A Safety, Tolerability, and Pharmacokinetics Study of LY3451838 in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

J1H-MC-LAJA Protocol (d) 
A Safety, Tolerability, and Pharmacokinetics Study of LY3451838 in Health Subjects 
NCT03692949 
Approval Date: 13 Aug 2019 

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Protocol J1H-MC-LAJA (d)
A Safety, Tolerability, and Pharmacokinetics Study of 
LY3451838 in Healthy Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of
LY3451838, 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.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Protocol Amendment Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 13-Aug-2019 GMT

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Table of Contents
A Safety, Tolerability, and Pharmacokinetics Study of 
LY3451838 in Healthy Subjects
Section
Page
Protocol J1H-MC-LAJA (d) A Safety, Tolerability, and Pharmacokinetics 
Study of LY3451838 in Healthy Subjects............................................................................1
Table of Contents........................................................................................................................2
1
Protocol Synopsis................................................................................................................8
2
Schedule of Activities .......................................................................................................10
3
Introduction ......................................................................................................................13
3.1
Study Rationale............................................................................................................13
3.2
Background..................................................................................................................13
3.3
Benefit/Risk Assessment..............................................................................................14
4
Objectives and Endpoints..................................................................................................16
5
Study Design.....................................................................................................................17
5.1
Overall Design .............................................................................................................17
5.1.1
Part A (Single Ascending Dose IV Administration)..............................................17
5.1.2
Part B (Single Dose SC Administration)...............................................................18
5.2
Number of Participants.................................................................................................19
5.3
End of Study Definition ...............................................................................................19
5.4
Scientific Rationale for Study Design...........................................................................19
5.5
Justification for Dose ...................................................................................................20
6
Study Population...............................................................................................................22
6.1
Inclusion Criteria..........................................................................................................22
6.2
Exclusion Criteria ........................................................................................................23
6.3
Lifestyle and/or Dietary Requirements .........................................................................24
6.3.1
Meals and Dietary Restrictions.............................................................................25
6.3.2
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.3
Activity................................................................................................................25
6.3.4
Blood Collection..................................................................................................25
6.3.5
Male Contraceptive Requirements........................................................................25
6.4
Screen Failures.............................................................................................................26
7
Treatment..........................................................................................................................27
7.1
Treatment Administered...............................................................................................27
7.1.1
Packaging and Labeling .......................................................................................28

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7.2
Method of Treatment Assignment ................................................................................28
7.2.1
Selection and Timing of Doses.............................................................................28
7.3
Blinding .......................................................................................................................28
7.4
Dose Modification........................................................................................................29
7.4.1
Dose Escalation in Part A.....................................................................................29
7.4.1.1
Stopping Rules ...............................................................................................29
7.4.2
Decision to Initiate Part B ....................................................................................30
7.4.3
Special Treatment Considerations ........................................................................30
7.4.3.1
Premedication for Infusions............................................................................30
7.4.3.2
Management of Infusion Reactions.................................................................31
7.5
Preparation/Handling/Storage/Accountability...............................................................31
7.6
Treatment Compliance .................................................................................................31
7.7
Concomitant Therapy...................................................................................................32
7.8
Treatment after the End of the Study............................................................................32
8
Discontinuation Criteria ....................................................................................................33
8.1
Discontinuation from Study Treatment.........................................................................33
8.1.1
Discontinuation of Inadvertently Enrolled Subjects..............................................33
8.2
Discontinuation from the Study....................................................................................33
8.3
Subjects Lost to Follow-up...........................................................................................34
9
Study Assessments and Procedures ...................................................................................35
9.1
Efficacy Assessments...................................................................................................35
9.2
Adverse Events ............................................................................................................35
9.2.1
Serious Adverse Events........................................................................................36
9.2.1.1
Suspected Unexpected Serious Adverse Reactions..........................................37
9.2.2
Complaint Handling.............................................................................................37
9.3
Treatment of Overdose.................................................................................................37
9.4
Safety...........................................................................................................................37
9.4.1
Medical Assessment and Neurological Examinations ...........................................37
9.4.2
Vital Signs ...........................................................................................................38
9.4.3
Laboratory Tests ..................................................................................................38
9.4.4
Electrocardiograms ..............................................................................................38
9.4.4.1
Digital Electrocardiogram Storage..................................................................39
9.4.5
Safety Monitoring ................................................................................................39
9.4.5.1
Hepatic Safety................................................................................................39
9.4.5.2
Hypersensitivity reactions...............................................................................40
9.5
Pharmacokinetics .........................................................................................................40
9.5.1
Bioanalysis...........................................................................................................40
9.6
Pharmacodynamics ......................................................................................................40

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9.6.1
Immunogenicity Assessments ..............................................................................40
9.6.2
Exploratory Assessment of PACAP Concentration...............................................41
9.7
Genetics .......................................................................................................................41
9.8
Biomarkers...................................................................................................................41
9.9
Health Economics ........................................................................................................42
10
Statistical Considerations and Data Analysis.....................................................................43
10.1
Sample Size Determination ..........................................................................................43
10.2
Populations for Analyses..............................................................................................43
10.2.1
Study Participant Disposition ...............................................................................43
10.2.2
Study Participant Characteristics ..........................................................................43
10.3
Statistical Analyses ......................................................................................................43
10.3.1
Safety Analyses....................................................................................................43
10.3.2
Pharmacokinetic Analyses....................................................................................44
10.3.2.1
Pharmacokinetic Parameter Estimation...........................................................44
10.3.2.2
Pharmacokinetic Statistical Inference .............................................................44
10.3.3
Exploratory Pharmacodynamic Analyses .............................................................44
10.3.4
Evaluation of Immunogenicity .............................................................................44
10.3.5
Data Review During the Study.............................................................................44
10.3.6
Interim Analyses..................................................................................................45
11
References ........................................................................................................................46

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List of Tables
Table
Page
Table 4.1.
Objectives and Endpoints .......................................................................16
Table 5.1.
Margin of Safety for Intravenous Administration of LY3451838 
Based on Administered Dose and Predicted Exposure ............................21

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List of Figures
Figure
Page
Figure 5.1.
Illustration of study design for Protocol J1H-MC-LAJA. ........................17

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................47
Appendix 2.
Clinical Laboratory Tests........................................................................50
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................52
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............55
Appendix 5.
Blood Sampling Summary......................................................................56
Appendix 6.
Protocol Amendment J1H-MC-LAJA(a) Summary.................................57
Appendix 7.
Protocol Amendment J1H-MC-LAJA(b) Summary ................................60
Appendix 8.
Protocol Amendment J1H-MC-LAJA(c) Summary.................................65
Appendix 9.
Protocol Amendment J1H-MC-LAJA(d) Summary ................................66

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1 Protocol Synopsis
Title of Study:
A safety, tolerability, and pharmacokinetics study of LY3451838 in healthy subjects.
Rationale: 
LY3451838 is a fully human immunoglobulin G (IgG4-variant monoclonal antibody) that potently and selectively 
binds and neutralizes pituitary adenylate cyclase-activating polypeptide (PACAP).  LY3451838 is being developed 
as a treatment for primary headache conditions including prevention of episodic or chronic migraine and/or cluster 
headache.  This first-in-human study of LY3451838, J1H-MC-LAJA, will investigate the safety, tolerability, and 
pharmacokinetics (PK) of LY3451838 administered intravenously (IV) and subcutaneously (SC) in healthy subjects.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
Evaluate the safety and tolerability of a single dose of 
LY3451838 in healthy subjects

Adverse events

Serious adverse events
Secondary
Evaluate the pharmacokinetics of LY3451838 in 
healthy subjects following a single dose of 
LY3451838.

AUC

Cmax
Abbreviations: AUC = area under the concentration-time curve; Cmax = maximum drug concentration
Summary of Study Design:
Study J1H-MC-LAJA is a first-in-human, investigator- and subject-blind, placebo-controlled, randomized, 2-part 
study in healthy subjects to evaluate the safety, tolerability, and pharmacokinetics of LY3451838. In Part A, the 
single ascending doses of LY3451838 will be administered IV in up to 6 cohorts of 8 subjects each.  In Part B, a 
single dose of LY3451838 will be administered SC in up to 2 cohorts of 8 subjects each.
Safety / tolerability, pharmacokinetic, immunogenicity, and exploratory pharmacodynamic assessments will be 
performed at prescribed time points during the stay at the clinical research unit (CRU) and at subsequent study 
visits. 
All available safety and PK data will be reviewed before each dose escalation.  The proposed doses may be adjusted 
after review of available data from previous dose levels after consultation with a Safety Review Panel (SRP) that is 
independent of the team.
Treatment Arms and Planned Duration for an Individual Subject:  
In both parts, within each cohort, subjects will be randomly assigned to receive LY3451838 or placebo in a 6:2 ratio.
Part A: LY3451838 will be administered IV, at single ascending dose levels, starting at 25 mg and escalated up to 
1500 mg.
Part B: LY3451838 will be administered SC as a single dose, which is planned as a 250 mg dose or a dose that 
matches that of Cohort 3 in Part A. Up to 2 cohorts in Part B may be enrolled to explore various features of SC 
dosing at the same dose level.

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In both parts, subjects will be followed for approximately 20 weeks following administration of the study drug.
Number of Subjects:
Up to 80 healthy subjects may be enrolled so that approximately 6 subjects in each LY3451838 dosing group
complete the 20-week study.   Any subject who was withdrawn before completion of all study activities may be 
replaced at the discretion of the Sponsor.
Statistical Analysis:
Safety: The primary safety endpoints are the numbers and types of treatment-emergent serious adverse events and 
adverse events. Summary statistics for each cohort will be provided by dose level and for all placebo subjects 
combined.
Pharmacokinetics: Plasma LY3451838 PK (e.g., Cmax, AUC0-∞) will be calculated using noncompartmental methods.    
Pharmacokinetic parameters will be summarized by dose level using descriptive statistics. Dose proportionality will 
be assessed. Mean and individual LY3451838 plasma concentration-time curves will be presented. Absolute 
bioavailability will be calculated based on data from the IV and SC cohorts.

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2 Schedule of Activities

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Study Schedule Protocol JAH-MC-LAJA – Part A (Intravenous Administration) and Part B (Subcutaneous Administration)
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16a
Study Day
-28
-1
1
2
3
5
7
9 
(-1 to 
+2)
15 
(±2)
22 
(±3)
29 
(±3)
43 
(±3)
57 
(±4)
71 
(±4)
85 
(±7)
141 / 
ED 
(±7)
Visit Type
S
A
I
I
D
O
O
O
O
O
O
O
O
O
O
O
Informed consent
X
Medical history
X
Height/weightb
X
X
X
X
X
X
Medical Assessmentc
X
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
Xd
X
X
X
X
Electrocardiograme
X
Xd
Predose,
1, 3 h 
24 h
(± 90 m)
X
X
X
X
X
X
X
X
X
X
Vital signsf, g
X
Xd
Predose, 
EOIh, 1, 3 h
24 h
(± 90 m)
X
X
X
X
X
X
X
X
X
X
X
X
Orthostatic BP and pulse rate
Predose, 1 h
24 h
X
X
X
X
Pregnancy test (urine)
X
Xd
X
X
X
Screening tests
X
Eligibility review
Xd
Study drug administration
X
Hematology and chemistryi
Xd
Predose
X
X
X
X
X
X
X
X
X
X
X
X
X
C3, C4, CRP and ESR
X
Predose
X
X
X
X
Urine analysis
Xd
X
X
X
X
PK samplei
EOIh, 3, 6, 
8, 12 h
24 h
(± 60 
m), 36 h
(± 60 m)
48 h
(±60 m)
X
X
X
X
X
X
X
X
X
X
X
PACAP samplei
Predose,
EOIh 6, 12 h
24 h
48 h
X
X
X
X
X
X
Immunogenicity sample
Predose
X
X
X
X
X
X
Samples for infusion and 
hypersensitivity reactionsj
Predose
Non-genetic biomarker 
sample
Predose
X
PGx samplek
Predose

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Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16a
Study Day
-28
-1
1
2
3
5
7
9 
(-1 to 
+2)
15 
(±2)
22 
(±3)
29 
(±3)
43 
(±3)
57 
(±4)
71 
(±4)
85 
(±7)
141 / 
ED 
(±7)
Visit Type
S
A
I
I
D
O
O
O
O
O
O
O
O
O
O
O
Adverse events
X 
Concomitant medications
X 
Abbreviations:  A = CRU admission; BP = blood pressure; CRU = clinical research unit; D = CRU discharge; ED = early discontinuation; EOI = end of infusion; 
h = hour; I = inpatient stay; m = minute; O = outpatient; C3 = total complement C3; C4 = total complement C4; CRP = C reactive Protein; ESR = erythrocyte 
sediment rate; PACAP = pituitary adenylate cyclase-activating polypeptide; PGx = pharmacogenomics; S = screening.
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used: electrocardiogram, vital signs, and 
venipuncture.  Unless otherwise specified, predose samples may be taken at any time prior to dosing, based on CRU activity schedule.
a
in case of early discontinuation/withdrawal, the subject should undergo all Visit 16 activities.
b Height will be collected at Screening only.
c
Full medical assessment prior to first dose (on Day -1 or Day 1), discharge, and discontinuation visits. Symptom-driven medical assessment as deemed 
necessary by the Investigator.
d Day -1 samples/activities could be collected/performed up to 5 days before the scheduled day of dosing. The medical assessment, neurological examination 
and eligibility review may be performed pre-dose on Day 1. If screening visit is within 1 week (inclusive) of Day -1, neurological examination, ECG,  
hematology and chemistry do not need to be repeated.
e
Single electrocardiogram will be collected at Screening and CRU admission only. Triplicate electrocardiograms will be collected at all other timepoints.
f
Vital signs include blood pressure, pulse rate, and body temperature.  Single measurements at Screening and CRU admission.  Supine triplicate blood pressure 
and pulse rate at all other timepoints.
g Body temperature to be obtained as single measurement.
h End of infusion procedures are only required for Part A of the study – to be performed within 10 minutes from infusion completion.. 
i
Predose and 24 h (postdose) samples to be collected after at least 8 hours of fasting. PK samples on day 5 and beyond should be obtained at approximately 
(± 2 hr) the same time of day as the dosing time on day 1.
j
Samples for infusion reactions and hypersensitivity reactions will be collected and stored for all subjects. Post treatment samples (up to 3) will only be 
collected in subjects who experience moderate to severe infusion reactions or hypersensitivity reactions (as defined in Section 9.4.5.2).
k If sample not collected as indicated in Study Schedule table, it may be collected a following visit.

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3 Introduction
3.1 Study Rationale
LY3451838 is a fully human immunoglobulin G (IgG4-variant monoclonal antibody) that 
potently and selectively binds and neutralizes pituitary adenylate cyclase-activating polypeptide 
(PACAP).  LY3451838 will be assessed for clinical efficacy in primary headache conditions 
including prevention of episodic or chronic migraine and/or treatment of cluster headache.  This 
first-in-human study of LY3451838, J1H-MC-LAJA, will investigate the safety, tolerability, and 
pharmacokinetics (PK) of LY3451838 administered intravenously (IV) and subcutaneously (SC) 
in healthy subjects.
3.2 Background
PACAP is a member of the glucagon/secretin/VIP (Vasoactive Intestinal Peptide) family of 
neuropeptides.  The peptide is encoded by the ADCYAP1 gene and is expressed as a 
prepro-protein that undergoes posttranslational processing to either a PACAP27 or PACAP38 
form with the first 27 amino acids being identical.  PACAP is evolutionarily conserved with 
sequence identity across all mammalian species including rodent and primates.  PACAP is 
expressed in the central nervous system as well as in peripheral tissue.  As a neuropeptide found 
in neurons, PACAP undergoes release, and modulates adjacent synaptic activity.  The PACAP38 
form predominates in most tissues, though a greater percentage of PACAP27 localizes to the 
trigeminal ganglia, a potential site of action for headache disorders.
Migraine is a disabling neurological disorder typically characterized by recurring moderate-to-
severe, unilateral throbbing headache that lasts for 4-72 hours associated with varying 
combinations of nausea, vomiting, photophobia, phonophobia, and aggravation of symptoms by 
physical activity.  Plasma PACAP levels are elevated during a migraine attack (Zagami et al. 
2014). Human provocation studies have shown that PACAP38 administration induces migraine 
attacks in migraine patients. These data implicate PACAP in the pathophysiology of primary 
headaches including migraine.  
LY3451838 binds to both PACAP27 and PACAP38 with similar affinity. In the nonclinical 
pharmacology studies, LY3451838 blocked PACAP27 and PACAP38 activation of human 
PAC1, vasoactive intestinal polypeptide receptor 1 (VPAC1) and VPAC2 receptors, without 
blocking VIP activation of VPAC1 and VPAC2 in vitro. LY3451838 blocked PACAP38-
induced increases plasma cAMP in vivo. In addition, LY3451838 inhibits the trigeminal ganglia 
stimulation-induced increase in dura plasma protein extravasation. These data suggest 
LY3451838 may be effective for the migraine prevention by blocking the PACAP pathway in 
humans.
The toxicity of LY3451838 was assessed in 2-month rat and monkey studies and in an in vitro 
human tissue cross-reactivity study. In the tissue cross-reactivity study, there was no unexpected 
binding observed in a panel of human tissues. The rat and monkey studies used weekly SC
dosing of 0, 10, and 50 mg/kg and weekly IV dosing of 250 mg/kg.  There were no adverse 
effects in the rat study. In the monkey study, minimal-to-mild vascular/perivascular 

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inflammation was observed, but was attributed to immune complex deposition and, therefore, not 
expected to be relevant to human safety.  In addition to the vasculitis, which was not evident 
clinically, a greater incidence of transient neurological effects was observed in treated compared 
to control monkeys. This included decreased or absent flexor reflexes, proprioceptive 
positioning, placing reactions of limbs, and locomotor stereotypy all of which were considered 
nonadverse. More details about the toxicology studies are provided in Section 4 of the 
Investigator’s Brochure (IB 2018). 
3.3 Benefit/Risk Assessment
The nonclinical safety and pharmacology information for LY3451838 adequately supports the 
transition from preclinical status to a clinical, first-in-human study.  The risk evaluation of 
LY3451838 through its properties, nature of the target, non-clinical data in relevant species, 
target population and dose projections, suggest it not be considered a high risk molecule.
LY3451838 is a novel monoclonal antibody against PACAP, a neuropeptide that is expressed in 
both central nervous system and peripheral tissues. While pharmacology of this mechanism has 
not been directly evaluated in humans, AMG301, a monoclonal antibody against PAC1 receptor, 
has successfully completed phase 1 clinical testing, and is being evaluated for migraine 
prevention in an ongoing phase 2 trial. The study of AMG301 in phase 2 suggests that blocking 
at least part of the PACAP pathway did not lead to significant toxicity in humans.  The dose-
limiting toxicity of LY3451838 was minimal-to-mild vasculitis in multiple organs in monkeys 
assessed after 8 weekly IV doses of 250 mg/kg, similar to the presentation of vasculitis due to 
immune response in toxicology species observed with other monoclonal antibodies (Kronenberg
et al. 2017).  Immunohistochemistry studies of tissue samples from the 8-week monkey GLP 
toxicology study demonstrated that the vasculitis was due to immune complex deposition and 
complement activation. This type of immune response in a single animal species is considered to 
translate poorly to human safety (EMEA). For this first in human study, the highest dose is 
limited to 1500 mg, which is predicted to reach an exposure approximately 15-fold lower than 
the concentration in which vasculitis was observed in monkeys. In addition, PK data will be 
reviewed with each dose escalation, and an exposure limit will be implemented in this study so 
that the predicted mean exposure based on observed PK does not significantly exceed that of the 
no-observed-adverse-effect-level (NOAEL) exposure observed in monkeys.
Immunogenicity and hypersensitivity reactions, including infusion reactions, acute and delayed 
(including immune complex disease) hypersensitivity reactions are a potential risk for all 
monoclonal antibodies, including LY3451838. Hypersensitivity risk mitigation in this study 
includes the administration of a single dose of LY3451838 IV with subsequent close monitoring.
LY3451838 has not been administered to humans previously and accordingly this study has been 
designed following the principles outlined in the Guideline on Strategies to Identify and Mitigate 
Risks for First-in-Human Clinical Trials with Investigational Medicinal Products (EMEA CHMP
Jul 2017).  Any identified risks are considered to be monitorable and manageable at the planned 
dose range of 25 mg to 1500 mg single doses of LY3451838 in healthy subjects.
There is no anticipated therapeutic benefit for the subjects.

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More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY3451838 are found in the IB.

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4 Objectives and Endpoints
Table 4.1 shows the objectives and endpoints of the study.
Table 4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
Evaluate the safety and tolerability of a single 
dose of LY3451838 in healthy subjects

Adverse events

Serious adverse events
Secondary
Evaluate the pharmacokinetics of LY3451838 
in healthy subjects following a single dose of 
LY3451838.

AUC

Cmax
Exploratory
Assess immunogenicity of LY3451838
TEADA incidence and titers
Assess target engagement 
PACAP concentration
Abbreviations: AUC = area under the concentration-time curve; Cmax = maximum drug concentration; PACAP = 
pituitary adenylate cyclase-activating polypeptide; TEADA = treatment-emergent anti-drug antibodies

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5 Study Design
5.1 Overall Design
Study J1H-MC-LAJA is a first-in-human, Investigator- and subject-blind, placebo-controlled, 
randomized study in healthy subjects to evaluate the safety, tolerability, and pharmacokinetics of 
LY3451838.
The study will be comprised of 2 parts: Part A (single ascending dose with IV administration), 
and Part B (single dose SC administration).  Part B of the study will only be initiated if the 
review of safety and tolerability data from Part A are supportive.
Screening will occur in the 28 days prior to Day 1. Eligible subjects will be assigned sequentially 
into up to 8 cohorts, and randomly assigned within each cohort to receive LY3451838 or placebo 
in a 6:2 ratio. Subjects will be followed for safety / tolerability, PK and immunogenicity, and 
will be discharged from the study approximately 20 weeks after dosing.  If the investigator 
decides not to administer the first dose to a subject or not to enroll a subject on a particular day, 
the subject may be rescheduled to participate in the study and any procedures performed up to 
that point may be repeated.  Subjects who discontinue from the study (Section 8.2) before its 
completion are required to complete the early discontinuation (ED) procedures (Section 2) before 
their discharge from the study.
Figure 5.1.
Illustration of study design for Protocol J1H-MC-LAJA.
Abbreviations: D = day; W = week
5.1.1 Part A (Single Ascending Dose IV Administration)
Part A of the study is designed to assess the safety and tolerability of a single IV dose of 
LY3451838 compared to placebo in 6 cohorts of healthy subjects. Up to 6 doses of LY3451838 
at a planned dose range of 25 to 1500 mg will be evaluated. The planned dose levels for the 
6 cohorts are: 25, 75, 250, 500, 1000 and 1500 mg single dose via IV infusion.

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Eligible subjects will be admitted to the clinical research unit (CRU) on Day -1 and eligibility 
will be confirmed prior to dosing on Day 1.  Subjects will be confined for a minimum of 
48 hours postdose and may be discharged on Day 3 after all study procedures have been 
completed, at the discretion of the investigator.  Subjects will return to the CRU as outpatients at 
predetermined visits up to approximately 20 weeks postdose for safety assessment and collection 
of PK and immunogenicity samples, and will be discharged from the study if deemed appropriate 
by the investigator.  Subjects who discontinue from the study before its completion will be 
requested to attend an ED visit according to the schedule of activities (Section 2).
Safety will be assessed by monitoring of AEs, immunogenicity, electrocardiograms (ECGs), vital 
signs (blood pressure, pulse rate, body temperature, and respiratory rate), and physical and 
clinical laboratory tests.  
Sentinel dosing for the first 2 subjects of each cohort will be performed in a blinded manner, 
with 1 subject receiving LY3451838 and the other receiving placebo.  All safety data through 
Day 5 for these subjects will be evaluated prior to dosing the remaining subjects (5 LY3451838
and 1 placebo), who will be dosed no earlier than 7 days after dosing of the first 2 subjects.  All 
IV infusions will be administered sequentially, with one subject having completed the infusion 
administration before the next subject is dosed. These precautions enable close monitoring and 
management of potential for infusion and hypersensitivity reactions.
Subjects who are randomized but not administered treatment may be replaced to ensure that 
adequate subject data will be available for safety and exposure assessments in this phase of 
clinical development.  The replacement subject should be assigned to the same treatment arm as 
the discontinued subject.
The dose escalation decision to the next cohort will be made after review of safety data up to 
Day 15 and PK data from Day 2 of at least 5 subjects who received LY3451838 and 1 subject 
who receive placebo. Further information on dose escalation is provided in Section 7.4.1.
5.1.2 Part B (Single Dose SC Administration)
Part B is designed to assess safety, tolerability, and PK of LY3451838 after SC administration of 
LY3451838. A single dose of LY3451838 or placebo will be administered SC in up to 2 cohorts
(Cohorts 7 and 8) of 8 subjects each, in a 6:2 ratio. Cohort 7 dosing may be initiated after safety 
and tolerability data have been reviewed from the first 3 cohorts in Part A as described in 
Section 7.4.1, and may be conducted in parallel with Cohort 4 dosing in Part A. The planned 
dose level is 250 mg; however, the dose level may be adjusted based on all available data from 
the first 3 cohorts of Part A, and will be matched to that used in Cohort 3. Safety, tolerability,
and PK data from Cohort 7 will be reviewed to determine if Cohort 8 is necessary to explore 
additional properties of SC dosing regimen, such as different LY3451838 concentration in the 
formulation, however, the dose for Cohort 8 will match the dose tested in Cohort 7.
Sentinel dosing will not be implemented for Part B because the dose and exposure is expected to 
not exceed that of Cohort 3 in Part A.

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Eligible subjects will be admitted to the CRU on Day -1. LY3451838 or placebo will be 
administered SC on Day 1, with maximal number of injections not exceeding 4. Subjects will be 
discharged after completion of all Day 3 activities; and will return to the CRU for safety, PK,
and immunogenicity follow-up and end-of-study visits per Section 2.
Study governance is described in detail in Appendix 3.
5.2 Number of Participants
Up to 80 healthy subjects may be enrolled so that approximately 6 subjects in each dosing group 
(including that of pooled placebo groups in Part A) complete the study. Subjects who 
discontinued from the study before study completion may be replaced at the discretion of the 
sponsor.
A subject completes the study when all scheduled procedures shown in the Schedule of 
Activities (Section 2) have been finished.  
5.3 End of Study Definition
End of the study is the date of the last visit (Visit 16) shown in the Schedule of Activities
(Section 2) for the last subject.
5.4 Scientific Rationale for Study Design
This study is designed to evaluate safety, tolerability, and PK of LY3451838 after single IV and 
SC dose administration in healthy subjects to provide the most unbiased assessment of safety and 
tolerability in this first-in-human study.
Hypersensitivity reactions, including both acute hypersensitivity reactions and immune complex 
diseases, are potential risks for all therapeutic antibodies, including LY3451838. Subjects with a 
history of clinically significant hypersensitivity reactions / conditions, or autoimmune diseases 
are excluded from the study to minimize risks for hypersensitivity reactions in the subjects in this 
study, and to avoid confounded interpretation of the safety data. Additional measures will be 
implemented to monitor and manage infusion reactions (Section 7.4.3.2), immunogenicity, and 
hypersensitivity reactions (Section 9.6.1). While vasculitis observed in the monkey toxicology 
studies was attributed to immune complex deposition, additional precautions, such as reviewing 
PK data before each dose escalation, limiting the dose range and implementing the exposure to 
that of the monkey NOAEL are designed into the protocol to address the uncertainty of the 
mechanism for vasculitis.
Because of the distribution of PACAP in the nervous system, and to follow-up on the subtle 
non-adverse changes in the neurological examination in the 2-month monkey toxicology study, 
neurological examinations will be performed to detect any early signals on the effects of 
LY3451838 on the nervous system. 
Pharmacokinetic data will be used to guide dose escalation for all cohorts in Part A of the study; 
dose modification criteria are described in Section 7.4.1. Because the exposure after SC dosing is

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expected to be less than with IV dosing for the same dose, sentinel dosing is not required in Part 
B of the study.
The predicted half-life of LY3451838 is 12 days, based on the allometric scaling from monkey 
PK data.  A parallel-group design is used in both Part A and Part B of the study to avoid a 
prolonged washout period between doses and to avoid the potential to confound 
treatment-emergent antidrug antibody (TEADA) assessment.  The monitoring period for this 
study is approximately 20 weeks after the last dose.  This monitoring period duration supports
adequate immunogenicity monitoring during the washout of LY3451838.
All parts of the study will be placebo-controlled.  Study participants and investigators will be 
blinded to treatment assignment.  This design allows for a more objective assessment of AEs, 
and enables a comparison of the safety profile between different treatment groups.  The sponsor 
will not be blinded to the treatment assignment to enable prompt management of any emergent 
safety trend and to perform periodic review of PK and immunogenicity data.  Plans to maintain 
the blind are discussed in Section 7.3.
5.5 Justification for Dose
Based on current preclinical and toxicology data, a dose range of 25 mg to 1500 mg IV is 
proposed for the singe ascending dose (SAD).  
 
 
 
 
 
 
 
 
 
 
 
 
CCI

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CCI
CCI

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6 Study Population
Study eligibility will be determined by the history, physical examination, vital signs, clinical 
laboratory tests and electrocardiogram (ECG) at screening. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 28 
days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1 Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening as specified in the criteria below:
1. Are healthy male or female subjects, as determined by medical history and physical 
examination
a.
Male subjects must adhere to contraception restrictions specified in Section 6.3.5:
b. Female subjects of non-childbearing potential due to:
i. Menopause: spontaneous amenorrhea for at least 12 months not induced 
by a medical condition such as anorexia nervosa and not taking 
medications that induced the amenorrhea (e.g., oral contraceptives, 
hormones, gonadotropin releasing hormone, anti-estrogens, selective 
estrogen receptor modulators, or chemotherapy)
ii. Surgical sterilization
2. Are aged at least 21 to 65 years, inclusive, at screening
3. Have a body mass index of 18 to 35 kg/m2, inclusive, at screening
4. Have clinical laboratory test results within normal reference range for the population or 
investigative site, or results with acceptable deviations that are judged to be not clinically 
significant by the investigator at screening and enrollment
5. Have an estimated glomerular filtration rate ≥60 mL/minute/1.73 m2 at screening and 
enrollment; 
6. Have venous access sufficient to allow for blood sampling as per the protocol
7. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures

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8. Are able and willing to give signed informed consent approved by the sponsor and the 
Institutional Review Board (IRB) governing the site
6.2 Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
9. Are Eli Lilly and Company employees, employees of third-party organizations involved 
with this study, investigator or site personnel affiliated with this study, or the immediate 
family of any of these.  Immediate family is defined as a spouse, parent, child or sibling, 
whether biological or legally adopted
10. Are currently enrolled in, or discontinued from, within the last 30 days, a clinical trial 
involving an investigational drug or device or off-label use of a drug or device, or any 
other type of medical research judged not to be scientifically or medically compatible 
with this study
11. Have previously completed or withdrawn from this study or any other study investigating 
this study drug
12. Have a history or presence of medical illness including, but not limited to, any 
cardiovascular, hepatic, respiratory, hematological, renal, endocrine, psychiatric or 
neurological disease, or any clinically significant laboratory abnormality that, in the 
judgment of the investigator, indicates a medical problem that would preclude study 
participation
13. Have history (within past 5 years) of, or presence of, uncontrolled asthma, significant 
atopy, significant rheumatological or autoimmune diseases, including but not limited to 
systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's Syndrome 
(SS), or vasculitis; or have positive antinuclear antibody (ANA) that is considered to be 
clinically significant by the investigator, rheumatoid factor (RF), or anti-neutrophil 
cytoplasmic antibody (ANCA) at screening; or hereditary angioedema, or common 
variable immune deficiency.
14. Have had lymphoma, leukemia, or any malignancy within the past 5 years, or have had 
breast cancer within the past 10 years, except for basal cell or squamous epithelial 
carcinomas of the skin that have been resected with no evidence of metastatic diseases for 
3 years.
15. Have used or intended to use prescription or over the counter medications, including 
herbal medications within 14 days prior to dosing. Vitamins/ mineral supplements (not 
providing more than 100% of the recommended daily amount), occasional paracetamol 
and stable doses of thyroid hormone replacement are allowed.
16. 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, subjects with the 
following findings will be excluded:

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a.
Confirmed Fridericia’s corrected QT (QTcF) interval >450 msec for men and 
>470 msec for women. One additional ECG may be performed if necessary
17. 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
18. Have donated blood of more than 450 mL or have participated in a clinical study that 
required similar blood volume drawn within the past 3 calendar months.
19. Are unwilling to stop alcohol consumption while resident in the CRU.
20. Have an average weekly alcohol intake that exceeds 21 units per week for male subjects 
and 14 units per week for female subjects (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)
21. Are a current smoker of more than 10 sticks of cigarettes or the equivalent of other 
tobacco products per day and are unable/unwilling to stop smoking tobacco products 
while resident in the CRU.  Heavy smokers as per judgment of the investigator should be 
excluded from the study
22. Have an abnormal blood pressure (supine) defined as diastolic blood pressure >90 or 
<60 mmHg and/or systolic blood pressure >140 or <90 mmHg; or with minor deviation 
judged to be acceptable by the investigator.  Retesting may occur once during the 
screening visit within 2 hours of the initial abnormal blood pressure measurement at the
discretion of the investigator
23. Have clinically significant proteinuria or hematuria at screening and enrollment
24. Regularly use known drugs of abuse 
25. 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.
26. Have significant allergies to monoclonal antibodies, common antihistamines, 
epinephrine; or have significant allergies or intolerance to methylprednisolone or 
other systemic corticosteroids.
27. Have clinically significant multiple or severe drug allergies, or intolerance to 
systemic and topical corticosteroids, or severe post treatment hypersensitivity 
reactions (including, but not limited to, erythema multiforme major, linear IgA 
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis)
28. In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study
6.3 Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  

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6.3.1 Meals and Dietary Restrictions
Subjects will only consume meals provided by the CRU during inpatient study days. Otherwise, 
subjects will maintain their own dietary habit during the study.
6.3.2 Caffeine, Alcohol, and Tobacco
Consumption of caffeine- and xanthine-containing products is allowed provided that the 
subject’s consumption has been consistent for the past 30 days.  However, during the inpatient 
days, consumption of caffeinated drinks may be limited to 2 servings each day.
Subjects will not be permitted to consume alcohol from 48 hours before each visit/admission 
until discharge from the CRU.  When not resident in the CRU, male subjects should be advised 
to limit alcohol consumption to no more than 21 units per week, and female subjects to no more 
than 14 units per week.  All subjects should be advised to limit alcohol consumption to no more 
than 3 units in a day and not to exceed their habitual alcohol consumption during the study.  
Subjects will not be permitted to use tobacco-containing products from 48 hours prior to 
admission or outpatient visits to the CRU until discharge from the CRU.  
6.3.3 Activity
Subjects must refrain from strenuous exercise throughout the study.
6.3.4 Blood Collection
Blood collection via venous catheter during inpatient days.
6.3.5 Male Contraceptive Requirements
Male subjects, regardless of their fertility status, with non-pregnant female partners of 
childbearing potential must agree to either remain abstinent (if this is their preferred and usual 
lifestyle) or use condoms as well as one additional highly effective (less than 1% failure rate) 
method of contraception (such as combination oral contraceptives, implanted contraceptives, or 
intrauterine devices) or effective method of contraception (such as diaphragms with spermicide 
or cervical sponges) for 90 days after study drug dosing.
Men and their partners may choose to use a double–barrier method of contraception.  Barrier
protection methods without concomitant use of a spermicide are not an effective or acceptable 
method of contraception.  Thus, each barrier method must include use of a spermicide.  It should 
be noted, however, that the use of male and female condoms as a double barrier method is not 
considered acceptable due to the high failure rate when these barrier methods are combined.
Male subjects with pregnant partners should use condoms during intercourse for the duration of 
the study and until the end of estimated relevant potential exposure in women of childbearing 
potential, predicted to be 90 days following last dose of study drug.
Male subjects should refrain from sperm donation for the duration of the study and until 90 days 
following last dose of study drug.

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Male subjects who are in exclusively same sex relationships (as their preferred and usual 
lifestyle) are not required to use contraception.
6.4 Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be
re-screened, although screening tests such as labs, vital signs / ECGs may be repeated at the 
discretion of the investigator. Subjects who meet the enrollment criteria, yet are not enrolled 
within 28 days may be enrolled on a later date, as long as the enrollment criteria are met on 
Day -1.

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7 Treatment
7.1 Treatment Administered
LY3451838 and/or placebo will be administered IV or SC.
Part A: The planned dose levels of LY3451838 are 25 mg, 75 mg, 250 mg, 500 mg, 1000 mg, 
and 1500 mg.  LY3451838 will be administered IV.  
After overnight fasting (with water restriction at least 2 hours before dosing), the study drug will 
be administered as a slow IV infusion over at least 30 minutes for the first 4 cohorts, or over at 
least 60 minutes for cohorts 5 and 6. Infusion duration may be increased or stopped as deemed 
necessary based on the standard operation procedure, or if an infusion reaction is observed
(Section 7.4.3.2). Sites must have resuscitation equipment, emergency drugs, and appropriately 
trained medical staff available during the infusion and for at least 6 hours after subjects have 
completed their infusion.  The actual start and stop time of infusion will be recorded in the 
electronic data capture (EDC). If the infusion is terminated early, this will also be recorded in the 
EDC. Subject may resume water at least 1 hour after the infusion is completed, and resume 
meals at least 2 hours after the infusion is completed.
Section 7.4 details dose modifications.
Part B: The planned dose level of LY3451838 in Part B is 250 mg. The dose may be adjusted 
based on all available data from first 3 cohorts of Part A, the SC dose is intended to match the 
dose of Cohort 3 in Part A. After overnight fasting (with water restriction at least 2 hours before 
dosing), the study drug will be administered SC in the abdominal area.  Subject may resume 
water at least 1 hour after the injection is completed, and resume meals at least 2 hours after the 
injection is completed. Subcutaneous injections should be administered to the abdominal region 
approximately 5 cm from the umbilicus and the treatment administered with the needle applied at 
an appropriate angle, with pinching of the skin if necessary.  Sites must have resuscitation 
equipment, emergency drugs, and appropriately trained personnel available for at least 6 hours 
after subjects have completed their dosing. The actual dosing time will be defined as the time 
that the injection starts, and will be recorded in the EDC. Only a limited number of individuals 
will perform SC administration of LY3451838 for consistency reasons.  The same type of 
syringe and needle should be used for all subjects to ensure that injections are delivered to a 
consistent depth target into the SC space.
LY3451838 Drug Product is a monoclonal antibody formulated for IV or SC administration. 
LY3451838 for Injection is supplied for clinical trial use as a solution in a single-use glass vial. 
The vial is manufactured to deliver 200 mg of LY3451838 at 50 mg/mL or 100 mg/mL. In order 
to ensure complete withdrawal and delivery of the label amount of 200 mg of LY3451838, vials 
contain an approximate 10% volume overfill. The drug product is filled into a glass vial, and 
sealed with a stopper and flip-off 2 piece aluminum seal. LY3451838 for Injection vials are 
stored in refrigerated condition (2ºC to 8ºC).
This study is double-blinded and the placebo prepared at the site by unblinded dispensing 
personnel will be 0.9% sodium chloride for injection, BP.  This solution is indistinguishable in 

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appearance from the reconstituted active drug solution. Study drug preparation will be conducted 
and verified by unblinded personnel. Study drug will be administered by blinded personnel.
The unblinded dispensing personnel will receive training and instructions for preparation of each 
dose of LY3451838 and the preparation of the placebo solutions.
The investigator or designee is responsible for:

explaining the correct use of the study drug to the subjects

verifying that instructions are followed properly

maintaining accurate records of study drug dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.
7.1.1 Packaging and Labeling
The drug product will be manufactured, tested, packaged, and labeled in accordance with all 
applicable Good Manufacturing Practice (GMP) requirements and country’s regulatory 
requirements.  A certificate of analysis confirming the materials are released for human use in 
clinical trials will be supplied.  LY3451838 drug products are for investigational use only and are 
to be used only within the context of this study.
7.2 Method of Treatment Assignment
In both parts of the study, within each cohort, eligible subjects will be enrolled sequentially, and 
will be randomly assigned to receive either LY3451838 or placebo in a 6:2 ratio.  Treatment 
assignment will be determined by a computer-generated randomization sequence using an 
interactive web response system (IWRS).
7.2.1 Selection and Timing of Doses
The single dose of the study drug will be administered at the CRU by a trained staff member.
7.3 Blinding
The study is double-blinded; subjects, investigator, and CRU personnel performing trial-related 
activities or with the ability to influence study outcomes will be blinded with respect to 
LY3451838 and placebo treatment.  To preserve the blinding, only a minimum number of Lilly 
personnel may have access to the randomization table and codes or IWRS before the study is 
complete.  Site staff who are responsible for drug preparation will not be blinded; laboratory 
personnel will also not be blinded.  
Emergency unblinding will be performed through the IWRS. This option may be used only if the 
subject’s well-being requires knowledge of the subject’s treatment assignment. All unblinding 
events will be recorded and reported by the IWRS.

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In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a subject’s treatment assignment is warranted for medical management of the 
event. The subject’s safety must always be the first consideration in making such a 
determination. If the Investigator decides that unblinding is warranted, it is the responsibility of 
the Investigator to promptly document the decision and rationale and notify Lilly as soon as 
possible.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the Investigator obtains specific approval from a Lilly medical monitor for the 
study participant to continue in the study.  During the study, emergency unblinding should occur 
only by accessing the IWRS.
7.4 Dose Modification
Dose levels, sampling schedule, timing of procedures (e.g., time of PK sample collection, ECGs) 
may be adjusted in view of emerging safety or PK data during the study.  If considered 
appropriate, previous dose levels may be repeated, or lower/intermediate dose levels may be 
tested. The magnitude of the dose escalation may be reduced after data review.  Since these 
adjustments to timings or dose levels are allowable changes permitted by the protocol, they will
not require a protocol amendment.  
A Safety Review Panel (SRP), comprising experts in early phase medicine independent of the 
study team and investigative site, will be established by the sponsor.  Any changes to the 
protocol planned dose levels, together with the supporting data, will be reviewed and approved 
by the SRP before implementation.
7.4.1 Dose Escalation in Part A
Safety and PK data will be the primary criteria for the dose escalation.  In addition, if available at 
the time of dose escalation decision, antidrug antibody (ADA) data will be used as supporting 
data for dose escalation, but such data are not required.  No dose decision can occur without 
prior discussion and agreement between the investigator and the Lilly medical monitor.
Six dose levels are planned for Part A.  Safety data up to Day 15 and PK data up to Day 2 from 
at least 5 subjects who received LY3451838 and 1 subject who received placebo will be 
reviewed before each dose escalation decision can be made.
After review of these data, an agreement on the appropriate dose will be made by the investigator 
and sponsor for the next cohort/dose level.  The magnitude of dose escalations may be adjusted 
following data review.  The dose will not exceed 1500 mg.
7.4.1.1 Stopping Rules
If any of the following occur, dosing at the current level and further dose escalation will be 
discontinued:
1. A single subject experiences an SAE that is related to LY3451838

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a.
If an SAE occurs during the infusion of study drug, irrespective of causality, the 
study drug is discontinued immediately in that subject.  No redosing or 
completion of dosing is considered for that subject regardless of causality.  If the 
infusion SAE is considered related to LY3451838, then the remaining subjects in 
that cohort are not dosed.
2. Two or more cumulative subjects develop clinically significant acute infusion AEs 
considered related to LY3451838 during or within 6 hours of completing the infusion that 
do not resolve with a reduced infusion rate and/or supportive care.
3.
Two or more cumulative subjects develop clinically significant hypersensitivity AEs 
considered related to LY3451838
4. Two or more cumulative subjects experience similar clinically significant events (CSEs) 
considered related to LY3451838.  A CSE will be defined as a moderate-to-severe AE, 
abnormal clinical sign, or clinical laboratory finding that may pose a risk to the 
well-being of the subject.
5. 50% or more subjects at a dose level experience moderate or severe AEs that impair 
normal activities, but do not meet the CSE criteria, and are considered related to 
LY3451838.
Two or more subjects experience severe adverse reactions, irrespective of their nature.
7.4.2 Decision to Initiate Part B
No dose escalations are planned in Part B.  The dosing will begin only after review of safety data 
from the first 3 cohorts of Part A indicates no stopping rules (specified in Section 7.4.1.1) are 
met.  The dose for Part B will be the same as that of Cohort 3 of Part A, unless adjustment is 
required based on the review of available safety and PK data.
7.4.3 Special Treatment Considerations
7.4.3.1 Premedication for Infusions
Premedication for the infusions is not planned.  However, if an infusion reaction occurs, 
appropriate medication may be used as determined by the study investigator(s).  If infusion 
reactions are observed, but review of the data suggests that dose escalation may continue, 
administration of acetaminophen, 500 to 1000 mg, and/or an antihistamine (such as 
chlorpheniramine or its equivalent) may be administered orally 30 to 60 minutes prior to the start 
of infusion for subsequent subjects.
The decision to implement premedication for infusions in subsequent cohorts will be made by 
the investigator and sponsor and recorded in the study documentation, along with the dose-
escalation decision.
Any premedications given will be documented as a concomitant therapy (see Section 7.7).

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7.4.3.2 Management of Infusion Reactions
There is a risk of infusion reaction with any biological agent; therefore, all subjects should be 
monitored closely.  Symptoms and signs that may occur as part of an infusion reaction include, 
but are not limited to: fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, 
throat irritation, rash, pruritus, myalgia, and dizziness.  In the event that a significant infusion 
reaction occurs, the following guidance should be followed:

The drug product infusion should be slowed (for example, reduce infusion rate by 50% 
[for example, an infusion rate of 12 mL/hr becomes 6 mL/hr or slower]) or stopped based 
on severity and in accordance with the investigator’s assessment:
o
if slowed, the infusion should be completed at the slower rate, as tolerated
o
if determined by the investigator that the infusion should no longer continue, no 
further attempts to dose the subject should be made

Supportive care will be administered as required

If it is determined the subject should not receive further doses of study drug, the subject
should complete adverse event and other follow-up procedures per Section 2 of this 
protocol.
Storage samples should be collected for possible immune safety laboratory testing 
(Section 9.4.5.2).
7.5 Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by Sponsor, during transit for all study drug received and any 
discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study drug or study materials, and only 
authorized site staff may supply or administer study drug. All study drug should be stored in an
environmentally controlled and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation and final disposition records).
Detailed instructions for the preparation and handling of LY3451838 will be provided to the 
unblinded site pharmacy personnel by the Sponsor.
Vials of LY3451838 are stable and must be stored refrigerated (2ºC to 8ºC).
7.6 Treatment Compliance
The study drug will be administered at the CRU, and documentation of treatment administration 
will occur at the site.

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7.7 Concomitant Therapy
Subjects on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  These medications will be reviewed by the 
investigator at screening and eligibility will be determined.  
Occasional acetaminophen (<2 g/ 24 hours), stool softeners, or medication of topical use without 
prior consultation with Lilly medical monitor is allowed. Additional drugs are to be avoided 
during the study unless required to treat an AE, or if used as a premedication prior to infusion.
If the need for other concomitant medication arises, inclusion or continuation of the subject may 
be at the discretion of the investigator preferably after consultation with a Lilly medical monitor.  
Any medication used during the course of the study must be documented.
7.8 Treatment after the End of the Study
Not applicable.

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8 Discontinuation Criteria
Subjects discontinuing from the study prematurely for any reason must complete adverse event 
and follow-up procedures per Section 9.2 of this protocol.
8.1 Discontinuation from Study Treatment
Subjects may be discontinued from the study treatment if an SAE occurs during the study drug 
infusion, or injections irrespective of causality. 
Subjects in Part A who discontinue from treatment before infusion end for any reason should 
complete ED procedures per Section 2 of this protocol, after AE follow up is completed.
Subjects in Part B who discontinue from the treatment before all injections have been completed 
may be allowed to complete the rest of the study activities (according to the planned Schedule of 
Activities in Section 2). The decision to allow a subject to complete the study activities should be 
made jointly by both sponsor and investigator, and only if the reason for discontinuation does not 
affect the interpretation of the safety and PK/PD data, and continuation of the study activities 
does not increase risks for the subject. If it is decided that the subject should be discontinued 
from the study, subject should complete ED procedures according to Schedule of Activities. 
8.1.1 Discontinuation of Inadvertently Enrolled Subjects
If the Sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly medical monitor and the 
investigator to determine if the subject may continue in the study.  If both agree it is medically 
appropriate to continue, the investigator must obtain documented approval from the Lilly 
medical monitor to allow the inadvertently enrolled subject to continue in the study with or 
without continued treatment with study drug.  
8.2 Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving any study drug or enrollment in any 
other type of medical research judged not to be scientifically or medically compatible 
with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Subject Decision

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o
The subject requests to be withdrawn from the study.

Termination of the study by the Sponsor or regulatory authorities
8.3 Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the CRU.  The CRU personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the CRU.
Subjects who withdraw from the study before completion of all study activities may be replaced 
at the discretion of the Sponsor.

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9 Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual time must be recorded correctly in the EDC.  Failure or delays 
(i.e. outside stipulated time allowances) in performing procedures or obtaining samples due to 
legitimate clinical issues (e.g. equipment technical problems, venous access difficulty, or subject 
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will still be required to notify the sponsor in writing via a file 
note for data reconciliation purpose.  
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1 Efficacy Assessments
Not applicable.
9.2 Adverse Events
A clinical trial AE is any untoward medical event associated with the use of a drug or drug 
delivery system in humans, whether or not it is considered related to that drug or drug delivery 
system.
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The Investigator is responsible for the appropriate medical care of subject during the study.
Investigators must document their review of each laboratory safety report.
The Investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the study drug or the 
study related procedure, or that caused the subject to discontinue the study drug before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the Investigator.

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After the informed consent form (ICF) is signed, the CRU personnel will record, via EDC, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
Injection site reactions should be captured as AEs. Additional information including the time of 
day, time relative to injection, size, amount of erythema, induration, and pruritus will be 
recorded.
If a subject’s study drug is discontinued as a result of an AE, CRU personnel must report this to 
Lilly or its designee via EDC.
9.2.1 Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
The CRU personnel must alert the Lilly medical monitor, or its designee, of any SAE as soon as 
practically possible.
Additionally, CRU personnel must alert Lilly Global Patient Safety, or its designee, of any SAE 
within 24 hours of Investigator awareness of the event via a Sponsor-approved method.  If alerts 
are issued via telephone, they are to be immediately followed with official notification on study-
specific SAE forms.  This 24-hour notification requirement refers to the initial SAE information 
and all follow-up SAE information.
Although all AEs are recorded in the case report form or EDC after signing informed consent, 
SAE reporting to the Sponsor begins after the subject has signed informed consent and has 
received the study drug.  However, if an SAE occurs after signing informed consent, but prior to 
receiving the study drug, AND is considered Reasonably Possibly Related to a study procedure 
then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study.  Serious adverse events will be collected for 

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30 days after the last dose of study drug.  However, if the Investigator learns of any SAE, 
including a death, at any time after a subject has been discharged from the study, and he/she 
considers the event reasonably possibly related to the study treatment or study participation, the 
Investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to the study drug) does not meet the definition of an 
adverse event.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
The designated medical monitor of the Sponsor will monitor safety data throughout the course of 
the study. The Sponsor and/or its designee will review SAEs within appropriate timeframes to 
meet reporting obligations imposed by regulatory authorities. All serious and unexpected AEs 
for this study will be reported to regulatory authorities in accordance with local laws, directives, 
and regulations.
9.2.1.1 Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to study drug.  Lilly has procedures that will 
be followed for the recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidance.
9.2.2 Complaint Handling
Lilly collects product complaints on study drugs used in clinical trials in order to ensure the 
safety of study participants, monitor quality, and to facilitate process and product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug so that the situation can be assessed.
9.3 Treatment of Overdose
An overdose is not anticipated, as the study drug will be administered by a trained staff member.
Refer to the IB for treatment of overdose. 
9.4 Safety
9.4.1 Medical Assessment and Neurological Examinations
A complete medical assessment will be performed at times specified in Section 2. 
Symptom-driven assessments will be performed if deemed clinically necessary. 
A directed neurological examination will be performed by a physician at the time points 
specified in the Study Schedule (Section 2).  If abnormalities are noted at these time points, 
additional examinations should be performed at daily intervals until the subject has returned to 
baseline.  The examiner should be familiar with the subject’s baseline examination.  Mandated 
elements of the examination include inspection for cranial nerves, tremor, extraocular 
movements, brachial and patellar deep tendon reflexes, finger-nose pointing, and Romberg sign.  

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Work up for subjects with clinically significant changes in neurological examination should be 
considered. 
9.4.2 Vital Signs
For each subject, vital signs, including blood pressure, pulse rate and temperature measurements 
should be conducted according to the Schedule of Activities (Section 2).
Single measurements will be taken at Screening and CRU admission.  Supine triplicate blood 
pressure and pulse rate will be collected at all other timepoints.  Body temperature to be obtained 
as single measurement. Predose vital signs should be taken approximately 1 hour prior to the 
schedule dosing.
At time points when orthostatic measurements are obtained, subjects should be supine for at least 
5 minutes and stand for approximately 2 minutes.  When triplicate blood pressure or pulse rate
measurements precede the orthostatic measurement, the last supine blood pressure or pulse rate
measurement will be used for orthostatic calculations. If the subject feels unable to stand, supine 
vital signs only will be recorded.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.4.3 Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
With the exception of safety laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor, if a central vendor is used for the study.
9.4.4 Electrocardiograms
For each subject, a 12-lead digital ECG will be collected in triplicate according to the schedule 
of activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 
samples.  Subjects must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection.  Consecutive replicate ECGs will be obtained at 
approximately 1-minute intervals.  Electrocardiograms may be obtained at additional times, 
when deemed clinically necessary.  
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant visits 
and for immediate subject management, should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the subject can continue in the study.  The investigator 

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or qualified designee is responsible for determining if any change in subject management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point.
9.4.4.1 Digital Electrocardiogram Storage
Digital ECGs collected from both parts of the study will be electronically transmitted to a central 
ECG laboratory designated by Lilly.  The central ECG laboratory will perform a basic quality 
control check (for example, demographics and study details) then store the ECGs in a database.  
At a future time, the stored ECG data may be overread at the central ECG laboratory for further 
evaluation of machine-read measurements or to meet regulatory requirements.  
The machine-read ECG intervals and heart rate will be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report, in which case the overread data would be used.
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the study drug, should be reported to Lilly, or its designee, as an 
AE via EDC. 
9.4.5 Safety Monitoring
The Lilly medical monitor will monitor safety data throughout the course of the study.
9.4.5.1 Hepatic Safety
If a study subject experiences elevated alanine aminotransferase (ALT) ≥3X upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2X ULN, or elevated total bilirubin (TBL) ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, aspartate 
aminotransferase (AST), ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and 
creatinine kinase to confirm the abnormality and to determine if it is increasing or decreasing.  If 
the abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator based on consultation with the Lilly medical monitor.  Monitoring should continue 
until levels normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥ 5X ULN on two or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥ 2X ULN on 2 or more consecutive blood tests 

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be a SAE.

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9.4.5.2 Hypersensitivity reactions
Acute and serious hypersensitivity reactions will be assessed and managed as clinically indicated.
The clinical information, including examination findings, laboratory testing and treatment for all 
serious adverse events, including hypersensitivity reactions, will be captured in the EDC.
Non-acute hypersensitivity reactions, including type 3 hypersensitivity reaction will be assessed 
by clinical presentation.  Routine monitoring of vital signs with regular physical examinations, 
and laboratory testing (including hematology, liver and renal testing, complements C3 and C4, c-
reactive protein [CRP] and erythrocyte sedimentation rate [ESR], and urine analysis) will be 
undertaken to assess for the development of vasculitis, serum sickness and other manifestations 
of type 3 hypersensitivity reactions. 
Stored serum samples for possible immune safety laboratory testing (including, but not limited 
to:  β-tryptase, total IgE, immune-complex testing, and cytokine panel) will be collected for all 
subjects before study drug administration (Section 2).  Additional, unscheduled, stored serum 
samples for possible immune safety laboratory testing should also be collected approximately 60 
to 120 minutes and 4 to 6 weeks after moderate or severe infusion reactions or hypersensitivity 
reactions.
9.5 Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 2 mL each will be collected to determine the serum concentrations of
LY3451838.  The sampling times may be modified at the discretion of the sponsor, based on 
review of interim PK data as they become available.  
The actual date and time of each sampling must be recorded.
9.5.1 Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Serum concentrations of LY3451838 will be assayed using a validated ELISA (enzyme linked 
immunosorbent assay).  Placebo samples are not planned to be analyzed.
Bioanalytical samples collected to measure study drug concentrations will be retained for a 
maximum of 1 year following last subject visit for the study.  
9.6 Pharmacodynamics
9.6.1 Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 10 mL each will be collected to determine antibody production against 
LY3451838. In the event of drug hypersensitivity reactions (immediate or non-immediate), 
additional samples will be collected as close to the onset of the event as possible, at the 
resolution of the event, and 30 days following the event. Blood samples for LY3451838 and 
PACAP concentration will be collected concurrently with these unscheduled immunogenicity 

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samples. Instructions for the collection and handling of blood samples will be provided by the 
sponsor.  The actual date and time of each sampling will be recorded.
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of the study drug at a laboratory approved by the sponsor.  Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study drug.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and Ethical Review Boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
study drug.  Any samples remaining after 15 years will be destroyed.
9.6.2 Exploratory Assessment of PACAP Concentration
At the visits and times specified in the Schedule of Activities (Section 2), blood samples of 
approximately 10 mL each will be collected to determine the PACAP plasma concentration.
Blood samples for PACAP concentration measurement will be stored for up to 5 years, and may 
be used to explore the effects of LY3451838 on other biomarkers related to target engagement 
and/or migraine / cluster headache pathology.
9.7 Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to study 
drug.  Assessment of variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.
Molecular technologies are expected to improve during the 15 year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.8 Biomarkers
Biomarker samples relevant to drug disposition, target engagement, PD, mechanism of action, 
variability of patient response (including safety), and clinical outcome will be collected.  This 
may include genetic testing (DNA, RNA), proteins, lipids, and other cellular elements as well as 
metabolic assays.

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Serum and plasma samples for non-pharmacogenetic biomarker research will be collected at the 
times specified in the schedule of activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to
LY3451838, pathways associated with migraine, mechanisms of action of LY3451838, research 
methods, or for validating diagnostic tools or assays related to migraine or other primary 
headaches.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRBs impose shorter time limits, at a facility selected by Lilly 
or its designee.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of LY3451838 or after LY3451838 is commercially available.
9.9 Health Economics
This section is not applicable for this study.

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10 Statistical Considerations and Data Analysis
10.1Sample Size Determination
The sample size is customary for Phase 1 studies evaluating safety and PK, and is not powered 
on the basis of statistical hypothesis testing.
Subjects who are randomized but not administered treatment may be replaced to ensure that 
enough subjects may complete the study.
10.2Populations for Analyses
10.2.1
Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. All subjects 
who discontinue from the study will be identified, and the extent of their participation in the 
study will be summarized by treatment.  If known, a reason for their discontinuation will be 
given.
10.2.2
Study Participant Characteristics
Subject demographics (age, gender, race, ethnicity, height, weight, and body-mass index [BMI]) 
will be summarized by treatment. 
10.3Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee. Statistical analyses will be detailed in the statistical analysis plan.
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least one 
dose of the study drug and have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
For continuous variables, summary statistics will include number of subjects, mean, median, 
standard deviation, minimum, and maximum.  Categorical endpoints will be summarized using 
number of subjects, frequency, and percentages.
10.3.1
Safety Analyses
All treatment and protocol procedure AEs will be listed, and if the frequency of events allows, 
safety data will be summarized using descriptive methodology. Summary statistics for AE and 
SAE will be provided by dose level and for all placebo subjects combined. 

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Safety assessments include laboratory tests, vital signs, ECGs, injection site reactions, and 
physical examination.  The parameters will be listed, and summarized using standard descriptive 
statistics.  Additional analysis will be performed as required.
10.3.2
Pharmacokinetic Analyses
10.3.2.1
Pharmacokinetic Parameter Estimation
All subjects dosed with LY3451838 who have evaluable concentrations will be included in the 
PK analyses.  Pharmacokinetic parameter estimates for LY3451838 will be computed by 
standard non-compartmental methods.
The primary PK endpoints for analysis will be Cmax and AUC of LY3451838.  Other PK 
endpoints such as half-life, apparent clearance, apparent volume of distribution, and absolute 
bioavailability may be reported.
Mean and individual LY3451838 plasma concentration-time curves will be graphically 
presented. The PK endpoints will be summarized using descriptive statistics.
The relationship between LY3451838 PK and PD and/or safety measures may be evaluated.  
Other analyses may be performed as needed.
10.3.2.2
Pharmacokinetic Statistical Inference
Dose proportionality for exposure (AUC, Cmax) may be assessed using the power model 
approach, as appropriate. Additional analyses may be performed if deemed necessary.
10.3.3
Exploratory Pharmacodynamic Analyses
Summary statistics for each exploratory endpoint may be provided by dose level and time for 
subjects randomized to LY3451838 and for all placebo subjects combined. Additional analyses 
may be conducted as appropriate.
10.3.4
Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with TEADA+ to 
LY3451838 will be tabulated.  Treatment-emergent ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline if ADAs were detected at baseline (treatment-boosted ADA).  For the TEADA+ 
subjects, the distribution of maximum titers will be described.  The frequency of neutralizing 
antibodies may also be tabulated in TEADA+ subjects.
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to LY3451838 may be assessed.
10.3.5
Data Review During the Study
Interim access to safety data is scheduled to occur throughout the study.  The investigator and the
Lilly medical monitor will make the determination regarding dose escalation based on their 
review of the blinded safety, tolerability and PK data.  Review of ADA data is scheduled on a

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rolling basis throughout the study to guide dose selections.  Individual PK/PD/ADA data will not 
be reviewed by the investigator until the study is complete to avoid unblinding. A small number 
of individuals from Lilly sponsor team will be unblinded during these reviews.   
10.3.6
Interim Analyses
At least 1 interim analysis is planned for this study. It will be conducted after the 12-week ADA 
data from the first two cohorts are available. All available safety, tolerability, PK and ADA data 
up to that point will be reviewed by the sponsor. The interim analysis will be used to guide the 
design of this and subsequent studies.
Additional interim analyses may be conducted without protocol amendment, as the primary 
objective for this study is not based on inferential statistical analyses.  No adjustments for 
multiple comparisons will be made.

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11 References
[EMEA CHMP] European Medicines Agency. Guidance on strategies to identify and mitigate 
risks for first-in-human and early clinical trials with investigational medicinal product. 
Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC50
0232186.pdf. Accessed on 27 Aug 2018.
[IB] Eli Lilly and Company. Investigator’s Brochure for LY3451838, Sep 2018.
Kronenberg S, Husar E, Schubert C, Freichel C, Emrich T, Lechmann M, et al. Comparative 
assessment of immune complex-mediated hypersensitivity reactions with biotherapeutics in 
the non-human primate: Critical parameters, safety and lessons for future studies. Regulatory 
Toxicology and Pharmacology. 2017;88:125-137.
Zagami AS, Edvinsson L, Goadsby PJ. Pituitary adenylate cyclase activating polypeptide and 
migraine. Annals of Clinical and Translational Neurology. 2014;1(12):1036-1040.

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
antidrug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal
(investigational) product.
ANA
antinuclear antibody
ANCA
Anti-cytoplasmic antibody
AUC
area under the concentration-time curve
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not. A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received
BP
blood pressure
CGRP
calcitonin gene-related peptide
Cmax
maximum drug concentration
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.
CRP
C-reactive protein
CRU
clinical research unit
CSE
clinically significant event
ED
early discontinuation
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.

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IRB
institutional review board
ESR
erythrocyte sedimentation rate
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate. Informed consent is documented by means of a 
written, signed and dated informed consent form.  
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
Intravenous
MABEL
minimal anticipated biological effect level
MTD
maximum tolerated dose
NOAEL
no observed adverse effect level
randomize
the process of assigning subjects to an experimental group on a random basis
PACAP
pituitary adenylate cyclase-activating polypeptide
PK/PD
pharmacokinetic/pharmacodynamic
RA
rheumatoid arthritis
RF
rheumatoid factor
SAE
serious adverse event
SC
Subcutaneous
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.  
SLE
systemic lupus erythematosus
SUSARs
suspected unexpected serious adverse reactions
SS
Sjogren’s Syndrome

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SRP
Safety Review Panel
TEADA
treatment-emergent anti-drug antibodies
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
tmax
time to Cmax
VPAC
vasoactive intestinal polypeptide receptor
VIP
vasoactive intestinal peptide 

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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistryb
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Glucosea
Leukocytes (WBC)
Blood urea 
Platelets
Total cholesterol
Differential WBC [Absolute counts] of:
Total protein
Neutrophils
Albumin
Lymphocytes
Total bilirubin/direct bilirubin
Monocytes
Alkaline phosphatase (ALP)
Eosinophils
Aspartate aminotransferase 
(AST)
Basophils
Alanine aminotransferase (ALT)
Erythrocyte sedimentation rate (ESR)
Creatinine
C-reactive protein (CRP)
Total complement C3 (C3)
Total complement C4 (C4)
Urinalysis
Specific gravity
pH
Hepatitis B surface antigenc
Protein
Hepatitis C antibodyc
Glucose
HIV
c
Ketones
Pregnancy test (urine)
Bilirubin
Urobilinogen
Blood
Nitrite
Leukocytes
Microscopyd
Antinuclear antibody (ANA)c
Rheumatoid factor (RF)c
Anti-neutrophil cytoplasmic antibody (ANCA)c
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; C3 = Total 
complement C3; C4 = Total complement C4.
a
Fasting glucose performed at Screening, Predose and 24 h (postdose) only
b Results of these assays will be validated by the local laboratory at the time of testing. Additional tests may be 
performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed. Some of the 
above parameters are calculated from measured values. Omission of calculated values will not be considered as a 
protocol violation.

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c
Performed at screening only
d If clinically indicated, per investigator’s discretion.  

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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject.  This includes obtaining the 
appropriate signatures and dates on the ICF prior to the performance of any protocol 
procedures and prior to the administration of investigational product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  Individual 
investigators may have additional local requirements or processes.  Study specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by ICH guidelines and other applicable laws and 
regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the CRU.  Lilly or its representatives must approve the ICF before it is used 
at the CRU.  All ICFs must be compliant with the ICH guideline on GCP.
The CRU’s ERB(s) should be provided with the following:

the current IB 

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:

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1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
Final Report Signature
The Sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the CRU, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the CRU.

be available for consultation and stay in contact with the CRU personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the CRU.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data

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An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the Sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly medical monitor or its designee.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
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, total
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability

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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol J1H-MC-LAJA Sampling Summary – Part A and B
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
21
1
21
Hematology and chemistry -
laboratory tests (fasting)a
10
2
20
Hematology and chemistry -
laboratory tests (non-fasting)a
8
13
104
Pharmacokinetics 
2
19
38
Blood discard for cannula patency
0.3
8
2.4
Pharmacodynamics (PACAP)
10
12
120
Immunogenicity
10
7
70
Pharmacogenetics
10
1
10
Non-pharmacogenetics
10
2
20
Infusion/Hypersensitivity 
reactionsa
8.5
1
8.5
Total
413.9
Total for clinical purposes [rounded up to nearest 10 mL]
420
a
CRP, ESR, C3 and C4 will be tested using chemistry and/or hematology samples. Additional samples, including 
for hypersensitivity analyses, may be drawn if needed for safety purposes.

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Appendix 6.
Protocol Amendment J1H-MC-LAJA(a) 
Summary
Protocol J1H-MC-LAJA, A Safety, Tolerability, and Pharmacokinetics Study of LY3451838 in 
Healthy Subjects, has been amended in response to queries raised by Health Science Authorities 
(HSA), Singapore. Additional minor amendments to the protocol are made to add tests for early 
detection of hypersensitivity reactions and to ensure consistency of the randomization and 
unblinding procedures. The new protocol is indicated by Amendment (a) and will be used to 
conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section # and Name
Description of Change
Brief Rationale
2. Schedule of Activities
9.4.5.2 Hypersensitivity Reactions
Total complement C3 and total 
complement C4 tests will be 
performed at screening and Visits 4, 
7, 9, and 11. 
C3 and C4 tests can aid in the early 
detection of type III hypersensitivity 
reactions.
5.1 Overall Design
5.1.1 Part A (Single Ascending Dose 
IV Administration)
7.1 Treatment Administered
The planned dose levels in Part A 
updated to: 25, 75, 250, 500, 1000 
and 1500 mg single dose via IV 
infusion. The second planned dose 
level is updated from 125 mg to 75 
mg.
To address HSA query about dose 
increment between Cohort 1 and 
Cohort 2.
6.2 Exclusion Criteria
Criterion #22 updated to exclude 
subjects with hypertension (diastolic 
blood pressure >90 or <60 mmHg 
and/or systolic blood pressure >140 
or<90 mmHg)
Criteria updated to enroll only 
normotensive subjects in the study, 
in response to HSA query.
7.2 Method of Treatment 
Assignment
7.3 Blinding
Randomized method updated from 
paper based method to interactive 
web response system (IWRS)
The randomization and unblinding 
will be implemented via IWRS, 
rather than randomization table.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
Section 2
Schedule of Activities
Total complement C3 and total complement C4 tests added to Screening and Visits 4, 7, 9, and 
11.
Section 5
Study Design
Section 5.1
Overall Design
Section 5.1.1 Part A (Single Ascending Dose IV Administration)
Part A of the study is designed to assess the safety and tolerability of a single IV dose of 
LY3451838 compared to placebo in 6 cohorts of healthy subjects. Up to 6 doses of LY3451838 
at a planned dose range of 25 to 1500 mg will be evaluated. The planned dose levels for the 6 
cohorts are: 25, 75125, 250, 500, 1000 and 1500 mg single dose via IV infusion.
Section 6
Study Population
Section 6.2
Exclusion Criteria
22.
Have an abnormal blood pressure (supine) defined as diastolic blood pressure >9095 or 
<6050 mmHg and/or systolic blood pressure >140160 or <90 mmHg; or with minor deviation 
judged to be acceptable by the investigator.  Retesting may occur once during the screening visit 
within 2 hours of the initial abnormal blood pressure measurement at the discretion of the 
investigator
Section 7
Treatment
Section 7.1
Treatment Administered
Part A: The planned dose levels of LY3451838 are 25 mg, 75125 mg, 250 mg, 500 mg, 1000 
mg, and 1500 mg.  LY3451838 will be administered IV.
Section 7.2
Method of Treatment Assignment
In both parts of the study, within each cohort, eligible subjects will be enrolled sequentially, and 
will be randomly assigned to receive either LY3451838 or placebo in a 6:2 ratio.  Treatment 
assignment will be determined by a computer-generated randomization sequence using an 
interactive web response system (IWRS). A randomization table will be created by a computer 
software program.  The randomization list will be provided to the designated unblinded site staff 
for subject randomization and dispensing purposes and kept in a secure location, accessible to 
the designated unblinded site staff only.
Section 7.3
Blinding

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The study is double-blinded; subjects, investigator, and CRU personnel performing trial related 
activities or with the ability to influence study outcomes will be blinded with respect to 
LY3451838 and placebo treatment.  To preserve the blinding, only a minimum number of Lilly 
personnel may have access to the randomization table and codes or IWRS before the study is 
complete.  Site staff who are responsible for drug preparation will not be blinded; laboratory 
personnel will also not be blinded.  
Emergency unblinding will be performed through the IWRS. This option may be used only if the 
subject’s well-being requires knowledge of the subject’s treatment assignment. All unblinding 
events will be recorded and reported by the IWRS. One set of sealed envelopes containing the 
randomization code will be made available to the Investigator at the start of the trial.  A code 
envelope, which reveals the treatment for a specific study subject, may be opened during the 
study only if the subject’s well-being requires knowledge of the subject’s treatment assignment.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the Investigator obtains specific approval from a Lilly medical monitor for the 
study participant to continue in the study.  During the study, emergency unblinding should occur 
only by accessing the study subject’s emergency codeIWRS.
At the end of the study, unopened envelopes will be returned to Lilly or its designee, or 
destroyed according to site procedures.
Section 9
Study Assessments and Procedures
Section 9.4.5.2
Hypersensitivity Reactions 
Non-acute hypersensitivity reactions, including type 3 hypersensitivity reaction will be assessed 
by clinical presentation.  Routine monitoring of vital signs with regular physical examinations, 
and laboratory testing (including hematology, liver and renal testing, complements C3 and C4, c-
reactive protein [CRP] and erythrocyte sedimentation rate [ESR], and urine analysis) will be 
undertaken to assess for the development of vasculitis, serum sickness and other manifestations 
of type 3 hypersensitivity reactions.
Appendix 2
Clinical Laboratory Test
Total complement C3 and total complement C4 tests added to the list of Safety Laboratory Tests.
Appendix 5
Blood Sampling Summary
Footnote ‘a’ updated to indicate that C3 and C4 will be tested using chemistry and/or 
hematology samples.

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Appendix 7.
Protocol Amendment J1H-MC-LAJA(b) 
Summary
Protocol J1H-MC-LAJA, A Safety, Tolerability, and Pharmacokinetics Study of LY3451838 in 
Healthy Subjects, has been amended in response to address issues identified during the 
implementation of the study. The new protocol is indicated by Amendment (b) and will be used 
to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section # and Name
Description of Change
Brief Rationale
2. Schedule of Activities
Window for Visits 8 to 12 increased 
To improve flexibility of subject 
scheduling
2. Schedule of Activities
Optimized Day -1 procedures as follows:

The medical assessments, 
neurological examination, and 
eligibility review may be performed 
pre-dose on Day 1.

If screening is within 1 week of day -
1, neurological examinations, ECGs, 
hematology and chemistry does not 
need to be repeated;

C3, C4, CRP and ESR are moved to 
predose on Day 1
To reduce subject burden
2. Schedule of Activities
Window for Visit 8 changed to -1 up to +2
To prevent overlap in PK draw days
6.1 Inclusion Criteria
Inclusion #3 updated to allow subjects with 
BMI between 18 to 35 kg/m2 to be enrolled.
To improve enrollment, and increase 
BMI up to 35 Kg/m2 is not expected 
to affect safety of LY3451838.
6.2 Exclusion Criteria
Criterion #13 updated to allow subjects with 
non-clinically significant positive ANA titer 
to be enrolled
The observed prevalence of ANA in 
subjects during the screening for 
Study LAJA is significantly higher 
than the reported ANA prevalence in 
healthy population in literature. In 
healthy subjects without any history 
or symptoms or signs of connective 
tissue disease, an ANA titer is 
considered clinically significant only 
if the titer exceeds 1:160.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.

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Section 2
Schedule of Activities
Study Schedule Protocol JAH-MC-LAJA – Part A (Intravenous Administration) and Part B (Subcutaneous Administration)
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16a
Study Day
-28
-1
1
2
3
5
7
9 
(-1 
±up 
to +2)
15 
(±2)
22 
(±32)
29 
(±32)
43 
(±32)
57 
(±4)
71 
(±4)
85 
(±7)
141 / 
ED 
(±7)
Visit Type
S
A
I
I
D
O
O
O
O
O
O
O
O
O
O
O
Informed consent
X
Medical history
X
Height/weightb
X
X
X
X
X
X
Medical Assessmentc
X
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examination
X
Xd
X
X
X
X
Electrocardiograme
X
Xd
Predose,
1, 3 h 
24 h
(± 90 m)
X
X
X
X
X
X
X
X
X
X
Vital signsf, g
X
Xd
Predose, 
EOIh, 1, 
3 h
24 h
(± 90 m)
X
X
X
X
X
X
X
X
X
X
X
X
Orthostatic BP and pulse rate
Predose, 1 
h
24 h
X
X
X
X
Pregnancy test (urine)
X
Xd
X
X
X
Screening tests
X
Eligibility review
Xd
Study drug administration
X
Hematology and chemistryi
Xd
Predose
X
X
X
X
X
X
X
X
X
X
X
X
X
C3, C4, CRP and ESR
X
Xd
Predose
X
X
X
X
Urine analysis
Xd
X
X
X
X
PK samplei
EOIh, 3, 6, 
8, 12 h
24 h
(± 60 m), 
36 h
(± 60 m)
48 h
(±60 m)
X
X
X
X
X
X
X
X
X
X
X
PACAP samplei
Predose, 
EOIh 6, 
12 h
24 h
48 h
X
X
X
X
X
X

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Immunogenicity sample
Predose
X
X
X
X
X
X
Samples for infusion and 
hypersensitivity reactionsj
Predose
Non-genetic biomarker 
sample
Predose
X
PGx samplek
Predose
Adverse events
X 
Concomitant medications
X 
Abbreviations:  A = CRU admission; BP = blood pressure; CRU = clinical research unit; D = CRU discharge; ED = early discontinuation; EOI = end of infusion; 
h = hour; I = inpatient stay; m = minute; O = outpatient; C3 = total complement C3; C4 = total complement C4; CRP = C reactive Protein; ESR = erythrocyte 
sediment rate; PACAP = pituitary adenylate cyclase-activating polypeptide; PGx = pharmacogenomics; S = screening.
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used: electrocardiogram, vital signs, and 
venipuncture.  Unless otherwise specified, predose samples may be taken at any time prior to dosing, based on CRU activity schedule.
a
in case of early discontinuation/withdrawal, the subject should undergo all Visit 16 activities.
b Height will be collected at Screening only.
c
Full medical assessment prior to first dose (on Day -1 or Day 1), discharge, and discontinuation visits. Symptom-driven medical assessment as deemed 
necessary by the Investigator.
d Day -1 samples/activities could be collected/performed up to 5 days before the scheduled day of dosing. The medical assessment, neurological examination 
and eligibility review may be performed pre-dose on Day 1.  If screening visit is within 1 week (inclusive) of Day -1, neurological examination, ECG, 
hematology and chemistry do not need to be repeated..
e
Single electrocardiogram will be collected at Screening and CRU admission only. Triplicate electrocardiograms will be collected at all other timepoints.
f
Vital signs include blood pressure, pulse rate, and body temperature.  Single measurements at Screening and CRU admission.  Supine triplicate blood pressure 
and pulse rate at all other timepoints.
g Body temperature to be obtained as single measurement.
h End of infusion procedures are only required for Part A of the study – to be performed within 10 minutes from infusion completion.. 
i
Predose and 24 h (postdose) samples  to be collected after at least 8 hours of fasting. PK samples on day 5 and beyond should be obtained at approximately 
(± 2 hr) the same time of day as the dosing time on day 1.
j
Samples for infusion reactions and hypersensitivity reactions will be collected and stored for all subjects. Post treatment samples (up to 3) will only be 
collected in subjects who experience moderate to severe infusion reactions or hypersensitivity reactions (as defined in Section 9.4.5.2).
k
If sample not collected as indicated in Study Schedule table, it may be collected a following visit.

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Section 6.1
Inclusion Criteria
3.
Have a body mass index of 18 to 3532 kg/m2, inclusive, at screening
Section 6.2
Exclusion Criteria
13.
Have history (within past 5 years) of, or presence of, uncontrolled asthma, significant 
atopy, significant rheumatological or autoimmune diseases, including but not limited to 
systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren's Syndrome 
(SS), or vasculitis; or have positive antinuclear antibody (ANA) that is considered to be 
clinically significant by the investigator, rheumatoid factor (RF), or anti-neutrophil 
cytoplasmic antibody (ANCA) at screening; or hereditary angioedema, or common 
variable immune deficiency.

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Appendix 8.
Protocol Amendment J1H-MC-LAJA(c) 
Summary
Protocol J1H-MC-LAJA, A Safety, Tolerability, and Pharmacokinetics Study of LY3451838 in 
Healthy Subjects, has been amended in response to address issues identified during the 
implementation of the study. The new protocol is indicated by Amendment (c) and will be used 
to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section # and Name
Description of Change
Brief Rationale
7.1 Treatment 
Administered
Additional vial capacity that can deliver 
LY3451838 at 100 mg/mL was added.
Availability of additional vials that 
can deliver LY3451838 at 
100 mg/mL.
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
Section 7.1
Treatment Administered
LY3451838 Drug Product is a monoclonal antibody formulated for IV or SC administration. 
LY3451838 for Injection is supplied for clinical trial use as a solution in a single use glass vial. 
The vial is manufactured to deliver 200 mg of LY3451838 at 50 mg/mL or 100 mg/mL. In order 
to ensure complete withdrawal and delivery of the label amount of 200 mg of LY3451838, vials 
contain an approximate 10% volume overfill.  The drug product is filled into a glass vial, and 
sealed with a stopper and flip-off 2 piece aluminum seal. LY3451838 for Injection vials are 
stored in refrigerated condition (2ºC to 8ºC).

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Appendix 9.
Protocol Amendment J1H-MC-LAJA(d) 
Summary
Protocol J1H-MC-LAJA, A Safety, Tolerability, and Pharmacokinetics Study of LY3451838 in 
Healthy Subjects, has been amended in response to address issues identified during the 
implementation of the study. The new protocol is indicated by Amendment (d) and will be used 
to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section # and Name
Description of Change
Brief Rationale
3.3 Benefit/Risk 
Assessment
5.4 Scientific Rationale for 
Study Design
Vasculitis seen in monkey tox data was 
confirmed to be due to immune complex 
deposition and complement activation.
Confirmed by IHC studies 
conducted on tissue samples from 
the 8-week monkey GLP tox study.
5.5 Justification for Dose
7.4.1. Dose Escalation in 
Part A
PK information updated due to current 
prediction based on observed human PK and 
discussion of 3 points of justification added.
Human PK, safety, and 
immunogenicity data suggest that 
dosing slightly beyond the NOAEL 
exposure should pose little 
additional risks to participants.
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
3.2
Background
The toxicity of LY3451838 was assessed in 2-month rat and monkey studies and in an in vitro 
human tissue cross-reactivity study.  In the tissue cross-reactivity study, there was no unexpected 
binding observed in a panel of human tissues.  The rat and monkey studies used weekly SC 
dosing of 0, 10, and 50 mg/kg and weekly IV dosing of 250 mg/kg.  There were no adverse 
effects in the rat study. In the monkey study, minimal-to-mild vascular/perivascular 
inflammation most suggestive of was observed, but was attributed to immune complex 
deposition and, therefore, not expected to be relevant to human safety.  In addition to the 
vasculitis, which was not evident clinically, a greater incidence of transient neurological effects 
was observed in treated compared to control monkeys. This included decreased or absent flexor 
reflexes, proprioceptive positioning, placing reactions of limbs, and locomotor stereotypy all of 
which were considered nonadverse.  More details about the toxicology studies are provided in 
Section 4 of the Investigator’s Brochure (IB 2018).
3.3
Benefit Risk Assessment
The nonclinical safety and pharmacology information for LY3451838 adequately supports the 
transition from preclinical status to a clinical, first-in-human study.  The risk evaluation of 

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LY3451838 through its properties, nature of the target, non-clinical data in relevant species, 
target population and dose projections, suggest it not be considered a high risk molecule.
LY3451838 is a novel monoclonal antibody against PACAP, a neuropeptide that is expressed in 
both central nervous system and peripheral tissues. While pharmacology of this mechanism has 
not been directly evaluated in humans, AMG301, a monoclonal antibody against PAC1 receptor, 
has successfully completed phase 1 clinical testing, and is being evaluated for migraine 
prevention in an ongoing phase 2 trial. The study of AMG301 in phase 2 suggests that blocking 
at least part of the PACAP pathway did not lead to significant toxicity in humans.  The dose-
limiting toxicity of LY3451838 was minimal-to-mild vasculitis in multiple organs in monkeys 
assessed after 8 weekly IV doses of 250 mg/kg, similar to the presentation of vasculitis due to 
immune response in toxicology species observed with other monoclonal antibodies (Kronenberg 
et al. 2017).  Immunohistochemistry studies of tissue samples from the 8-week monkey GLP 
toxicology study demonstrated that the vasculitis was due to immune complex deposition and 
complement activation. This type of immune response in a single animal species is considered to 
translate poorly to human safety (EMEA).  The weight of evidence suggests that the most likely 
mechanism of vasculitis was immune complex deposition, rather than an excessive on target 
pharmacology. For this first in human study, the highest dose is limited to 1500 mg, which is 
predicted to reach an exposure approximately 1615-fold lower than the concentration in which 
vasculitis was observed in monkeys.  In addition, PK data will be reviewed with each dose 
escalation, and an exposure limit will be implemented in this study so that the predicted mean 
exposure based on observed PK does not significantly exceed that of the no-observed-adverse-
effect-level (NOAEL) exposure observed in monkeys significantly.
Immunogenicity and hypersensitivity reactions, including infusion reactions, acute and delayed 
(including immune complex disease) hypersensitivity reactions are a potential risk for all 
monoclonal antibodies, including LY3451838. Hypersensitivity risk mitigation in this study 
includes the administration of a single dose of LY3451838 IV with subsequent close monitoring.
LY3451838 has not been administered to humans previously and accordingly this study has been 
designed following the principles outlined in the Guideline on Strategies to Identify and Mitigate 
Risks for First-in-Human Clinical Trials with Investigational Medicinal Products (EMEA CHMP 
Jul 2017).  Any identified risks are considered to be monitorable and manageable at the planned 
dose range of 25 mg to 1500 mg single doses of LY3451838 in healthy subjects.
There is no anticipated therapeutic benefit for the subjects.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY3451838 are found in the IB.
5.4
Scientific Rationale for Study Design
Hypersensitivity reactions, including both acute hypersensitivity reactions and immune complex 
diseases, are potential risks for all therapeutic antibodies, including LY3451838. Subjects with a 
history of clinically significant hypersensitivity reactions / conditions, or autoimmune diseases 
are excluded from the study to minimize risks for hypersensitivity reactions in the subjects in this 
study, and to avoid confounded interpretation of the safety data. Additional measures will be 

J 1 H -M C -L A J A ( d) Cli ni c al Pr ot o c ol
P a g e 6 8
L Y 3 4 5 1 8 3 8
i m ple me nte d t o m o nit or a n d ma na ge i nf usi on reacti o ns ( Secti o n 7. 4. 3. 2 ), i m m u n o ge nicity,  a n d 
h y perse nsit i vity react i ons ( Secti o n 9. 6. 1 ).  W hile vasc ulitis o bser ve d i n t he m o n ke y t o xic ol og y  
st u dies were s u g gest i ve of  was attrib ute d t o i m m u ne c om p le x disease de p osi tio n , a d ditio n al  
preca uti o ns, s uc h as re vie wi n g P K data bef ore eac h d ose escalat i on, li mit i n g t he d ose ra n ge a n d 
i m ple me nti n g t he e x p os ure t o t hat of t he m o n ke y N O A E L are desi g ne d i nt o t he pr ot oc ol t o 
a d dress t he u ncert ai nt y of  t h e mec ha nis m for vasc uli tis.
Beca use of t he distri b uti o n of P A C A P i n t he ner v o us s yste m, a n d t o f oll o w - u p o n t he s u btle 
n o n- a d verse c ha n ges i n t he ne ur o l ogi cal e xa mi nat i o n i n t he 2-m o nt h m o n ke y t o xi c o l og y  st u d y, 
ne ur o l ogi cal e xa mi natio ns will be p erf or me d t o detect a n y  earl y si g nals o n t he effects of 
L Y 3 4 5 1 8 3 8 o n t he ner v o us s yste m. 
5. 5
J ustific ati o n f or D ose
Base d o n c urre nt precli nical a n d t o xic o l og y  data, a d ose ra n ge of 2 5 m g t o 1 5 0 0 m g I V i s 
pr o p ose d f or t he si n ge asce n di n g d ose ( S A D) .  T he pre dicte d efficaci o us d ose is 5 0 0 m g I V 
base d o n a ll ometric scali n g of P K para meters fr o m m o n ke y a n d t he a bilit y t o ac hie ve a tar get 
c o nce ntrati o n of 1 5 µ g/ m L at 3 0 da ys p ost-d ose.  T he tar get c o nce ntrati o n selecte d f or 
L Y 3 4 5 1 8 3 8 is t he galca nez u ma b tr o u g h c o nce ntrati o n at a n effecti ve d ose of 1 2 0 m g m o nt hl y  in 
mi grai ne patie nts.  T he rati o nale f or select i n g t his tar get c o nce ntrati o n f or L Y 3 4 5 1 8 3 8 is t he 
o verl a p i n P A C A P a n d calcit o ni n ge ne-relate d pe ptide ( C G R P ) e x pressi o n pr ofile, p ote nc y o f t he 
ne ur o pe pt i des f or t h eir tar get(s) i n t he sa me c o nce ntrati o n ra n ge, a n d si milarit y i n t he p ote nc y of 
t he a nt i b o dies a gai nst t heir tar gets.
T he pr o p ose d starti n g d ose of 2 5 m g is 2 0-f ol d l ower t ha n t he pre dicte d efficaci o us d ose, w hic h 
is e x pecte d t o be a mi ni mal a ntici pate d bi ol ogi c al effect le v el ( M A B E L).  I n a d ditio n, t he 
starti n g d ose has a mar gi n of safet y of  more t ha n 5 0- f ol d bas e d o n d ose, area u n der t he 
c o nce ntrati o n-ti me c ur ve ( A U C), a n d ma xi m u m dr u g c o nce ntratio n ( C ma x ) for b ot h rat a n d 
m o n ke y t o xic ol o g y  st u dies ( Ta ble 5. 1 Ta ble 5 . 1).
T he hi g hest pla n ne d d ose f or t his st u d y  is 1 5 0 0 mg I V.  T his d ose is pre dicte d t o ac hie ve a n 
e x p os ure a p pr o xi matel y 3-times hi g her t ha n t he pre dicte d efficaci o us e x p os ure.  A si n gle 
1 5 0 0 m g I V d ose has a mar gi n o f safety of  2 base d o n d ose a n d 0. 9 0. 8 base d o n A U C relat i ve t o 
t he mo n k e y  N O A E L. W hile mar g i n of safety ( M O S) base d o n mo n ke y  A U C is sli g htl y less t ha n 
1, t hi s is dee me d acce pta ble beca use t he pre dicte d e x p os ure after a si n gle 1 5 0 0- m g d ose base d 
o n t he o bser ve d h u ma n P K i n t he first 3 c o h orts of t his st u d y  is >1 6 1 5 -f ol d l ower t ha n t he d ose 
i n w hic h t o xicit y was o bser ve d (i.e., 2 5 0 mg/ k g I V).  F urt her m ore, it is pla n ne d t o li mit t he 
pre di cte d mea n e x p os ure t o t hat o bser ve d at t he m o n ke y  N O A E L, s uc h t hat t he mea n pre dicte d 
A U C 0- ∞at a gi ve n d ose le vel will n ot e xcee d 9 8, 0 0 0 µ g/ m L * h base d o n t he o bser ve d P K fr o m 
pri or c o h orts.   F urt her m ore, t he mea n pre dicte d h u ma n A U C 0- ∞of  a p pr o xi matel y 1 2 2, 5 0 0 
µ g/ m L * h, i s o nl y sli g htl y hi g her ( 1. 2 5 x) t ha n t he m on ke y N O A E L A U C 0- 1 6 8 h (i.e., 5 0 mg/ k g 
S C).    Base d o n t he a vaila ble t o xic o l og y  a n d cli nical data, t he ris k of reac hi n g t his e x p os ure is 
acce pta ble i n t his si n gle d ose st u d y.  Firstl y, t he N O A E L defi ni n g t o xicity i n m o n ke ys was 
wi de- s prea d vasc ulitis.  T he i m m u n o hist oc he mistr y res ults c o nfir me d t he i nitial h y p ot hesis t hat 
t he vasc ulit is o bserve d i n m o n ke ys was d ue t o i m m u ne -c o m p le x de p ositi on.  I n ge neral, 

J 1 H -M C -L A J A ( d) Cli ni c al Pr ot o c ol
P a g e 6 9
L Y 3 4 5 1 8 3 8
tra nslat i on of i m m u ne -r elate d res p o nses bet wee n a si n gle t o xic o l og y  s pecies a n d h u ma ns has 
bee n p o or ( E M E A C H M P J ul 2 0 1 7 ).  Sec o n dl y, L Y 3 4 5 1 8 3 8 has bee n a d mi nistere d t o 4 0 healt h y 
s u bjects at u p t o 1 0 0 0 m g d ose.  N o s u bjects e x perie nce d a n y S A Es, or disc o nti n ue d fr om st u d y 
d ue t o a n A E.  T he i m m u n o ge nicit y d at a f r o m t he first 2 c o h orts ha ve bee n re vie we d, a n d o nl y 1 
s u bject de vel o pe d treat me nt-e mer ge nt a ntidr u g a nti b o d y  at fairl y lo w ti ter. Thir dl y, t he vasc ulit is 
was o bser ve d i n a 2 -m o nt h ( 8 wee kl y d oses) m o n ke y  st u d y, w hile c urre nt cli nical st u d y in v o l ves 
si n gle d oses. T he ris k f or de vel o pi n g i m m u ne-c o m ple x disease is l o w after a si n gle d ose.
T he pl a n ne d S C d ose f or Part B is 2 5 0 m g.  T his d ose i s feasi ble with t he c urre nt f or m ulat i on 
( Sectio n 7. 1 ) a n d will all o w f or a n a de q uate safety,  t olera bilit y a nd P K e val uat i on f oll owi n g S C 
a d mi nistrati o n.  It ma y be a dj uste d t o matc h t he d ose a d mi nistere d t o s u bjects i n C o h ort 3 Part A.
T a bl e 5. 1
M ar gi n of S af et y f or I ntr a v e n o u s A d mi ni str ati o n of L Y 3 4 5 1 8 3 8
B a s e d o n A d mi ni st er e d D o s e a n d Pr e di ct e d E x p o s ur e
I V Refere nce 
D ose ( m g)
D ose
( m g/ k g)
D ose
M ulti ple
a
A U C
( µ g•hr/ m L) b
C ma x
(µ g/ m L )
E x p os ure 
M ulti ple
( A U C)a
E x p os ure 
M ulti ple
( Cma x )a
H u m a n
1 5 0 0 
2 5  
–
1 1 0, 0 0 0
1 2 2, 5 0 0 c
5 1 0
4 5 0 c
–
–
2 5
0. 4 
–
1, 8 0 0 d
8. 5 d
–
–
R at
N O A E L d e
1 5 0 0
2 5 0 (I V)
1 0
4 3 0, 0 0 0
1 4, 0 0 0
3. 9 3. 5
2 8 3 1
2 5
6 0 0
2 4 0
1, 6 0 0
M o n ke y 
N O A E L ef
1 5 0 0
5 0 ( S C)
2
9 8, 0 0 0
7 4 0
0. 9 0. 8
1. 5 6
2 5
1 2 0
5 4
8 7
A b bre viati o ns:  A U C = area u n der t he c o nce ntrati o n -ti me c ur ve; Cma x = ma xi m u m dr u g c o nce ntrati o n; 
I V = i ntra ve n o us; N O A E L = n o -o bser ve d -a d verse-effect le vel; S C = s u bc uta ne o us.
a
D ose m ulti ple is t he d ose i n a ni mals/ d ose i n h u ma ns base d o n m g/ k g .  E x p os ure m ulti ple is t he calc ulate d 
e x p os ure i n a ni mals / pre dicte d e x p os ure i n h u ma ns. ( Refer t o Secti o n 4 of t he I B.)
( N ote: r o ute of a d mi nistrati o n is I V i n h u ma ns a n d rat a n d S C i n m o n ke y).
b
T he A U Cs are A U C 0- ∞after a si n gle d ose i n h u ma n; A U C 0- 9 6 h o n Da y 5 0 after wee kl y d osi n g i n rat; A U C 0- 1 6 8 h
o n da y 5 0 after wee kl y d osi n g i n m o n ke y.
c
Plas ma p har mac o ki netics at t he 1 5 0 0 m g d ose were pre dicte d base d o n t he o bser ve d h u ma n P K at d oses of 2 5, 
7 5, a n d 2 5 0 m g L Y 3 4 5 1 8 3 8
d
Base d o n all o metric scali n g fr o m m o n ke y P K ( 8 3 6 3 7 5 1 ), p las ma p har mac o ki netics were esti mate d f oll o wi n g 
si n gle d ose of L Y 3 4 5 1 8 3 8 i n h u ma ns
de N O A E L deter mi ne d i n a 2- m o nt h re peat d ose t o xicit y st u d y ( 5 0 0 2 6 3 8 ).
ef N O A E L deter mi ne d i n a 2 -m o n t h re peat d ose t o xicit y st u d y ( 5 0 0 2 6 3 9).
7. 4. 1
D ose Esc al ati o n i n P art A
After re vie w of t hese data, a n a gree me nt o n t he a p pr o priate d ose will be ma de b y t he i n vest i gat or 
a n d s p o ns or f or t he ne xt c o h ort/ d ose le vel.  T he ma g nit u de of d ose escalat i ons ma y be a dj uste d 
f oll owi n g data re vie w.  T he d ose will n ot e xcee d 1 5 0 0 m g . a n d t he mea n A U C 0- ∞at a give n d ose 
will n ot e xcee d t hat o bser ve d i n t he m o n ke y N O A E L (i.e., 9 8 0 0 0 µ g/ m L * h ).

Leo Document ID = 3bc2d3dc-33dc-4d74-a6d1-ebe923f6c4d3
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Approval Date & Time: 13-Aug-2019 16:58:19 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-Aug-2019 19:52:22 GMT
Signature meaning: Approved
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