A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of Oral Single-Doses of LY3526318 on Cinnamaldehyde-Induced Dermal Blood Flow in Healthy Females
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol J2D-MC-CVAB (a) 
 
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of Oral Single-
Doses of LY3526318 on Cinnamaldehyde-Induced Dermal Blood Flow in Healthy Females 
 
NCT04183283 
 
Approval Date: 15-Nov-2019 

J 2 D -M C -C V A B ( a) 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 B ( a)
A R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -C o ntr oll e d St u d y  t o 
E v al u at e t h e Eff e ct s of Or al Si n gl e -D o s e s of L Y 3 5 2 6 3 1 8 o n 
Ci n n a m al d e h y d e -I n d u c e d D er m al Bl o o d Fl o w i n H e alt h y  
F e m al e s
2 0 1 9 -0 0 3 6 1 3 -3 4
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s pr ot o c ol i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c 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 er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
A p pr o v al D at e: 1 5- N o v- 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 o l 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.

J2D-MC-CVAB(a) Clinical Protocol
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Table of Contents
Section
Page
Protocol J2D-MC-CVAB A Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Effects of Oral Single-Doses of 
LY3526318 on Cinnamaldehyde-Induced Dermal Blood Flow in 
Healthy Females .................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................12
3.1.
Study Rationale............................................................................................................12
3.2.
Background..................................................................................................................12
3.3.
Benefit/Risk Assessment..............................................................................................13
4.
Objectives and Endpoints..................................................................................................14
5.
Study Design.....................................................................................................................15
5.1.
Overall Design .............................................................................................................15
5.2.
Number of Participants.................................................................................................15
5.3.
End of Study Definition ...............................................................................................15
5.4.
Scientific Rationale for Study Design...........................................................................16
5.5.
Justification for Dose ...................................................................................................16
6.
Study Population...............................................................................................................17
6.1.
Inclusion Criteria..........................................................................................................17
6.2.
Exclusion Criteria ........................................................................................................18
6.3.
Lifestyle and/or Dietary Requirements .........................................................................20
6.3.1.
Meals and Dietary Restrictions.............................................................................20
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................20
6.3.3.
Activity................................................................................................................20
6.4.
Screen Failures.............................................................................................................20
7.
Treatment..........................................................................................................................21
7.1.
Treatment Administered...............................................................................................21
7.1.1.
Packaging and Labeling .......................................................................................21
7.2.
Method of Treatment Assignment ................................................................................21
7.2.1.
Selection and Timing of Doses.............................................................................21
7.3.
Blinding .......................................................................................................................22
7.4.
Dose Modification........................................................................................................22
7.5.
Preparation/Handling/Storage/Accountability...............................................................22

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7.6.
Treatment Compliance .................................................................................................23
7.7.
Concomitant Therapy...................................................................................................23
7.8.
Treatment after the End of the Study............................................................................23
8.
Discontinuation Criteria ....................................................................................................24
9.
Study Assessments and Procedures ...................................................................................26
9.1.
Efficacy Assessments...................................................................................................26
9.2.
Adverse Events ............................................................................................................26
9.2.1.
Serious Adverse Events........................................................................................27
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................27
9.2.2.
Complaint Handling.............................................................................................28
9.3.
Treatment of Overdose.................................................................................................28
9.4.
Safety...........................................................................................................................28
9.4.1.
Laboratory Tests ..................................................................................................28
9.4.2.
Vital Signs ...........................................................................................................28
9.4.3.
Electrocardiograms ..............................................................................................28
9.4.4.
Physical Examination...........................................................................................29
9.4.5.
Safety Monitoring ................................................................................................29
9.4.5.1.
Hepatic Safety................................................................................................29
9.5.
Pharmacokinetics .........................................................................................................30
9.6.
Pharmacodynamics ......................................................................................................30
9.6.1.
Dermal Blood Flow (DBF) Measurements by Laser Doppler 
Imaging (LDI) and Laser Speckle Contrast Imaging (LSCI).................................30
9.7.
Genetics .......................................................................................................................31
9.8.
Biomarkers...................................................................................................................31
9.9.
Health Economics ........................................................................................................31
10.
Statistical Considerations and Data Analysis.....................................................................32
10.1. Sample Size Determination ..........................................................................................32
10.2. Populations for Analyses..............................................................................................32
10.2.1.
Study Participant Disposition ...............................................................................32
10.2.2.
Study Participant Characteristics ..........................................................................32
10.2.3.
Concomitant Medications.....................................................................................32
10.3. Statistical Analyses ......................................................................................................32
10.3.1.
Safety Analyses....................................................................................................32
10.3.2.
Pharmacokinetic Analyses....................................................................................33
10.3.3.
Pharmacodynamic Analyses.................................................................................33
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................33
10.3.5.
Interim Analyses..................................................................................................33
11.
References ........................................................................................................................34

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12.
Appendices .......................................................................................................................36

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List of Tables
Table
Page
Table 4-1
Objectives and Endpoints .......................................................................14
Table 5-1
Treatment Sequence ...............................................................................15

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................37
Appendix 2.
Clinical Laboratory Tests........................................................................40
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................41
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............44
Appendix 5.
Blood Sampling Summary......................................................................45

J2D-MC-CVAB(a) Clinical Protocol
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1. Protocol Synopsis
Title of Study:
A randomized, double-blind, placebo-controlled study to evaluate the effects of oral single-doses of LY3526318 on
cinnamaldehyde-induced dermal blood flow in healthy females.
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 agonist 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 a subset of patients. LY3526318 has been 
demonstrated to be safe and well tolerated in Study CVAA. The effect of LY3526318 on cinnamaldehyde
(CA)-induced dermal blood flow (DBF) will be compared to placebo.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To assess target engagement of TRPA1 after a single 
dose of LY3526318
Decrease in CA-induced dermal blood flow (DBF)
relative to placebo measured by laser Doppler Imaging 
(LDI) at 3 hours post-dose
Secondary
To evaluate the safety and tolerability in healthy 
females following single oral doses of LY3526318 

Treatment-emergent adverse events

Serious adverse events
To assess target engagement of TRPA1 after a single 
dose of LY3526318 using an alternate imaging method
Decrease in CA-induced DBF relative to placebo
measured by Laser Speckle Contrast Imaging (LSCI) at 
3 hours post-dose
To assess the pharmacokinetics of LY3526318
following single oral doses of LY3526318
Summary of LY3526318 plasma concentrations by 
dose and time point
Summary of Study Design, Treatment Arms and Planned Duration for an Individual Participant:
Study CVAB is a randomized, double-blind, placebo-controlled, 4-way crossover study of LY3526318 in healthy 
female participants.
All participants will have 2 screening visits with the first to evaluate the health of the participant and the second visit 
to undergo a laser Doppler imaging (LDI) assessment to ensure a response of at least 100% increase in DBF
between pre- and post-CA challenge. 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 assessments are completed on Day 2 of each 
dosing period. 
Each participant will be randomly assigned to receive 4 unique doses of study drug in a ratio of 
3 LY3526318: 1 placebo, in a crossover manner with at least 6 days of washout between doses. The planned dose 
levels of LY3526318 will be between 10 and 100 mg.

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The LDI and laser speckle contrast imaging (LSCI) assessment will be performed at approximately 3 hours and 24 
hours following study drug administration. The change in DBF before and after CA application will be compared 
between LY3526318 and placebo.
All participants will attend scheduled visits at the CRU for follow-up safety assessments.
Number of Participants:
Sufficient number of participants will be screened to achieve 16 randomized participants.
Statistical Analysis:
For the primary endpoint, summary statistics for each cohort will be provided by treatment. 
All participants who receive at least one dose of study drug and for whom the data are considered sufficient and 
interpretable will be included in the analyses. Additional exploratory analyses will be conducted as deemed 
appropriate. 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. 
Plasma concentration data will be summarized and may be combined with pharmacodynamic (PD) data and
pharmacokinetic (PK) data from Study CVAA, to perform population PK/PD analyses in order to inform the design 
of future studies. 

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2. Schedule of Activities

J2D-MC-CVAB(a) Clinical Protocol
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S
Treatment Period 1
Treatment Period 2
Treatment Period 3
Treatment Period 4
FU
EDd
Study Day
≤28
-1b
1
2
8
14b
15
16
22
28b
29
30
36
42b
43
44
50
-
Visit Window (days)
-
-
-
-
±1
-
-
-
±1
-
-
-
±1
-
-
-
±2
-
Visit
1a
2a
3c
4
5c
6
7c
8
9c
10
Admit to CRU
X
X
X
X
Discharge from CRU
X
X
X
X
CRU visit
X
X
X
X
X
X
X
Informed consent
X
Medical history
X
Height
X
Weight
X
X
X
X
Physical examination 
C
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
C
C
Urine drug screen and ethanol test
X
X
X
X
X
X
X
Hematology and clinical chemistry
X
P
24h
P
24h
P
24h
P
24h
X
X
Urinalysise
X
P
X
X
β-hCG pregnancy test
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
Vital signs including temperature
X
P and 3h
24h
P and 3h
24h
P and 3h
24h
P and 3h
24h
X
X
ECGf
X
P and 3h
24h
P and 3h
24h
P and 3h
24h
P and 3h
24h
X
X
Randomization
X
Study drug administrationg
X
X
X
X
PK blood sampleh
P and 3h
24h
X
P and 3h
24h
X
P and 3h
24h
X
P and 3h
24h
X
X
DBF by LDIa,i
X
DBF by LDI and LSCIi
P and 3h
24h
P and 3h
24h
P and 3h
24h
P and 3h
24h
AE / Con Med
X 
Abbreviations: AE = adverse events; C = compete physical examination; Con Med = concomitant medications CRU = clinical research unit; C-SSRS= Columbia-Suicide Severity Rating Scale;
D = directed physical examination; DBF = dermal blood flow; ECG = electrocardiogram; ED = early discontinuation; FU = safety follow-up; h = hour; LSCI = laser speckle contrast imaging;
LDI = laser Doppler imaging; P = pre-dose assessment; PK = pharmacokinetic; S = Screening.
Note: In the event that assessments are planned for the same time, assessments should be conducted in following order: LSCI DBF assessment, LDF DBF assessment, PK sample, and ECG/vital signs. 
The PK sample should be collected as soon as the LDI/LSCI DBF assessment is completed. The ECG and vital signs measurement should be obtained at least 30 minutes after the PK sample is 
drawn.

J2D-MC-CVAB(a) Clinical Protocol
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a
Screening visits will be performed within 28 days before the administration of first dose. All participants will have 2 screening visits with the first to evaluate the health of the participant and the 
second visit to undergo the LDI DBF assessment.
b
Can be performed on a day prior to dosing or pre-dose on day of dosing.
c
All participants will remain in the CRU until completion of all procedures that occur the day following each dose.
d
Participants who discontinue the study prior to study completion will complete the ED visit procedures.
e
A standard urine dipstick may be used.   
f
A single 12 lead ECGs will be obtained in the supine position after at least 10 minutes rest.
g
Study drug will be administered in a fasting state (8 hours pre-dose until 4 hours post-dose). The exact time study drug is administered will be recorded.
h
The timing of PK sample collections may be adjusted based on clinical needs. The exact sample collection dates and times must be recorded. 
i
All participants will have an LDI and LSCI procedure with cinnamaldehyde challenge to measure DBF at stipulated time points. The pre-dose measurement will include at least 30 minutes of 
acclimatization, followed by a dermal blood flow measurement, without cinnamaldehyde application. Each post-dose measurements will include at least 30 minutes of acclimatization, followed by a 
pre-cinnamaldehyde dermal blood flow measurement (about 10 minutes before cinnamaldehyde application). Next, cinnamaldehyde will be applied and a post-cinnamaldehyde measurement at 20 
minutes following the cinnamaldehyde application will be performed. The LDI assessment will be performed following completion of LSCI assessment.

J 2 D -M C -C V A B ( a) Cli ni c al Pr ot o c ol
P a g e 1 2
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
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 yrin 1 
( T R P A 1), a calci u m-per mea ble n o nselect i ve catio n c ha n nel, e x presse d b y  peri p heral 
pai n -se nsi n g n ocice pt ors, w hic h pla y a pi v otal r ole i n ge nerati on of pai n ( Maat uf
et al. 2 0 1 9). A 
n o ncli nical efficac y  phar mac o l og y  st u d y usi n g a f or mali 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 ociate d wit h ce ntral ner v o us s yste 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 rats , m o n ke ys, a n d i n vitr o s yste ms (see 
Secti o n 3. 2 ). 
As o n Se pte m ber 2 0 1 9 , L Y 3 5 2 6 3 1 8 or m atc hi n g place b o has bee n a d mi nistere d t o 4 0 healt h y 
parti ci pa nt s i n t he si n gle asce n di n g d ose (S A D ) p orti o n of  t he first-i n-h u ma n ( FI H ) st u d y 
J 2 D-M C -C V A A [ C V A A] . I n C V A A, si n gle L Y 3 5 2 6 3 1 8 d oses bet wee n 1 0 m g a n d 3 0 0 m g ha ve 
bee n f o u n d t o be safe a n d well t olerate d . T h is C V A B st u d y is i nte n de d t o de m o nstrate tar get 
e n ga ge me nt of T R P A 1 meas ure d b y der mal bl o o d fl o w ( D B F) res p o nse t o ci n na mal de h y de ( C A) 
wi t h L DI .
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 uality 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 ds are p ote nt b ut ca use se dati o n a n d ha ve 
a d dict i ve p ote ntial, 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 he r ol e of T R P A 1 i n pai n a n d i nfla m mat i on a n d its l ocalizat i on i n se ns or y ne ur o ns has 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). T R P A 1 a g o nists e v o ke 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 marti ni et al. 2 0 1 7; 
Maat uf
et al. 2 0 1 9; Wa n g
et al. 2 0 1 9). A d ditio nall y , t here is ge netic e vi de nce f or t he c o ntri b uti on 
of  T RP A 1 t o c hr o nic pai n (Kre me yer et al. 2 0 1 0).
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 safe t y ( O D M-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 di ores pirat 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 xi cit y/ muta ge nici t y batt er y justif ie d pr ocee di n g t o h u ma n cli nical st u dies.
A C N S safet y p har mac o l og y  st u d y in t he rat a n d a car dio vasc ular res pi r at 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 ndi 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 da y 
re peat-d osi n g st u d y i n m o n ke ys ( St u d y  # 0 0 9 2 6 0 4 4
C CI
; hi g hest d ose was 1 0 0 0 m g/ k g/ da y). 
 
 

J 2 D -M C -C V A B ( a) Cli ni c al Pr ot o c ol
P a g e 1 3
L Y 3 5 2 6 3 1 8
 
O n g o i n g re vie w of t he bli n de d data fr o m t he C V A A st u d y  i n dicate d t hat si n gle oral d oses of 
L Y 3 5 2 6 3 1 8 or place b o at stu die d d ose le vels ( 1 0, 5 0, 1 0 0, 2 0 0 a n d 3 0 0 m g) were safe a n d well 
t olerate d. A ll re p orte d a d verse e ve nts ( A Es) were n o nseri o us a n d mil d i n se verity . N o cli nicall y 
sig nifica nt o bser vat i ons were re p orte d i n cli nical la b orat or y , vit al si g ns, a n d electr ocar dio gr a m  
(E C G ) data. Si n gle d ose a d mi nistrati o n of  L Y 3 5 2 6 3 1 8 i n t he 1 0 t o 3 0 0 m g d ose ra n ge res ulte d i n 
meas ura ble L Y 3 5 2 6 3 1 8 c o nce ntrati o n s.
3. 3.
B e n efit/ Ri s k A s s e s s m e nt
 
N o cli nicall y  sig nifica nt safet y or t ol era bilit y c o ncer ns ha ve bee n i de ntifie d i n fe male 
parti ci pa nts i n St u d y C V A A u p t o t he hi g hest si n gle d ose a d mi nistere d (3 0 0 m g ).
T his st u d y  is bei n g c o n d ucte d pri or t o n o n- cli nical e val uat i ons assessi n g t he ris k of
de vel o p me ntal a n d re pr o d ucti ve t o xicit y b y L Y 3 5 2 6 3 1 8 a n d its acti ve meta b o lite, M 6.  W o me n
of  c hil d-beari n g p ote ntial ( W O C B P) c o uld bec o me  preg na nt d uri n g t he st u d y , a n d t h us e x p ose
t he msel ves a n d t heir c o nce pt us t o L Y 3 5 2 6 3 1 8 a n d its meta b o lite M 6 at l e vels w here effects are 
u n k n o w n .  H o we ver, t hese ris ks are miti gate d b y n o n-cli nical e val uati o ns a n d cli nical st u d y 
desi g n . St u dies i n t w o a ni mal s pecies t hat eac h were 2 8 -da y re peat d ose desi g ns ac hie vi n g hi g her 
c o nce ntrati o ns t ha n pla n ne d f or t his cli nical st u d y , i de ntifie d n o a d verse effects o n fe male 
or ga ns.  T he ris k of har m t o a c o nce pt us is mi ni mize d d uri n g t he earl y sta ges of pre g na nc y base d
o n i n vitr o tests f or ge n ot o xicity a n d muta ge nicit y t hat s h o we d n o effects b y L Y 3 5 2 6 3 1 8 a n d 
M 6.
Cli nical l y, W O C B P m ust a d here t o hi g hl y  effecti ve c o ntrace ptio n a n d will be m o ni t ore d t o 
e xcl u de pre g na nc y i ncl u di n g d o c u m e ntatio n of  t he partici pa nts last me nstr ual  p erio d a n d a 
ne gat i ve pre g na nc y test as per Sc he d ule of Act i vities ( Sectio n 2 ).
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 Es of L Y 3 5 2 6 3 1 8, al o n g wit h s afet y data fr o m C V A A st u d y , is 
pr o vi de d i n t he I n vest i gat or’s Br oc h ure (Lill y 2 0 1 9 ).
A d dit i onal i nf or mati o n o n scie ntific rati onale 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.
C CI

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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
To assess target engagement of TRPA1 after a single 
dose of LY3526318
Decrease in CA-induced dermal blood flow (DBF)
relative to placebo measured by laser Doppler imaging 
(LDI) at 3 hours post-dose
Secondary
To evaluate the safety and tolerability in healthy 
females following a single oral dose of LY3526318 
Treatment-emergent adverse event
Serious adverse event
To assess target engagement of TRPA1 after a single 
dose of LY3526318 using an alternate method
Decrease in CA-induced DBF relative to placebo
measured by laser speckle contrast imaging (LSCI) at 3 
hours post-dose
To assess the pharmacokinetics of LY3526318
following single oral doses of LY3526318
Summary of LY3526318 plasma concentrations by 
dose and time points
Exploratory
To assess target engagement of TRPA1 after a single 
dose of LY3526318
Decrease in CA-induced DBF relative to placebo 
measured by LDI at 24 hours post-dose
Decrease in CA-induced DBF relative to placebo 
measured by LSCI at 24 hours post-dose
To explore the relationship between LY3526318 
plasma concentration and DBF in healthy females 
following a single oral LY3526318 dose
LY3526318 plasma concentrations
DBF

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5. Study Design
5.1.
Overall Design
This is a Phase 1 randomized, double-blind, placebo-controlled, 4-way crossover study of 
LY3526318 in healthy female participants.
All participants will have 2 screening visits with the first to evaluate the health of the participant
and the second visit to undergo a laser Doppler imaging (LDI) assessment to ensure a response 
of at least 100% increase in DBF between pre- and post-CA challenge. 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 assessments are completed on Day 2 of each dosing period.
As summarized in Table 5-1, each participant will be randomly assigned to 1 of 4 treatment 
sequences, with a ratio of 3 LY3526318: 1 placebo. Each participant will receive 3 doses of 
LY3526318 and 1 dose of placebo in a crossover manner, with at least 6 days of washout 
between doses. The planned dose levels of LY3526318 are anticipated not to exceed the 
maximum administered dose in the SAD portion of Study CVAA.
Table 5-1
Treatment Sequence
Sequence
Period 1
Period 2
Period 3
Period 4
P132 (n=4)
P
D1
D3
D2
12P3 (n=4)
D1
D2
P
D3
231P (n=4)
D2
D3
D1
P
3P21 (n=4)
D3
P
D2
D1
Abbreviations: D= LY3526318 dose; n = number of participants; P = placebo.
The LDI and laser speckle contrast imaging (LSCI) assessments will be performed at timepoints 
provided in Schedule of Activities (Section 2). The change in DBF before and after CA
application will be compared between LY3526318 and placebo (refer to Section 9.6.1 for further 
details on DBF assessment).
All assessments will be performed as defined in Schedule of Activities (Section 2). 
All participants will attend a safety follow-up visit about 7 days following the last dose of study 
drug.
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Sufficient number of participants will be screened to achieve 16 randomized participants.
For purposes of this study, a participant completes the study when all scheduled procedures 
shown in the Schedule of Activities (Section 2) have been finished.
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.

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5.4.
Scientific Rationale for Study Design
LY3526318 is a small molecule TRPA1 inhibitor.  TRPA1 mediates neurogenic vasodilation and 
both TRPA1 channels and neurogenic vasodilation are activated by topical CA application. This 
study will assess the pharmacodynamic effects of LY3526318 following administration of single 
LY3526318 doses. In response to TRPA1 inhibition by LY3526318, the DBF increase induced 
by topical application of CA and measured by LDI and LSCI is anticipated to be reduced. Non-
clinical pharmacology studies have demonstrated target engagement of other TRPA1 antagonists 
through changes in DBF for TRPA1 activation and antagonism (Aubdool et al. 2016).  The use 
of two methods to measure reactive blood flow in the skin provides complementary information 
(Millet et al. 2011) improving the ability to translate preclinical LDI and pain reduction data to 
clinical data.
No SAEs are expected because doses of LY3526318 in this study were previously shown to be 
safe and tolerable in Study CVAA. In addition, topical application of CA has been shown to be 
safe and well tolerated in prior clinical studies (Buntinx et al. 2017).
5.5.
Justification for Dose
The doses administered in this study will not exceed the maximum dose administered in the SAD 
portion of Study CVAA; which was found to be safe and well tolerated in healthy participants.
The proposed doses for this study are anticipated to be in the target engagement dose range, 
while providing the maximum achievable safe LY3526318 exposure, to address the study 
objectives.

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6. Study Population
Eligibility of participants for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment. If the time of screening and 
randomization is prolonged to greater than 28 days, the extent of rescreening will be discussed 
between the investigator and sponsor.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are 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. Healthy female participants as determined by medical history and physical examination.
a.
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)
b. Nonpregnancy will be confirmed for all female participants through a serum 
pregnancy test at screening, at (each) admission to the CRU and, at other time points
specified in the Schedule of Activities (Section 2). Follicle-stimulating hormone will 
be tested at screening for all female participants.
c.
Healthy female participants of child-bearing potential who have a fertile male sexual 
partner must be willing and able to practice effective contraception from screening 
visit ≤ 28 days to 30 days after the final visit. 
d. Sexually active participants must use a combination of 2 of the following methods of 
contraception, including so called 'barrier' methods:
i. Hormonal contraceptive associated with inhibition of ovulation (oral, 
transdermal patches, vaginal or injectable)
ii. Intrauterine device with or without hormones
iii. Condom, diaphragm or cervical cap ('barrier' methods)
Contraceptive requirements do not apply for participants who are sexually abstinent or
exclusively in same-sex relationships.

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2. Have given written informed consent, approved by the sponsor and the Institutional Review 
Board (IRB) governing the site, prior to any study-specific procedures 
3. Aged 18 to 45 years, inclusive.
4. Have a body-mass index of 18 to 30 kg/m2, inclusive.
5. Are reliable and willing to make themselves available for the duration of the study.
6. Are willing to follow CRU specific study procedures including, 
a.
no drugs (except study drug, hormonal contraceptives) 7 days prior to each DBF
assessment and until discharge from CRU;
b. no chocolate, alcohol, or caffeine containing products 24 hours prior to initiation of 
each DBF assessment and until discharge from CRU;
c.
a complete 4 hour fast (water is allowed) prior to initiation of each DBF assessment.
7. Have suitable skin characteristics for the dermal CA challenge (as determined by CRU-staff 
judgment) and have demonstrated at least a 100% increase in dermal flow following CA
challenge as part of the screening procedures and measured through LDI.
8. 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:
1. Are male. 
2. Are currently enrolled in or discontinued within the last 30 days or 5 half-lives of the study 
drug (whichever is longer), from 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.
3. Have received treatment with biological agents (such as monoclonal antibodies, including 
marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to dosing.
4. Have previously completed or withdrawn from this study or any other study investigating 
this study drug.
5. 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.
6. 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  >470 msec  One repeat ECG may be 
performed if required.
7. Have a history of clinically significant multiple or severe drug allergies or severe 
post-treatment hypersensitivity reactions, which in the opinion of the investigator may 
hamper participation in the study.
8. Are 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. 
9. Are Eli Lilly and Company (Lilly) employees or contractors or an immediate family member 
of employees or contractors.
10. 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.
11. Have donated blood of more than 500 mL within the previous month.
12. Have an abnormal blood pressure (supine) defined as a diastolic blood pressure >90 or 
<50 mmHg and/or a systolic blood pressure >140 or <90 mmHg. 
13. A history of drug abuse which, in the opinion of the investigator, is clinically significant or 
who test positive for drugs of abuse at screening or admission.
14. Cannot avoid excessive tanning (any exposure to sunlight or a tanning bed which would 
cause a sunburn reaction) throughout the study and cannot cover forearm for 24 hours prior 
to each treatment period.
15. Use lotions, oils, depilatory preparations, makeup, or other topical treatments on the arms on 
a regular basis, which cannot be discontinued for the duration of the study. Participants who 
have used any topical treatments within 7 days prior to CA application will not be enrolled in 
the study.
16. Are a habitual and heavy consumer of coffee or caffeinated beverages (more than 
approximately 4 cups of tea, coffee, or cola drinks/day). Participants who have reduced their 
consumption to a maximum of 4 cups of coffee/day at least 1 week prior to enrollment may 
participate. Participants who cannot refrain from caffeinated beverages 24 hours prior to CA
application will not be enrolled in the study.
17. Are unable to refrain from drinking alcohol 24 hours prior to each DBF assessment.
18. Cannot refrain from being around second-hand smoke 24 hours prior to CA application or 
use nicotine-containing products. Ex-smokers should have ceased smoking at least 6 months 
prior to screening.

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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
The participants need to undertake fasting 8 hours pre-dose until 4 hours post-dose (water is 
allowed). In addition, they also need to undertake fasting 4 hours (water is allowed) before each 
DBF assessment.
Standard meals, according to the CRU standard operating procedures, will be provided during 
the stay at the CRU. 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 chocolate, caffeine, and alcohol from 24 hours prior to 
each DB assessment until discharge from the CRU. At all other times, the participants will be 
instructed to abstain from drinking more than 2 alcoholic beverages per day. Caffeinated 
products are limited to no more than 4 consumptions per day.
Participants will need to refrain from being around second-hand smoke 24 hours prior to CA
application. Ex-smokers must have ceased smoking at least 6 months prior to screening. 
Smoking is not allowed during the study.
6.3.3. Activity
Participants must refrain from new strenuous exercise routines 5 days prior to each CRU 
confinement period and throughout their CRU stay. 
6.4.
Screen Failures
At screening and throughout the study, procedure/lab re-tests may be conducted at the discretion 
of the investigator and do not constitute a re-screen. 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 in a fasted state (8 hours pre-dose until 4 hours post-
dose; water is allowed).
Based on assigned treatment sequence, each participant will receive 3 doses of LY3526318
(between 10 mg and 100 mg) and 1 dose of placebo. Each dose will be separated by at least
6 days of washout period. 
All 4 doses of study drug will be administered by trained CRU personnel.
The LY3526318 drug product is supplied as a hard gelatin capsule in dosage strengths of 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

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
Eligible participants will be randomly assigned to a cohort and dosing sequence (Table 5-1). 
Each dosing sequence will determine the administration order of 3 doses of LY3526318 and 
1 dose of placebo.
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
The doses will be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the participant’s case report form (CRF).

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A trained CRU personnel will administer all doses of the study drug at CRU.
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.
Unblinding:  In case of an emergency, the investigator, or authorized designee, has the sole 
responsibility when unblinding of an individual participant occurs.  If the investigator, or 
authorized designee, determines unblinding of a participant’s treatment assignment is warranted 
for medical management of the event, documentation must include the actual study product, 
dose, date of unblinding, and signature of the investigator or authorized designee. 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
Dose modification is not allowed.
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.
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

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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 product.
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 CRF.
7.7.
Concomitant Therapy
No drugs will be allowed 7 days prior to each DBF assessment until discharge from CRU. 
Acetaminophen cannot be administered within 24 hours before each study drug administration.
If the need for concomitant medication 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:

Enrolment 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 or study conduct, 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 CRF. 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 CRF, the occurrence and nature of 
each participant’s preexisting conditions. 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 CRF.

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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 CRF 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 Global Patient Safety 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 investigator’s brochure and that the investigator reports as related to investigational 
product or procedure.  Lilly has procedures that will be followed for the recording and expedited 

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reporting of SUSARs that are consistent with global regulations and the associated detailed 
guidance.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
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).
9.4.2. Vital Signs
For each participant, vital signs 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 10 minutes before ECG collection and remain 
supine but awake during ECG collection. Electrocardiograms may be obtained at additional 
times, when deemed clinically necessary. 
In the event the assessments are planned for the same time, assessments should be conducted in 
following order: LSCI DBF assessment, LDI DBF assessment, PK sample, and ECG/vital signs.
The PK sample should be collected as soon as the LDI/LSCI DBF assessment is completed. The 

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ECG and vital sign measurement should be obtained at least 30 minutes after the PK sample is 
drawn. The exact time of each procedure will be recorded.
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 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. Safety Monitoring
The sponsor will monitor safety data throughout the course of the study periodically will review 
evolving aggregate safety data within the study through appropriate methods..
9.4.5.1.
Hepatic Safety
If a study participant experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatinine 
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 ≥5X ULN on two or more consecutive blood tests

elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests 

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
participant discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be a SAE.
9.5.
Pharmacokinetics
For all participants, blood samples of up to 3 mL each for the determination of the concentrations 
LY3526318 and metabolite(s) of interest 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. Pre-dose samples should be obtained between waking up and dosing. 
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.
Plasma 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.
9.6.
Pharmacodynamics
9.6.1. Dermal Blood Flow (DBF) Measurements by Laser Doppler 
Imaging (LDI) and Laser Speckle Contrast Imaging (LSCI)
Dermal blood flow will be measured at visits and time points as specified in the Schedule of 
Activities (Section 2).  All measurements for assessment should be performed while the 
participants are resting in a supine position on a comfortable bed in a quiet, ambient 
temperature-controlled room after at least 30 minutes acclimatization period. 
Measurements of DBF will be taken with or without the application of a reactive agent to the 
skin.  Based on the presumptive mechanism of action for LY3526318, CA will be used as the 
reactive agent to induce DBF.  
Two methods will be used to measure DBF at each time point: DBF measurements from LDI 
(PeriScan PIM 3 system, Perimed, Stockholm, Sweden) and LSCI (PeriCam PSI System, 
Perimed, Stockholm, Sweden). The LDI assessment will be performed following LSCI 
assessment. The screening LDI measurements will be used to determine study eligibility.
Given that an upper extremity (forearm) requires approximately 5-days to recover from a 
reactive DBF measurement, the schedule between the screening and first study drug 
administration should account for this frequency limitation.  During the first period, the 
extremity used for the first post-dose DBF measurements is chosen and the contralateral forearm 

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will be used for the 24-hour post-dose time point.  Subsequent study periods should use the same 
schedule of DBF based on forearm and time point.
During each visit (screening and study periods), each patient will undergo at least 30 minutes 
acclimatization and placement of 3 rubber O-rings on the volar surface of the forearm.  Prior to 
study drug administration, a pre-drug DBF will be collected without CA.  For each time point 
following study drug administration, pre-CA measurements will be performed for the areas 
defined by the rings within 10 minutes before CA application.  After the pre-CA measurements, 
a 20 µL topical dose of 10% CA will be applied in the proximal O-ring of the participant’s 
forearm. Using the same procedure, a 20 µL topical dose of 3% CA will be applied in the medial 
ring, followed by a 20 µL topical dose of the vehicle solution to the distal ring.  LDI/LSCI
measurements will again be performed approximately 20 minutes after CA and vehicle 
applications.  Specific details of the procedure will be agreed upon and documented between the 
sponsor and investigator and research staff operating the equipment.
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
10.1. Sample Size Determination
The sample size is justified based on the statistical power to meet the primary endpoint of DBF 
measurements from LDI assay at tmax. The power calculation used 10% CA-induced absolute 
DBF in comparison between LY3526318 and placebo arms. For a 20% reduction in DBF 
(assuming mean observed placebo DBF of 444.3 arbitrary perfusion units (PU) with standard 
deviation of 55.1 PU) and a significance level of 0.05, a paired t-test with 16 patients results in 
98% power to reject the null hypothesis. Incorporating a Bonferroni adjustment to account for 
multiplicity (changing the significance level to 0.05/3) lowers the power slightly to 96%. 
10.2. Populations 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, race, ethnicity, height, and weight) will be summarized by 
treatment.
10.2.3. Concomitant Medications
Concomitant medications will be listed.
10.3. Statistical 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 and PK/PD 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.
10.3.1. Safety Analyses
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. 

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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.
10.3.2. Pharmacokinetic Analyses
Pharmacokinetic data will be presented as LY3526318 and M6 plasma concentration summaries.
10.3.3. Pharmacodynamic Analyses
The primary endpoint is the percent change from pre-CA to CA-induced DBF as measured by 
LDI, compared to placebo at 3 hours post-dose. Summary statistics for each cohort will be 
provided by treatment. Mixed-effect model for repeated measure (MMRM) will be used to 
evaluate the primary endpoint including covariates such as treatment, period, carry-over, and 
sequence. Similar analyses will also be conducted for LDI at 24 hours post dose as well as DBF
outcomes as measured by LSCI (laser speckle contrast imaging) at 3 hours and 24 hours.
10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic and PD data may be combined with PK data from previous studies, to perform 
population PK/PD analyses in order to inform the design of future studies. 
10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly medical monitor or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.

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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 September 12, 2019.
Aubdool AA, Kodji X, Abdul-Kader N, et al. TRPA1 activation leads to neurogenic 
vasodilation: involvement of reactive oxygen nitrogen species in addition to CGRP and NO. 
Br J Pharamcol. 2016;173(15):2419-33.
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 
September 12, 2019.
Kremeyer B, Lopera F, Cox JJ, et al. A gain-of-function mutation in TRPA1 causes familial 
episodic pain symdrome. Neuron. 2010;66(5):671-80.
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.
Millet C, Roustit M, Blaise S, Cracowski JL. Comparison between laser speckle contrast 
imaging and laser Doppler imaging to assess skin blood flow in humans. Microvasc Res.
2011;82(2):147-51.

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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 
participant 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
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his 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
CA
cinnamaldehyde
CNS
central nervous system
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
DBF
dermal blood flow
enroll
The act of assigning a participant to a treatment.  Participants who are enrolled in the study 
are those who have been assigned to a treatment.
enter
Participants entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ECG
electrocardiogram
ED
early discontinuation
ERB
ethical review board
FIH
first-in-human
FU
safety follow-up
GCP
good clinical practice
HIV
human immunodeficiency virus

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IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
IND
Investigational New Drug:  An application to the FDA to allow testing of a new drug in 
humans.
informed consent
A process by which a participant voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are relevant 
to the participant’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
IRB
institutional review board
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
LSCI
laser speckle contrast imaging
LDI
laser Doppler imaging
randomize
the process of assigning participant to an experimental group on a random basis
PK/PD
pharmacokinetic/pharmacodynamic
SAD
single ascending dose
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
TBL
total bilirubin
TRPA1
Transient receptor protein ankyrin 1
ULN
upper limit of normal
WOCBP
woman 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
Alcohol breath test (ethanol)c
Urinalysis Dipstick
Urine Drug Screena
Specific gravity
Nicotine metabolites
pH
Amphetamine (including XTC)
Protein
Barbiturates
Glucose
Benzodiazepine
Ketones
Cannabinoids
Bilirubin
Cocaine
Urobilinogen
Methadone
Blood
Opiates
Nitrite
RBC and WBC counts
Hepatitis B surface antigen
Hepatitis C antibody
HIVb
FSH
Pregnancy Test (Serum, Quantitative β-hCG)
Abbreviations:  β-hCG =  beta subunit of human chorionic gonadotropin; FSH = follicle-stimulating hormone; HIV 
= human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
a
Urine drug screen may be repeated prior to admission to the clinical research unit and at other times indicated in 
the Schedule of Activities.  
b
Performed at screening only
c
Breath sample for ethanol test 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.
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.

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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 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 = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability

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Appendix 5. Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol J2D-MC- CVAB Sampling Summary
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
10
65
Pharmacokinetics 
3
16
48
Total (rounded-up)
125
a
Additional samples may be drawn if needed for safety purposes.

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Appendix 6. Protocol Amendment J2D-MC-CVAB(a) 
Summary
Protocol J2D-MC-CVAB has been amended in response to queries raised by Federal Agency for 
Medicines and Health Products (FAMHP), Belgium. The new protocol is indicated by 
Amendment (a), dated 15 Nov 2019, 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 # and Name
Description of Change
Brief Rationale
6.1. Inclusion Criteria
Contraception language changed 
(Criterion 1.d.i) per 
‘Recommendations related to 
contraception and pregnancy testing 
in clinical trials of the Clinical Trial 
Facilitation Group (CTFG)’
Criterion updated in response to 
FAMHP query.  
Revised Protocol Sections
6.1. Inclusion Criteria
1. Healthy female participants as determined by medical history and physical examination.
a.
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)
b. Nonpregnancy will be confirmed for all female participants through a serum 
pregnancy test at screening, at (each) admission to the CRU and, at other time points 
specified in the Schedule of Activities (Section 2). Follicle-stimulating hormone will 
be tested at screening for all female participants.
c.
Healthy female participants of child-bearing potential who have a fertile male sexual 
partner must be willing and able to practice effective contraception from screening 
visit ≤ 28 days to 30 days after the final visit. 
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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d. Sexually active participants must use a combination of 2 of the following methods of 
contraception, including so called 'barrier' methods:
i. Hormonal contraceptive associated with inhibition of ovulation (oral, 
transdermal patches, vaginal or injectable)
ii. Intrauterine device with or without hormones
iii. Condom, diaphragm or cervical cap ('barrier' methods)
Contraceptive requirements do not apply for participants who are sexually abstinent or 
exclusively in same-sex relationships.

Leo Document ID = 36fbadb3-6a3d-466d-93b0-69a2e8274c2d
Approver: 
Approval Date & Time: 15-Nov-2019 15:45:35 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 15-Nov-2019 16:37:06 GMT
Signature meaning: Approved