administered to 
participants in the fasted state (at least 8 hours predose and 4 hours postdose), followed by a washout period of at 
least 1 week and a second dose administration after a standardized high-fat meal. Only female participants will 
undergo fed dose administration in the 100-mg cohort. Following a review of the 100- and 400-mg fed and fasted 
data, subsequent cohorts may be administered with food. The exact time study drug is administered will be 
recorded.
i
On Day 1, PK samples will be collected at time zero (predose) and at approximately 1, 2, 4, 6, 8, and 12 hours 
after dosing. One PK sample will be taken at 24 and 48 hours postdose (Days 2 and 3), and if applicable, at the 
ED Visit. PK sample collection times are provided as a guidance and may be modified based on clinical needs. 
Actual dates and times of sample collection must be recorded. The following time collection intervals are 
proposed: predose samples may be obtained between waking up and dosing. Postdose samples may be obtained 
within ±5% of the scheduled collection time. The ±5% time window also applies to the start and end times of 
urine collection intervals. Post-assay remainder PK plasma samples may be stored for metabolite identification.
j
Urine collection interval is 0 to 24 hours postdose. The total urine volume of the 0- to 24-hour collection will be 
recorded.

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Table 2-2
Study Schedule Protocol J2D-MC-CVAA: Part A Cohort 10
(3-Period Food Effect Cohort)
S
Treatment/ In CRU
Posttreatment
EDa
Study Day (visit window)
≤28
-1
1
2
3
4
10 (± 2)
Period
1-3
3
1-3
Visits
1b
2c
3
CRU admission
X
CRU discharge
X
Participant information (including I/E 
criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination
(complete [C] or directed [D])
C
D
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
Vital signs including temperature
X
X
X (predose, 2 h, 
4 h, 8 h)
X
X
X
X
Hematology and clinical chemistry
X
X
Xd
Xd
X
X
Urinalysise
X
X
Pregnancy test (serum beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X (predose, 2 h, 
4 h, 8 h) 
X
X
C-SSRS
X
X
X
X
Randomization
Xh
Study drug administrationi
X
PK blood samplej
X
X
X
X
X
PK 24-hour urine collectionk
X 
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; 
h = hour; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; PK = pharmacokinetics; S = screening; 
SAD = single-ascending dose.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of the first dose being administered.
c
All participants will remain in the CRU until completion of Day 4 procedures.
d
Hematology and clinical chemistry sample to be taken in the morning.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest.

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h
randomization will occur during first period only.
i
Doses are planned to be administered as follows in each period:

Period 1-Fed standardized high fat meal to start 30 minutes prior to dose administration

Period 2-Fasted at least 8-hours predose with a standardized high fat meal administered 30 minutes
post dose

Period 3-Fasted at least 8-hours predose with a standardized high fat meal administered 1 hour post
dose
Periods will be separated by a washout of at least 1 week.  The meals administered in all treatment periods
should be consumed within 30 minutes. The exact time study drug is administered will be recorded.
j
In each treatment period, on Day 1, PK samples will be collected at time zero (predose) and at approximately 1, 
2, 4, 6, 8, and 12 hours after dosing. One PK sample will be taken at 24, 48, and 72 hours postdose (Days 2, 3, 
and 4), and if applicable, at the ED Visit. PK sample collection times are provided as a guidance and may be 
modified based on clinical needs. Actual dates and times of sample collection must be recorded. The following 
time collection intervals are proposed: predose samples may be obtained between waking up and dosing.
Postdose samples may be obtained within ±5% of the scheduled collection time. The ±5% time window also 
applies to the start and end times of urine collection intervals. Post-assay remainder PK plasma samples may be 
stored for metabolite identification.
k
Urine collection interval is 0 to 24 hours postdose. The total urine volume of the 0- to 24-hour collection will be 
recorded.

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Table 2-3
Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 7
S
Treatment/In CRU
Post
treatment
EDa
Study Day
≤28
-1
1
2
3
5
8
14
15
23
Visit Window (days)
±2
Visits
1b
2
3
CRU admission
X
CRU discharge 
X
Participant information (including I/E criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination (complete [C] or directed [D])
C
D
D
D
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
Vital signs including temperaturec
X
X
X
X
X
X
X
X
X
X
Hematology and clinical chemistryd
X
X
X
X
X
X
X
Urinalysise
X
X
Pregnancy test (serum beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X
X
X
X
C-SSRS
X
X
X
X
X
Randomization
X
Study drug administrationh
X 
PK blood samplei
X
X
X
X
X
X
X
X
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation;
h = hours; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; MAD = multiple-ascending dose; PK = 
pharmacokinetic; S = screening.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of first dose administration.
c
Vital signs and temperature should be measured at following time points: Days 1 and 14 – predose and 2 hours, 
4 hours, and 8 hours postdose; predose on all other indicated dosing days.
d
Hematology and chemistry sample should be collected predose on stipulated visits.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest at following time points:
Days 1 and 14 – predose and 2 hours, 4 hours, and 8 hours postdose.
h
Study drug will be administered once daily in the CRU through Day 14, and the exact time of administration will 
be recorded.  All doses are planned to be administered in a fasting state; however, following a review of the food 
effect data from Part A, all doses may be administered with food. Fasting on PK sampling days is defined as at 
least 8 hours predose and 4 hours postdose. Fasting on non-PK and predose only PK sampling days is defined as 
at least 8 hours predose and 2 hours postdose on all other indicated days. 

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i
On Days 1 and Day 14, PK samples will be collected at time zero (predose) and at approximately at 1, 2, 4, 6, 8, 
and 12 hours after dosing. On Day 2 (at predose) and on Day 15 (prior to discharge), 1 PK sample will be taken 
at 24 hours postdose. Predose PK samples will also be obtained on Days 3, 5, and 8. If applicable, a sample will 
be collected at the ED visit. PK sample collection times are provided as a guidance and may be modified based 
on clinical needs. Actual dates and times of sample collection must be recorded. The following time intervals are 
proposed: predose samples may be obtained between waking up and dosing. Postdose samples may be obtained 
within ±5% of the scheduled collection time. Post-assay remaining PK plasma samples may be stored for 
metabolite identification.

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Table 2-4
Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 8
S
Treatment/In CRU
Post
treatment
EDa
Study Day
≤28
-1
1
2
3
5
8
14
15
16
17
18
23
Visit Window (days)
±2
Visits
1b
2
3
CRU admission
X
CRU discharge
X
Participant information (including 
I/E criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination (complete [C] 
or directed [D])
C
D
D
D
D
D
D
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
Vital signs including temperaturec
X
X
X
X
X
X
X
X
X
X
Hematology and clinical chemistryd
X
X
X
X
X
X
X
Urinalysise
X
X
Pregnancy test (serum beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X
X
X
X
C-SSRS
X
X
X
X
X
Randomization
X
Study drug administrationh
X 
PK blood samplei
X
X
X
X
X
X
X
X
X
X
X
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; 
h = hours; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; MAD = multiple-ascending dose; PK = 
pharmacokinetic; S = screening.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of first dose administration.
c
Vital signs and temperature should be measured at following time points: Days 1 and 14 – predose and 2 hours, 
4 hours, and 8 hours postdose; predose on all other indicated dosing days.
d
Hematology and chemistry sample should be collected predose on stipulated visits.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest at following time points:
Days 1 and 14 – predose and 2 hours, 4 hours, and 8 hours postdose.

J2D-MC-CVAA (c) Clinical Protocol
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h
Study drug will be administered once daily in the CRU through Day 14, and the exact time of administration will 
be recorded.  All doses are planned to be administered in a fasting state; however, following a review of the food 
effect data from Part A, all doses may be administered with food. Fasting on PK sampling days is defined as at 
least 8 hours predose and 4 hours postdose. Fasting on non-PK and predose only PK sampling days is defined as 
at least 8 hours predose and 2 hours postdose on all other indicated days. 
i
On Day 1 and Day 14, PK samples will be collected at time zero (predose) and at approximately at 1, 2, 4, 6, 8, 
and 12 hours after dosing. Predose PK samples will also be obtained on Days 2, 3, 5, and 8. One PK sample will 
be taken at approximately 24, 48, 72, and 96 hours post Day 14 dose on Days 15, 16, 17, and 18, respectively.  If 
applicable, a sample will be collected at the ED visit. PK sample collection times are provided as a guidance and 
may be modified based on clinical needs. Actual dates and times of sample collection must be recorded. The 
following time intervals are proposed: predose samples may be obtained between waking up and dosing. 
Postdose samples may be obtained within ±5% of the scheduled collection time. Post-assay remaining PK plasma 
samples may be stored for metabolite identification.

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Table 2-5
Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 9
S
Treatment/In CRU
Post
treatment
EDa
Study Day
≤28
-1
1
2
3
5
8
14
15
16
17
18
19
23
Visit Window (days)
±2
Visits
1b
2
3
CRU admission
X
CRU discharge
X
Participant information 
(including I/E criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination 
(complete [C] or directed [D])
C
D
D
D
D
D
D
D
D
D
D
D
D
C
C
Urine drug screen and ethanol 
test
X
X
Vital signs including 
temperaturec
X
X
X
X
X
X
X
X
X
X
Hematology and clinical 
chemistryd
X
X
X
X
X
X
X
Urinalysise
X
X
Pregnancy test (serum 
beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X
X
X
X
C-SSRS
X
X
X
X
X
Randomization
X
Study drug administrationh
X 
PK blood samplei
X
X
X
X
X
X
X
X
X
X
X
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; 
h = hours; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; MAD = multiple-ascending dose; PK = 
pharmacokinetic; S = screening.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of first dose administration.
c
Vital signs and temperature should be measured at following time points: Days 1 and 14 – predose and 2 hours, 
4 hours, and 8 hours postdose; predose on all other indicated dosing days. 
d
Hematology and chemistry sample should be collected predose on stipulated visits.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest at following time points: 
Days 1 and 14 – predose and 2 hours, 4 hours, and 8 hours postdose.

J2D-MC-CVAA (c) Clinical Protocol
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h
Study drug will be administered once daily in the CRU through Day 14, and the exact time of administration will 
be recorded.  All doses are planned to be administered in a fasting state; however, following a review of the food 
effect data from Part A, all doses may be administered with food. Fasting on PK sampling days is defined as at 
least 8 hours predose and 4 hours postdose. Fasting on non-PK and predose only PK sampling days is defined as 
at least 8 hours predose and 2 hours postdose on all other indicated days. 
i
On Day 1 and Day 14, PK samples will be collected at time zero (predose) and at approximately at 1, 2, 4, 6, 8, 
and 12 hours after dosing. Predose PK samples will also be obtained on Days 2, 3, 5, and 8. One PK sample will 
be taken at approximately 24, 48, 72, and 120 hours post Day 14 dose on Days 15, 16, 17, and 19, respectively.  
If applicable, a sample will be collected at the ED visit. PK sample collection times are provided as a guidance 
and may be modified based on clinical needs. Actual dates and times of sample collection must be recorded. The 
following time intervals are proposed: predose samples may be obtained between waking up and dosing. 
Postdose samples may be obtained within ±5% of the scheduled collection time. Post-assay remaining PK plasma 
samples may be stored for metabolite identification.

J 2 D -M C -C V A A ( c) Cli ni c al Pr ot o c ol
P a g e 2 1
L Y 3 5 2 6 3 1 8
3
I ntr o d u cti o n
3. 1
St u d y R ati o n al e
St u d y  J 2 D-M C -C V A A is a first -i n-h u ma n ( FI H) st u d y  desi g ne d t o e val uate safet y, t olera bilit y, 
a n d p har mac o ki net ics ( P K) of  or al  L Y 3 5 2 6 3 1 8 i n healt h y parti ci pa nt s. L Y 3 5 2 6 3 1 8 is a s mall 
m o lec ule desi g ne d t o i n hi bit tra nsie nt rece pt or pr otei n a n k yri n 1 ( T R P A 1), a calci u m-per mea ble 
n o n selecti ve cati on c ha n nel , e x presse d b y peri p heral pai n-se nsi n g n oci ce pt ors, w hic h pla y a
pi v otal  r ole i n ge nerati on of pai n ( Ma at uf et al. 2 0 1 9). A n o ncli nical efficac y p har mac o l og y  
st u d y usi n g a f or m ali n-i n d uce d fli nc h m o del i n rats s h o we d a n a nal gesic effect after a si n gle 
d ose of L Y 3 5 2 6 3 1 8. T he p ote ntial of L Y 3 5 2 6 3 1 8 t o pr o d uce u n wa nte d p har mac o l ogi cal effects 
ass ociat e d wit h ce ntral ner v o us s yst e m ( C N S), car dio vasc ular, or res pirat or y  fu nct i oni n g was 
deter mi ne d i n r ats a n d m o n ke ys, a n d i n vitr o s yste ms (see Secti on 3. 2 ). T hese e val uati o ns
s u p p ort a d va nci n g L Y 3 5 2 6 3 1 8 t o a FI H st u d y wit h t he i nitial de vel o p me nt f oc usi n g o n c hr o nic
pai n re d uctio n .
3. 2
B a c k gr o u n d
C hr o nic pai n is a maj or healt h iss ue affecti n g t he q uali ty of  life of milli ons of patie nts . 
N o nster oi dal a nt i-i nfla m mat or y dr u gs are t he pri mar y  c h oice of dr u gs f or c hr o nic pai n treat me nt; 
h o we ver , efficac y is li mite d i n ma n y patie nts. O pi oi d s are p ote nt b ut se dati n g a n d ha ve a d dict i ve 
p ote nti al, rele gati n g t he m t o t hir d- a n d f o urt h-li ne treat me nt o pti o ns i n c hr o nic pai n (K o et al. 
2 0 1 9 ). 
T R P A 1’s r ole i n pai n a n d i nfla m mati on a n d its l ocalizat i on i n se ns or y ne ur o ns ha ve bee n 
c haracterize d (B o d ki n a n d Brai n 2 0 1 1 ; Üc kert et  al. 2 0 1 7). It e v o kes pai n a n d a n a d verse 
res p o nse w he n a d mi nistere d e x o ge n o usl y (Berta et al. 2 0 1 7; De m art i ni et al. 2 0 1 7; Ma at uf et al. 
2 0 1 9 ; Wa n g
et al. 2 0 1 9). A d dit i onall y t here is ge netic e vi de nce f or t he c o ntri b ut i on of  T R P A 1 t o 
c hr o nic pai n.
T R P A 1 a nta g o nists are u n der g oi n g e val uat i on i n cli nical trials, w here t here is e vi de nce of 
efficac y a nd safet y ( O DM - 1 0 8, N C T 0 2 4 3 2 6 6 4 ; G R C 1 7 5 3 6 , E U Cli nical Trial Re gister 2 0 1 2 -
0 0 2 3 2 0- 3 3 ).
T he res ults of t he ge neral t o xic ol o g y  st u dies, t he be ha vi oral a n d car diores pi r at or y safet y 
p har mac o l og y  st u dies, t he i n vitr o h u ma n et her -à- g o- g o c ha n nel assa y, a n d t he i n vitr o a n d 
i n viv o ge n ot o xicit y/ m uta ge nicit y batter y  j ustify m o vi n g f or war d i nto h u ma n cli nical st u dies.
T he C N S safet y p har mac o l og y  st u d y i n t he rat a n d car di o vasc ular res pirat or y st u d y ( St u d y # 
0 0 9 2 6 0 4 6 ) i n m o n ke ys s h o we d n o a d verse fi n di n gs u p t o t he hi g hest d ose ( 3 0 0 m g/ k g) of  
L Y 3 5 2 6 3 1 8 teste d. N o test article -relate d t o xicit y was see n at a n y d ose i n t he 2 8-d a y re peat-
d osi n g st u d y  in m o n ke ys ( St u d y # 0 0 9 2 6 0 4 4 ).
 
 
3. 3
B e n efit/ Ri s k A s s e s s m e nt
C CI
T here i s n o be nefit a ntici pate d f or healt h y part ici pa nts a d mi nistere d L Y 3 5 2 6 3 1 8 .

J 2 D -M C -C V A A ( c) Cli ni c al Pr ot o c ol
P a g e 2 2
L Y 3 5 2 6 3 1 8
 
N o ncli nical t o xic o l og y  a n d safety p har m a c olo g y  st u dies wit h L Y 3 5 2 6 3 1 8 s u p p ort t he 
a d mi nistrati o n of L Y 3 5 2 6 3 1 8 t o h u ma ns, f or t he pri mar y  o bjecti ve of t he pl a n ne d st u d y t o 
e val uate safet y a n d t olera bility of  L Y3 5 2 6 3 1 8 i n heal t h y parti ci pa nt s.
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 5 2 6 3 1 8 is pr o vi de d i n t he I n vesti gat or’s 
Br oc h ure ( Lill y 2 0 1 9 ).
S i nce L Y3 5 2 6 3 1 8 has pre vi o usl y n ot bee n a d mi nistere d t o h u ma ns , t he st u d y will be desi g ne d 
a n d c o n d ucte d i n acc or da nce wit h t he “ G ui deli ne o n Str ate gies t o I de ntify a n d Miti g ate Risks f or 
First -i n-H u m a n Cli nic al Tri als w it h I nvesti g ati o n al Me dici n al Pr o d ucts” 
( E M E A/ C H M P/ S W P/ 2 8 3 6 7/ 0 7 Re v. 1 - J ul y 2 0 1 7).
A d dit i onal i nf or mati o n o n scie ntific rati onal e f or t he st u d y desi g n a n d justificat i on f or pla n ne d 
L Y 3 5 2 6 3 1 8 d oses are pr o vi de d i n Sect i ons 5. 4 a n d 5. 5
C CI
, res pectivel y.
Ta ki n g all t hese fi n di n gs i nt o c o nsi derat i on , n o a d dit i onal h u ma n safety p har mac o l og y  ris ks are 
e x pecte d f or healt h y parti ci pa nt s i n t he FI H st u d y of L Y 3 5 2 6 3 1 8.

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4 Objectives and Endpoints
Table 4-1 shows the objectives and endpoints of the study.
Table 4-1
Objectives and Endpoints
Objectives
Endpoints
Primary (Part A)
To evaluate safety and tolerability of LY3526318 in 
healthy participants following a single oral dose

AEs 

SAEs
Primary (Part B)
To evaluate safety and tolerability of LY3526318 in 
healthy participants following multiple once-daily oral 
doses for 14 days

AEs 

SAEs
Secondary (Part A)
To evaluate the plasma pharmacokinetics of LY3526318 
in healthy participants following a single oral dose

AUC

Cmax

tmax
Secondary (Part B)
To evaluate the plasma pharmacokinetics of LY3526318 
in healthy participants following multiple once-daily
oral doses for 14 days

AUC

Cmax

tmax
Exploratory (Part A)
To explore the pharmacokinetics of LY3526318 in fed 
versus fasted conditions
To explore the single-dose pharmacokinetics of 
LY3526318 in urine

AUC

Cmax

tmax

LY3526318 urine concentration

Amount of LY3526318 excreted in 24-hour urine
Abbreviations: AE = adverse event; AUC = area under the concentration versus time curve; Cmax = maximum 
observed drug concentration; SAE = serious adverse event; tmax = time to Cmax.

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5 Study Design
5.1 Overall Design
This is a Phase 1, single-ascending dose (SAD, Part A) and multiple-ascending dose (MAD, 
Part B) study of LY3526318 in healthy participants. Both parts are randomized, double-blind, 
and placebo-controlled.
Part A (SAD):
The single-ascending doses of LY3526318 or placebo will be administered, at planned dose 
levels of 10, 50, 100, 400, 800, and 1000 mg, in 7 cohorts of 8 participants each, except the 
expanded 100-mg cohort that will include 12 participants (8 female and 4 male) to accommodate 
a food effect assessment in the female participants only. 
Following a screening period of up to 28 days, eligible participants will be confined to the 
clinical research unit (CRU) from Day -1 until all study assessments are completed on Day 3. A 
sentinel dosing strategy will be implemented for the first dose level (Cohort 1, 10 mg).
Two participants will receive a sentinel dose (1 each with LY3526318 and placebo) and the
remaining participants will be administered LY3526318 after review of safety data up to 
48 hours postdose. Participants in Cohort 1 will not be stratified by sex, given that sentinel 
dosing coupled with stratification by sex may compromise blinding. A fixed number of females 
and males will be randomized in Cohorts 2 and 3 and the participants will be stratified to ensure 
equal distribution between females and males. The Part A stratification by sex scheme is shown 
in Table 5-1.
Table 5-1
Part A Stratification Based on Sex
Cohort
(Planned dose level a)
Number of Females 
Randomized
Number of Males 
Randomized
Total Participants 
Randomized
Cohort 1 (10 mg)
Up to 8b
Up to 8b
8
Cohort 2 (50 mg)
4
4
8
Cohort 3 (100 mg)
8c
4
12
Cohort 4 (400 mg)
8c
NA
8
Cohort 5 (800 mg)
8
NA
8
Cohort 6 (1000 mg)
8
NA
8
Cohort 10 (100 mg)
8 d
NA
8

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Abbreviation:  NA = not applicable.
a    Doses may be adjusted based on data obtained in previous study cohorts.
b
Cohort 1 will not have a defined stratification by sex scheme. Eight participants will be randomized including 
males and/or females.
c
Female participants in Cohorts 3 and 4 will receive study drug in fasted and fed conditions, separated by a 
washout period of at least 1 week.
d
All 8 female participants in Cohort 10 will receive LY3526318 in a 3-period crossover with standardized high fat 
meals administered prior to dose, and at 30 min and 1 hour post dose.  Participants receiving meals post dose 
administration will receive their dose in the fasted state.  Periods are separated by a washout period of at least 1 
week.
Cohorts administered above LY3526318 100 mg are anticipated to exceed the approximate 10x 
margin to the projected no-observed-adverse-event-level (NOAEL)-equivalent exposure for 
males; for this reason, only female participants will be enrolled at dose levels higher than 
100 mg. Additionally, if exposure data from previous cohorts does not support dose escalation in 
males through 100 mg, males will be discontinued from further dosing in the study.
The effect of food on LY3526318 PK will be explored in female participants only, in the 100-mg 
cohort and in the 400-mg cohort. In the 100-mg cohort, the initial dose will be administered after 
an approximately 8-hour fast in 8 female and 4 male participants, followed by a washout period 
of at least 1 week. A second dose will be administered after a standardized high-fat meal in 
female participants only. In the 400-mg cohort, the initial dose will be administered after an 
approximately 8-hour fast; following a washout period of at least 1 week, the second dose will be 
administered after a standardized high-fat meal. Except for the food effect assessment cohorts, 
all other doses are to be administered after an approximately 8-hour fast. Following a review of 
the 100-mg and/or 400-mg fed and fasted data, subsequent cohorts may be administered with 
food.
An additional cohort (Cohort 10) will assess the effect of food on LY3526318 PK in 8 female 
participants. All participants in this cohort will received 100 mg LY3526318 with standardized 
high fat meal in an open-label, 3-way crossover manner (meal administered prior to dose, at 
30 minutes and at 1 hour post dose; Table 2-2). Participants receiving meals post dose 
administration will receive their dose after an approximately 8-hour fast. Periods will be 
separated by a washout period of at least 1 week.
All participants will return to the CRU for a final visit approximately 9 days after study drug 
administration or after the fed-state dose for female participants in 100- and 400-mg cohorts.
Part B (MAD):
The multiple-ascending doses of LY3526318 or placebo will be administered, at planned dose 
levels of 100, 400, and 1000 mg, once daily for 14 days in 3 cohorts of 8 female participants 
each.
Following a screening period of up to 28 days, eligible participants will receive once-daily 
treatment with study drug for 14 days. Participants will be confined to the CRU from Day -1 
until all study assessments are completed on Day 15 (Cohort 7), Day 18 (Cohort 8) or Day 19 

J2D-MC-CVAA (c) Clinical Protocol
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(Cohort 9). Within each cohort, eligible participants will be randomly assigned to receive 
LY3526318 or placebo in a 6:2 ratio. The first cohort will be administered LY3526318 following 
a review of safety and PK data through Part A 400-mg cohort and fed period of the 100-mg 
cohort.
Dose levels will not exceed those administered in Part A. Dose levels in Part B are anticipated to 
exceed the approximate 10x margin to the projected NOAEL-equivalent exposures for males; for 
this reason, only female participants will be enrolled in Part B.
All doses are planned to be administered in an 8-hour fasting state. However, following a review 
of the food effect data from Part A, all doses may be administered with food.
Participants will return to the CRU for a final visit on approximately Day 23.
Safety, PK, and other assessments will be performed at time points prescribed in Section 2.
Study governance considerations are described in detail in Appendix 3.
Figure 5.1 illustrates the study design.  
Abbreviations: SAD = single-ascending dose (Orange); MAD = multiple-ascending dose (Green).
Note: Doses may be adjusted based on data obtained in previous study cohorts and parts.  The timeline listed is an 
approximation intended to illustrate relative cohort timing within and between Parts A and B.  Additional cohorts 
may be added.
Figure 5.1
Illustration of study design for Protocol J2D-MC-CVAA.
5.2 Number of Participants
Part A: Approximately 52 participants will be randomized to achieve 8 evaluable participants per 
cohort, except the 100-mg cohort that will include 8 evaluable females and 4 evaluable males 
and 100-mg food assessment cohort (Cohort 10) that will include 8 evaluable females.
The Part A stratification by sex scheme is shown in Table 5-1 and method of treatment 
assignment is provided in Section 7.2.

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Part B: Approximately 24 female participants will be randomized to achieve 8 evaluable 
participants per cohort (6 LY3526318:2 placebo).
Additional cohorts of up to 8 participants may be enrolled in either part of the study. Such 
additional cohorts may be enrolled in case intermediate or additional dose level(s) need to be 
studied or additional food effect need to be studied at other than planned dose levels.
Participants who withdraw from the study before completion of all study activities may be 
replaced at the discretion of the sponsor.
For purposes of this study, a participant completes the study when all scheduled procedures 
shown in the Schedule of Activities (Section 2) have been completed.
5.3 End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of
Activities (Section 2) for the last participant.
5.4 Scientific Rationale for Study Design
LY3526318 is a small-molecule TRPA1 inhibitor proposed for FIH dosing in a low uncertainty 
target and will use a clinical study design with a single cohort (Cohort 1) sentinel dosing
strategy. Two oral TRPA1 inhibitors have been administered in healthy participants after being
developed by other sponsors (GRC 17536 and ODM-108). Available data show that ODM-108 
was well tolerated in healthy participants (NCT02432664) and GRC 17536 was well tolerated 
both in healthy participants and in patients with chronic pain conditions (EU Clinical Trial 
Register 2012-002320-33). Nonclinical pharmacology studies have demonstrated target 
engagement through changes in dermal blood flow for TRPA1 activation and antagonism 
(Aubdool et al. 2016). Cinnamaldehyde-induced dermal blood flow as measured through laser 
Doppler imaging (LDI) has been demonstrated to be a translationally relevant biomarker for 
TRPA1 activation and target engagement (Buntinx et al. 2017). Serious adverse events in this
14-day study are not anticipated based on the 28-day multiple-dose nonclinical toxicology 
studies. 
This study will include a pilot assessment of food effect in female participants only. In the food 
effect cohorts, the  doses will be administered in fed and fasted states, as indicated. Residual
exposure will be minimized with a washout period of at least 1 week between doses. The 
100- and 400-mg doses and the high-fat meal were chosen because preclinical data suggest that 
study drug administration with a high-fat meal may increase exposures of LY3526318 by 
approximately 5-fold, compared to administration in the fasted state. Having a food assessment 
at 2 different dose levels will help inform the mode of study drug administration in the MAD and 
subsequent studies. In addition, because LY3526318 preclinical PK was subproportional to dose, 
and the effect of food may also be nonlinear, assessing the food effect at 2 different dose levels 
will provide a better understanding of LY3526318 PK.

J 2 D -M C -C V A A ( c) Cli ni c al Pr ot o c ol
P a g e 2 8
L Y 3 5 2 6 3 1 8
 
T he c urre nt st u d y  r e q uires safety a n d P K data f or d ose escalat i on . H o we ver, the first d ose 
escalat i on will rel y o n safe t y d at a o nl y beca use t he 1 0 mg d ose is a ntici pate d t o res ult i n 
e x p os ures t hat ha ve n o cli nical effect base d o n precli nical efficac y  mo dels t hat use di rect T R P A 1 
a g o nists. I n a d dit i on, 1 0 m g is a nt ici pate d t o pr o d uce e x p os ures > 1 0 0 x bel o w t he N O A E L i n 
male s a n d > 1 0 0 0 x bel o w t he N O A E L i n fe males.
Acc or di n g t o t he I nter nati o nal C o u ncil f or Har m o nisati o n ( I C H) g ui deli nes (I C H 2 0 0 9), w o me n 
of  c hil d-beari n g p ote ntial ( W O C B P) ca n be i ncl u de d i n earl y cli nical trials wit h o ut n o ncli nical 
de vel o p me ntal t o xicit y st u dies (e. g. e m br yo -fetal st u dies) i n certai n circ u msta nces. I n t his st u d y, 
parti ci pa nt s w h o are W O C B P will recei ve 2 wee ks of t reat me nt w hile mai ntai ni n g a d here nce t o 
hi g hl y  effecti ve c o ntrace pti o n t o mit i gate t he ris k of pre g na nc y.
5. 5
J u stifi c ati o n f or D o s e
T he or al  d ose ra n ges pr o p ose d f or t his st u d y  are 1 0 m g u p t o 1 0 0 0 m g f or t he S A D, a n d 1 0 0 m g 
u p t o 1 0 0 0 m g o nce dail y f or t he MA D . C o h orts i n t he S A D wit h d oses hi g her t ha n 1 0 0 m g a n d 
all c o h orts i n t he M A D will o nl y e nr o ll fe male partici pa nt s (see just ificati on i n Secti on 5. 4
C CI
). T he 
pl a n ne d d ose le vels ma y be m o difie d (i ncrease d or decrease d) base d o n an assess me nt of  safety
data a n d of  a vaila ble P K data d uri n g t he st u d y.
T he pr o p ose d d ose ra n ge of  1 0 t o 1 0 0 0 m g is s u p p orte d b y precli nical p har mac o l og y st u dies. I n 
a st u d y in rat s, d oses of  3 m g/ k g or greater (a p pr o xi matel y 3 0 m g i n h u ma ns) elicite d a 
sig nifica nt bl oc k a de of  ci n na mal de h y de-e v o ke d der mal blo o d fl o w c ha n ges as m eas ure d t hr o u g h 
L DI. I n a d dit i on, d o ses as l o w as 0. 3 m g/ k g (a p pr o xi matel y 3 m g i n h u ma ns) a n d u p t o 3 m g/ k g 
s h o we d efficac y i n a rat c o m p lete Fre u n d adj u va nt -i n d uce d c ol d h y peral gesia m o del; a n d d oses 
of  3 a n d 1 0 mg/ k g ( a p pr o xi matel y 3 0 a n d 1 0 0 m g i n h u ma ns) s h o we d efficac y i n a rat m o del of 
f or mali n-i n d uce d pai n be ha vi or. T he L DI assa y a n d f or mali n -i n d uce d pai n m o del are e x pecte d t o 
be m o re pre dict i ve of tar get e n ga ge me nt i n h u ma ns beca use t he y use e x o ge n o us a p plicati on of 
ci n na mal de h y de a n d f or mali n t hat are direct a g o nists of T R P A 1 rece pt or, f or w hic h L Y is a 
di rect a nta go nist. Base d o n t hese data, t he pr o p ose d starti n g d ose f or t his st u d y is 1 0 m g, w hic h 
is i nte n de d t o be l o wer t ha n t he a nt ici pate d ra n ge of tar get e n ga ge me nt.
 
 
 
 
 
 
 
C CI

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Based on the short elimination half-life (t1/2) observed in monkeys after administration of a 
capsule formulation of LY3526318 hydrate and in a 28-day cynomolgus monkey toxicokinetic 
study (2 to 4 hours across doses; Study # 00926044), no accumulation is expected upon multiple 
dosing. Therefore, the margins of safety can be expected to be similar for both single and 
multiple dose administrations.
Modeling of preclinical data in GastroPlus™suggests that the bioavailability of LY3526318
may increase by approximately 3- to 5-fold when administered with a high-fat meal, relative to 
administration in the fasted state. Consequently, the 100-mg cohort (females only) was chosen to 
explore the effect of food administration, considering that even if a 5-fold increase in exposure is 
observed, it would not exceed the exposure at the maximum planned dose of 1000 mg. The 
400-mg dose was chosen because even if there was a 5-fold increase in exposure, it would 
provide acceptable margins of safety of 5x and 10x for the NOAEL in female rats and monkeys 
respectively, based on dose multiples. Of note, there were no findings for either female rats or 
monkeys in the toxicology studies, hence the NOAEL is the maximum administered dose in 
those studies.
Thus, the proposed doses for both the SAD and MAD portions of the study are anticipated to be 
in the target engagement dose range, while providing adequate margins of safety to address the 
study objectives.

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6 Study Population
Eligibility of participants for the study will be based on the investigator’s judgment on results of 
screening medical history, physical examination, vital signs, clinical laboratory tests, and 
electrocardiogram (ECG). The nature of any conditions present at the time of the physical 
examination and any pre-existing conditions will be documented. 
Screening may occur up to 28 days prior to enrollment. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1 Inclusion Criteria
Participants are eligible for inclusion in the study only if they meet all of the following criteria at 
screening. The timeframes included in the following criteria are relative to screening unless 
otherwise noted.
1. Aged 18 to 65 years, inclusive.
Part A Cohorts through 100 mg: 
2. Healthy male participants (including self-reported surgically sterile males), as determined 
through medical history and physical examination, must agree to the following:
a.
When engaging in sex with a WOCBP, both the male participant and his female 
partner must use highly effective contraception consisting of 2 forms of birth control 
(1 of which must be a male barrier method such as a latex or polyurethane condom) 
from start of dosing throughout the clinical study period, and for 90 days after the 
final study drug administration. 
b. Nonsurgically sterile male participants must not donate sperm at any time from start 
of dosing until 90 days beyond the administration of study drug.
All Part A and Part B cohorts:
3. Female participants must be nonpregnant and not lactating, or of nonchildbearing potential 
(either surgically sterilized [e.g. tubal occlusion, hysterectomy, bilateral salpingectomy] or 
physiologically incapable of becoming pregnant, or postmenopausal with amenorrhea for at 
least 12 consecutive months). Nonpregnancy will be confirmed for all female participants 
through a serum pregnancy test at screening and at admission to the CRU and at a final study 
visit. Follicle-stimulating hormone will be tested at screening for all female participants.
Healthy female participants of child-bearing potential who have a fertile male sexual partner
must be willing and able to practice effective contraception from admission to 30 days after 
the final visit.
Sexually active participants must use a combination of 2 of the following methods of 
contraception, including at least 1 so-called ‘barrier’ method:

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a.
Hormonal contraceptive (oral, transdermal patches, vaginal or injectable)
b. Intrauterine device with or without hormones
c.
Condom (‘barrier’ method)
d. Diaphragm or cervical cap
e.
Sexual abstinence
Contraceptive requirements do not apply for participants who are exclusively in same-sex 
relationships.
4. Have a body mass index 18 to 32 kg/m2.
5. Have given informed consent prior to any study-specific procedures.
6. Are reliable and willing to make themselves available for the duration of the study and are 
willing to follow CRU-specific study procedures.
7. Have clinical laboratory test results within normal reference range for the population or 
CRU, or results with acceptable deviations that are judged not clinically significant by the 
investigator.
6.2 Exclusion Criteria
Participants will be excluded from study enrollment if they meet any of the following criteria at 
screening, unless otherwise noted:
1. 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. 
2. Have previously completed or withdrawn from this study or any other study investigating 
this study drug.
3. Have a history or presence of medical illness including, but not limited to, any 
cardiovascular, hepatic, respiratory, hematological, endocrine, psychiatric or neurological 
disease, convulsions, or any clinically significant laboratory abnormality that, in the 
judgment of the investigator, indicate a medical problem that would preclude study 
participation.
4. In the opinion of the investigator are considered to be a danger to themselves, or who have 
answered “yes” to either Question 4 or Question 5 on Suicidal Ideation portion of the 
Columbia-Suicide Severity Rating Scale (C-SSRS); or answered yes to any of the 
suicide-related behaviors on the Suicidal Behavior portion of C-SSRS; and the ideation and 
behavior occurred within the past 6 months
5. Have an abnormality in the 12-lead ECG that, in the opinion of the investigator, increases the 
risks associated with participating in the study. In addition, participants with the following 
findings will be excluded:

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a.
confirmed Frederica’s corrected QT interval >450 msec for men and >470 msec for 
women. One repeat ECG may be performed if required.
6. Have a history of clinically significant multiple or severe drug allergies or severe 
posttreatment hypersensitivity reactions, which in the opinion of the investigator may hamper 
participation in the study.
7. Are an investigator or CRU personnel directly affiliated with this study, or are immediate 
family members of investigator or CRU personnel. Immediate family is defined as a spouse, 
parent, child or sibling, whether biological or legally adopted. 
8. Are Eli Lilly and Company (Lilly) employees or contractors or an immediate family member 
of employees or contractors.
9. Show evidence of human immunodeficiency virus (HIV) and/or positive human HIV 
antibodies, hepatitis C and/or positive hepatitis C antibody, or hepatitis B and/or positive 
hepatitis B surface antigen.
10. Have donated blood of more than 500 mL within the previous month.
11. Are unwilling to stop alcohol and caffeinated beverage consumption and smoking/use of 
tobacco while resident in the CRU.
12. Have an average weekly alcohol intake that exceeds 21 units per week (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).
13. Have an abnormal blood pressure (supine) defined as a diastolic blood pressure >90 or 
<45 mmHg and/or a systolic blood pressure >160 or <90 mmHg. Re-testing may occur once 
during the screening visit within 2 hours of the initial abnormal blood pressure measurement 
at the discretion of the investigator.
14. Participants with a history of drug abuse which, in the opinion of the investigator, is 
considered to be clinically significant or who test positive for drugs of abuse at screening or 
admission.
15. Have received treatment with biologic agents (such as monoclonal antibodies, including 
marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to dosing.
16. Are unwilling to comply with the dietary restrictions required for this study, including the 
avoidance by 5 days prior to study drug administration until the final ambulatory visit the 
ingestion of fruits, sauces, and juices containing furanocoumarins that irreversibly inhibit 
cytochrome P450 (CYP)3A4. The following fruits, sauces, and juices are excluded:  
grapefruit, Seville oranges, pomelos, cranberry, Goji berry, and apple.
17. Are unable to successfully complete a capsule swallow test, which may be performed at 
screening for any participant assigned to a dose level where more than 3 capsules will be 
administered. 

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6.3 Lifestyle and/or Dietary Requirements
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study.  
6.3.1 Meals and Dietary Restrictions
Standard meals, according to the CRU standard operating procedures, will be provided during 
the stay at the CRU. A standardized high-fat meal for the food effect assessment cohorts will be 
provided at the CRU prior to dose administration. Unless otherwise instructed by CRU personnel, 
participants will maintain their own dietary habit throughout the ambulatory phases of the study. 
6.3.2 Caffeine, Alcohol, and Tobacco
Participants will need to abstain from alcohol and caffeinated drinks from 48 hours prior to entry 
in the CRU until discharge.
Smoking outside the CRU should be restricted to 5 cigarettes a day or fewer during study 
participation. No smoking/tobacco use will be allowed during the stay at the CRU.
6.3.3 Activity
Participants must refrain from new strenuous exercise routines 48 hours prior to each CRU
confinement period and throughout their CRU stay.
6.4 Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be
re-screened once at the discretion of the investigator with sponsor’s approval. If a participant is 
re-screened, they would be assigned a new participant number and would need to sign a new 
informed consent form (ICF).

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7 Treatment
7.1 Treatment Administered
Treatment drugs will be administered orally. Doses are planned to range between 10 and
1000 mg once daily.
Part A:
The planned dose levels are 10, 50, 100, 400, 800, and up to 1000 mg. LY3526318 or matching 
placebo will be administered to participants as a single dose by trained CRU personnel. Dose 
levels may be modified based on safety and available PK, but which are not intended to exceed 
the NOAEL.
All doses are planned to be administered in a fasting state (at least 8 hours predose and 4 hours 
postdose), with the exception of the indicated doses in the food effect cohorts (100 and 400 mg),
where the study drug will be administered in both the fasted and fed states, as specified.
Approximately 50% of the total caloric content of the meal should be from fat. Study participants 
should eat this meal in 30 minutes or less; and the study drug should be administered 30 minutes 
after the start of the meal. In all cases, study drug should be taken with 1 glass (approximately 
240 mL) of water and no food should be allowed for at least 4 hours postdose. Water can be 
allowed as desired except for 1 hour before and after drug administration.
Following a review of the 100- and/or 400-mg fed and fasted data, subsequent cohorts may be 
administered with food.
Part B:
The planned dose levels in Part B (100, 400, and up to 1000 mg) will not exceed those studied in 
Part A. LY3526318 or matching placebo is planned to be administered in a fasting state once 
daily for 14 days. However, based on the food effect data from Part A, all doses may be 
administered with food. Fasting on PK sampling days is defined as at least 8 hours predose and 
4 hours postdose. Fasting on non-PK and predose only PK sampling days is defined as at least 
8 hours predose and 2 hours postdose.
LY3526318 or matching placebo will be administered once daily by trained CRU personnel
through Day 14 in the CRU. 
For 800- and 1000-mg cohorts, 8 to 10 capsules of study drug will be administered. In case of 
administration of multiple capsules, the participant may drink extra water, as needed. 
Section 7.4 details the dose-escalation strategy.
The LY3526318 drug product is supplied as a hard gelatin capsule in dosage strengths of 10 to
100 mg. Placebo capsules will be identical in size and shape.
The investigator or designee is responsible for

explaining the correct use of the investigational product(s) to the participant

verifying that the instructions are followed properly

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
maintaining accurate records of investigational product dispensing and collection, and

returning all unused medications to Lilly or its designee at the end of the study.
Note: In some cases, CRU may destroy the material if, during the CRU selection, the evaluator 
has verified and documented that the CRU has appropriate facilities and written procedures to 
dispose of clinical materials.
7.1.1 Packaging and Labeling
The drug product will be manufactured, tested, packaged, and labeled in accordance with all 
applicable good manufacturing practice requirements and country’s regulatory requirements. A 
certificate of analysis will be supplied confirming that the materials are released for human use 
in clinical trials. LY3526318 drug products are for investigational use only and are to be used 
only within the context of this study.
7.2 Method of Treatment Assignment
Randomization in the first cohort (10 mg, Cohort 1) will not be stratified by sex and participants 
will receive either LY3526318 or placebo in a 6:2 ratio, unless otherwise indicated.
A fixed number of females and males will be randomized in Cohorts 2 and 3 and the 
randomization will be stratified to ensure equal distribution between females and males. 
Randomization to either LY3526318 or placebo will be 3:1 within each cohort or stratum, 
respectively.
Participants in Cohorts 4 and onwards will receive either LY3526318 or placebo in a 6:2 ratio,
except for Cohort 10 where all participants will receive LY3526318.
Refer to Part A study design in Section 5.1 and Table 5-1 for stratification by sex.
In Part B, eligible participants will be randomly assigned to receive either LY3526318 or 
placebo in a 6:2 ratio. 
A randomization table will be created by a computer software. The randomization list will be 
provided to the designated unblinded CRU personnel for participant randomization and 
dispensing purposes and kept in a secure location, accessible to the designated unblinded CRU
personnel only.
7.2.1 Selection and Timing of Doses
In Part A, the single dose of the study drug will be administered at the CRU approximately 
between 08:00 AM and 11:00 AM.
In Part B, all doses will be administered at the CRU approximately between 08:00 AM and 
11:00 AM.
A trained CRU personnel member will administer all doses of the study drug at the CRU.

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7.3 Blinding
Participants, investigators, and CRU personnel performing trial-related activities or with the 
ability to influence study outcomes will be blinded with regards to LY3526318 and placebo 
treatment. To preserve the blinding of the sponsor, only a minimum number of Lilly personnel 
may have access to the randomization table and codes before the study is complete. Clinical 
research unit personnel who are responsible for participant-specific study drug preparation will 
not be blinded; laboratory personnel, including bioanalytical laboratory personnel, will also not 
be blinded. Drug product and placebo will be identical in appearance.
One set of sealed envelopes containing the randomization code will be provided to the 
investigator at the start of the trial. A code envelope, which reveals the treatment for a specific 
study participant, may be opened during the study only if the participant’s well-being requires 
knowledge of the participant’s treatment assignment.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event. The 
participant’s safety must always be the first consideration in making such a determination. If 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.
Unless the investigator obtains Lilly medical monitor approval stating otherwise, a participant
whose study treatment assignment is unblinded must be discontinued from the study. During the 
study, emergency unblinding should occur only by accessing the study participant’s emergency 
code.
At the end of the study, unopened envelopes will be returned to Lilly or its designee, or 
destroyed according to CRU procedures.
7.4 Dose Modification
Six cohorts in Part A and 3 cohorts in Part B are planned. Additional cohorts may be enrolled in 
either part of the study in case intermediate or additional dose level(s) need to be studied or 
additional food effect need to be studied at other than planned dose levels. The planned doses in 
each part of the study may be modified after review of the safety and PK data of each 
administered dose.
7.4.1 Dose Escalation
Safety data will be the primary criteria for the dose escalation within each part of the study. In 
addition, available PK data will be used in support of dose escalation, with the exception of the 
first dose in Part A (10 mg; see justification in Section 5.4). A dose-escalation report (DER) will 
be provided by the investigator to the independent ethics committee (IEC) following completion 
of each dose level. Escalation to the next higher dose will proceed only if safety and tolerability 
data from at least 6 participants from the previous dose level are acceptable to the investigator 
and the sponsor and, if deemed necessary by the IEC following their review of the protocol, after 

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a statement of no objection of the DER from the IEC. The planned dose levels (defined in 
Section 7.1) may be adjusted based on safety and PK data.
7.4.1.1 Part A
Dose escalation from the 10-mg cohort to the 50-mg cohort may occur after review of safety data 
from at least 6 participants in the 10-mg cohort.  The subsequent dose escalations may occur 
after review of safety and available PK data through 48 hours postdose from at least 
6 participants in the prior cohort. The second dose of the 100-mg cohort, food effect assessment, 
may occur after review of safety and available PK data from the first 3 days of fasted dose in at 
least 6 participants in Cohort 4 (400-mg dose). The second dose of the 400-mg cohort, in the fed 
state, may occur after review of Cohort 6 (1000-mg dose) safety and available PK data for at 
least 6 participants through 48 hours postdose.
7.4.1.2 Part B
Part A safety and PK data will be reviewed to support initiation of Part B. Based on a review of 
these data, it will also be decided if the study drug should be administered in the fasted or fed 
state, and if adjustments to higher dose levels and/or sample collection times in the Part B are 
deemed necessary.
Dose escalation to Cohort 8 may occur after review of safety and available PK data through 
15 days from at least 6 participants of Cohort 7.
Dose escalation to Cohort 9 may occur after review of safety and available PK data through
15 days from at least 6 participants of Cohort 8.
7.4.2 Stopping Rules
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be discontinued
1. a participant experiences an SAE or a clinically significant event that is related to 
LY3526318 administration, or
2. 3 or more participants develop AEs within 14 days of dosing that are considered to be 
related to study drug and graded as at least moderate, clinically significant, and not 
responsive to supportive care.
Dosing may be resumed at a lower dose level, with prior discussion and agreement between the 
investigator and the sponsor.
Individual participants or study discontinuation criteria are provided in Section 8. 
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 products
received and any discrepancies are reported and resolved before use of the study drug. Detailed 
records of the amounts of study drug received, dispensed and remaining at the end of the study 
will be maintained.

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The LY3526318 drug products are used in accordance with the protocol and will be stored in a 
secure and locked area with strictly limited access and monitored for temperature (manual or 
automated) in accordance with the labeled storage conditions. LY3526318 drug products are 
allocated and dispensed by appropriately trained personnel.
Unblinded pharmacy personnel will be responsible for providing either LY3526318 or placebo to 
the blinded study personnel for administration based on the randomization schedule. Unblinded 
pharmacy personnel will follow detailed pharmacy instructions for the preparation and handling 
of LY3526318 drug products for both Parts A and B.
LY3526318 capsules are stable when stored refrigerated between 2°C and 8°C.
7.6 Treatment Compliance
The study drug will be administered at the CRU, and documentation of study drug administration 
will occur at the CRU.
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the participants 
have swallowed the study drug.
Participants’ hands will also be verified to ensure that the study drug was ingested. Dose 
administration will be documented in the electronic case report form (CRF).
7.7 Concomitant Therapy
Drugs that are known inducers or inhibitors of CYP3A4 or 2C9 are to be specifically excluded 
(see Appendix 6 for a list of excluded medications). Additional drugs are to be avoided during 
the study unless required to treat an AE or for the treatment of an ongoing medical problem.
In general, concomitant medication should be avoided; however, over-the-counter medications 
may be administered at the investigator’s discretion (e.g. acetaminophen for treatment of 
headache). If the need for concomitant medication (other than over-the-counter medications) 
arises, inclusion or continuation of the participant may be at the discretion of the investigator 
after consultation with the sponsor. Any medication used during the course of the study must be 
documented.
7.8 Treatment after the End of the Study
Not applicable. 

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8 Discontinuation Criteria
Participants may be withdrawn from the study if any of the following criteria are observed:

Enrollment in any other clinical study involving an investigational product or other medical 
research judged not to be scientifically or medically compatible with this study.

Investigator’s decision: the investigator may decide that the participant should be 
discontinued from the study for the following reasons:
o
If, in the investigator’s opinion, continuation in the study would be detrimental to the 
participant’s well-being, in particular in case of an AE
o
Lost to follow up after 3 attempts to contact the participant through phone, text message, 
or mail.
If the investigator withdraws a participant for a study drug-related reason (according to the 
judgment of the investigator), he/she is considered a dropout. Dropouts may be replaced, where 
the sponsor deems this necessary.

Participant’s Decision: the participant requests to be discontinued from the study.

Sponsor’s Decision: Lilly stops the study or stops the participant’s participation in the study 
for medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice (GCP). 

Discontinuation due to a hepatic event of liver test abnormality: Participants who are 
discontinued from using study drug due to a hepatic event or liver test abnormality should 
have additional hepatic safety data collected. Discontinuation of the study drug for abnormal
liver tests should be considered by the investigator when a participant meets 1 of the 
following conditions after consultation with the Lilly-designated medical monitor:
o
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of 
normal (ULN)
o
ALT or AST >3 × ULN, sustained for more than 2 weeks or
o
ALT or AST >3 × ULN and total bilirubin level (TBL) >2 × ULN or prolonged 
prothrombin time with international normalized ratio >1.5 or
o
ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
o
Alkaline phosphatase (ALP) >3 × ULN
o
ALP >2.5 × ULN and TBL >2 × ULN
o
ALP >2.5 × ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or
tenderness, fever, rash, and/or eosinophilia (>5%).

Pregnancy: If the pregnancy test (planned or unplanned) of female participant of 
child-bearing potential is positive at any time during the stay at CRU, the female participant
will be discontinued from the study. 

Requirement of prohibited concomitant medication

Participant’s failure to comply with protocol requirements or study-related procedures

Termination of the study by the sponsor or regulatory authorities

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Participants discontinuing from the study prematurely for any reason should complete AE and 
other follow-up procedures (Early Discontinuation Visit) per Section 2 (Schedule of Activities) 
of this protocol.
Every effort must be made to contact participants who do not return for a planned visit and the 
reason for withdrawal should be documented in the electronic data capture (EDC). The 
participant can only be declared as ‘lost to follow-up’ if the investigator has had no success in 
contacting the participant. Participants who withdraw from the study before completion of all 
study activities may be replaced at the discretion of the sponsor.

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9 Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results. Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1 Efficacy Assessments
Not applicable.
9.2 Adverse Events
A clinical trial AE is any untoward medical event associated with the use of a drug or drug 
delivery system in humans, whether or not it is considered related to that drug or drug delivery 
system.
Investigators are responsible for monitoring the safety of participants 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 participant.
The investigator is responsible for the appropriate medical care of participants during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate healthcare option, 
AEs that are serious or otherwise medically important, considered related to the study drug or a 
study-related procedure, or that caused the participant to discontinue the study drug before 
completing the study. The participant should be followed up until the event resolves, stabilizes 
with appropriate diagnostic evaluation, or is reasonably explained. The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the ICF is signed, the CRU personnel will record, via EDC, the occurrence and nature of 
each participant’s preexisting conditions, including clinically significant signs and symptoms of 
the disease under treatment in the study. Additionally, CRU personnel will record any change in 
the condition(s) and the occurrence and nature of any AEs.  
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a participant’s study drug is discontinued because of an AE, CRU personnel must report this to 
Lilly or its designee via EDC.

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9.2.1 Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e. 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 1 of the 
other outcomes listed in the definition above.
The CRU personnel must alert the Lilly medical monitor, or its designee, of any SAE as soon as 
practically possible.
Additionally, CRU 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 up with official notification on 
study-specific SAE forms. This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the case report form or EDC after signing informed consent, 
SAE reporting to the sponsor begins after the participant has signed informed consent and has 
received the study drug. However, if an SAE occurs after signing informed consent, but prior to 
receiving the study drug, AND is considered reasonably possibly related to a study procedure 
then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in participants once they have 
discontinued from and/or completed the study. Serious adverse events will be collected for 
30 days after the last dose of study drug. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and he/she 
considers the event reasonably possibly related to the study drug or study participation, the 
investigator must promptly notify Lilly within 24 hours. 
Pregnancy (maternal or paternal exposure to the study drug) 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.
The designated medical monitor of the sponsor will monitor safety data throughout the course of 
the study. The sponsor and/or its designee will review SAEs within appropriate timeframes to 
meet reporting obligations imposed by regulatory authorities. All serious and unexpected AEs 
for this study will be reported to regulatory authorities in accordance with local laws, directives, 
and regulations.
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 (Lilly 2019) and that the investigator reports as related to investigational product or 

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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 guidance.
9.2.2 Complaint Handling
Lilly collects product complaints on study drug used in clinical trials to ensure the safety of study 
participants, monitor quality, and to facilitate process and product improvements.
Participants should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug so that the situation can be assessed.
9.3 Treatment of Overdose
An overdose is not anticipated in the study, as all study drugs will be administered by a trained 
CRU member.
In case of overdose, use supportive therapy. There is no known antidote to LY3526318 therapy.
9.4 Safety
9.4.1 Laboratory Tests
For each participant, 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 participant, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).
It is suggested that systolic and diastolic blood pressure and heart rate should be measured in 
supine position just after the ECG (if the ECG is recorded at the same time point) and before any 
other procedures according to the Schedule of Activities (Section 2).
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.
9.4.3 Electrocardiograms
For each participant, ECGs should be collected according to the Schedule of Activities 
(Section 2).
Participant must be supine for approximately 5 minutes before ECG collection and remain 
supine but awake during ECG collection. Electrocardiograms may be obtained at additional 
times, when deemed clinically necessary. 

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In the event that assessments are planned for the same time, the order of assessments should be 
arranged in such a way that PK blood samples will be taken after the ECG and vital sign 
recordings have been conducted, with PK blood sampling times adhered to as closely as possible.
All ECGs recorded should be stored at the CRU.
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
participant receives the first dose of the investigational product, should be reported to Lilly, or its 
designee, as an AE via EDC.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the CRU as soon after the time of ECG collection as possible, and ideally while the
participant is still present, to determine whether the participant meets entry criteria at the relevant 
visit(s) and for immediate participant management, should any clinically relevant findings be 
identified.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the participant for symptoms (e.g. palpitations, near 
syncope, syncope) to determine whether the participant can continue in the study. The 
investigator or qualified designee is responsible for determining if any change in participant
management is needed and must document his/her review of the ECG printed at the time of 
evaluation from at least 1 of the replicate ECGs from each time point.
9.4.4 Physical Examination
A complete or directed physical examination will be conducted according to the Schedule of 
Activities (Section 2).
9.4.5 Columbia-Suicide Severity Rating Scale
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered according to the 
Schedule of Activities (Section 2).
Columbia-Suicide Severity Rating Scale: A scale that captures the occurrence, severity, and 
frequency of suicidal ideation and/or behavior during the assessment period. The scale includes 
suggested questions to solicit the type of information needed to determine if suicidal ideation 
and/or behavior occurred. The C-SSRS is administered by an appropriately trained healthcare 
professional with at least 1 year of patient care/clinical experience or some or all of the patients 
may have these data solicited through interactive web-response system or electronic 
patient-reported outcome technology. This tool was developed by the National Institute of 
Mental Health trial group (Treatment of Adolescent Suicide Attempters) for the purpose of being 
a counterpart to the Columbia Classification Algorithm of Suicide Assessment categorization of 
suicidal events. 
The nonleading AE collection should occur prior to the collection of the C-SSRS. If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, CRU should not change the AE form. If an event is serious or leads to 

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discontinuation, this is an exception where the SAE and/or AE leading to discontinuation should 
be included on the AE form and the process for reporting SAEs should be followed. 
Terms captured by the use of the C-SSRS can be mapped to Columbia Classification Algorithm 
for Suicide Assessment (Posner et al. 2007) to facilitate future pooling of data. 
The first time the scale is administered in this study, the C-SSRS “Lifetime/Recent-Clinical” 
version will be used, and the findings will constitute the baseline assessment. The “Since Last 
Visit-Clinical” version will be used for all subsequent assessments. If a suicide-related thought or 
behavior is identified at any time during the study, a thorough evaluation will be performed by a 
study physician, and appropriate medical care will be provided. If, based on administration of the 
C-SSRS, it is determined that suicide-related behaviors have occurred, then additional 
information will be collected to allow for a more complete assessment of these behaviors. 
9.4.6 Safety Monitoring
The sponsor will monitor safety data throughout the course of the study and periodically will 
review evolving aggregate safety data within the study through appropriate methods.
9.4.6.1 Hepatic Safety
If a study participant 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 creatine kinase to confirm the 
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 medical monitor. 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

elevation of 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 

participant discontinued from study drug due to a hepatic event or abnormality of liver tests

hepatic event considered to be an SAE.
9.5 Pharmacokinetic Assessments
9.5.1 Blood Sampling and Processing
For all participants, blood samples of up to 3 mL each for the determination of LY3526318 and 
metabolite(s) of interest concentrations will be collected at time points specified in the Schedule 
of Activities (Section 2). Instructions for the collection and handling of blood samples will be 
provided by the sponsor. 
Sampling times for PK evaluation are provided as a guidance to be adhered to as closely as 
possible. The actual date and time (24-hour clock time) of each sample collection must be 
recorded. Predose samples should be obtained between waking up and dosing.

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The sampling schedule may be modified following a review of PK data from the initial cohorts.
A maximum of 3 additional PK samples may be drawn at other time points during the study, if 
warranted and agreed upon by both the investigator and the sponsor. A PK sample should be 
obtained at the early termination visit, if applicable.
9.5.2 Urine Sampling and Processing
In Part A only, urine samples for LY3526318 and metabolite(s) of interest analyses will be 
collected at specified intervals, as specified in the Schedule of Activities (Section 2).
On Day 1 (Part A), participants will be asked to empty their bladders within approximately 
60 minutes prior to the scheduled dosing time. This urine will not be collected. Participants will
be instructed to collect all urine samples for 24 hours from the time of dosing, as indicated in the 
Schedule of Activities (Section 2). Urine will be refrigerated as soon as possible after the sample 
is provided by the participant. At the end of the collection time, the total urine volume will be 
measured, and aliquots will be prepared for the measurement of the concentration of LY3526318
and of metabolite(s) of interest. 
Instructions for the collection and handling of urine samples will be provided by the sponsor. 
9.5.3 Bioanalysis
Plasma and urine sample analyses of LY3526318 and possible metabolite(s) of interest will be 
performed using validated procedures and methods. Placebo samples are not planned to be 
analyzed.
Bioanalytical samples collected to measure study drug concentrations will be retained for a 
maximum of 1 year following last participant visit for the study.
Residual PK plasma samples may be used for LY3526318 metabolite identification.
9.6 Pharmacodynamics
Not applicable.
9.7 Genetics
Not applicable.
9.8 Biomarkers
Not applicable.
9.9 Health Economics
Not applicable.

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10 Statistical Considerations and Data Analysis
10.1Sample Size Determination
The sample size is customary for Phase 1 studies evaluating safety and PK, and is not powered 
based on statistical hypothesis testing.
10.2Populations for Analyses
10.2.1 Study Participant Disposition
All participants who discontinue from the study will be identified, and the extent of their 
participation in the study will be summarized by treatment. If known, a reason for their 
discontinuation will be given.
10.2.2 Study Participant Characteristics
Participant demographics (age, sex, race, ethnicity, height, and weight) will be summarized by 
treatment.
10.2.3 Concomitant Medications
Concomitant medications will be listed. 
10.3Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
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.
For continuous variables, summary statistics will include number of participants, mean, median, 
standard deviation, minimum, and maximum. Categorical endpoints will be summarized using 
number of participants, frequency, and percentages. Additional analyses of the data will be 
conducted as deemed appropriate and may be fully detailed in a statistical analysis plan.
Any p-values to be calculated according to the statistical analysis plan will be interpreted in the 
perspective of the explorative character of this study.
10.3.1 Safety analysis
All study drug and protocol procedure AEs will be listed, and if the frequency of events allows, 
safety data will be summarized using descriptive methodology. Summary statistics for AE and 
SAE will be provided by dose level and for all placebo participants combined. 
Safety assessments include laboratory tests, vital signs, ECGs, and physical examination. The 
parameters will be listed and summarized using standard descriptive statistics. Additional 
analysis will be performed as required.

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10.3.2 Pharmacokinetic Analyses
10.3.2.1 Pharmacokinetic Population
All participants administered with LY3526318 who have evaluable plasma and/or urine 
LY3526318 concentrations will be included in the PK analyses. Pharmacokinetic parameter 
estimates for LY3526318 will be computed using standard noncompartmental methods of 
analysis. 
10.3.2.1.1
Plasma Pharmacokinetic Parameter Estimation
Part A 
Primary plasma LY3526318 PK parameters, including but not limited to the area under the 
concentration versus time curve (AUC) from time zero to the last measurable concentration 
(AUC0-t), AUC from time zero to 24 hours (AUC0-24), AUC from zero to infinity (AUC0-inf),
maximum observed drug concentration (Cmax), and the time to Cmax (tmax) will be calculated 
using noncompartmental methods. Other PK parameters, such as apparent t1/2, apparent clearance 
(CL/F), and apparent volume of distribution (Vz/F) will also be calculated. 
For the food effect exploration, the geometric means of the ratios of the log-transformed 
exposure measures (AUC, Cmax) between the fed and fasted conditions, and the 90% confidence 
intervals for the ratios will be reported. 
Pharmacokinetic parameters will be calculated individually and presented with summary 
statistics. Additional PK parameters may be calculated if deemed appropriate.
Mean and individual plasma concentration versus time curves will be graphically presented for 
LY3526318 and possibly metabolites.
Part B
Plasma LY3526318 PK parameters will be calculated using noncompartmental methods as 
described for Part A, after single- and multiple-dose administration (on Days 1 and 14, 
respectively). Additional PK parameters may be calculated if deemed appropriate. 
Pharmacokinetic parameters will be summarized by dose level using descriptive statistics. Mean 
and individual plasma concentration versus time curves will be graphically presented for 
LY3526318 and possibly metabolites.
Steady state will be graphically evaluated. Accumulation will be estimated.
Additional analyses will be performed as deemed necessary upon review of the data.
The relationship between LY3526318 PK and safety measures may be evaluated. Other analyses 
may be performed as needed.
10.3.2.1.2
Urine Pharmacokinetic Parameter Estimation
In Part A, urine LY3526318 PK parameters including Ae0-24), Fe, and renal clearance will be
calculated. Creatinine clearance will also be calculated for each participant.

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10.3.2.2 Pharmacokinetic Statistical Inference
Dose proportionality may be assessed using the power model approach (Smith et al. 2000), as 
appropriate. Additional analyses will be performed as deemed necessary upon review of the data.
10.3.3 Data Review during the Study
Data will be reviewed following each cohort prior to dose escalation as described in Section 7.4.

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11 References
[00926043] Eli Lilly and company. Study report of HB-IC-SS #49. A 28-day study of HX-260 
by oral gavage in rats with a 14-day recovery period. July 2018. Data on file.
[00926044] Eli Lilly and company. Study report of HB-IC-SS #50. A 28-day study of HX-260 
by oral gavage in cynomolgus monkeys with a 14-day recovery period. July 2018 Data on file.
[00926046] Eli Lilly and company. Study report of HB-IC-SS #52. HX-260: Cardiovascular and 
respiratory assessment following oral dose administration to conscious, 
radiotelemetry-instrumented cynomolgus monkeys. July 2018 Data on file.
[Lilly] Eli Lilly and Company. May 2019. Investigator’s Brochure for LY3526318.
[NCT02432664] National Institutes of Health. US National Library of Medicine. Clinical Trials 
Registry NCT02432664. Available at: https://clinicaltrials.gov/ct2/show/NCT02432664. 
Accessed April 12, 2019.
Aubdool AA, Kodji X, Abdul-Kader N, Heads R, Fernandes ES, Bevan S, Brain SD. TRPA1 
activation leads to neurogenic vasodilatation: involvement of reactive oxygen nitrogen species 
in addition to CGRP and NO. Br J Pharmacol. 2016;173(15):2419-2433.
Berta T, Qadri Y, Tan PH, Ji RR. Targeting dorsal root ganglia and primary sensory neurons for 
the treatment of chronic pain. Expert Opin Ther Targets. 2017;21(7):695-703.
Bodkin JV, Brain SD. Transient receptor potential ankyrin 1: emerging pharmacology and 
indications for cardiovascular biology. Acta Physiol (Oxf). 2011;203(1):87-98.
Buntinx L, Chang L, Amin A, Morlion B, de Hoon J. Development of an in vivo 
target-engagement biomarker for TRPA1 antagonists in human. Br J Clin Pharmacol. 
2017;83(3):603-611.
Demartini C, Tassorelli C, Zanaboni AM, Tonsi G, Francesconi O, Nativi C, Greco R. The role 
of the transient receptor potential ankyrin type-1 (TRPA1) channel in migraine pain: 
evaluation in an animal model. J Headache Pain. 2017;18(1):94.
EU Clinical Trial Register 2012-002320-33. Available at: 
https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-002320-33/results. Accessed 
April 02, 2019.
ICH Harmonised Tripartite Guideline. Guidance on nonclinical safety studies for the conduct of 
human clinical trials and marketing authorization for pharmaceuticals. Available at:
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/
M3_R2/Step4/M3_R2__Guideline.pdf. 11 June 2009. Accessed April 12, 2019.
Ko M, Ganzen L, Coskun E, Mukadam A, Leung YF, van Rijn R. A critical evaluation of 
TRPA1-mediated locomotor behavior in zebrafish as a screening tool for novel anti-
nociceptive drug discovery. Sci Rep. 2019;9(1):2430.
Maatuf Y, Geron M, Priel A. The role of toxins in the pursuit for novel analgesics. Toxins. 
2019;11(2):131-164.

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Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-1043.
Smith BP, Vandenhende FR, De Sante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. 
Confidence interval criteria for assessment of dose proportionality. Pharm Res. 
2000;17(10):1278-1283.
Ückert S, Albrecht K, Bannowsky A, Sohn M, Kuczyk MA, Hedlund P. Expression and 
distribution of the transient receptor potential cationic channel A1 (TRPA1) in the human 
clitoris-comparison to male penile erectile tissue. Int J Impot Res. 2017;29(5):179-183.
Wang X-L, Cui L-W, Zhen L, Gao Y-M, Wang S, Li H, Liu H-X, Yu LJ. Effects of TRPA1 
activation and inhibition on TRPA1 and CGRP expression in dorsal root ganglion neurons. 
Neural Regen Res. 2019;14(1):140-148.

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12 Appendices

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Appendix 1.
Abbreviations and Definitions

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Term
Definition
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
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
Blinding
A procedure in which 1 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 staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not. A double-blind study 
is one in which neither the participant nor any of the investigator or sponsor staff who are 
involved in the treatment or clinical evaluation of the participants are aware of the treatment 
received
Cmax
maximum observed drug concentration
CNS
central nervous system
CRF
case report form
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
DER
dose-escalation report
ECG
electrocardiogram
EDC
electronic data capture
ERB
ethical review board
FIH
first-in-human
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure

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ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
LDI
laser Doppler imaging
MAD
multiple-ascending dose
NOAEL
no-observed-adverse-event level
PK
pharmacokinetic(s)
SAD
single-ascending dose
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin level
TRPA1
transient receptor protein ankyrin 1
ULN
upper limit of normal
WOCBP
women of child-bearing potential

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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Glucose (fasting)
Mean cell volume 
Blood urea nitrogen (BUN)
Mean cell hemoglobin 
Total cholesterol
Mean cell hemoglobin concentration 
Total protein
Leukocytes (WBC) 
Albumin
Platelets
Total bilirubin
Differential WBC (Absolute counts and %) of:
Alkaline phosphatase (ALP)
Neutrophils
Aspartate aminotransferase (AST)
Lymphocytes
Alanine aminotransferase (ALT)
Monocytes
Creatinine
Eosinophils
Gamma-glutamyl transferase (GGT)
Basophils
Urine drug screena,b
Urinalysis Dipstick
Alcohol (ethanol)
Specific gravity
Nicotine metabolites
pH
Amphetamine (including XTC)
Protein
Barbiturates
Glucose
Benzodiazepine
Ketones
Cannabinoids
Bilirubin
Cocaine
Urobilinogen
Methadone
Blood
Opiates
Nitrite
Hepatitis B surface antigena
Hepatitis C antibodya
HIV
FSHa
Beta-hCG
Abbreviations:  FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin; HIV = human 
immunodeficiency virus; RBC = red blood cell; WBC = white blood cell.
a
Performed at screening only.
b
Urine drug screen may be repeated prior to admission to the clinical research unit and at other times indicated in 
the Schedule of Activities.

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Appendix 3.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for

ensuring that the participant understands the nature of the study, the potential risks and 
benefits of participating in the study, and that his/her participation is voluntary.

ensuring that informed consent is given by each participant or legal representative. This 
includes obtaining the appropriate signatures and dates on the ICF prior to the performance 
of any protocol procedures and prior to the administration of investigational product.

answering any questions the participant may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the participant’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 participants. Individual 
investigators may have additional local requirements or processes. Study-specific recruitment 
materials 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 the 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 CRU. Lilly or its representatives must approve the ICF before it is used at 
the CRU. All ICFs must be compliant with the ICH guideline on GCP.
The study site’s ERB(s) should be provided with the following:

study protocol and any amendments during the course of the study

the current IB and updates during the course of the study

ICF

relevant site personnel curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with

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1. consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
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 medical officer responsible 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.  
Final Report Signature
The sponsor’s medical officer responsible 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 materials to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators. This training will give 
instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel through mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site. The study may be audited by Lilly and/or 
regulatory agencies at any time. Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data. This might include laboratory tests, 
medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.

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Data Collection Tools/Source Data
An EDC 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 participant personal information collected will be provided in a written 
document to the participant by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 4.
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 medical monitor.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cell; WBC = white blood cell.
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 J2D-MC-CVAA Sampling Summary – Part A (Cohorts 1-6) (SAD)
Purpose
Blood Volume per Sample 
(mL)
Number of Blood Samples
Total Volume (mL)
Screening testsa
11.5
1
11.5
Clinical laboratory testsa,b
6.5
4
26
Pharmacokineticsb
3
9
27
Total for all cohorts, except for 100-mg cohort female participants and 400-mg participants
64.5
Total for 100-mg cohort female participants and 400-mg cohort participantsb
111
a
Additional samples may be drawn if needed for safety purposes.
b
Female participants in the 100-mg cohort and all participants in the 400-mg cohort will receive study drug twice, 
once in fasted state and once in fed state. Hence, clinical laboratory and pharmacokinetic samples will be 
collected twice, except for the follow-up clinical laboratory sample that will be collected only after fed-state 
study drug administration.
Protocol J2D-MC-CVAA Sampling Summary – Part A (Cohort 10) (SAD)
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Number of Periods 
Samples are Collected
Total Volume 
(mL)
Screening testsa
11.5
1
1
11.5
Clinical 
laboratory testsa,b
6.5
4
3
78
Pharmacokineticsb
3
11
3
99
Total
188.5
a
Additional samples may be drawn if needed for safety purposes.
b
Cohort 10 participants will receive study drug once in 3 different periods. Hence, clinical laboratory and 
pharmacokinetic samples will be collected three times, except for the follow-up clinical laboratory sample that 
will be collected only after the final period.
Protocol J2D-MC-CVAA Sampling Summary – Part B, Cohort 7 (MAD)
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
11.5
1
11.5
Clinical laboratory testsa
6.5
5
32.5
Pharmacokinetics 
3
19
57
Total
101
a
Additional samples may be drawn if needed for safety purposes.

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Protocol J2D-MC-CVAA Sampling Summary – Part B, Cohorts 8-9 (MAD)
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
11.5
1
11.5
Clinical laboratory testsa
6.5
5
32.5
Pharmacokinetics 
3
22
66
Total
110
a
Additional samples may be drawn if needed for safety purposes.

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Appendix 6.
List of Excluded Concomitant Medications
This is a list of moderate and strong CYP3A4 and CYP2C9 inhibitors and inducers (effectors) to 
inform clinical development for CYP3A4 and CYP2C9 substrates.

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Strong and moderate clinical inducers of CYP3A4 (Updated 04 Mar 2019)
Drug
Special status 
Category
Aminoglutethimide
VL. Possibly available in Egypt, 
Lithuania
strong
Apalutamide
strong
Avasimibe
strong
Carbamazepine
strong
Enzalutamide
strong
fosphenytoin (see also phenytoin)
strong
Ivosidenib
strong
Lumacaftor
strong
Mitotane
strong
Phenobarbital
strong
Phenytoin
strong
Rifabutin
strong
rifampicin (rifampin)
strong
Rifapentine
strong
St. John’s wort
SF
strong
Almorexant
moderate
Bosentan
moderate
Dabrafenib
moderate
daclatasvir and asunaprevir and beclabuvir
moderate
danshen (Salvia miltiorrhiza)
SF
moderate
Efavirenz
moderate
Encorafenib
P
moderate 
Etravirine
moderate
faldaprevir and efavirenz
moderate
Genistein
SF
moderate
lenisurad
moderate
Lersivirine
moderate
lopinavir (alone)
moderate
Lorlatinib
moderate
Modafinil
moderate
nafcillin (intravenous)
VL; available in the US
moderate
Pentobarbital
VL
moderate
Primidone
moderate
telotristat ethyl
moderate
thioridizine
VL: available in the US; importable 
into the UK
moderate
tipranavir and ritonavir
moderate
tocilizumab (atlizumab)
NT
moderate
NT: nontraditional mechanism: reverses the IL-6-mediated suppression of CYP3A activity in patients with rheumatoid arthritis
P: probable moderate inducer based on observed autoinduction
SF: supplement or food/drink
VL: very limited use
FDA https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm

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Strong and moderate clinical inhibitors of CYP3A4 (Updated 04 Mar 2019)
Drug
Special status
Inhibition category
Boceprevir
strong
Clarithromycin
strong
Cobicistat
strong
Conivaptan
strong
danoprevir and ritonavir
strong
Diltiazem
strong
elvitegravir and ritonavir
strong
grapefruit juice
SF
strong
Idelalisib
strong
indinavir and ritonavir
strong
Itraconazole
strong
Ketoconazole
VL
strong
lopinavir and ritonavir 
strong
Nefazodone
VL; Available in the US
strong
Nelfinavir
strong
Posaconazole
strong
Ribociclib
strong
Ritonavir
strong
saquinavir and ritonavir
strong
Telithromycin
strong
tipranavir and ritonavir
strong
Viekira Pak® (paritaprevir and ritonavir and ombitasvir and/or dasabuvir)
strong
Voriconazole
strong
Amprenavir
moderate
Aprepitant
moderate
atazanavir (see atazanavir and ritonavir)
moderate
atazanavir and ritonavir
moderate
Cimetidine
moderate
Ciprofloxacin
moderate
Clotrimazole
moderate
Crizotinib
moderate
Cyclosporine
moderate
Darunavir
moderate
Dronedarone
moderate
Duvelisib
moderate
Erythromycin
moderate
Fluconazole
moderate
Fluvoxamine
moderate
fosnetupitant and palonosetron (see also netupitant)
moderate
Imatinib
moderate
indinavir (see indinavir and ritonavir)
moderate
Isavuconazole
moderate
ledipasvir/sofosbuvir
moderate
Letermovir
moderate
magnolia vine (Schisandra 
SF
moderate

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sphenanthera)
Netupitant
moderate
Nilotinib
moderate
Tofisopam
moderate
Verapamil
moderate
SF: supplement or food/drink
VL: very limited use
University of Washington Drug Interaction Database https://www.druginteractioninfo.org/
Hansten PD, Horn JR. Top 100 Drug Interactions of 2018: A Guide to Patient Management. Freeland, WA: H&H Publications; 2018. 

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Moderate clinical inhibitors and inducers of CYP2C9
CYP2C9 Inhibitors
amiodarone, felbamate, fluconazole, miconazole, piperine
CYP2C9 Inducers
aprepitant, carbamazepine, enzalutamide, rifampin, ritonavir
Source:
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsl
abeling/ucm093664.htm. Accessed 22 Apr 2019.

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Appendix 7.
Protocol Amendment: J2D-MC-CVAA(a)
Protocol J2D-MC-CVAA has been amended; the new will be indicated as amendment (a) and 
will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section
Changes made
Rationale for the change
5.1 Overall Design
Footnotes added to Table 5.1 and 
Figure 5.1 to clarify that doses may 
be adjusted based on data obtained 
in previous cohorts (Part A only) 
and in previous cohorts and parts 
(Parts A and B)
Administrative updates
5.4 Scientific Rationale for Study 
Design
Text edited to clarify dosing in the 
food effect cohort.
Administrative updates
7.1 Treatment Administered
Text edited to clarify that the highest 
dose level to be tested is not 
intended to exceed the NOAEL
Administrative updates
Revised Protocol Sections
Note: Deletions have been identified by strikethroughs or grayed out for figures. Additions 
have been identified by the use of underscore.

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5.1
Overall Design
Table 5.1
Part A Stratification Based on Sex
Cohort
(Planned dose level a)
Number of Females 
Randomized
Number of Males 
Randomized 
Total Participants 
Randomized
Cohort 1 (10 mg)
Up to 8ba
Up to 8ba
8
Cohort 2 (50 mg)
4
4
8
Cohort 3 (100 mg)
8cb
4
12
Cohort 4 (400 mg)
8cb
NA
8
Cohort 5 (800 mg)
8
NA
8
Cohort 6 (1000 mg)
8
NA
8
Abbreviation:  NA = not applicable.
a    Doses may be adjusted based on data obtained in previous study cohorts.
ba Cohort 1 will not have a defined stratification by sex scheme. Eight participants will be randomized including 
males and/or females.
cb Female participants in Cohorts 3 and 4 will receive study drug in fasted and fed conditions, separated by a 
washout period of at least 1 week.
Abbreviations: SAD = single-ascending dose (Orange); MAD = multiple-ascending dose (Green).
Note: Doses may be adjusted based on data obtained in previous study cohorts and parts.  The timeline listed is an 
approximation intended to illustrate relative cohort timing within and between Parts A and B.
Figure 5.1
Illustration of study design for Protocol J2D-MC-CVAA.

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5.4
Scientific Rationale for Study Design
The study will include a pilot assessment of food effect in female participants only. Specifically, 
8 female participants in the Part A 100- and 400-mg dose cohorts will receive 2 sequential 
100- and 400-mg doses, respectively. In each of these In the food effect cohorts, the first dose 
will be administered in the fasted state, and the second dose in fed state.
7.1
Treatment Administered
Part A:
The planned dose levels are 10, 50, 100, 400, 800, and up to 1000 mg. LY3526318 or matching 
placebo will be administered to participants as a single dose by trained CRU personnel. Dose 
levels may be modified based on safety and available PK, but which will are not intended to
exceed the NOAEL.

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Appendix 8.
Protocol Amendment: J2D-MC-CVAA(b)
Protocol J2D-MC-CVAA has been amended; the new will be indicated as amendment (b) and 
will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section
Changes made
Rationale for the change
2. Study Schedule Protocol J2D-
MC-CVAA: Part B (MAD) and 
associated text throughout protocol
Two additional SOE tables for 
Cohorts 8 and 9 to clearly indicate 
differing in house stays for 
additional PK sample collection 
regimens between the MAD cohorts. 
For Cohorts 8 and 9, the revised PK 
sample collection schedule runs 
through 96 and 120 hours post Day 
14 dose, respectively, with only 3 
PK samples added in each cohort. 
SAD PK data resulted in a longer 
half-life than was predicted, so 
additional collections required to 
characterize the terminal elimination 
of LY3526318
2. Study Schedule Protocol J2D-
MC-CVAA: Part B (MAD)
Temperature timepoints revised to 
be consistent with Vital Sign 
timepoints
Administrative update
Appendix 5.  Blood Sampling 
Summary
Revised blood volume based on 
additional PK samples
Same as above.
7.1 Treatment Administered
Revised the capsule strengths from 
“10 mg and 100 mg” to “10 mg to 
100mg”
Capsules will be prepared at dosage 
strengths administered.
Revised Protocol Sections
Note: Deletions have been identified by strikethroughs or grayed out for figures. Additions 
have been identified by the use of underscore.

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2 Schedule of Activities
Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 7
S
Treatment/In CRU
Post
treatment
EDa
Study Day
≤28
-1
1
2
3
5
8
14
15
23
Visit Window (days)
±2
Visits
1b
2
3
CRU admission
X
CRU discharge 
X
Participant information (including I/E criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination (complete [C] or directed [D])
C
D
D
D
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
Vital signs including temperaturec
X
X
X
X
X
X
X
X
X
X
Hematology and clinical chemistryd
X
X
X
X
X
X
X
Urinalysise
X
X
Pregnancy test (serum beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X
X
X
X
C-SSRS
X
X
X
X
X
Randomization
X
Study drug administrationh
X 
PK blood samplei
X
X
X
X
X
X
X
X
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; 
h = hours; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; MAD = multiple-ascending dose; PK = 
pharmacokinetic; S = screening.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of first dose administration.
c
Vital signs and temperature should be measured at following time points: Days 1 and 14 – predose and 2 hours, 
4 hours, and 8 hours postdose; predose on all other indicated dosing days. Temperature should be measured 
predose on all indicated days.
d
Hematology and chemistry sample should be collected predose on stipulated visits.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest at following time points:
Days 1 and 14 – predose and 2 hours, 4 hours, and 8 hours postdose.
h
Study drug will be administered once daily in the CRU through Day 14, and the exact time of administration will 
be recorded.  All doses are planned to be administered in a fasting state; however, following a review of the food 
effect data from Part A, all doses may be administered with food. Fasting on PK sampling days is defined as at 

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least 8 hours predose and 4 hours postdose. Fasting on non-PK and predose only PK sampling days is defined as 
at least 8 hours predose and 2 hours postdose on all other indicated days. 
i
On Days 1 and Day 14, PK samples will be collected at time zero (predose) and at approximately at 1, 2, 4, 6, 8, 
and 12 hours after dosing. On Day 2 (at predose) and on Day 15 (prior to discharge), 1 PK sample will be taken 
at 24 hours postdose. Predose PK samples will also be obtained on Days 3, 5, and 8. If applicable, a sample will 
be collected at the ED visit. PK sample collection times are provided as a guidance and may be modified based 
on clinical needs. Actual dates and times of sample collection must be recorded. The following time intervals are 
proposed: predose samples may be obtained between waking up and dosing. Postdose samples may be obtained 
within ±5% of the scheduled collection time. Post-assay remaining PK plasma samples may be stored for 
metabolite identification.

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Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 8
S
Treatment/In CRU
Post
treatment
EDa
Study Day
≤28
-1
1
2
3
5
8
14
15
16
17
18
23
Visit Window (days)
±2
Visits
1b
2
3
CRU admission
X
CRU discharge
X
Participant information (including I/E criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination (complete [C] or directed [D])
C
D
D
D
D
D
D
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
Vital signs including temperaturec
X
X
X
X
X
X
X
X
X
X
Hematology and clinical chemistryd
X
X
X
X
X
X
X
Urinalysise
X
X
Pregnancy test (serum beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X
X
X
X
C-SSRS
X
X
X
X
X
Randomization
X
Study drug administrationh
X 
PK blood samplei
X
X
X
X
X
X
X
X
X
X
X
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; 
h = hours; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; MAD = multiple-ascending dose; PK = 
pharmacokinetic; S = screening.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of first dose administration.
c
Vital signs and temperature should be measured at following time points: Days 1 and 14 – predose and 2 hours, 
4 hours, and 8 hours postdose; predose on all other indicated dosing days.
d
Hematology and chemistry sample should be collected predose on stipulated visits and approximately 24 hours 
post Day 14 dose on Day 15.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest at following time points:
Days 1 and 14 – predose and 2 hours, 4 hours, and 8 hours postdose.

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h
Study drug will be administered once daily in the CRU through Day 14, and the exact time of administration will 
be recorded.  All doses are planned to be administered in a fasting state; however, following a review of the food 
effect data from Part A, all doses may be administered with food. Fasting on PK sampling days is defined as at 
least 8 hours predose and 4 hours postdose. Fasting on non-PK and predose only PK sampling days is defined as 
at least 8 hours predose and 2 hours postdose on all other indicated days. 
i
On Day 1 and Day 14, PK samples will be collected at time zero (predose) and at approximately at 1, 2, 4, 6, 8, 
and 12 hours after dosing. Predose PK samples will also be obtained on Days 2, 3, 5, and 8. One PK sample will 
be taken at approximately 24, 48, 72, and 96 hours post Day 14 dose on Days 15, 16, 17, and 18, respectively.  If 
applicable, a sample will be collected at the ED visit. PK sample collection times are provided as a guidance and 
may be modified based on clinical needs. Actual dates and times of sample collection must be recorded. The 
following time intervals are proposed: predose samples may be obtained between waking up and dosing. 
Postdose samples may be obtained within ±5% of the scheduled collection time. Post-assay remaining PK plasma 
samples may be stored for metabolite identification.

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Study Schedule Protocol J2D-MC-CVAA: Part B (MAD)-Cohort 9
S
Treatment/In CRU
Post
treatment
EDa
Study Day
≤28
-1
1
2
3
5
8
14
15
16
17
18
19
23
Visit Window (days)
±2
Visits
1b
2
3
CRU admission
X
CRU discharge
X
Participant information (including I/E criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination (complete [C] or directed 
[D])
C
D
D
D
D
D
D
D
D
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
Vital signs including temperaturec
X
X
X
X
X
X
X
X
X
X
Hematology and clinical chemistryd
X
X
X
X
X
X
X
Urinalysise
X
X
Pregnancy test (serum beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X
X
X
X
C-SSRS
X
X
X
X
X
Randomization
X
Study drug administrationh
X 
PK blood samplei
X
X
X
X
X
X
X
X
X
X
X
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; 
h = hours; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; MAD = multiple-ascending dose; PK = 
pharmacokinetic; S = screening.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of first dose administration.
c
Vital signs and temperature should be measured at following time points: Days 1 and 14 – predose and 2 hours, 
4 hours, and 8 hours postdose; predose on all other indicated dosing days. 
d
Hematology and chemistry sample should be collected predose on stipulated visits and approximately 24 hours 
post Day 14 dose on Day 15.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest at following time points: 
Days 1 and 14 – predose and 2 hours, 4 hours, and 8 hours postdose.
h
Study drug will be administered once daily in the CRU through Day 14, and the exact time of administration will 
be recorded.  All doses are planned to be administered in a fasting state; however, following a review of the food 
effect data from Part A, all doses may be administered with food. Fasting on PK sampling days is defined as at 

J2D-MC-CVAA (c) Clinical Protocol
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LY3526318
least 8 hours predose and 4 hours postdose. Fasting on non-PK and predose only PK sampling days is defined as 
at least 8 hours predose and 2 hours postdose on all other indicated days. 
i
On Day 1 and Day 14, PK samples will be collected at time zero (predose) and at approximately at 1, 2, 4, 6, 8, 
and 12 hours after dosing. Predose PK samples will also be obtained on Days 2, 3, 5, and 8. One PK sample will 
be taken at approximately 24, 48, 72, and 120 hours post Day 14 dose on Days 15, 16, 17, and 19, respectively.  
If applicable, a sample will be collected at the ED visit. PK sample collection times are provided as a guidance 
and may be modified based on clinical needs. Actual dates and times of sample collection must be recorded. The 
following time intervals are proposed: predose samples may be obtained between waking up and dosing. 
Postdose samples may be obtained within ±5% of the scheduled collection time. Post-assay remaining PK plasma 
samples may be stored for metabolite identification.
Section 5.1 Overall Design
Following a screening period of up to 28 days, eligible participants will receive once-daily 
treatment with study drug for 14 days. Participants will be confined to the CRU from Day -1 
until all study assessments are completed on Day 15 (Cohort 7), Day 18 (Cohort 8) or Day 19 
(Cohort 9). Within each cohort, eligible participants will be randomly assigned to receive 
LY3526318 or placebo in a 6:2 ratio. The first cohort will be administered LY3526318 following 
a review of safety and PK data through Part A 400-mg cohort and fed period of the 100-mg 
cohort.
Section 7.1 Treatment Administered
Part B
The LY3526318 drug product is supplied as a hard gelatin capsule in dosage strengths of 10 and 
to 100 mg. Placebo capsules will be identical in size and shape.
Appendix 5 Blood Sampling Summary
Protocol J2D-MC-CVAA Sampling Summary – Part B, Cohort 7 (MAD)
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
11.5
1
11.5
Clinical laboratory testsa
6.5
5
32.5
Pharmacokinetics 
3
19
57
Total
101
a
Additional samples may be drawn if needed for safety purposes.

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Protocol J2D-MC-CVAA Sampling Summary – Part B, Cohorts 8-9 (MAD)
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
11.5
1
11.5
Clinical laboratory testsa
6.5
5
32.5
Pharmacokinetics 
3
22
66
Total
110
a
Additional samples may be drawn if needed for safety purposes.

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Appendix 9.
Protocol Amendment: J2D-MC-CVAA(c)
Protocol J2D-MC-CVAA has been amended; the new will be indicated as amendment (c) and 
will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section
Changes made
Rationale for the change
2 Schedule of Activities
Part B Tables Cohorts 8 and 9
Deleted erroneous text regarding 
collection of Day 15 clinical lab 
samples
Administrative (error correction)
Throughout document-Added
additional SAD Cohort-(Cohort 10)
Added an additional cohort of 8 
female participants 
Revised food effect language 
throughout too
To further assess food effect on a 
single dose of LY in 3 period 
crossover design
Throughout document
Indicated that men would only 
continue to be dosed in the study if 
the exposure data from previous 
cohorts supported it
To further clarify dosing in men 
based on exposure data
Revised Protocol Sections
Note: Deletions have been identified by strikethroughs or grayed out for figures. Additions 
have been identified by the use of underscore.

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2
Schedule of Activities
Table 2-1 title updated as: Study Schedule Protocol J2D-MC-CVAA: Part A Cohorts 1-6 (SAD)
Table 2-2
Study Schedule Protocol J2D-MC-CVAA: Part A-Cohort 10-(3 Period Food Effect Cohort)
S
Treatment/ In CRU
Posttreatment
EDa
Study Day (visit window)
≤28
-1
1
2
3
4
10 (± 2)
Period
1-3
3
1-3
Visits
1b
2c
3
CRU admission
X
CRU discharge
X
Participant information (including I/E 
criteria)
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination
(complete [C] or directed [D])
C
D
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
Vital signs including temperature
X
X
X (predose, 2 h, 
4 h, 8 h)
X
X
X
X
Hematology and clinical chemistry
X
X
Xd
Xd
X
X
Urinalysise
X
X
Pregnancy test (serum beta-hCG)f
X
X
X
X
HIV, HCV, HBsAg
X
ECGg
X
X (predose, 2 h, 
4 h, 8 h) 
X
X
C-SSRS
X
X
X
X
Randomization
Xh
Study drug administrationi
X
PK blood samplej
X
X
X
X
X
PK 24-hour urine collectionk
X 
Adverse event
X 
Concomitant medications
X 
Abbreviations: C = complete physical examination; CRU = clinical research unit; C-SSRS= Columbia-Suicide 
Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; 
h = hour; HBsAg = hepatitis B surface antigen; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; I/E = inclusion/exclusion; PK = pharmacokinetics; S = screening; 
SAD = single-ascending dose.
a
Participants who discontinue from the study prior to study completion should complete the ED visit procedures.
b
Screening will be performed within 28 days of the first dose being administered.
c
All participants will remain in the CRU until completion of Day 4 procedures.
d
Hematology and clinical chemistry sample to be taken in the morning.
e
A standard urine test strip/dipstick may be used.
f
A serum beta-hCG test will be performed in all female participants, except in female participants with confirmed 
hysterectomy.
g
A single 12-lead ECG will be recorded in the supine position after 5 minutes of rest.

J 2 D -M C -C V A A ( c) Cli ni c al Pr ot o c ol
P a g e 8 1
L Y 3 5 2 6 3 1 8
h
Ra n d o mizati o n will occ ur d uri n g first peri o d o nl y.
i
D oses are pla n ne d t o be a d mi nistere d as f oll o ws i n eac h peri o d:

Peri o d 1 -Fe d sta n dar dize d hi g h fat meal t o start 3 0 mi n utes pri or t o d ose a d mi nistrati o n 

Peri o d 2 -Faste d at least 8 h o urs pre d ose wit h a sta n dar dize d hi g h fat meal a d mi nistere d 3 0 mi n utes 
p ost d ose

Peri o d 3 -Faste d at least 8 h o urs pre d ose wit h a sta n dar dize d hi g h fat meal a d mi nistere d 1 h o ur p ost 
d ose
Peri o ds will be se parate d b y a was h o ut of at least 1 wee k.  T he meals a d mi nistere d i n all treat me nt peri o ds 
s h o ul d be c o ns u me d wit hi n 3 0 mi n utes.  T he e xact ti me st u d y dr u g is a d mi nistere d will be rec or de d.
j
I n eac h treat me nt peri o d, o n Da y 1, P K sa m ples will be c ollecte d at ti me zer o ( pre d ose) a n d at a p pr o xi matel y 1, 
2, 4, 6, 8, a n d 1 2 h o urs after d osi n g. O ne P K sa m ple will be ta ke n at 2 4, 4 8, a n d 7 2 h o urs p ost d ose ( Da ys 2, 3, 
a n d 4), a n d if a p plica ble, at t he E D Visit. P K sa m ple c ollecti o n ti mes are pr o vi de d as a g ui da nce a n d ma y be 
m o difie d ba se d o n cli nical nee ds. Act ual dates a n d ti mes of sa m ple c ollecti o n m ust be rec or de d. T he f oll o wi n g 
ti me c ollecti o n i nter vals are pr o p ose d: pre d ose sa m ples ma y be o btai ne d bet wee n wa ki n g u p a n d d osi n g. 
P ost d ose sa m ples ma y be o btai ne d wit hi n ± 5 % of t he sc he d ule d c ollecti o n ti me. T he ± 5 % ti me wi n d o w als o 
a p plies t o t he start a n d e n d ti mes of uri ne c ollecti o n i nter vals. P ost -assa y re mai n der P K plas ma sa m ples ma y be 
st ore d f or meta b olite i de ntificati o n.
k
Ur i ne c ollecti o n i nter val is 0 t o 2 4 h o urs p ost d ose. T he t otal uri ne v ol u me of t he 0- t o 2 4-h o ur c ollecti o n will be 
rec or de d.
T a bles 2 -4 a n d 2 - 5, F o ot n ote d : He mat ol o g y a n d c he mistr y sa m ple s h o ul d be c ollecte d pre d ose 
o n sti p ulate d visits . a n d a p pr o xi matel y 2 4 h o urs p ost Da y 1 4 d ose o n Da y 1 5.
3. 3
Be nefit/ Ris k Assess me nt
 
5. 1
O ver all Desi g n
T a ble 5- 1
P art A Str atific ati o n B ase d o n Se x
C o h ort
( Pl a n ne d d ose le vel a)
N u m ber of Fe m ales 
R a n d o mize d
N u m ber of M ales 
R a n d o mize d
T ot al P artici p a nt s 
R a n d o mize d
C o h ort 1 ( 1 0 m g)
U p t o 8 b
U p t o 8 b
8
C o h ort 2 ( 5 0 m g)
4
4
8
C o h ort 3 ( 1 0 0 m g)
8 c
4
1 2
C o h ort 4 ( 4 0 0 m g)
8 c
N A
8
C o h ort 5 ( 8 0 0 m g)
8
N A
8
C o h ort 6 ( 1 0 0 0 m g)
8
N A
8
C o h ort 1 0 ( 1 0 0 m g)
8 d
N A
8
C CI

J2D-MC-CVAA (c) Clinical Protocol
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LY3526318
Abbreviation:  NA = not applicable.
a    Doses may be adjusted based on data obtained in previous study cohorts.
b
Cohort 1 will not have a defined stratification by sex scheme. Eight participants will be randomized including 
males and/or females.
c
Female participants in Cohorts 3 and 4 will receive study drug in fasted and fed conditions, separated by a 
washout period of at least 1 week.
d
All 8 female participants in Cohort 10 will receive LY3526318 in a 3-period crossover with standardized high fat 
meals administered prior to dose, and at 30 min and 1 hour post dose.  Participants receiving meals post dose 
administration will receive their dose in the fasted state.  Periods are separated by a washout period of at least 1 
week.
Cohorts administered above LY3526318 100 mg are anticipated to exceed the approximate 10x 
margin to the projected no-observed-adverse-event-level (NOAEL)-equivalent exposure for 
males; for this reason, only female participants will be enrolled at dose levels higher than 
100 mg. Additionally, if exposure data from previous cohorts does not support dose escalation in 
males through 100 mg, males will be discontinued from further dosing in the study.
An additional cohort (Cohort 10) will assess the effect of food on LY3526318 PK in 8 female 
participants. All participants in this cohort will received 100 mg LY3526318 with standardized 
high fat meal in an open-label, 3-way crossover manner (meal administered prior to dose, at 
30 minutes and at 1 hour post dose; Table 2-2). Participants receiving meals post dose 
administration will  receive their dose after an approximately 8-hour fast. Periods will be 
separated by a washout period of at least 1 week.
5.2
Number of Participants
Part A: Approximately 52 participants will be randomized to achieve 8 evaluable participants per 
cohort, except the 100-mg cohort that will include 8 evaluable females and 4 evaluable males
and 100 mg food assessment cohort (Cohort 10) that will include 8 evaluable females. 
5.4
Scientific Rationale for Study Design
This study will include a pilot assessment of food effect in female participants only. In the food 
effect cohorts, the first doses will be administered in fed and the fasted states, as indicated and 
the second dose in the fed state. Residual exposure will be minimized with a washout period of at 
least 1 week between doses. The 100  and 400-mg doses and the high-fat meal were chosen 
because preclinical data suggest that study drug administration with a high-fat meal may increase 
exposures of LY3526318 by approximately 5 fold, compared to administration in the fasted 
state. Having a food assessment at 2 different dose levels will help inform the mode of study 
drug administration in the MAD and subsequent studies. In addition, because LY3526318 
preclinical PK was subproportional to dose, and the effect of food may also be nonlinear, 
assessing the food effect at 2 different dose levels will provide a better understanding of 
LY3526318 PK.
7.1
Treatment Administered
Part A:

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LY3526318
All doses are planned to be administered in a fasting state (at least 8 hours predose and 4 hours 
postdose), with the exception of the indicated doses in the food effect cohorts second dose in the 
food effect assessment cohorts (100 and 400 mg), where the study drug will be administered in 
both the fasted and fed states, as specified with a high-fat meal. Approximately 50% of the total 
caloric content of the meal should be from fat. Study participants should eat this meal in 30 
minutes or less; and the study drug should be administered 30 minutes after the start of the meal. 
In all cases, study drug should be taken with 1 glass (approximately 240 mL) of water and no 
food should be allowed for at least 4 hours postdose. Water can be allowed as desired except for 
1 hour before and after drug administration.
7.2
Method of Treatment Assignment
Randomization in the first cohort (10 mg, Cohort 1) will not be stratified by sex and participants 
will receive either LY3526318 or placebo in a 6:2 ratio, unless otherwise indicated.
Participants in Cohorts 4 and onwards will receive either LY3526318 or placebo in a 6:2 ratio, 
except for Cohort 10 where all participants will receive LY3526318.
Appendix 5.
Blood Sampling Summary
Protocol J2D-MC-CVAA Sampling Summary – Part A (Cohort 10) (SAD)
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Number of Periods 
Samples are Collected
Total Volume 
(mL)
Screening testsa
11.5
1
1
11.5
Clinical 
laboratory testsa,b
6.5
4
3
78
Pharmacokineticsb
3
11
3
99
Total
188.5
a
Additional samples may be drawn if needed for safety purposes.
b
Cohort 10 participants will receive study drug once in 3 different periods. Hence, clinical laboratory and 
pharmacokinetic samples will be collected three times, except for the follow-up clinical laboratory sample that 
will be collected only after the final period.

Leo Document ID = 3c7d8dbf-d4dc-4709-9f97-f6e009fcb7da
Approver: 
Approval Date & Time: 16-Dec-2019 15:27:58 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 16-Dec-2019 17:49:00 GMT
Signature meaning: Approved