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

Protocol: J2D-MC-CVAC (c) 
 
A Safety, Tolerability and Pharmacokinetic Study of Single and Multiple Doses of LY3526318 in 
Healthy Participants 
 
NCT04682119 
Approval Date: 11-Mar-2021 

CONFIDENTIAL
Protocol J2D-MC-CVAC (c)
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Title Page
Confidential Information
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3526318, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: A Safety, Tolerability and Pharmacokinetic Study of Single and Multiple Doses 
of LY3526318 in Healthy Participants
Protocol Number: J2D-MC-CVAC
Amendment Number: c
Compound: LY3526318
Study Phase: 1
Short Title: A Safety, Tolerability, PK and Pilot Food Effect Study of LY3526318 in Healthy 
Participants
Acronym: CVAC
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA 46285
Regulatory Agency Identifier Number
EudraCT: 2020-004290-46
Approval Date: Protocol J2D-MC-CVAC (c) Electronically Signed and Approved by 
Lilly on date provided below.
Approval Date: 11-Mar-2021 GMT

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Protocol J2D-MC-CVAC (c)
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Medical monitor name and contact information will be provided separately.

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Protocol J2D-MC-CVAC (c)
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment (b)
15 February 2021
Amendment (a)
08 December 2020
Original Protocol
19 October 2020
Amendment (c)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment:
This amendment incorporates changes to allow for a high-fat meal or a light breakfast in the fed 
state to understand the effect of meal types on exposure. This amendment also corrects 
typographical errors.
Section # and 
Name
Description of Change
Brief Rationale
Sections 1.1, 4.1
5.3.1, and 6.1
Amended text to allow for a high-fat 
meal or a light breakfast in the fed 
state.
To allow for testing the effect of meal type on the 
PK of LY3526318.
Section 5.3.1
Revised text to clarify the meal 
schedule for Part B.
Clarification
Section 6.1
Revised wording in Part B regarding 
review of data from Part A dosing to 
align with text in Section 4.1.
Consistency
Abbreviation: PK = pharmacokinetics.

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Protocol J2D-MC-CVAC (c)
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Table of Contents
1.
Protocol Summary......................................................................................................7
1.1.
Synopsis.......................................................................................................................7
1.2.
Schema.......................................................................................................................10
1.3.
Schedule of Activities.................................................................................................11
2.
Introduction..............................................................................................................17
2.1.
Study Rationale ..........................................................................................................17
2.2.
Background ................................................................................................................17
2.3.
Benefit/Risk Assessment ............................................................................................18
3.
Objectives and Endpoints.........................................................................................19
4.
Study Design .............................................................................................................20
4.1.
Overall Design............................................................................................................20
4.2.
Scientific Rationale for Study Design .........................................................................21
4.3.
Justification for Dose..................................................................................................21
4.4.
End of Study Definition..............................................................................................22
5.
Study Population ......................................................................................................23
5.1.
Inclusion Criteria........................................................................................................23
5.2.
Exclusion Criteria.......................................................................................................24
5.3.
Lifestyle Considerations .............................................................................................26
5.3.1.
Meals and Dietary Restrictions ...................................................................................26
5.3.2.
Caffeine, Alcohol, and Tobacco..................................................................................26
5.3.3.
Activity ......................................................................................................................27
5.4.
Screen Failures...........................................................................................................27
6.
Study Intervention....................................................................................................28
6.1.
Study Intervention(s) Administered ............................................................................28
6.2.
Preparation/Handling/Storage/Accountability.............................................................28
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................29
6.3.1.
Method of Treatment Assignment...............................................................................29
6.3.2.
Selection and Timing of Doses ...................................................................................29
6.4.
Study Intervention Compliance...................................................................................30
6.5.
Concomitant Therapy .................................................................................................30
6.6.
Dose Modification......................................................................................................30
6.6.1.
Dose Escalation ..........................................................................................................30
6.7.
Intervention after the End of the Study........................................................................31
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................32
7.1.
Discontinuation of Study Intervention ........................................................................32
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................33
7.2.1.
Discontinuation of Inadvertently Enrolled Participants ...............................................33
7.3.
Lost to Follow-up .......................................................................................................34
8.
Study Assessments and Procedures .........................................................................35
8.1.
Efficacy Assessments .................................................................................................35
8.2.
Safety Assessments ....................................................................................................35

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8.2.1.
Physical Examinations................................................................................................35
8.2.2.
Vital Signs..................................................................................................................35
8.2.3.
Electrocardiograms.....................................................................................................36
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................36
8.2.5.
Safety Monitoring.......................................................................................................37
8.3.
Adverse Events and Serious Adverse Events ..............................................................38
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................38
8.3.2.
Method of Detecting AEs and SAEs ...........................................................................39
8.3.3.
Follow-up of AEs and SAEs.......................................................................................39
8.3.4.
Regulatory Reporting Requirements for SAEs............................................................39
8.3.5.
Pregnancy...................................................................................................................39
8.3.6.
Product Complaints ....................................................................................................40
8.4.
Treatment of Overdose ...............................................................................................41
8.5.
Pharmacokinetics........................................................................................................41
8.5.1.
Bioanalysis .................................................................................................................41
8.6.
Pharmacodynamics.....................................................................................................42
8.7.
Genetics .....................................................................................................................42
8.8.
Biomarkers.................................................................................................................42
8.9.
Immunogenicity Assessments.....................................................................................42
8.10.
Health Economics.......................................................................................................42
9.
Statistical Considerations.........................................................................................43
9.1.
Statistical Hypotheses.................................................................................................43
9.2.
Sample Size Determination.........................................................................................43
9.3.
Populations for Analyses ............................................................................................43
9.3.1.
Study Participant Disposition......................................................................................43
9.3.2.
Study Participant Characteristics.................................................................................43
9.4.
Statistical Analyses.....................................................................................................43
9.4.1.
Safety Analyses ..........................................................................................................44
9.4.2.
Pharmacokinetic Analyses ..........................................................................................44
9.4.3.
Other Safety Analyses ................................................................................................45
9.5.
Interim Analyses.........................................................................................................45
9.6.
Data Monitoring Committee .......................................................................................45
10.
Supporting Documentation and Operational Considerations ................................46
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................46
10.1.1.
Regulatory and Ethical Considerations........................................................................46
10.1.2.
Financial Disclosure ...................................................................................................46
10.1.3.
Informed Consent Process ..........................................................................................47
10.1.4.
Data Protection...........................................................................................................47
10.1.5.
Data Quality Assurance ..............................................................................................47
10.1.6.
Source Documents......................................................................................................48
10.1.7.
Study and Site Start and Closure.................................................................................49
10.1.8.
Publication Policy.......................................................................................................49
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................50
10.2.1.
Blood Sampling Summary..........................................................................................52

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................53
10.3.1.
Definition of AE.........................................................................................................53
10.3.2.
Definition of SAE.......................................................................................................54
10.3.3.
Recording and Follow-Up of AE and/or SAE .............................................................55
10.3.4.
Reporting of SAEs......................................................................................................57
10.4.
Appendix 4: Contraception Guidance for Men and Women ........................................58
10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................62
10.6.
Appendix 6: List of Excluded Concomitant Medications ............................................63
10.7.
Appendix 7: Abbreviations .........................................................................................66
11.
References.................................................................................................................69

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Protocol J2D-MC-CVAC (c)
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Safety, Tolerability and Pharmacokinetic Study of Single and Multiple Doses 
of LY3526318 in Healthy Participants
Short Title: A Safety, Tolerability, PK and Pilot Food Effect Study 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 healthy participant experience and 
preclinical evidence for TRPA1 antagonism in the alleviation of chronic pain. 
In the Phase 1 study, J2D-MC-CVAA (CVAA), LY3526318 was well-tolerated at all doses. 
Single doses up to 300 mg and multiple doses (MDs) of 100 mg daily for 14 days were 
administered. Plasma exposure increased with increasing doses of up to 100 mg but did not 
increase further at doses of 200 or 300 mg. The lowest animal-toxicology no-observed-adverse-
effect level (NOAEL) is approximately 3-fold higher than the higher human exposures achieved 
in Study CVAA. There were no serious adverse events (SAEs) observed in Study CVAA.
There was a high degree of interindividual variability in LY3526318 pharmacokinetics (PK).
When a meal was consumed near the time of dosing, LY3526318 maximum observed drug 
concentration (Cmax) and area under the concentration versus time curve from time zero to 24 
hours post dose (AUC0-24) decreased by approximately 80% and 86%, respectively. These 
exposure limitations are likely due to a conversion from a more soluble to a less soluble crystal 
form of LY3526318 in the gastrointestinal (GI) tract prior to absorption.
 
 
 
Study J2D-MC-CVAC (CVAC) will evaluate the PK parameters of the new LY3526318 
formulation in healthy participants after oral administration and includes a single-ascending-dose 
(SAD) portion (fasted and fed) (Part A) and a 5-day MD portion (Part B). The initial single dose 
level is 100 mg, the dose that produced maximum exposure in Study CVAA (56 µg·h/mL). Up 
to 2 additional single dose levels may be administered; these doses would be selected to maintain 
human exposure below the lowest animal-toxicology NOAEL (154 µg·h/mL, established in a 
1-month monkey study). Up to two of the single doses that were administered in a fasted state 
may also be administered in a fed state (a high-fat meal or a light breakfast), to determine if food 
affects LY3526318 PK when administered in the new formulation. Additionally, one of the 
single doses will be administered daily for 5 days to assess safety and exposure.
CCI

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Protocol J2D-MC-CVAC (c)
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Objectives and Endpoints
Objective
Endpoints
Primary (Part A – SAD)

To determine the pharmacokinetics of 
LY3526318 after a single oral dose 
administration

AUC

Cmax
Primary (Part B – MD)

To determine the pharmacokinetics of 
LY3526318 after multiple oral dose 
administrations 

AUC

Cmax
Secondary (Part A – SAD)

To estimate the safety and tolerability 
of LY3526318 after single (Part A) 
oral administration to healthy 
participants

To evaluate the effect of a meal on the 
pharmacokinetics of LY3526318 in 
fed versus fasted conditions

AEs 

SAEs

Cmax

tmax

AUC
Secondary (Part B – MD)

To estimate the safety and tolerability 
of LY3526318 after multiple oral 
administrations to healthy participants

AEs 

SAEs
Abbreviations: AE = adverse event; AUC = area under the concentration versus time curve; Cmax = maximum 
observed drug concentration; MD = multiple dose; SAD = single-ascending dose; SAE = serious adverse event; 
tmax = time to Cmax.
Overall Design
Study CVAC is a Phase 1, randomized, double-blind, placebo-controlled, SAD (Part A) and MD
(Part B) study of LY3526318 in healthy participants.
Disclosure Statement: This is a 2-part study with 2 arms (LY3526318:Placebo) that are 
participant and investigator blinded.
Number of Participants:
A maximum of 16 healthy male or female participants will be enrolled. Due to the relatively 
small size of the study, participants who discontinue may be replaced. 

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Protocol J2D-MC-CVAC (c) 
 
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Intervention Groups and Duration: 
Part A - SAD 
The SAD of LY3526318 or placebo will be administered, beginning at a dose of 100 mg, the 
dose level that produced the highest exposure in Study CVAA. A single cohort of 8 healthy 
participants will be randomized to a sequence in which LY3526318 or placebo will be 
administered in a 3:1 ratio. In each dosing period, different participants will receive placebo. In 
this adaptive dose study, subsequent dose levels will be selected based on safety and PK. Doses 
will be selected to maintain geometric mean AUC0-24 below the lowest NOAEL from animal-
toxicology studies (154 µg·h/mL).  
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.  
Sentinel dosing is not planned as this is not the first clinical study for LY3526318. Dose 
escalations to subsequent cohorts may occur at approximately 2-week intervals after review of 
safety data and available PK data through 24 hours post dose from at least 4 participants on 
active drug from the prior period. Of the 4 treatment periods planned for Part A, up to 3 single 
dose levels will be assessed in a fasted state (fasting at least 8 hours prior to and at least 4 hours 
after dosing). Up to two of these dose levels that were assessed in a fasted state may also be 
assessed in a fed state (a high-fat meal or a light breakfast 30 minutes prior to dosing). 
Participants will return to the CRU for a final follow-up visit approximately 10 days after the 
final study intervention administration. 
Part B - MD 
LY3526318 or placebo will be administered daily for up to 5 days at a dose level not to exceed 
the highest dose used in Part A. Part B will begin following a review of Part A safety and PK 
data. Participants will be confined to the CRU throughout this 5-day dosing period and for an 
additional 72 hours for PK sampling. Eight treatment-naïve participants will be randomized to 
receive LY3526318 or placebo in a 3:1 ratio. Part B will involve dosing in a fasted or fed state 
(e.g., standard meal or a light breakfast as described in site-specific manual) depending on the 
results from Part A. The dose regimen and fed/fasting will be selected with the intent not to 
exceed the AUC0-24 achieved in Part A.  
Participants will return to the CRU for a final visit on Day 14. 
Data Monitoring Committee: No 
 
 

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Protocol J2D-MC-CVAC (c)
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1.2.
Schema
Figure 1.1.
Study diagram.
Abbreviations: N = number of participants; n = number of participants in specific population; SAD = single 
ascending dose.
Figure 1.2.
Study treatments for the SAD and MD cohorts.

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Protocol J2D-MC-CVAC (c)
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1.3.
Schedule of Activities
Table 1.
Study Schedule Protocol J2D-MC-CVAC Single-Ascending Dose (SAD) – Part A 
S
Treatment Perioda
FU
EDb
Visit
1
2
3
4
5
Study Day
-28
-1c
1
2
3
4
5
10 (±1 day)
Admit to CRUd
X
Discharge from CRU
Xe
CRU visit
X
X
Xe
Xe
X
X
Informed consent
X
Medical history
X
X
C-SSRS
X
X
X
X
Height
X
Weight
X
X
X
X
Physical examination 
C
D
D
D
D
D
D
D
D
Urine drug screen 
X
X
X
X
Hematology and clinical 
chemistry
X
P
X
X
X
X
Urinalysisf
X
X
P
X
X
X
X
β-hCG pregnancy test
X
X
X
X
HIV, HCV, HBsAg
X
Con med
X
X
X
X
X
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
P, 2, 4, 6 h
X
X
X
X
X
X
Temperature
X
X
ECGg
See Table 2
Randomization
X
Study intervention
administrationh
X
PK blood samplei
See Table 2

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Protocol J2D-MC-CVAC (c)
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Abbreviations: C = complete physical examination; Con med = concomitant medications; COVID-19 = coronavirus disease 2019; CRU = clinical research unit; 
C-SSRS= Columbia-Suicide Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; FU = safety 
follow-up; HBsAg = hepatitis B surface antigen; β-hCG = beta subunit of human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; P = predose assessment; PK = pharmacokinetic; S = Screening; SOP = standard operating procedure.
Note: In the event that assessments are planned for the same time, assessments should be conducted in following order: ECG/vital signs/ PK sample The ECG 
and vital signs measurement can be obtained at least 30 minutes prior to the PK sample, which is drawn at the nominal time point.
Screening visits will be performed within 28 days before the administration of first dose.
a
The procedures for Days -1 through 5 will be repeated for up to 4 treatment periods.
b
Participants who discontinue the study prior to study completion will complete the ED visit procedures.
c
Day -1 procedures can be performed on a day prior to dosing or pre-dose on day of dosing.
d
All participants will remain in the CRU until completion of all procedures that occur that day. 
e
After participants have completed the required in-house stay, the remaining activities may be completed in house or ambulatory based upon the discretion of 
the investigator.
f
A standard urine dipstick may be used.
g
See Table 2. Triplicate 12-lead ECGs will be obtained with approximately 1 minute apart following at least 10 minutes in the supine position. Single 12-lead 
ECGs will be collected at the time points indicated.
h
The exact time that study intervention is administered will be recorded.
i
See Table 2.
Note: All local requirements regarding COVID-19 will be followed according to local/site SOP.

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Protocol J2D-MC-CVAC (c)
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Table 2. Scheduled Timesb for PK Blood Sample and ECG for Periods 1 to 4
Daya
Timeb
ECG (Fasted)
ECG (Fed)
PK Sample Periods 1-4
Day -28 to -1
Screening
Single ECG
Day 1
Predose
ECGc
Single ECG
X
Dose
Dose of LY3526318
1 h
X
2 h
ECGc
X
4 h
ECGc
X
6 h
ECGc
X
8 h
X
12 h
X
Day 2
24 h
ECGc
X
Day 3
48 h
X
Day 4
72 h
X
Day 5
96 h
X
Follow-up visit
Single ECG
Single ECG
X
Early 
Discontinuation 
Single ECG
Single ECG
X
Abbreviations: ECG = electrocardiogram; PK = pharmacokinetic.
a    The procedures for Days -1 through 5 will be repeated for up to 4 treatment periods.
b
Sampling times are given as targets to be achieved within reasonable limits. The timing of PK sample collections 
may be adjusted based on clinical needs. The exact sample collection dates and times must be recorded.
c
Following at least 10 minutes in a supine position, triplicate ECG are collected with approximately 1 minute
between measurements.

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Protocol J2D-MC-CVAC (c)
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Table 3.
Study Schedule Protocol J2D-MC-CVAC Multiple Dose (MD) – Part B
S
Treatment Period
FU
EDa
Visit
1
2
3
Study Day
-28
-1b
1
2
3
4
5
6
7
8
14
Admit to CRUc
X
Discharge from CRU
Xd
CRU visit
X
X
X
X
Informed consent
X
Medical history
X
X
C-SSRS
X
X
X
X
Height
X
Weight
X
X
X
X
Physical examination 
C
D
D
D
D
D
D
D
D
D
D
D
Urine drug screen
X
X
X
X
Hematology and clinical 
chemistry
X
P
P
P
P
X
X
X
X
X
Urinalysise
X
X
P
X
X
X
X
X
X
X
X
β-hCG pregnancy test
X
X
X
X
HIV, HCV, HBsAg
X
Con med
X
X
X
X
X
X
X
X
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
P and 4 h
X
X
X
X
X
X
X
X
X
Temperature
X
X
ECGf
See Table 4
Randomization
X
Study intervention
administrationg
X
X
X
X
X
PK blood sampleh
See Table 4
Abbreviations: C = complete physical examination; Con med = concomitant medications; COVID-19 = coronavirus disease 2019; CRU = clinical research unit; 
C-SSRS= Columbia-Suicide Severity Rating Scale; D = directed physical examination; ECG = electrocardiogram; ED = early discontinuation; FU = safety 
follow-up; HBsAg = hepatitis B surface antigen; β-hCG = beta subunit of human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; P = predose assessment; PK = pharmacokinetic; S = Screening; SOP = standard operating procedure.
a
Participants who discontinue the study prior to study completion will be expected to complete the ED visit procedures.

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Protocol J2D-MC-CVAC (c)
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b
Day -1 procedures can be performed on a day prior to dosing or predose on day of dosing.
c
Participants will be confined to the CRU from Day -1 until all study assessments are completed 72 hours after the last dose
d
After participants have completed the required in-house stay, the remaining activities may be completed in house or ambulatory based upon the discretion of 
the investigator.
e
A standard urine dipstick may be used.
f
A single 12-lead ECG will be obtained in the supine position after at least 10 minutes rest.
g
The exact time study intervention is administered will be recorded.
h
See Table 4 Part B Scheduled Times for PK Blood Samples.
Note: Screening visits will be performed within 28 days before the administration of first dose.
Note: In the event that assessments are planned for the same time, assessments should be conducted in following order: ECG/vital signs/PK sample. The ECG 
and vital signs measurement can be obtained at least 30 minutes prior to the PK sample, which is drawn at the nominal time point.
Note: All local requirements regarding COVID-19 will be followed according to local/site SOP.

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Protocol J2D-MC-CVAC (c)
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Table 4.
Part B Scheduled Times for PK Blood Samples and Single 12-lead ECGs
Day
Timea
PK Collectionsb
ECG
(fasted)
ECG
(fed)
Day 1
Predose
X
X
X
Dose
Dose of LY3526318
1 h
X
2 h
X
X
4 h
X
X
X
6 h
X
X
X
8 h
X
12 h
X
Day 2
Predose (24 hours after the preceding dose)
X 
X
X
Dose
Dose of LY3526318
Day 3
Predose (24 hours after the preceding dose)
X
Dose
Dose of LY3526318
Day 4
Predose (24 hours after the preceding dose)
X
Dose
Dose of LY3526318
Day 5
Predose (24 hours after the preceding dose)
X
X
X
Dose
Dose of LY3526318
1 h
X
2 h
X
X
4 h
X
X
X
6 h
X
X
X
8 h
X
12 h
X
Day 6
+24 h (24 hours after the preceding dose)
X
X
X
Day 7
+ 48 h
X
Day 8
+72 h
X
Follow-Up
X
Early 
Discontinuation
X
X
X
Abbreviations: ECG = electrocardiogram; PK = pharmacokinetic.
a
Sampling times are given as targets to be achieved within reasonable limits.
b
The timing of PK sample collections may be adjusted based on clinical needs. The exact sample collection dates 
and times must be recorded.

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Protocol J2D-MC-CVAC (c)
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2.
Introduction
2.1.
Study Rationale
Study CVAC is designed to evaluate safety, tolerability, and PK of oral LY3526318 in healthy 
participants when LY3526318 is administered as a new formulation. In a prior Phase 1 study 
(CVAA), exposure did not increase beyond that observed at 100 mg, and the concomitant food 
administration reduced exposure compared to the fasted state.
In this limited SAD study, a crossover design was chosen to limit the variability of PK, 
especially for the comparison of PK after fed and fasted conditions. Given treatment-emergent 
adverse events (TEAEs) were mild in the previous SAD and MD (to 14 days) studies, 
participants should be able to safely tolerate a maximum of 4 single doses with 14 days of 
washout between dosing periods. Placebo doses are included to assess TEAEs and limit bias. 
Similarly, given that a Phase 1 study was previously conducted, sentinel dosing is not necessary.
In addition, safety and PK will be assessed prior to each dose escalation to mitigate the 
possibility of more severe adverse events (AEs) and the PK exceeding the mean area under the 
concentration versus time curve (AUC) of the monkey NOAEL.
2.2.
Background
Chronic pain is a major health issue affecting the quality of life of millions of patients. 
Nonsteroidal anti-inflammatory drugs are the primary choice of drugs for chronic pain treatment; 
however, efficacy is limited in many patients. Opioids are potent but sedating and have addictive 
potential, relegating them to third- and fourth-line treatment options in chronic pain (Ko et al. 
2019). 
The role of TRPA1 in pain and inflammation and its localization in sensory neurons have been 
characterized (Bodkin and Brain 2011; Ückert et al. 2017). It evokes pain and an adverse 
response when administered exogenously (Berta et al. 2017; Demartini et al. 2017; Maatuf et al. 
2019; Wang et al. 2019). Additionally, there is genetic evidence for the contribution of TRPA1 
to chronic pain.
Transient receptor protein ankyrin-1 antagonists are undergoing evaluation in clinical trials, 
where there is evidence of efficacy and safety (ODM-108, NCT02432664 [NIH 2017]; GRC 
17536; EU Clinical Trial Register 2012-002320-33 [WWW]).
Two Phase 1 studies (CVAA and J2D-MC-CVAB [CVAB]) were conducted to assess 
tolerability and PK and to assess target engagement, respectively. Study CVAA included a SAD
portion, a 2-week multiple ascending dose portion achieving maximum doses of 300 and 
100 mg, respectively, and a pilot food-effect portion. Study CVAB assessed target engagement 
by measuring changes to dermal blood flow following a randomized sequence of 4-single doses: 
10 mg, 30 mg, 100 mg, and placebo. There were no clinically significant adverse effects in either 
of these studies. 
In the SAD, plasma exposure increased with increasing doses up to 100 mg, but exposure did not 
increase at doses of 200 or 300 mg. The geometric mean terminal elimination half-life (t1/2) 
ranged from 9.72 hours to 13.5 hours without an apparent effect of dose over the range of 10 mg 

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to 300 mg. In addition, when a meal was consumed 30 minutes prior to a 100-mg dose, exposure 
was approximately 11% of that observed when participants fasted for at least 8 hours prior to and 
4 hours after dosing. The new formulation being administered in the current study was developed 
to increase absorption and to decrease the impact of food.
2.3.
Benefit/Risk Assessment
There is no benefit anticipated for healthy participants administered LY3526318.
The current study will be conducted in accordance with principles outlined in the “Guideline on 
Strategies to Identify and Mitigate Risks for First-in-Human and Early Clinical Trials with 
Investigational Medicinal Products” (EMA 2017). In Study CVAA, no clinically significant 
safety or tolerability concerns were identified at the highest single dose administered (300 mg) or 
the highest multiple dose administered (100 mg once daily for 14 days). Because of the male-
only AE observed in rats (seminiferous tubule degeneration), dosing in CVAA was limited to 
100 mg for males, with higher doses being administered to females only. This effect was not 
observed in 2 subsequent male rat studies and was not observed in a 1-month monkey toxicology 
study, so males will be enrolled in the current study. As described in Section 4.3, subsequent 
dose regimens will be selected to maintain exposure below the nonclinical NOAEL exposure.
In a biomarker study (Study CVAB), there was evidence of target engagement at 3 hours, but not 
24 hours after a single dose of 100 mg. Regarding the current study that uses a new formulation 
of LY3526318, exposure following the proposed initial dose of 100 mg is projected to be similar 
to or slightly greater than the exposure achieved in the prior study.
The benefit-risk for the participants treated with LY3526318 remains unchanged in relation to 
the coronavirus disease 2019 (COVID-19) pandemic as currently based on the results from 
clinical and nonclinical data. There is no evidence that administration of LY3526318 will lead to 
suppression or modulation of the immune system. In addition, the mode of action does not 
appear to have a substantial effect on the respiratory or cardiovascular system critically affected 
by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. As the 
participants to be included in this study are generally young to middle aged and healthy (without 
major comorbidities), the study population is not considered to be a high-risk population for 
serious COVID-19 disease. Only persons with a negative SARS-CoV-2 test at admission to the 
CRU will be allowed to participate in the study. In addition, all appropriate measures to prevent 
SARS-CoV-2 infection during the study will be taken as detailed in site standard operating 
procedures (SOPs). 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3526318 may be found in the Investigator’s Brochure (IB).

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3.
Objectives and Endpoints
Objectives
Endpoints
Primary (Part A – SAD)

To determine the pharmacokinetics of 
LY3526318 after a single oral dose 
administration

AUC

Cmax
Primary (Part B – MD)

To determine the pharmacokinetics of 
LY3526318 after multiple oral dose 
administrations

AUC

Cmax
Secondary (Part A – SAD)

To estimate the safety and tolerability 
of LY3526318 after single (Part A) 
oral administration to healthy 
participants

To evaluate the effect of a meal on the
pharmacokinetics of LY3526318 in 
fed versus fasted conditions

AEs 

SAEs

Cmax

tmax

AUC
Secondary (Part B – MD)

To estimate the safety and tolerability 
of LY3526318 after multiple oral 
administrations to healthy participants

AEs 

SAEs
Abbreviations: AE = adverse event; AUC = are under the drug concentration versus time curve; Cmax = maximum 
observed drug concentration; MD = multiple dose; SAD = single-ascending dose; SAE = serious adverse event.

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4.
Study Design
4.1.
Overall Design
This is a Phase 1, SAD (Part A) and MD (Part B) study of LY3526318 in healthy participants. 
Both parts are randomized, double-blind, and placebo-controlled. A maximum of 16 participants 
(SAD and MD cohorts of size 8, randomized 3:1) will be randomly assigned to study 
intervention such that approximately 16 evaluable participants complete the study.
Part A (SAD): 
Single-ascending doses of LY3526318 or placebo will be administered under fasted conditions, 
beginning with a dose of 100 mg in a cohort of 8 participants. Up to 3 dose levels in a cohort of 
participants will be administered in a fasted state (fasted for at least 8 hours prior to dosing and 
for at least 4 hours after dosing). The dose escalation may be stopped if a projected dose may
exceed the toxicology NOAEL. Each dose will be separated by at least 1 week. The initial single 
dose level is the equivalent of 100-mg original formulation, the dose that produced maximum 
AUC0-inf (56 µg·h/mL) in Study CVAA. This dose level was selected because it produced the 
highest exposure when administered using the original formulation of LY3526318, and if the 
new formulation produces the maximum theoretical exposure increase of 2-fold compared to the 
prior study, a 2-fold exposure increase is considered safe and appropriate. Up to 2 additional 
single dose levels may be administered in a fasted state and these doses would be selected to 
maintain human AUC0-inf below the lowest animal-toxicology NOAEL (154 µg·h/mL, 
established in a 1-month monkey study). 
Doses that were administered in a fasted state may also be administered in a fed state to 
determine if food decreases exposure when LY3526318 is administered in the new formulation.
For the fed state, a standardized, high-fat meal or a light breakfast (as described in site-specific 
manual) will be consumed prior to dosing. Approximately 50% of the total caloric content of the
high-fat meal should be from fat. Study participants should eat this meal in 30 minutes or less,
and the study intervention should be administered 30 minutes after the start of the meal. In all 
cases, study intervention should be taken with 1 glass (approximately 240 mL) of water, and no
food should be allowed for at least 4 hours post dose. Water can be allowed as desired except for 
1 hour before and after drug administration.
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 Day 3. All participants will return to 
the CRU after the last study period for a final visit on Study Day 10.
Part B (MD):
After a dose is identified from Part A, multiple doses of LY3526318 or placebo will be 
administered for up to 5 days. Additional participants will be enrolled for a total cohort size of 8 
completers. The assignment to placebo or LY3526318 treatment will be determined at initial 
randomization to a treatment sequence. 
Participants will be confined to the CRU from Day -1 until all study assessments are completed 
72 hours after the last dose. Participants will begin receiving multiple once-daily doses of 
LY3526318 following a review of safety and PK data from Part A, and dose levels will not 

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exceed those administered in Part A. After review of the data from Part A, Part B doses may be 
administered in a fed or fasted state or either on different days.
Participants will return to the CRU for a final visit on approximately Day 14.
Safety, PK, and other assessments will be performed at time points, as prescribed in Section 1.3,
during the stay at the CRU and at subsequent study visits in Part A and Part B. 
Study governance considerations are described in detail in Section 10.1, Appendix 1. 
4.2.
Scientific Rationale for Study Design
In Study CVAA, all single doses and MDs were well tolerated, but exposure did not increase at 
doses above 100 mg. In addition, consumption of a meal was found to significantly decrease 
exposure compared to when participants fasted. This study will include dose escalation 
beginning with approximately 100 mg, the dose level associated with the highest exposure in the 
CVAA study, and will include an assessment of food effect. Residual exposure will be 
minimized due to a washout period of at least 1 week between doses. The PK sampling schedule 
is designed to measure LY3526318 concentrations over at least 5 half-lives.
Part B is a repeat-dose phase designed to assess tolerability and exposure with repeated doses.
4.3.
Justification for Dose
In a prior Phase 1 study (CVAA), there were no clinically significant adverse events at the 
highest doses administered: 300 mg in the SAD and 100 mg/day for 14 days in the MD. These 
doses were administered to females only, but there was no apparent difference in exposure or
tolerability at lower doses administered to males and females. 100 mg/day was selected as the 
highest dose for the MD, because plasma exposure did not increase with increasing dose beyond 
100 mg. In addition, when a meal was consumed 30 minutes prior to a 100 mg dose, exposure 
was approximately 11% of that observed when participants fasted. The new formulation being 
administered in the current study was developed to increase absorption and to decrease the 
impact of food. The current formulation could produce exposures up to 2.5 times those of the 
prior form for any given dose level. 
The NOAEL from Good Laboratory Practice toxicology studies was established in a 1-month 
monkey study (Study 00926044). There were no adverse effects in monkeys administered 
1000 mg/kg/day, and the mean AUC0-24 was 154 µg·h/mL. As summarized in Table 4.1, in the 
clinical study, CVAA, a dose of 100 mg resulted in a mean AUC0-inf of 56 µg·h/mL, and this is 
planned to be the starting dose in CVAC. The planned maximum dose of 275 mg is based on an 
assumption of a dose-proportional increase in exposure. The determinant of the maximum dose 
will be the NOAEL AUC of 154 µg·h/mL. In the event that a less-than-dose-proportional 
increase in exposure is observed, a unit dose higher than 275 mg may be used, as long as a mean 
AUC of 154 µg·h/mL is not exceeded. As a practical limit, the unit dose will not be more than 
1000 mg. In addition, if a dose lower than 100 mg is needed to maintain AUC ˂154 µg·h/mL, 
de-escalation is permitted. For the multiple-dose portion of the study, the dose regimen and 
fed/fasting will be selected with the intent not to exceed the AUC0-24 achieved in Part A.

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Table 4.1.
Margin of Safety for Oral Administration of LY3526318 Based on 
Administered Dose and Exposure
Dose
(mg/kg)
Dose
(mg/m2)
Dose
Multiplea
AUC 
(µg·h/mL)a
Exposure 
Multipleb
Human
Starting dose (100 mg)
1.67
61.7
56
Maximum dose (275 mg)c
4.6
170
154
Rat NOAELd
Male
1000
6000
97e
131
2.3e
35f
0.85f
Female
1000
6000
97e
295
5.3e
35f
1.9f
Monkey NOAELg
1000
12000
e
154
e
71f
1f
Abbreviations: AUC = area under the concentration versus time curve; AUC0-inf = area under the concentration 
versus time curve from time zero to infinity; AUCτ = area under the concentration versus time curve during a 
dosing interval; NOAEL = no-observed-adverse-effect level.
a
AUC for humans is AUC0-inf after a single dose. AUC for rat and monkey is AUCτ after multiple doses. 
b
Dose multiple is the dose in animals/dose in humans based on mg/m2. Exposure multiple is the calculated AUC 
in animals/observed or predicted AUC in humans. 
c
The planned maximum dose of 275 mg is based on an assumption of dose-proportional increase in exposure. The 
determinant of the maximum dose will be the NOAEL AUC of 154 µg·h/mL. In the event that a less-than-dose-
proportional increase in exposure is observed, a unit dose higher than 275 mg may be used, as long as a mean 
AUC of 154 µg·h/mL is never exceeded. As a practical limit, the unit dose will not be more than 1000 mg.
d
NOAELs from the 4-week, repeat-dose toxicity study (Study # 00926043).
e
Based on human exposure at 100 mg using the prior formulation (Study CVAA).
f
Based on the highest projected exposure (NOAEL of 154 µg·h/mL) at a 275 mg dose using the new formulation.
g
NOAEL from the 4-week, repeat-dose toxicity study (Study # 00926044; no LY3526318-related effects were 
noted.
4.4.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the SoA
(Section 1.3) for the last participant.

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5.
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.
5.1.
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. 
Age
1. Aged 18 to 65 years, inclusive.
Sex
2. Healthy male participants, as determined through medical history and physical 
examination.
a.
A nonvasectomized, male participant must agree to use a condom or abstain from 
sexual intercourse from start of dosing until 105 days beyond the last dose of study 
intervention.
b. No restrictions are required for a vasectomized male provided his vasectomy has been 
performed at least 4 months or prior to screening. A male who has been vasectomized 
˂4 months prior to screening must follow the same restrictions as a nonvasectomized
male
c.
Must agree not to donate sperm from start of dosing until 105 days beyond the last 
dose of study intervention.
3. 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 
105 days beyond the last dose of study intervention. Sexually active participants must use 
a combination of 2 of the following methods of contraception, including at least 1 so-
called ‘barrier’ method:
a.
hormonal contraceptives (oral, transdermal patches, vaginal, or injectable)
b. intrauterine device with or without hormones
c.
condom, diaphragm, or cervical cap (‘barrier’ method), and
d. sexual abstinence.

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Contraceptive requirements do not apply for participants who are exclusively in a same-sex 
relationship. Additional guidance is provided in Section 10.4, Appendix 4.
Weight
4. Have a body mass index of 18 to 32 kg/m2, inclusive.
Type of Participant and Disease Characteristics
5. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow CRU-specific study procedures.
6. 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.
Informed Consent
7. Capable of giving signed informed consent as described in Section 10.1.2, Appendix 1,
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if they meet any of the following criteria at screening, 
unless otherwise noted:
Medical Conditions
1. 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.
2. Any abnormalities identified following a physical examination of the participant that, in 
the opinion of the investigator, would jeopardize the safety of the participant or interfere 
with study conduct if they took part in the study.
3. Positive SARS-CoV-2 virus nasopharyngeal polymerase chain reaction test at Day -1.
4. Contact with SARS-CoV-2-positive or COVID-19 patient within the last 14 days prior to 
admission to the CRU.
5. 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.

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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:
a.
Confirmed Fridericia’s corrected QT (QTcF) interval >450 msec for men and 
>470 msec for women; one repeat ECG may be performed if required.
7. 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.
8. 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.
9. 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. Retesting may occur 
once during the screening visit within 2 hours of the initial abnormal blood pressure 
measurement at the discretion of the investigator.
Prior/Concomitant Therapy
10. 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.
11. Are unwilling to stop herbal supplements, over the counter, or prescription medicines, 
including drugs that are known inducers or inhibitors of CYP3A4 or 2C9 (see 
Section 10.6, Appendix 6, for a list of excluded medications), within 14 days prior to 
study intervention administration and for duration of study. An exception is for 
paracetamol at doses of ≤2 grams/day.
Prior/Concurrent Clinical Study Experience
12. Are currently enrolled in a clinical drug study or are within 30 days prior to (the first) 
drug administration or in more than 4 other drug studies in the 12 months prior to (the 
first) drug administration involving an investigational product or any other type of 
medical research judged not to be scientifically or medically compatible with this study.
13. Have previously completed or withdrawn from this study or any other study investigating 
this study intervention.
Other Exclusions
14. Participants with 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. 
15. Have an average weekly alcohol intake that exceeds 21 units per males and 14 units for 
females 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).

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16. Are unwilling to stop alcohol and caffeinated beverage consumption and smoking/use of 
tobacco while resident in the CRU.
17. Are unwilling to comply with the dietary restrictions required for this study, including the 
avoidance of, by 5 days prior to study intervention administration until the final 
ambulatory visit, the ingestion of fruits, sauces, and juices containing furanocoumarins
that irreversibly inhibit CYP3A4. The following fruits, sauces, and juices are excluded: 
grapefruit, Seville oranges, pomelos, cranberries, Goji berries, and apples.
18. 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.
19. Have donated blood of more than 450 mL within 60 days prior to (the first) drug 
administration.
20. Are the investigator or CRU personnel directly affiliated with this study or are immediate 
family members of the investigator or CRU personnel. Immediate family is defined as a 
spouse, parent, child, or sibling, whether biological or legally adopted.
21. Are Eli Lilly and Company (Lilly) employees or contractors or an immediate family 
member of employees or contractors.
5.3.
Lifestyle Considerations
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study.
5.3.1.
Meals and Dietary Restrictions
Standard meals, according to the CRU SOPs, will be provided during the stay at the CRU. 
During the fasted dosing periods, participants will fast overnight for at least 8 hours prior to the 
morning dose and then fast for at least 4 hours after the morning dose. During the food-effect 
period, a standardized high-fat meal or a light breakfast will be provided at the CRU 30 minutes 
prior to dose administration following an overnight fast of at least 8 hours. During Part B on 
Days 1 and 5, participants will fast overnight for at least 8 hours prior to the morning dose and 
then fast for at least 4 hours after the morning dose.  On days 2 through 4 participants can eat 
according to site procedure for non-fasted dosing.  Unless otherwise instructed by CRU
personnel, participants will maintain their own dietary habit throughout the ambulatory periods 
of the study.
5.3.2.
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.

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5.3.3.
Activity
Participants must refrain from new strenuous exercise routines 48 hours prior to each CRU 
confinement period and throughout their CRU stay. 
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once at the discretion of the investigator with sponsor’s approval. If a participant is 
rescreened, that participant would be assigned a new participant number and would need to sign 
a new ICF.

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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.
6.1.
Study Intervention(s) Administered
The study intervention, LY3526318, will be administered orally. Doses are planned to range 
between 100 mg and 1000 mg once daily (see Section 4.3, Dose Justification), and de-escalation 
is permitted.
Part A
The planned dose levels range from 100 mg to 1000 mg. LY3526318 or matching placebo will 
be administered to participants as a single dose by trained CRU personnel. Up to 3 single dose 
levels will be assessed in a fasted state (fasting at least 8 hours prior to and at least 4 hours after 
dosing). Up to two of these dose levels that were assessed in a fasted state will also be assessed 
in a fed state (a high-fat meal or a light breakfast 30 minutes prior to dosing). Dose levels may be 
modified based on safety and available PK but will not exceed the NOAEL.
Part B
The planned dose levels in Part B will not exceed those studied in Part A. After review of the 
data from Part A, Part B doses may be administered in a fed or fasted state or either on different 
days.
The placebo capsules will be identical in appearance to LY3526318 and are prepared 
extemporaneously. Placebo capsules will contain only microcrystalline cellulose.
LY3526318 and placebo capsules should be stored at 15°C to 30°C.
6.2.
Preparation/Handling/Storage/Accountability

Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, monitored (manual or automated) 
area in accordance with the labeled storage conditions, with access limited to the 
investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
CCI

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
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual. Note: in some cases, sites may destroy the study 
intervention if, during the investigative site selection, the evaluator has verified and 
documented that the site has appropriate facilities and written procedures to dispose of 
study intervention.
6.3.
Measures to Minimize Bias: Randomization and Blinding
6.3.1.
Method of Treatment Assignment
On Day 1 participants will be assigned a unique number (randomization number). Participants 
who meet all criteria for enrollment will be randomly assigned to receive either LY3526318 or 
placebo. A randomization table will be created using a computer software program. The 
randomization list will be provided to the designated unblinded CRU staff for participant
randomization and dispensing purposes and kept in a secure location, accessible to the
designated unblinded CRU staff only.
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 (Figure 1.2). 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 intervention
preparation will not be blinded; laboratory personnel, including bioanalytical laboratory 
personnel, will also not be blinded.
A sealed envelope that contains the study intervention assignment for each participant will be 
provided to the investigator. The investigator (or representative) will retain the sealed envelope
in a secured area. In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participants’ intervention assignment is warranted. Participant 
safety must always be the first consideration in making such a determination. If a participant’s 
intervention assignment is unblinded, the sponsor must be notified immediately after breaking 
the blind. Once the study is complete, all envelopes (sealed and opened) must be inventoried and 
returned to the sponsor.
In the event of a quality assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site to verify that randomization/dispensing has been done accurately.
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a sponsor 
clinical research physician (CRP) for the participant to continue in the study.
6.3.2.
Selection and Timing of Doses
All doses of the study intervention will be administered at the CRU approximately between 
0800 hours and 1100 hours.
A trained CRU personnel member will administer all doses of the study intervention at the CRU.

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6.4.
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the electronic case report form (eCRF). The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. Study 
site personnel will examine each participant’s hands and mouth to ensure that the study 
intervention was ingested.
6.5.
Concomitant Therapy
Drugs that are known inducers or inhibitors of CYP3A4 or 2C9 are to be specifically excluded 
(see Section 10.6, 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.
Any medication or vaccine (including over the counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is receiving 
at the time of enrollment or receives during the study must be recorded along with

reason for use

dates of administration including start and end dates, and

dosage information, including dose and frequency for concomitant therapy of special 
interest.
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention until 
completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, the 
medication will not interfere with the study.
Paracetamol, at doses of 2 grams/day, is permitted for use at any time during the study. Other 
concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the medical monitor if required.
6.6.
Dose Modification
6.6.1.
Dose Escalation
The decision to proceed to the next dose level (either an increase or a decrease) will be made by 
the study team and the investigator based on safety, tolerability, and preliminary PK data 
obtained at the prior dose level.
By nature of being a dose escalation study, data will be evaluated on an ongoing basis until the
mean LY3526318 exposure is projected to reach the NOAEL.

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No dose decision can occur without prior discussion and agreement between the investigator and 
the sponsor’s medical monitor.
In the SAD, the decision to escalate to the next dose will be based on vital signs, AEs, ECGs,
and clinical laboratory assessments from predose to Day 4 from at least 4 individuals randomized 
to LY3526318. Pharmacokinetics data through at least 24 hours after the current dose will be 
used to inform the dose escalation decision. 
Safety data, AEs, SAEs, and adverse laboratory abnormalities will be independently assessed by 
the investigator and will be considered related to the investigational product unless there is clear 
evidence that the event is not related.
After review of these data, the investigator and sponsor will make an agreement on the 
appropriate dose for the next cohort/dose level. The magnitude of dose escalations may be 
reduced following data review, but subsequent escalations cannot be increased by more than 
approximately 3-fold (a half-log increment). Doses lower than the initial dose of 100 mg may 
also be administered. 
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be discontinued:
1. a single participant experiences a SAE or clinically significant event that is related to 
LY3526318 administration, or
2. if ˃3 participants at 1 dose level experience moderate treatment-related AEs that impair 
normal activities.
6.7.
Intervention after the End of the Study
Study intervention will not be made available after completion of the study to participants.

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Participants discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 1.3 of this protocol.
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for early discontinuation procedures. See the 
SoA, Section 1.3, for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed.
Discontinuation due to a hepatic event or liver test abnormality: 
Laboratory tests (Section 10.2, Appendix 2), including alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBL), direct bilirubin, 
gamma-glutamyl transferase (GGT), and creatine kinase (CK), should be repeated within 48 to 
72 hours to confirm the abnormality and to determine if it is increasing or decreasing, if 1 or
more of these conditions occur:
If a participant with baseline results 
of:
develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥3x ULN
ALP <1.5x ULN
ALP ≥2x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for participants with Gilbert’s 
syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥2x baseline (except for participants with 
Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (eg, heart 
failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, and history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.

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If a clinically significant finding is identified (including, but not limited to clinically significant 
changes from baseline in QTcF) after enrollment, the investigator or qualified designee will 
determine if the participant can continue in the study and if any change in participant
management is needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE.
If a participant becomes pregnant during the study, refer to Section 8.3.5.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.2.
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study 

at any time at his/her own request 

at the request of his/her designee (eg, parents or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons

if the participant becomes pregnant during the study

if enrolled in any other clinical study involving an investigational product or enrolled in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

if the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent, or

receives a positive SARS-CoV-2 virus test or evidence of COVID-19 during the study
Discontinuation is expected to be uncommon.
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See the SoA (Section 1.3) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed.
The participant will be permanently discontinued both from the study intervention and from the 
study at that time.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
7.2.1.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant should be discontinued from study treatment unless 
there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment. If the investigator and the sponsor CRP agree it is medically 

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appropriate to continue, the investigator must obtain documented approval from the sponsor CRP 
to allow the inadvertently enrolled participant to continue in the study with or without treatment 
with investigational product. Safety follow-up is as outlined in Section 1.3 (Schedule of 
Activities), Section 8.2 (Safety Assessments), and Section 8.3 (Adverse Events and Serious 
Adverse Events) of the protocol.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get investigational product. Public sources may be searched for vital status 
information. If vital status is determined to be deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1
(see Section 10.1.7).

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8.
Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 1.3.). Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Section 10.2 lists the laboratory tests that will be performed for this study.
Section 10.2.1 provides a summary of the maximum number and volume of invasive samples, 
for all sampling, during the study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results. Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
8.1.
Efficacy Assessments
Not applicable.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations
A complete or directed physical examination will be conducted according to the SoA 
(Section 1.3).
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, GI, and neurological systems. Height and weight will also be measured and recorded
at times noted in the SoA (Section 1.3).
A directed physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
Investigators should pay special attention to clinical signs related to previous serious illnesses.
8.2.2.
Vital Signs
For each participant, vital signs measurements should be conducted according to the SoA
(Section 1.3) and as clinically indicated.
It is suggested that systolic and diastolic blood pressure and heart rate should be measured in a 
supine position just after the ECG (if the ECG is recorded at the same time point) and for a 

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minimum of 10 minutes before any other procedures according to the SoA, (Section 1.3). These 
procedures should be performed prior to collection of blood samples if scheduled at the same 
time. 
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.
8.2.3.
Electrocardiograms
For each participant, ECGs should be collected according to the SoA (Section 1.3). 
Participants must be supine for approximately 10 minutes before ECG collection and remain 
supine but awake during ECG collection. Triplicate ECG’s should be obtained approximately 
1 minute between tracings. Electrocardiograms may be obtained at additional times, when 
deemed clinically necessary. 
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 as an AE in
the electronic data capture (EDC) system.
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 (eg, 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.
8.2.4.
Clinical Safety Laboratory Assessments
Refer to Section 10.2, Appendix 2 for the list of clinical laboratory tests to be performed and to 
the SoA (Section 1.3) for the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the case report form 
(eCRF). The laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 72 hours after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the
investigator or medical monitor.

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
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol-specified laboratory assessments, performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF on the AEs page. Serious 
Adverse events will be reported on the Sponsor Form and faxed to Lilly Global Patient 
Safety.
8.2.5.
Safety Monitoring
The sponsor will monitor safety data throughout the course of the study.
Lilly will review SAEs within the time frames mandated by company procedures. The medical
monitor will periodically review the following data:

trends in safety data

laboratory analytes, and

SAEs and non-SAEs, including monitoring of GI events, hypoglycemia, injection-site 
reactions, hypersensitivity reactions, and reported and adjudicated pancreatitis.
When appropriate, the Lilly medical monitor will consult with the functionally independent 
Global Patient Safety therapeutic area physician or clinical research scientist.
8.2.5.1.
Hepatic Monitoring
Laboratory tests (Section 10.5, Appendix 5), including ALT, AST, ALP, TBL, direct bilirubin, 
GGT, and CK, should be repeated within 48 to 72 hours to confirm the abnormality and to 
determine if it is increasing or decreasing, if 1 or more of these conditions occur:
If a participant with baseline 
results of ... 
develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥3x ULN
ALP <1.5x ULN
ALP ≥2x ULN
TBL <1.5x ULN
TBL ≥2x ULN (except for participants with Gilbert’s 
syndrome)
ALT or AST ≥1.5x ULN
ALT or AST ≥2x baseline
ALP ≥1.5x ULN
ALP ≥2x baseline
TBL ≥1.5x ULN
TBL ≥2x baseline (except for participants with Gilbert’s 
syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal.

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If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests, should be initiated by the investigator in consultation 
with the Lilly-designated medical monitor. At a minimum, this evaluation should include 
physical examination and a thorough medical history, including symptoms, recent illnesses (eg, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, and history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.
8.3.
Adverse Events and Serious Adverse Events
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE, and they remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the participant to discontinue the study intervention or study (see 
Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs will be actively collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 1.3) and until 30 days after the last dose for 
spontaneously reported SAEs.
All AEs will be collected from the signing of the ICF until the follow-up visit OR participation 
in the study has ended.
Adverse events that begin before the start of study intervention but after signing of the ICF will 
be recorded on the AE CRF.
Although all AEs after signing the ICF are recorded by the site in the CRF/electronic data entry, 
SAE reporting to the sponsor begins after the participant has signed the ICF and has received 
study intervention. However, if an SAE occurs after signing the ICF, but prior to receiving study 
intervention, it needs to be reported ONLY if it is considered reasonably possibly related to study 
procedures.
All SAEs will be recorded and reported to the sponsor or designee immediately, and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. 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 to be reasonably 

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related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
Pregnancy (maternal or paternal exposure to the study intervention) 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 SAEs and unexpected AEs for 
this study will be reported to regulatory authorities in accordance with local laws, directives, and 
regulations (Section 8.3.4).
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, assessing causality of AE and SAE, and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE
occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 3 (Section 10.3).
8.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification of an SAE by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs), and investigators.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5.
Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 30 days after the final visit, which corresponds to more than 5 terminal 
half-lives after the last dose of LY3526318.

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Details of all pregnancies in female partners of male participants will be collected until 90 days 
after last administration of LY3526318.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
about the pregnancy and should follow the procedures outlined Appendix 4 (Section 10.4).
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Product Complaints
A product complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
trial intervention. 
The sponsor collects product complaints on investigational products used in clinical studies in 
order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
NOTE: AEs/SAEs that are associated with a product complaint will also follow the processes 
outlined in Section 8.3.3 and Appendix 10.3 of the protocol.
8.3.6.1.
Time Period for Detecting Product Complaints
Product complaints that result in an AE will be detected, documented, and reported to the 
sponsor during all periods of the study in which the drug is used.
If the investigator learns of any product complaint at any time after a participant has been 
discharged from the study and such incident is considered reasonably related to a drug provided 
for the study, the investigator will promptly notify the sponsor.
8.3.6.2.
Prompt Reporting of Product Complaints to Sponsor
Product complaints will be reported to the sponsor within 24 hours after the investigator becomes 
aware of the complaint.
The Product Complaint Form will be sent to the sponsor by the method provided in the form. If 
the primary method is unavailable, then an alternative method provided in the form should be 
utilized.
8.3.6.3.
Follow-up of Product Complaints
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations, as indicated, to elucidate the nature and/or causality of the product complaint.
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the investigator and submitted to the sponsor.

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8.4.
Treatment of Overdose
An overdose is not anticipated in the study, as a trained CRU member will administer all study 
intervention.
In case of overdose, use supportive therapy. There is no known antidote to LY3526318 therapy.
Any dose of LY3526318 greater than the daily dose assigned through randomization will be 
considered an overdose. Treatment for overdose is supportive care.
In the event of an overdose, the investigator should
1. contact the medical monitor immediately
2. closely monitor the participant for any AE/SAE and laboratory abnormalities until 
LY3526318 can no longer be detected systemically (at least 14 days)
3. obtain a plasma sample for PK analysis within 14 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis), and
4. document the quantity of the excess dose, as well as the duration of the overdose, in the 
CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5.
Pharmacokinetics
For all participants, blood samples of up to 3 mL each for the determination of concentrations in 
plasma of LY3526318 and metabolite(s) of interest will be collected at time points specified in 
the SoA (Section 1.3). 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. 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.
8.5.1.
Bioanalysis
Samples will be analyzed for LY3526318 and LSN3528305 at Pharmaceutical Research 
Associates using a validated method. Placebo samples will not be analyzed.
Bioanalytical samples collected to measure study intervention concentrations will be retained for 
a maximum of 1 year following the last participant visit for the study. 
Residual PK plasma samples may be used for LY3526318 metabolite identification.

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8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
Not applicable.
8.10.
Health Economics
Not applicable.

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9.
Statistical Considerations
9.1.
Statistical Hypotheses
No formal hypothesis testing will occur. Exposure, safety, and tolerability endpoints will be 
summarized for the SAD and MD portions descriptively by dose and fed status and also provided 
in patient listings.
9.2.
Sample Size Determination
A maximum of 16 participants (SAD and MD cohorts of size 8, randomized 3:1) will be 
randomly assigned to study intervention such that approximately 16 evaluable participants 
complete the study.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
Entered
All participants who sign the ICF.
Safety
All participants randomly assigned to study intervention and who take at least 
1 dose of study intervention. Participants will be analyzed according to the 
intervention they actually received.
Pharmacokinetic Analysis
All participants who received at least 1 dose of study treatment and have at 
least 1 postbaseline evaluable PK sample.
Abbreviations: ICF = informed consent form; PK = pharmacokinetic.
9.3.1.
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.
9.3.2.
Study Participant Characteristics
Participant demographics (age, sex, race, ethnicity, height, and weight) will be summarized.
9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of the sponsor and its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan and the clinical study report. 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.
The statistical analysis plan will be finalized prior to database lock, and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 

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is a summary of the planned statistical analyses of the most important endpoints, including 
primary and key secondary endpoints.
Pharmacokinetic analyses will be conducted on data from all participants who received a dose of
LY3526318 and have evaluable PK.
Safety analyses will be conducted for all enrolled participants who received study intervention,
whether or not they completed all protocol requirements.
For continuous variables, summary statistics will include the 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.
9.4.1.
Safety Analyses
All study intervention 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 
AEs and SAEs will be provided by treatment arm 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.
9.4.2.
Pharmacokinetic Analyses
All participants who have evaluable plasma LY3526318 concentrations will be included in the 
PK analyses. Pharmacokinetic parameter estimates for LY3526318 and relevant metabolites will 
be computed using standard noncompartmental methods of analysis. 
9.4.2.1.
Pharmacokinetic Parameter Estimation
Primary plasma LY3526318 and relevant metabolite PK endpoints, including but not limited to 
the AUC from time zero to the last measurable concentration (AUC0-t), AUC0-24, AUC during a 
dosing interval (AUCτ), AUC from zero to infinity (AUC0-inf), 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), apparent volume of distribution (Vz/F), and apparent 
volume of distribution at steady state (Vss/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 (CIs) for the ratios will be reported. Time to Cmax will be analyzed using a Wilcoxon 
signed rank test. Estimates of the median difference based on the observed medians, approximate 
90% CIs, and p-values from the Wilcoxon test will be calculated.
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. Population PK modeling may be performed, with or 
without pooling with observations from other studies.

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9.4.2.2.
Pharmacokinetic Statistical Inference
Dose proportionality may be assessed using the power model approach (Smith et al. 2000), as
appropriate. Additional analyses, including but not limited to population PK modeling with or 
without data from other studies, will be performed as deemed necessary upon review of the data.
9.4.2.3.
Other Pharmacokinetic Analyses
Other analyses, such as assessment of the relationship between LY3526318 concentration and 
QTcF, may be conducted if appropriate based on the data.
9.4.3.
Other Safety Analyses
All safety analyses will be made on the Safety Population.
9.5.
Interim Analyses
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.
Although no formal interim analyses are planned to occur, interim access to safety and PK data 
to support dose escalation and selection will occur, as outlined in Section 4.1.
9.6.
Data Monitoring Committee
A Data Monitoring Committee will not be used in this study.

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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

applicable International Council for Harmonization (ICH) Good Clinical Practice (GCP) 
Guidelines, and

applicable laws and regulations.
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC
before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, and

providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for Clinical Studies (if applicable), and all other applicable local 
regulations.
Investigator sites are compensated for participation in the study as detailed in the Clinical Trial 
Agreement (CTA).
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.

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10.1.3.
Informed Consent Process
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or his/her legally authorized representative and answer all
questions regarding the study.
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center.
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative and must be kept on file.
Participants who are rescreened are required to sign a new ICF.
10.1.4.
Data Protection
Participants will be assigned a unique identifier by the contract research organization (CRO). 
Any participant records, datasets, or tissue samples that are transferred to the sponsor will 
contain the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The CRO has processes in place to ensure data protection, information security, and data 
integrity. These processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach.
10.1.5.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF, if applicable.

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The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management, Mitigation Strategies, and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues, and monitoring 
techniques are provided in the Monitoring Plan.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the CTA unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
In addition, the sponsor 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 the 
sponsor, its representatives, and/or regulatory agencies at any time. Investigators will be given 
notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An EDC system will be used in this study for the collection of CRF data. The investigator 
maintains a separate source for the data entered by the investigator or designee into the 
sponsor-provided EDC system. If applicable, the investigator is responsible for the identification 
of any data to be considered source and for the confirmation that data reported are accurate and 
complete by signing the CRF.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and reports will be provided to the investigator for review 
and retention
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system.
10.1.6.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.

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Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents, or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available.
The definition of what constitutes source data can be found in the data management plan.
10.1.7.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to

failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

inadequate recruitment of participants by the investigator, or

discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and assure appropriate participant therapy 
and/or follow-up.
10.1.8.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance.

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10.2.
Appendix 2: Clinical Laboratory Tests
The tests detailed below will be performed by a local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5
of the protocol.
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations.
Pregnancy testing: See Section 5.1 (inclusion criteria for screening pregnancy criteria) and 10.4
(Appendix 4: Contraceptive Guidance for Men and Women).
Investigators must document their review of each laboratory safety report.
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel.

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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 Urine Test
Urinalysis Dipstick
Urine Drug Screena
Specific gravity
Amphetamine (including XTC)
pH
Barbiturates
Protein
Benzodiazepine
Glucose
Cannabinoids
Ketones
Cocaine
Bilirubin
Methadone
Urobilinogen
Opiates
Blood
Nitrite
Hepatitis B surface antigenb
Hepatitis C antibodyb
HIVb
FSHb
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 cell; XTC = MDMA (methylenedioxymethamphetamine);
WBC = white blood cell.
a
Urine drug screen may be repeated prior to admission to the clinical research unit and at other times as indicated 
in the Schedule of Activities.
b
Performed at screening only.

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10.2.1.
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-CVAC Sampling Summary
Part A
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
13
84.5
Pharmacokinetics 
3
45
135
Total
21
59
231
Part B
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
8
52
Pharmacokinetics 
3
21
63
Total
21
30
126.5
a
Additional samples may be drawn if needed for safety purposes.

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: an AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though they may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such an overdose should be reported regardless of sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

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10.3.2.
Definition of SAE
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to the 
hospital for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during hospitalization 
are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
10.3.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested 
by the sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.

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Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:

Mild - An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate - An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe - An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event, and both AEs and SAEs can be assessed as severe.
o
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than that a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the sponsor or designee. 
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the sponsor 
or designee.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
or designee to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor or designee within 
24 hours of receipt of the information.
10.3.4.
Reporting of SAEs
SAE Reporting via Paper CRF

Facsimile transmission or secure e mail of the SAE paper CRF is the preferred method 
to transmit this information to the sponsor or designee.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Clinical Trial Serious Adverse Event 
(SAE) Instruction Guidelines for Completion of the SAE and Pregnancy Reporting 
forms.

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10.4.
Appendix 4: Contraception Guidance for Men and Women
The table below describes contraception guidance for men.
Topic
Guidance
For all men
Should refrain from sperm donation for the duration of 
the study and for ≥90 days after the last dose of study 
intervention
Contraception for men with partners of childbearing 
potential 

either remain abstinent (if this is their 
preferred and usual lifestyle), or

must use condoms during intercourse for the 
duration of the study, and 

for duration of the study and for ≥90 days 
after the last dose of study intervention
Contraception for men in exclusively same-sex 
relationships, as their preferred and usual lifestyle
Are not required to use contraception
The table below provides examples of highly effective, effective, and unacceptable methods of 
contraception.
Methods
Examples
Highly effective contraception 

combination oral contraceptive pill and mini-
pill

implanted contraceptives

injectable contraceptives

contraceptive patch (only women <198 
pounds or 90 kg)

total abstinence

vasectomy (if the only sexual partner)

fallopian tube implants (if confirmed by 
hysterosalpingogram)

combined contraceptive vaginal ring, or 

intrauterine devices
Effective contraception 

male or female condoms with spermicide 

diaphragms with spermicide or cervical 
sponges

barrier method with use of a spermicide
o
condom with spermicide
o
diaphragm with spermicide, or
o
female condom with spermicide
Note: The barrier method must include the use of a 
spermicide (ie, condom with spermicide, diaphragm 
with spermicide, female condom with spermicide) to 
be considered effective.

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Methods
Examples
Ineffective forms of contraception

spermicide alone 

immunocontraceptives

periodic abstinence

fertility awareness (calendar method, 
temperature method, combination of above 2, 
cervical mucus, symptothermal)

withdrawal

postcoital douche

lactational amenorrhea

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
Women of childbearing potential (WOCBP) may participate in this trial.

Women not of childbearing potential may participate in this trial.
Word/Phrase
Definition
Women of 
childbearing
potential
Females are considered a woman of childbearing potential if

they have had at least 1 cycle of menses, or

they have Tanner 4 breast development.
Any amount of spotting should be considered menarche. If Tanner Staging of breasts 
is performed as a part of study procedures, please refer to the Reproductive, Pregnancy 
and Pediatrics Safety Committee Safety Guidance for Children in Clinical Trials
regarding Tanner Staging.
Women not of 
childbearing
potential
Females are considered women not of childbearing potential if

they have a congenital anomaly such as Mullerian agenesis, 

they are infertile due to surgical sterilization, or 

they are postmenopausal.
Examples of surgical sterilization include hysterectomy, bilateral oophorectomy, tubal 
ligation.
Postmenopausal 
state
The post-menopausal state should be defined as:
1.
A woman at any age at least 6 weeks postsurgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note 
2.
A woman at least 40 years of age up to 55 years old with an intact uterus, not 
on hormone therapy,a who has had cessation of menses for at least 12 
consecutive months without an alternative medical cause, AND with a 
follicle-stimulating hormone >40 mIU/mL 
3.
A woman at least 55 years of age not on hormone therapy, who has had at 
least 12 months of spontaneous amenorrhea, or
4.
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy
a  Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, selective 
estrogen receptor modulators (SERMs), or chemotherapy that could induce transient 
amenorrhea.

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Please see guidance for specific participant populations below:
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle
Must…
Must not…
agree to either remain abstinent, or

use periodic abstinence methods
o
calendar 
o
ovulation 
o
symptothermal, or
o
post-ovulation 

declare abstinence just for the duration 
of the trial, or
stay in a same-sex relationship without sexual 
relationships with males, as their preferred and usual 
lifestyle

use the withdrawal method
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or in a 
same-sex relationship, as part of their preferred and usual lifestyle
Topic
Explanation
Pregnancy testing
Negative urine result at screening followed by a negative serum result within 24 hours 
prior to treatment exposure
Note: subsequent pregnancy testing is compound specific.
Contraception
Agree to use 2 forms of effective contraception, where at least 1 form must be highly 
effective (˂1% failure rate)

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10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
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; Lilly = Eli 
Lilly and Company; 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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10.6.
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. This list is not exhaustive,
and the sponsor should be consulted in the case of any questions or uncertainty.
Strong and moderate clinical inducers of CYP3A4 (Updated 04 Mar 2019)
Drug
Special Status
Inducer Category
Aminoglutethimide
VL
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
Lesinurad
Moderate
Lersivirine
Moderate
Lopinavir (alone)
Moderate
Lorlatinib
Moderate
Modafinil
Moderate
Nafcillin (intravenous)
VL
Moderate
Pentobarbital
VL
Moderate
Primidone
Moderate
Telotristat ethyl
Moderate
Thioridazine 
VL: available in 
the UK
Moderate
Tipranavir and ritonavir
Moderate
Tocilizumab (atlizumab)
NT
Moderate

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Strong and moderate clinical inducers of CYP3A4 (Updated 04 Mar 2019)
Abbreviations: IL-6 = interleukin 6; 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.
Strong and moderate clinical inhibitors of CYP3A4 
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
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/or ombitasvir)
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

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Strong and moderate clinical inhibitors of CYP3A4 
Drug
Special status
Inhibition category
Fluvoxamine
Moderate
Fosnetupitant and palonosetron
Moderate
Imatinib
Moderate
Indinavir
Moderate 
Isavuconazole
Moderate
Ledipasvir/sofosbuvir
Moderate
Letermovir
Moderate
Magnolia vine (Schisandra 
sphenanthera)
SF
Moderate
Netupitant 
Moderate
Nilotinib
Moderate
Tofisopam
Moderate
Verapamil
Moderate
Abbreviations: SF = supplement or food/drink; VL = very limited use.
Source: University of Washington Drug Interaction Database https://www.druginteractioninfo.org/ and 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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10.7.
Appendix 7: Abbreviations
Term
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUCτ
AUC during a dosing interval
AUC0-inf
AUC from time zero to infinity
AUC0-t
AUC from time zero to the last measurable concentration
AUC0-24
AUC from time zero to 24 hours post dose
blinding/masking
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.
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL/F
apparent clearance
Cmax
maximum observed drug concentration
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization

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Term
Definition
CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CTA
Clinical Trial Agreement
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
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.
GCP
good clinical practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
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.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
Institutional Review Boards

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Term
Definition
Lilly
Eli Lilly and Company
MD
multiple dose
NOAEL
no-observed-adverse-effect level
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PK
pharmacokinetic(s)
QTcF
Fridericia’s corrected QT interval
SAD
single-ascending dose
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
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. 
SoA
Schedule of Activities
SOP
standard operating procedure
TBL
total bilirubin
TEAE
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
tmax
time to Cmax
TRPA1
transient receptor protein ankyrin-1
t1/2
elimination half-life
Vss/F
apparent volume of distribution at steady state
Vz/F
apparent volume of distribution
WOCBP
women of childbearing potential

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11.
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