A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of LY3451838 in Adults With Treatment-Resistant Migraine
Phase: PHASE2
Conditions: Migraine
Sponsor: Eli Lilly and Company

 
J1H-MC-LAJB(b) Clinical Protocol 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of LY3451838 in Adults With 
Treatment-Resistant Migraine 
 
 
NCT04498910 
 
 
Approval Date: 19-Nov-2021 

J1H-MC-LAJB(b) Clinical Protocol
Page 1
LY3451838
Protocol J1H-MC-LAJB(b)
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study of LY3451838 in Adults with Treatment-Resistant 
Migraine
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators. It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
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.
LY3451838
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 20 January 2020
Protocol Amendment (a) Electronically Signed and Approved by Lilly:  22 July 2020
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 19-Nov-2021 GMT

J1H-MC-LAJB(b) Clinical Protocol
Page 2
LY3451838
Table of Contents
Section
Page
Protocol J1H-MC-LAJB(b) A Phase 2, Randomized, Double-Blind, 
Placebo-Controlled Study of LY3451838 in Adults with Treatment-
Resistant Migraine ..............................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3
Benefit/Risk Assessment..............................................................................................15
4.
Objectives and Endpoints..................................................................................................16
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................20
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle Restrictions....................................................................................................26
6.4.
Screen Failures.............................................................................................................26
7.
Treatments........................................................................................................................28
7.1.
Treatments Administered .............................................................................................28
7.1.1.
Packaging and Labelling ......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................29
7.2.1.
Selection and Timing of Doses.............................................................................29
7.3.
Blinding .......................................................................................................................29
7.4.
Dosage Modification....................................................................................................30
7.5.
Preparation/Handling/Storage/Accountability...............................................................30
7.6.
Special Treatment Considerations ................................................................................30
7.6.1.
Management of Infusion Reactions ......................................................................30
7.7.
Treatment Compliance .................................................................................................31
7.8.
Concomitant Therapy...................................................................................................31

J1H-MC-LAJB(b) Clinical Protocol
Page 3
LY3451838
7.9.
Treatment after the End of the Study............................................................................32
8.
Discontinuation Criteria ....................................................................................................33
8.1.
Discontinuation from Study Treatment.........................................................................33
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................33
8.1.2.
Discontinuation of Inadvertently Enrolled Patients...............................................34
8.2.
Discontinuation from the Study....................................................................................34
8.3.
Lost to Follow-Up........................................................................................................34
9.
Study Assessments and Procedures ...................................................................................35
9.1.
Efficacy Assessments...................................................................................................35
9.1.1.
Primary Efficacy Assessments .............................................................................35
9.1.2.
Secondary Efficacy Assessments..........................................................................35
9.1.3.
Appropriateness of Assessments ..........................................................................35
9.2.
Adverse Events ............................................................................................................35
9.2.1.
Adverse Event Monitoring with a Systematic Questionnaire ................................36
9.2.2.
Serious Adverse Events........................................................................................36
9.2.2.1.
Suspected Unexpected Serious Adverse Reactions..........................................37
9.2.3.
Complaint Handling.............................................................................................38
9.3.
Treatment of Overdose.................................................................................................38
9.4.
Safety...........................................................................................................................38
9.4.1.
Physical and Neurological Examinations..............................................................38
9.4.2.
Vital Signs ...........................................................................................................38
9.4.3.
Electrocardiograms ..............................................................................................38
9.4.3.1.
Digital Electrocardiogram Storage..................................................................39
9.4.4.
Laboratory Tests ..................................................................................................39
9.4.5.
Immunogenicity Assessments ..............................................................................39
9.4.6.
Safety Monitoring ................................................................................................40
9.4.6.1.
Hepatic Safety Monitoring..............................................................................40
9.4.6.2.
Vasculitis........................................................................................................40
9.4.6.3.
Hypersensitivity Reaction...............................................................................41
9.4.6.4.
Infusion Reaction ...........................................................................................42
9.4.6.5.
Suicidal Ideation and Behavior Risk Monitoring.............................................42
9.4.6.6.
Cognition........................................................................................................42
9.5.
Pharmacokinetics .........................................................................................................43
9.5.1.
Bioanalysis...........................................................................................................43
9.6.
Pharmacodynamics ......................................................................................................43
9.6.1.
Exploratory Assessment of PACAP Concentrations .............................................43
9.7.
Genetics .......................................................................................................................43
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................43

J1H-MC-LAJB(b) Clinical Protocol
Page 4
LY3451838
9.8.
Biomarkers...................................................................................................................44
9.8.1.
Blood Biomarkers ................................................................................................44
9.8.2.
Digital Biomarkers...............................................................................................44
9.9.
Health Economics ........................................................................................................45
10.
Statistical Considerations ..................................................................................................46
10.1. Sample Size Determination ..........................................................................................46
10.2. Populations for Analyses..............................................................................................46
10.3. Statistical Analyses ......................................................................................................47
10.3.1.
General Statistical Considerations ........................................................................47
10.3.2.
Treatment Group Comparability...........................................................................47
10.3.2.1.
Patient Disposition..........................................................................................47
10.3.2.2.
Patient Characteristics ....................................................................................47
10.3.2.3.
Concomitant Therapy .....................................................................................48
10.3.2.4.
Treatment Compliance....................................................................................48
10.3.3.
Efficacy Analyses ................................................................................................48
10.3.3.1.
Primary Analyses ...........................................................................................48
10.3.3.2.
Secondary Analyses........................................................................................48
10.3.3.3.
Exploratory Analyses .....................................................................................48
10.3.4.
Safety Analyses....................................................................................................48
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................49
10.3.5.1.
Pharmacokinetic Analyses..............................................................................49
10.3.5.2.
Exploratory Pharmacodynamic Analyses........................................................49
10.3.6.
Evaluation of Immunogenicity .............................................................................49
10.3.7.
Other Analyses.....................................................................................................50
10.3.7.1.
Health Economics...........................................................................................50
10.3.7.2.
Analysis of C-SSRS Data ...............................................................................50
10.3.8.
Interim Analyses..................................................................................................50
11.
References ........................................................................................................................51
12.
Appendices .......................................................................................................................54

J1H-MC-LAJB(b) Clinical Protocol
Page 5
LY3451838
List of Tables
Table
Page
Table LAJB 2.1 Schedule of Activities....................................................................................11
Table LAJB 7.1 Treatments Allowed and Treatments Not Allowed as Concomitant 
Therapy .........................................................................................................31
Table LAJB 12.1 Treatments Allowed and Treatments Not Allowed as Concomitant 
Therapy .........................................................................................................70

J1H-MC-LAJB(b) Clinical Protocol
Page 6
LY3451838
List of Figures
Figure
Page
Figure LAJB 5.1 Illustration of study design for Clinical Protocol J1H-MC-LAJB. ..................19

J1H-MC-LAJB(b) Clinical Protocol
Page 7
LY3451838
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................55
Appendix 2.
Clinical Laboratory Tests...............................................................................58
Appendix 3.
Study Governance Considerations..................................................................59
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................64
Appendix 5.
Recommended Laboratory Testing for Hypersensitivity Events .....................65
Appendix 6.
Migraine and Headache Endpoint Definitions................................................67
Appendix 7.
Protocol Amendment J1H-MC-LAJB(b) Summary........................................68

J1H-MC-LAJB(b) Clinical Protocol
Page 8
LY3451838
1. Synopsis
Title of Study:
A Phase 2, randomized, double-blind, placebo-controlled study of LY3451838 in adults with 
treatment-resistant migraine.
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). Evidence suggests that PACAP-38 is involved in migraine pathophysiology. 
Provocation studies have shown that PACAP infusion can induce migraine episodes in migraine 
patients, and plasma PACAP levels are elevated during a migraine attack. The objective of the 
Study J1H-MC-LAJB (LAJB hereafter) is to evaluate the safety and efficacy of LY3451838 to 
placebo in a treatment-resistant, adult patient population with episodic or chronic migraine. 
Objectives/Endpoints:
Primary
To test the hypothesis that LY3451838 is superior to 
placebo in the prevention of migraine in 
treatment-resistant migraine patients
The mean change from baseline in the number of
monthly migraine headache days during the 1-month 
treatment phase (episodic and chronic migraine)a
Secondary
To compare LY3451838 with placebo with respect to 
prevention of monthly headache days
The mean change from baseline in the number of 
monthly headache days during the 1-month treatment 
phase
To compare LY3451838 with placebo with respect to 
50% response rate
The percentage of patients with ≥50% reduction from 
baseline in monthly migraine headache days during the 
1-month treatment phase
To evaluate the safety and tolerability of a single dose 
of LY3451838 in treatment-resistant migraine patients
TEAEs
SAEs
To characterize the pharmacokinetics of LY3451838 
following a single IV dose in treatment-resistant 
migraine patients
LY3451838 Cmax and AUC
Abbreviations: AEs = adverse events; AUC = area under the concentration-time curve from time 0 to infinite; 
Cmax = maximum observed drug concentration; ECGs = electrocardiograms; SAEs = serious adverse events; 
TEAEs = treatment-emergent adverse events
a
Episodic migraine is defined as 4 to 14 migraine headache days and <15 headache days per 1-month period in the 
prospective baseline period. Chronic migraine is defined as at least 15 headache days per 1-month period in the 
prospective baseline period, of which at least 8 are migraine.
Summary of Study Design:  
Study LAJB is a multicenter, randomized, double-blind, parallel, placebo-controlled study of 
LY3451838 in patients who meet the International Classification of Headache Disorders 
version 3 (ICHD-3) criteria for a diagnosis of migraine with or without aura, or chronic 
migraine, and who have previously failed 2 to 4 categories of standard-of-care treatments for 
migraine prevention. The study has 4 periods, including the screening period, baseline for 

J1H-MC-LAJB(b) Clinical Protocol
Page 9
LY3451838
eligibility, double-blind treatment phase, and follow-up assessment of headache episodes and 
related information.
Treatment Arms and Duration:  
The study has 2 treatment arms: LY3451838 (1500 mg intravenous [IV]) and matching placebo.
Following a 4-week prospective baseline period, eligible patients will be stratified by type of 
migraine (episodic or chronic) and then randomly assigned in a 1:1 ratio within each stratum to 
receive a single dose of LY3451838 or placebo. Patients will be followed for approximately 
140 days post the study drug administration for safety assessment. 
Number of Patients:
The study will screen an estimated 110 potential patients to ensure randomization of 
approximately 60 migraine patients, of which approximately 30 patients with chronic migraine.
Statistical Analysis:
A Bayesian analysis for the primary endpoint will be performed using an analysis of covariance 
(ANCOVA). The ANCOVA model for the change from baseline in the monthly number of 
migraine headache days will include terms for treatment and type of migraine, and baseline 
number of migraine headache days as a covariate will be used.
Frequentist analyses for change from baseline in the monthly number of migraine headache days 
and change from baseline in the monthly number of headache days will be performed using the
same ANCOVA model.
Comparisons between the treatments in rate of responders will be conducted using Cochran 
Mantel Haenszel tests that are stratified by the type of migraine.
For continuous variables, descriptive statistics will include the number of patients, mean, 
median, standard deviation, minimum, and maximum. Categorical variables will be summarized 
using the number and percentage of patients.

J1H-MC-LAJB(b) Clinical Protocol
Page 10
LY3451838
2. Schedule of Activities

J1H-MC-LAJB(b) Clinical Protocol
Page 11
LY3451838
Table LAJB 2.1
Schedule of Activities
Screening
Baseline
Treatment Phase
Follow-up
EDb
(Target) Interval (days) since previous visit
-
-
30
15
15
15
15
15
15
30
30
Allowable range (days) between visits
3-90
30-40a
Interval allowance (days)
+5
±3
±3
±3
±3
±3
±3
±3
±3
Visit
1
2
3
4
5
6
7
8
9
10
11
Month
-
-
0
.5
1
1.5
2
2.5
3
4
5
Informed consent
X
Demographics
X
Physical examinationc
X
X
P
X
X
X
X
X
X
X
X
X
Neurological examination
X
X
P
X
X
X
X
X
X
X
Heightd and weight
X
P
X
X
Medical historye and concurrent conditions
X
Vital signsf
X
P, 1 h
X
X
X
X
X
X
X
X
X
12-lead ECGg
X
X
P
X
X
X
X
X
X
Serum pregnancy test (WOCBP only) or FSH
X
Urine pregnancy test (WOCBP only)h
X
P
X
X
X
X
X
X
HIV, hepatitis B and C
X
Hematology, chemistryi (include eGFR)
X
X
P
X
X
X
X
X
X
X
X
X
Creatine kinase (Total CK)
X
P
X
X
X
X
X
HbA1c
P
X
Urinalysis
X
X
P
X
X
P
X
X
ePRO and headache medication log training
X
Inclusion and exclusion criteria
X
X
P
ePRO daily patient diary entry
X
X
X
X
X
X
X
X
Headache medication log
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
P
Study drug administration
X
MSQ v2.1
X
X
X
X
HIT-6
X
X
X
X
CCI
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 12
LY3451838
Screening
Baseline
Treatment Phase
Follow-up
EDb
(Target) Interval (days) since previous visit
-
-
30
15
15
15
15
15
15
30
30
Allowable range (days) between visits
3-90
30-40a
Interval allowance (days)
+5
±3
±3
±3
±3
±3
±3
±3
±3
Visit
1
2
3
4
5
6
7
8
9
10
11
Month
-
-
0
.5
1
1.5
2
2.5
3
4
5
C-SSRS Baseline and Screening
X
C-SSRS Since Last Visit
X
X
X
X
X
X
X
X
X
X
X
Self-Harm Supplement Form
X
X
X
X
X
X
X
X
X
X
X
X
Self-Harm Follow-up Formk
X
X
X
X
X
X
X
X
X
X
X
X
Cogstate Brief Batteryl
X
P
X
X
X
X
AEm / Concomitant medications
X 
PK samplen
P, EOI, 3h
X
X
X
X
X
X
X
X
X
Immunogenicity samplen
P
X
X
X
X
X
PACAP sample
P, EOI, 3h 
X
X
X
X
X
X
X
X
X
IRR/Hypersensitivity sampleo
IRR/Hypersensitivity Follow-up Formp
Pharmacogenetic sample
P
Biomarker sample (serum and plasma)
P
X
Abbreviations: AE = adverse event; ANCA = anti-neutrophil cytoplasmic antibody; 
 
ECG = electrocardiogram; ED = early discontinuation; eGFR: estimated glomerular filtration rate; EOI = end of 
infusion; ePRO = electronic patient-reported outcomes; 
; h = hours after end of infusion;
HbA1C = glycosylated hemoglobin; HIT-6 = Headache Impact Test-6; HIV = human immunodeficiency virus; IRR = infusion related reaction; 
MSQ = Migraine-Specific Quality of Life Questionnaire; P = predose assessment; PK = pharmacokinetic; PACAP = pituitary adenylate cyclase-activating 
polypeptide; WOCBP = women of child-bearing potential
a
The eligibility period of the prospective baseline assessment will last from 30 to 40 days. Investigators and patients may have up to an additional 5 days to 
schedule their Visit 3 appointment (beyond the 40 days); however, eligibility will be based on the 30- to 40-day period.
b
Patients who discontinue the study prior to study completion should complete the ED visit procedures.
c
Complete physical examination at screening, Visit 11 and ED. Targeted physical examination to be performed at the remaining visits, which includes
examination of skin, lungs, and skeletomuscular system; symptom-driven physical examination may also be performed at these visits based on PI discretion. 
CCI
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 13
LY3451838
d
Height collected at Visit 1 only.
e
Includes substance usage (drugs, alcohol, tobacco, and caffeine) and family history of premature cardiovascular disease.
f
Includes body temperature, sitting blood pressure, and pulse. Predose vital signs should be taken approximately 1 hour prior to the scheduled dosing. For all 
post-dose time points, the vital signs should be performed before any blood sample is drawn.
g
For all post-dose time points, the ECG should be performed before any blood sample is drawn.
h
A positive test must be followed by a serum pregnancy test for confirmation.
i
Chemistry should be collected in a fasting state.
j
Wearing of the device and entering data in the exploratory app is expected unless an exemption is allowed by the investigator and approved by Lilly.
k
Required if triggered by the Self-Harm Supplement Form per instructions.
l
For the Cogstate Brief Battery, two pre-baseline familiarization assessments will be conducted at Baseline/Visit 2, with at least 15 minutes break in-between. 
The baseline for the Cogstate Brief Battery will be assessed at Visit 3 and must occur prior to administration of study drug to provide a treatment free 
evaluation of cognition.
m Nonleading AE collection should occur prior to administration of C-SSRS, except for screening C-SSRS administration.
n
For all post-dose time points, immunogenicity sample should be collected as close to PK blood draw as possible.  
o
Post-treatment samples (up to 3) will only be collected in patients who experience moderate to severe infusion reactions or hypersensitivity reactions (as 
defined in Sections 7.6.1, 9.4.6.2, and 9.4.6.4).
p
Required if triggered by a suspected systemic allergic/hypersensitivity reaction.
q
In event of suspected vasculitis (Section 9.4.6.2) evaluations may include ANCA, LY concentration, and immunogenicity samples. Skin biopsy may also be 
considered.

J1H-MC-LAJB(b) Clinical Protocol
Page 14
LY3451838
3. Introduction
3.1.
Study Rationale
The purpose of Study J1H-MC-LAJB (LAJB) is to assess the efficacy and safety of LY3451838 
in a treatment-resistant episodic and chronic migraine population. Blocking calcitonin 
gene-related peptide (CGRP) has been shown to reduce the migraine burden in both migraine 
phenotypes, including patients who had not responded to other anti-migraine preventive drug 
classes. Treatment resistant population, in this study, will be defined as previous failure to 
respond to 2 to 4 different standard-of-care migraine preventive medications either due to 
inadequate efficacy and/or due to safety/tolerability reasons, including the new anti-CGRP 
medications. 
Additional rationale for the study design is provided in Section 5.4.
3.2.
Background
According to the global burden of disease study, among 289 diseases and injuries that cause 
sequelae and disability, migraine appears as the third in global sequelae prevalence, behind 
dental caries of permanent teeth and tension-type headache; and as the eighth in global years 
lived with disability (Vos et al. 2012).  
No approved migraine preventive treatment completely blocks the onset of migraine attacks. A 
substantial number of patients does not improve satisfactorily and/or is burdened with 
unacceptable side effects with a significant impact on productivity and quality of life. 
(Blumenfeld et al. 2011; Lanteri-Minet et al. 2011; Abu Bakar et al. 2016). Approximately 43% 
of the patients have a history of previous preventive medication failure or treatments switching. 
(Pike et al. 2016).  
Pituitary adenylate cyclase-activating peptide-38 (PACAP-38) is a peptide belonging to the 
secretin/glucagon/vasoactive intestinal peptide (VIP) superfamily and is widely expressed in 
nociceptive pathways within the central and peripheral nervous systems (Jolivel et al. 2009; 
Vaudry et. al 2009). There is evidence to suggest that PACAP-38 is involved in migraine 
pathophysiology. Contrary to VIP, intravenous PACAP-38 injections provoke migraine-like 
attacks in migraineurs (Schytz et al. 2009). The plasma levels of PACAP-38 (Tuka et al. 2013) 
rise during migraine attacks (Zagami et al. 2014), suggesting an association between the plasma 
PACAP-38 levels and migraine episodes. 
LY3451838 is a 
 that 
potently and selectively binds and neutralizes PACAP. In the preclinical pharmacology studies, 
LY3451838 demonstrated selective binding and prevention of PACAP activities. The general 
toxicity of LY3451838 was assessed in 8-week rat and monkey studies and reproductive and 
developmental toxicity was assessed in rats (male and female fertility) and in pregnant rats and 
rabbits (embryofetal development). 
Safety, tolerability and pharmacokinetics of LY3451838 were evaluated in a single ascending 
dose study in healthy subjects within a dose range of 25 to 1500 mg administered intravenously 
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 15
LY3451838
(IV), or a single subcutaneous (SC) dose of 250 mg. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Further details about LY3451838 PK in healthy subjects can 
be found in the Investigator’s Brochure (IB). 
3.3
Benefit/Risk Assessment
LY3451838 is being developed as a novel therapy for migraine prevention, as PACAP was 
hypothesized as another mediator of migraine attacks. Preclinical pharmacology data indicated 
that LY3451838 bound and prevented PACAP activities in vitro. 
 
These 
data support testing the efficacy of LY3451838 in patients with treatment-resistant migraine.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of LY3451838 are to be found in the IB.
CCI
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 16
LY3451838
4.
Objectives and Endpoints
Objective
Endpoint
Primary
To test the hypothesis that a single IV dose of 
LY3451838 is superior to placebo in the prevention of 
migraine in treatment-resistant migraine patients
The mean change from baseline in the number of
monthly migraine headache days during the 1-month
treatment phase (episodic and chronic migraine)a
Secondary
To compare LY3451838 with placebo with respect to 
prevention of monthly headache days
The mean change from baseline in the number of 
monthly headache days during the 1-month treatment 
phase
To compare LY3451838 with placebo with respect to 
50% response rate
The percentage of patients with ≥50% reduction from 
baseline in monthly migraine headache days during the 
1-month treatment phase
To evaluate the safety and tolerability of a single dose 
of LY3451838 in treatment-resistant migraine patients
TEAEs
SAEs
To characterize the pharmacokinetics of LY3451838 
following a single IV dose in treatment-resistant 
migraine patients
LY3451838 Cmax and AUC
ExploratoryCCI

J1H-MC-LAJB(b) Clinical Protocol
Page 17
LY3451838
Abbreviations: AUC = area under the concentration-time curve; CAS = Cranial Autonomic Symptoms; 
Cmax = maximum observed drug concentration; HIT-6 = Headache Impact Test; MSQ = Migraine Specific 
Quality of Life Questionnaire; SAEs = serious adverse events; TEAEs = treatment-emergent adverse events; 
TE-ADA = treatment-emergent antidrug antibody
a
Episodic migraine is defined as 4 to 14 migraine headache days and <15 headache days per 1-month period in the 
prospective baseline period. Chronic migraine is defined as at least 15 headache days per 1-month period in the 
prospective baseline period, of which at least 8 are migraine.
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 18
LY3451838
5. Study Design
5.1.
Overall Design
Study LAJB is a multicenter, randomized, double-blind, parallel, placebo-controlled study of 
LY3451838 in patients who meet the International Classification of Headache Disorders
version 3 (ICHD-3) criteria for a diagnosis of migraine with or without aura, or chronic 
migraine, and who have previously failed 2 to 4 categories of standard-of-care treatments for 
migraine prevention. The study has 4 periods as described below.
Figure LAJB 5.1 illustrates the study design.
Study Period I (Screening): The study and potential risks will be explained to the patient at 
Visit 1. The informed consent form (ICF) must be signed before any study procedures are 
performed, which includes discontinuing excluded medications. Patients are required to 
discontinue all excluded medications or treatments for migraine prevention at least 2 weeks prior 
to Visit 2. Botulinum toxin A or B in the head or neck area for therapeutic use must be 
discontinued at least 3 months prior to Visit 2. Nerve blocks or device use, such as transcranial 
magnetic stimulation, in the head or neck area for migraine prevention are not allowed within 
30 days before Visit 2.  
The screening visit (Visit 1) will consist of a full clinical assessment (see Schedule of Activities, 
Section 2). Visit 1 will be complete when the last scheduled procedure of the screening 
assessment for the patient is completed.
Study Period II (Baseline): Qualified patients will enter Study Period II (prospective baseline) 
to determine their eligibility for the study and to establish baseline data for comparison of 
endpoints during the treatment phase. Beginning at Visit 2, patients will log in daily to the 
electronic patient-reported outcomes (ePRO) system to answer questions about the occurrence of 
headaches, headache duration, headache features, severity of headache, and whether any acute
headache medication was taken. At Visit 2 and if available, patients will receive the devices 
required for digital biomarkers assessments as well as the necessary instructions and training. 
Also beginning at Visit 2, patients will record the name, dose, and date of any acute headache 
medication on a headache medication log which will be returned to site staff at each study visit.
At the end of the prospective baseline period, sites will be notified whether their patient met 
criteria and are eligible to be randomized at Visit 3.
To avoid biased reporting, patients must not be told the number of migraine or headache 
days on which study qualification is based.
Study Period III (Double-Blind Treatment): At the start of the 1-month double-blind 
treatment phase (Visit 3), patients meeting all eligibility requirements will be stratified by type of 
migraine (episodic or chronic) and then randomly assigned in a 1:1 ratio within each stratum to 
receive a single dose of LY3451838 or placebo.
Patients will be given IV study drug (LY3451838 or placebo) at the study site. Patients will 
continue to log in and complete the ePRO diary each day. Patients may continue to take their 

J1H-MC-LAJB(b) Clinical Protocol
Page 19
LY3451838
allowed acute migraine headache medication (with some limitations; see Section 7.8) during the 
treatment phase and will continue to record this use. 
Study Period IV (Follow-up): Patients who complete the double-blind treatment phase (Study 
Period III) will be followed for safety for 140 days postdose. Patients will continue to have 
safety assessed, including daily completion of the ePRO diary and recording of acute headache 
medication use (see Schedule of Activities, Section 2). 
Figure LAJB 5.1
Illustration of study design for Clinical Protocol J1H-MC-LAJB.
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
The study will screen an estimated 110 potential patients to ensure randomization of 
approximately 60 migraine patients, of which approximately 30 patients have episodic migraine
(defined as 4 to 14 migraine headache days and <15 headache days per 1-month period in the 
prospective baseline period). To ensure an appropriate balance of patients with episodic and 
chronic migraine, the sponsor will stop enrollment of patients with chronic migraine if the 
number of patients exceeds approximately 50%. Chronic migraine will be defined as at least 
15 headache days per 1-month period in the prospective baseline period, of which at least 8 are 
migraine. Similar frequency of headache days must also be present during the 2 months previous 
to baseline for both episodic and chronic categories, according to investigator’s assessment.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.

J1H-MC-LAJB(b) Clinical Protocol
Page 20
LY3451838
5.4.
Scientific Rationale for Study Design
The double-blind, randomized, placebo-controlled design is the internationally recommended
approach to test efficacy of migraine preventive medications by the International Headache 
Society (IHS; Tfelt-Hansen et al. 2012). In line with the recommendations for migraine clinical 
trials, we include a 3-month retrospective migraine history, and a 1-month baseline period to 
confirm the headache diagnosis and frequency. Patients selection, diagnostic criteria, and 
outcome measurements are in accordance with current IHS recommendations and have been 
used in similar preventive clinical trials.
Since LY3451838 
 or matching placebo will be administered only once, the 
1-month treatment period is adequate in length. Nevertheless, ePRO daily data entry will 
continue for up to 12 weeks, allowing further analyses in possible late headache outcomes. 
Because blocking PACAP signaling is an attractive alternative to anti-CGRP mAb treatments,
which have proved to be efficacious in patients who experienced previous preventive treatment 
failures, this study is designed to specifically select treatment-resistant patients.
The safety / tolerability of LY3451838 has previously been assessed in a Phase 1 study (LAJA). 
Study LAJB will enable a clinical assessment of LY3451838 in a treatment-resistant migraine 
patient population, including patients who may potentially have failed up to 4 different 
categories of standard-of-care migraine preventives. Treatment resistance is more prevalent 
among patients with chronic migraine than episodic; however, the episodic form of migraine (ie, 
4 to 14 migraine headache days and fewer than 15 headache days per month) is the most 
common, with approximately 7% of the migraine population suffering from the chronic form (ie, 
at least 15 headache days per month, of which at least 8 are migraine; Buse et al. 2012; 
Katsarava et al. 2012; Blumenfeld et al. 2013; ICHD-3 2018). 
5.5.
Justification for Dose
The planned LY3451838 dose for this study is 
 IV 
 for a 60-kg individual). 
This dose is selected based on the available preclinical pharmacology, toxicology, and clinical 
data.
Based on the 
 model, the predicted therapeutic concentration of 
LY3451838 is approximately 
 
 In Study LAJA the observed plasma concentration of 
LY3451838 28 days after a single IV dose of
 
 
 This dose is chosen to ensure 
adequate target engagement that enables testing the efficacy of LY3451838 for migraine 
prevention, and to account for uncertainty in the translation of preclinical model to human 
efficacy. 
The 
 dose was the highest dose administered in the single ascending dose study, LAJA. 
Interim analysis of the ongoing LAJA study suggested that LY3451838 was well-tolerated after 
a single IV dose up to 
 No dose-limiting toxicity was identified in this study, and no 
evidence of immune complex disease or vasculitis was observed. Vital signs and safety 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 21
LY3451838
laboratory tests were also unremarkable. The available safety / tolerability data from the ongoing 
study LAJA support the administration of 
single IV dose in Study LAJB.
This dose is also supported by the available toxicology data.
 
 
summarized in IB Section 4.2). 
 
 
 
 
 
Based on the available toxicology and limited clinical data, this dose is acceptable in this 
single-dose efficacy study.
CCI
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 22
LY3451838
6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at
Visit 1, unless stated otherwise in respective criterion:
1. Are 18 to 75 years of age (inclusive).
2. Have a diagnosis of migraine as defined by IHS ICHD-3 guidelines (1.1, 1.2.1.1, or 1.3) 
(ICHD-3 2018), with a history of migraine headaches of at least 1 year prior to Visit 1, and 
migraine onset prior to age 50.
3. Prior to Visit 1, have a history of at least 4 migraine headache days and at least 1 
headache-free day per month on average within the past 3 months (documented by medical 
record or by physician’s confirmation).
4. From Visit 2 to 3 (prospective baseline period), have a frequency of 4 or more migraine 
headache days and at least 1 headache-free day over 30 day period. If more than 15 headache 
days are present, at least 8 of them must fulfill criteria for migraine.
5. From Visit 2 to 3 (prospective baseline period), must achieve sufficient compliance with 
ePRO daily headache entries as demonstrated by completion of at least 80% of daily diary 
entries.
6. Prior to Visit 1, have documentation (by medical or pharmacy record or by physician’s 
confirmation) of previous failure of 2 to 4 standard-of-care migraine preventive medication 
categories from the following list and in the past 10 years due to inadequate efficacy (that is, 
maximum tolerated dose for at least 2 months, (3 months in case of Botulinium toxin A or B) 
and/or safety/tolerability reasons:
a.
Propranolol or metoprolol
b. Topiramate
c.
Valproate or divalproex
d. Amitriptyline or nortriptyline
e.
Flunarizine
f.
Candesartan
g. Anti-CGRP antibodies (either ligand or receptor)
h. Botulinium toxin A or B (if documented that botulinium toxin was taken for chronic 
migraine)
i.
Rimegepant ODT
j.
Atogepant
7. Are available and willing to give signed informed consent.
8. Are reliable and willing to follow study procedures.
9. Women of child-bearing potential must test negative for pregnancy prior to initiation of 
treatment as indicated by a negative serum pregnancy test at the screening visit followed by a 
negative urine pregnancy test within 24 hours prior to exposure.

J1H-MC-LAJB(b) Clinical Protocol
Page 23
LY3451838
10. Women of child-bearing potential who are abstinent (if this is complete abstinence, as their 
preferred and usual lifestyle) or in a same sex relationship (as part of their preferred and 
usual lifestyle) must agree to either remain abstinent or agree to avoid sexual relationships 
with males. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception.
11. Women of child-bearing potential who are not abstinent, as defined above, must agree to use 
one highly effective method (less than 1% failure rate) of contraception, or a combination of 
two effective methods of contraception for the entirety of the study as well as 5 months after 
study drug administration.
Highly effective methods of contraception include combination oral contraceptives, 
implanted contraceptives or intrauterine device. Effective methods of contraception include 
male or female condoms with spermicide, and diaphragms with spermicide or cervical 
sponges. The patient may choose to use a double barrier method of contraception. Barrier 
protection methods without concomitant use of a spermicide are not a reliable or acceptable 
method. Thus, each barrier method must include use of a spermicide. It should be noted 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 methods are combined.
12. Women not of child-bearing potential may participate and include those who are:
a.
infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal 
ligation), congenital anomaly such as mullerian agenesis; or
b. post-menopausal – defined as either
i. a woman at least 40 years of age with an intact uterus, not on hormone 
therapy, who has cessation of menses for at least 1 year without an alternative 
medical cause, and a follicle-stimulating hormone >40 mIU/mL; or
ii. a woman 55 or older not on hormone therapy, who has had at least 12 months 
of spontaneous amenorrhea; or
iii. a woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
13. Agree not to voluntarily change habits or routines that represent a potential migraine trigger 
factor or protective measure including, but not limited to, substantial diet changes, physical 
exercise, or sleep habits.
14. Agree not to post any personal medical data related to the study or information related to the 
study on any website or social media site (eg, Facebook, Twitter, LinkedIn, YouTube, 
Instagram, etc.) excluding the patient’s personal health care providers’ site(s) until the entire 
study has completed.
15. Men, regardless of their fertility status, with non-pregnant women of child-bearing potential
(WOCBP) partners must agree to either remain abstinent (if this is their preferred and usual 
lifestyle) or use condoms plus one additional highly effective (less than 1% failure rate) 
method of contraception (such as combination oral contraceptives, implanted contraceptives 
or intrauterine device) or effective method of contraception, (such as diaphragms with 

J1H-MC-LAJB(b) Clinical Protocol
Page 24
LY3451838
spermicide or cervical sponge) for the duration of the study as well as 5 months after study 
drug administration.
a.
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.)
b. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception.
16. Men with pregnant partners should use condoms during intercourse for the duration of the 
study as well as 5 months after study drug administration.
17. Men should refrain from sperm donation for the duration of the study as well as 5 months 
after study drug administration.
18. Men who are in exclusively same sex relationships (as their preferred and usual lifestyle) are 
not required to use contraception.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
Visit 1, unless stated otherwise in respective criterion:
19. Are currently enrolled in any other clinical study involving an investigational product or any 
other type of medical research judged not to be scientifically or medically compatible with 
this study.
20. Have participated, within the last 30 days or 5-half-lives (whichever is longer), in a clinical 
study involving any investigational product. If the half-life of the investigational product is 
unknown, 6 months should have passed prior to Visit 1.
21. Have previously completed or withdrawn from this study or any other study investigating 
LY3451838.
22. Known hypersensitivity or intolerance to monoclonal antibodies or other therapeutic 
proteins, or to common antihistamines, epinephrine, methylprednisone or other systemic 
corticosteroids.
23. Are currently receiving medication or other treatment for prevention of migraine headaches. 
Patients must have discontinued such medications or treatments at least 2 weeks prior to 
Visit 2. Botulinum toxin A and B that has been administered in the head or neck area use 
must be discontinued at least 3 months prior to Visit 2. Nerve blocks or device use (such as 
transcranial magnetic stimulation or electrical nerve stimulation) in the head or neck area for 
migraine treatment must be discontinued at least 30 days prior to Visit 2. Anti-CGRP 
antibodies (to either ligand or receptor) must be discontinued at least 5 half-lives prior to 
Visit 2.
24. Have previously failed more than 4 migraine preventive medication categories in the past 
10 years from the medication list in Inclusion Criterion # 6 due to inadequate efficacy (that 
is, maximum tolerated dose for at least 2 months) and/or safety/tolerability reasons. Previous
failures to medications not on the above list will not be considered toward this exclusion.

J1H-MC-LAJB(b) Clinical Protocol
Page 25
LY3451838
25. History of cluster headache or migraine subtypes including hemiplegic (sporadic or familial) 
migraine, ophthalmoplegic migraine, retinal migraine, typical aura without headache, 
complications of migraine and migraine with brainstem aura (basilar-type migraine) defined 
by IHS ICHD-3.
26. In the 3 months prior to randomization, have other types of headache besides migraine, 
tension type headache, or medication overuse headache (MOH) as defined by IHS ICHD-3. 
(In other words, patients can have migraine, tension type headache, or MOH in the 3 months 
prior to randomization, but they cannot have other types of headache in that time.)
27. History of head or neck injury within 6 months prior to Visit 1.
28. History of traumatic cervical or head injury associated with significant change in the quality 
or frequency of their headaches.
29. Have reading of electrocardiogram (ECG) at Visit 1 showing abnormalities compatible with 
acute cardiovascular events and/or serious cardiovascular risk, or have had myocardial
infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, 
or stroke within 6 months of screening, or have planned cardiovascular surgery or 
percutaneous coronary angioplasty. Fridericia-corrected QT interval (QTcF) >450 msec for 
males or >470 msec for females based on the reading of the ECG at Visit 1 must be discussed 
and judged not clinically significant by the principal investigator and Lilly Medical prior to 
enrollment.
30. Any liver tests outside the normal range at Visit 1 that are clinically significant. Alanine 
aminotransferase (ALT) >2X upper limit of normal (ULN), or total bilirubin (TBL) >1.5X 
ULN, or alkaline phosphatase (ALP) >2X ULN must be discussed and judged not clinically 
significant by the principal investigator and Lilly Medical prior to enrollment.
31. Evidence of significant active or unstable cognitive, behavioral or psychiatric disease by 
medical history, such as bipolar disorder, schizophrenia, personality disorders, or other 
serious mood or anxiety disorders. Note: Patients with major depressive disorder (MDD) or 
generalized anxiety disorder (GAD) whose disease state is considered stable and expected to 
remain stable throughout the course of the study, in the opinion of the investigator, may be 
considered for inclusion if they are not on excluded medications.
32. Patients who, in the clinician’s judgment, are actively suicidal and therefore deemed to be at 
significant risk for suicide, or have had clinically significant suicidal ideation within the past 
month (eg, includes some plan or intent to act), or have had any suicidal behavior within the 
past month.
33. Women who are pregnant or nursing.
34. Patients who have used opioids or barbiturate-containing analgesic >4 days per month for the 
treatment of pain in each of the past 3 months.
35. History of drug or alcohol abuse/dependence within 1 year prior to Visit 1 (excessive or 
compulsive use as judged by the investigator), or currently using drugs of abuse (including 
opioids, barbiturates, and marijuana), or any prescribed or over-the-counter medication in a 
manner that the investigator considers indicative of abuse/dependence.
36. Have a positive urine drug screen for illicit drugs at Visit 1. Prescribed drugs compatible with 
the protocol and not considered by the investigator to be used abusively are allowed. Note: A 
retest is allowed if the urine drug screen is positive for any prescribed substance or, if in the 

J1H-MC-LAJB(b) Clinical Protocol
Page 26
LY3451838
judgment of the investigator, there is an acceptable medical explanation for the positive 
result. The results of the retest must be negative at or prior to Visit 2.
37. Have an acute, serious, or unstable medical condition that, in the judgment of the 
investigator, indicates a medical problem that would preclude study participation.
38. In the opinion of the investigator, have other issues which would interfere with compliance 
with the study requirements and completion of evaluations required for this study.
39. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted.
40. Are Eli Lilly and Company employees.
41. Are unwilling or unable to comply with the use of data collection devices. Wearable digital 
biomarker device and/or investigational app may be exempted by the study investigator if 
approved by Lilly.
42. Have clinically significant proteinuria or hematuria at screening and enrollment.
44. Show evidence of human immunodeficiency virus (HIV) and/or positive human HIV 
antibodies; current hepatitis C infection with positive hepatitis C antibody and positive 
hepatitis C virus RNA; or hepatitis B and/or positive hepatitis B surface antigen.
45. Have an abnormal blood pressure (supine) defined as diastolic blood pressure >95 or 
<50 mmHg and/or systolic blood pressure >160 or <90 mmHg. Retesting may occur once 
during the screening visit within 2 hours of the initial abnormal blood pressure measurement 
at the discretion of the investigator.
46. Have a history or presence of serious or unstable illnesses including cardiovascular, hepatic, 
renal, gastrointestinal, respiratory, endocrine, immunologic, hematologic disease,
neurological (excluding migraine) and other conditions that, in the investigator’s opinion, 
could interfere with the analyses in this study, or increase risk for study intervention 
administration, or result in a participant’s life expectancy of <24 months.
6.3.
Lifestyle Restrictions
No changes in lifestyle or dietary requirements are required during the study.
Patients should be instructed not to donate blood or blood products during the study or for 
5 months following the last administration of investigational product.
Women of child-bearing potential and men should adhere to the contraceptive requirements as 
specified in the protocol (Section 6.1). No contraception is required for women of non-
child-bearing potential, except in compliance with specific local government study requirements.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
considered for rescreen with approval from Lilly Medical.
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 27
LY3451838
Patients using a concomitant medication that requires a stable dose for a specific duration prior 
to Visit 2 may be rescreened if additional time is needed to meet the duration requirement.
Repeating of laboratory tests during the screening period does not constitute rescreening.

J1H-MC-LAJB(b) Clinical Protocol
Page 28
LY3451838
7. Treatments
7.1.
Treatments Administered
This study involves a comparison of LY3451838 
with placebo and is administered once
by IV infusion. Trained site staff will administer LY3451838 or placebo at the study site during 
the double-blind treatment phase.  
The study drug will be administered as a slow IV infusion over at least 60 minutes. Infusion 
duration may be increased or stopped as deemed necessary based on the standard operation 
procedure, or if an infusion reaction is observed (Section 7.6.1). Sites must have resuscitation 
equipment, emergency drugs, and appropriately trained medical staff available during the 
infusion and for at least 6 hours after patients have completed their infusion. The actual start and 
stop time of infusion will be recorded in the electronic data capture (EDC) system. If the infusion 
is terminated early, this will also be recorded in the EDC.
LY3451838 Drug Product is a 
antibody formulated for IV administration. 
LY3451838 is supplied for clinical trial use as a solution in a single-use glass vial. The vial is 
manufactured to deliver 
 of LY3451838 at 
. In order to ensure complete 
withdrawal and delivery of the label amount of 
 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.
This study is double-blinded and the placebo prepared at the site by unblinded dispensing 
personnel will be 0.9% sodium chloride for injection, compendial. This solution is 
indistinguishable in 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 his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the patient

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study, returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law.
7.1.1. Packaging and Labelling
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 
CCI
CCI
CCI
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 29
LY3451838
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
Following a 1-month prospective baseline period, eligible patients will be stratified by type of 
migraine (episodic or chronic) and then randomly assigned in a 1:1 ratio within each stratum to 
receive LY3451838 or placebo. Treatment assignment will be determined by a 
computer-generated randomization sequence using an interactive web response system (IWRS).
To ensure an appropriate balance of patients with episodic and chronic migraine, the sponsor will 
stop enrollment of patients with chronic migraine if the number of patients exceeds 
approximately 50%.  
7.2.1. Selection and Timing of Doses
This is a fixed-dose study where the single dose of the study drug will be administered at the site
by a trained staff member. The actual time of dose administration will be recorded in the EDC.
7.3.
Blinding
This is a double-blind study; subjects, investigator, and site 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 will see the randomization table and treatment assignments before the study is 
complete. Site staff who are responsible for drug preparation will not be blinded; laboratory 
personnel will also not be blinded.
After the reporting database is locked for statistical analysis of the double-blind treatment phase, 
a limited number of sponsor personnel will be unblinded to complete the study report. However, 
any sponsor personnel continuing with the management and oversight of the study will remain 
blinded to patients’ treatment assignments.
Emergency unblinding may be performed through the IWRS. This option may be used only if the 
patient’s well-being requires knowledge of the patient’s treatment assignment. All unblinding 
events will be recorded and reported by the IWRS.
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a patient’s treatment assignment is warranted for medical management of the 
event. The patient’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 an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study. In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from a Lilly Medical for the 

J1H-MC-LAJB(b) Clinical Protocol
Page 30
LY3451838
patient to continue in the study. During the study, emergency unblinding should occur only by 
accessing the IWRS.
7.4.
Dosage Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, 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.
LY3451838 for Injection vials are to be stored in refrigerated condition (2ºC to 8ºC).
7.6.
Special Treatment Considerations
7.6.1. Management of Infusion Reactions
There is a risk of infusion reactions with any biological agent; therefore, all patients 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. Infusion site reactions may include 
erythema, induration, pain, pruritus, and edema. 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 patient should be made

Supportive care will be administered as determined by the study investigator(s)

J1H-MC-LAJB(b) Clinical Protocol
Page 31
LY3451838

Appropriate medication may be used as determined by the study investigator(s)
For specific laboratory testing, please see Section 9.4.6.4.
7.7.
Treatment Compliance
The study drug will be administered at the site. Investigators will be required to document the 
administration of study drug in the EDC.
Study drug must be administered per Section 2 of this protocol. If the investigator is unable to 
administer the study drug in the allowed window, the situation should be discussed with Lilly to 
determine if the patient may continue.
7.8.
Concomitant Therapy
Table LAJB 7.1 contains the list of medications that are, and are not, allowed in this study. Any 
changes in the list of allowed/not allowed medications will be communicated to investigators and 
will not constitute a protocol amendment. The concomitant use of acute medications to treat 
migraine is allowed, with some limitations. Treatments used for the prevention of migraine, 
including nutraceuticals and non-pharmacological interventions, are not allowed at any time 
during Treatment Phase and Follow-up Phase. Patients should have washed out all migraine 
preventive treatments at least 5 days prior to Visit 2. Botulinum toxin A or B in the head or neck 
area for therapeutic use is not allowed within 3 months prior to Visit 2. Nerve blocks or use of 
therapeutic devices (such as transcranial magnetic stimulation) in the head or neck area or for 
migraine prevention are not allowed within 30 days before Visit 2. Anti-CGRP antibodies (to 
either ligand or receptor) must be discontinued at least 5 half-lives prior to Visit 2.
Patients will capture whether they took any acute headache medication as part of their daily diary 
entry during Treatment Phase and Follow-up Phase. Acute headache medication name, dose, and 
date will be recorded by patients during Treatment Phase and Follow-up Phase on a headache 
medication log, which will be returned to site staff at each study visit.  
Table LAJB 7.1
Treatments Allowed and Treatments Not Allowed as Concomitant 
Therapy
A. Medications allowed for the ACUTE treatment of migraine headaches or other pain 
or injury:
Acetaminophen (paracetamol) up to 3000 mg/day, NSAIDs; Triptans; Ergotamine and derivatives; 
Isometheptene mucate, dichloralphenazone and acetaminophen combination (Midrin); or combinations thereof;
ubrogepant;
The following medications are allowed with restrictions:
1.Opioid and barbiturates no more than 4 days/month.
2.Single dose of injectable steroids allowed only once during the study, in an emergency setting (SP II, III, IV).
3.Short term use of steroids, < 7days,  for medical circumstances that may arise.
B. Medications, Procedures or Devices not allowed for any reason/indication in Study 
Period II (Baseline), III (Double-Blind Treatment), and IV (Follow-up):
ACE inhibitors 
Acetazolamide

J1H-MC-LAJB(b) Clinical Protocol
Page 32
LY3451838
Acupuncture
Anticonvulsants/Antiepileptics
Antipsychotics
Angiotensin receptor blockers (ARBs)
Beta-blockers 
Botulinum toxin applied to head/neck area for therapeutic use 
Cannabis / Cannabinoids / Cannabidiol
Chiropractic procedures, physiotherapy, TENS or other electric devices on head and neck
Corticosteroids for oral use
Flunarizine
Gabapentin
Herbals with anti-inflammatory effect (feverfew, willow bark, petasites/butterbur)  
Monoamine oxidase inhibitors (MAOIs)
Memantine
Methysergide
Nerve block in head/neck area
Oxetorone
Pizotifen
Pregabalin
Serotonin 5HT2a/2c antagonists, eg, trazodone, nefazodone  
Stimulants (prescription strength), eg, methylphenidate, dextroamphetamine, mixed amphetamine salts
Tizanidine
Tricyclic antidepressants (TCAs)
Triptans for prophylaxis of menstrual related migraine 
Venlafaxine
Verapamil
C. Restricted medication during Study Period III (Double-Blind Treatment) and Study 
Period IV (Follow-up): Use of the following medications for indications other than 
migraine prevention is allowed providing the dose is stable 2 months prior to Visit 2 and 
is expected to remain stable during the Treatment Phase. 
Benzodiazepines
Bupropion 
Calcium-channel blockers (except verapamil, flunarizine, and lomerizine)
Clonidine 
Guanfacine 
Mirtazapine 
SSRIs/NRIs/SNRIs (other than venlafaxine) 
Use of electric devices (ie, TENS), physiotherapy, chiropractic procedures on low back and extremities
D. Restricted medication during Study Period IV (Follow-up):
Medications from List B.
Medications or treatments for migraine prevention.
Medications in List C may now be started, stopped, or have dose modification as long as not being used for 
migraine prevention.
Abbreviations: 5HT = 5-hydroxytryptamine; ACE = angiotensin-converting enzyme; NRI = norepinephrine 
reuptake inhibitor; NSAID = nonsteroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake 
inhibitor; SP = Study Period; SSRI = selective serotonin reuptake inhibitor; TENS = transcutaneous electrical 
nerve stimulation.
7.9.
Treatment after the End of the Study
Not applicable.

J1H-MC-LAJB(b) Clinical Protocol
Page 33
LY3451838
8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of the study drug:

Unacceptable toxicity

Patient request

Pregnancy

Discontinuation due to a hepatic event or liver test abnormality:

Patients who are discontinued from study drug due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected and entered into EDC.
o
Discontinuation of the study drug for abnormal liver tests should be considered 
by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly designated medical monitor:

ALT or aspartate aminotransferase (AST) >8X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and TBL >2X ULN or international 
normalized ratio (INR) >1.5 

ALT or AST >3X ULN with the appearance of fatigue, nausea, 
vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)

ALP >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, 
right quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

If the investigator, after consultation with the sponsor-designated medical monitor, 
determines that a systemic hypersensitivity reaction has occurred related to study drug 
administration, the participant should be permanently discontinued from the 
investigational drug.

In addition, study drug may be discontinued if participants
o
answered “yes” to Question 4 or Question 5 on the “Suicidal Ideation” portion of 
the Columbia-Suicide Severity Rating Scale (C-SSRS), or
o
answered “yes” to any of the suicide-related behaviors on the Suicidal Behavior 
portion of the C-SSRS.
A psychiatrist or appropriately trained professional may assist in the decision to 
discontinue the participant.

J1H-MC-LAJB(b) Clinical Protocol
Page 34
LY3451838
Patients discontinuing from the study drug prematurely for any reason should complete adverse 
event and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment. If the investigator and the Lilly medical monitor agree it is medically 
appropriate to continue, the investigator must obtain documented approval from the Lilly 
medical monitor to allow the inadvertently enrolled patient to continue in the study with or 
without treatment with investigational product. Safety follow up is as outlined in Section 2
(Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

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 or patient request

patients discontinuing from the study prematurely for any reason should complete 
adverse event and other follow-up procedures per Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel are expected to make diligent 
attempts to contact patients who fail to return for a scheduled visit or were otherwise unable to 
be followed up by the site.

J1H-MC-LAJB(b) Clinical Protocol
Page 35
LY3451838
9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results. Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
ePRO Diary: Patients will be asked to use an ePRO instrument to record headache information, 
including reporting frequency, intensity, features (eg, locations and quality), and whether any 
acute headache medication was taken. The system also will be used to collect information about
migraine-associated symptoms (
, photophobia, phonophobia, nausea, and/or vomiting).
9.1.2. Secondary Efficacy Assessments
Secondary efficacy assessments in this study (Section 4) are intended to facilitate the collection 
and analysis of information such as response (≥50% reduction from baseline in the number of 
migraine headache days per month and number of monthly headache days) with data from the 
ePRO Diary (see above), and safety and tolerability of the study drug via analysis of TEAEs and 
SAEs.
9.1.3. Appropriateness of Assessments
The efficacy and safety assessments used in this study have been well documented and are 
generally regarded as reliable, accurate, and relevant in this patient population.
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 patients 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 patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report and ECG.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 36
LY3451838
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study. The patient 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.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect. However, any worsening of the primary study condition should be 
recorded as an AE.
After the ICF is signed, study site personnel will record via EDC the occurrence and nature of 
each patient’s pre-existing conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study. In addition, site personnel will record via eCRF any change 
in the condition(s) and any new conditions as AEs. Investigators should record their assessment 
of the potential relatedness of each AE to protocol procedure or investigational product via EDC.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, and pathologies.
A “reasonable possibility” means that there potentially is a cause and effect relationship between 
the investigational product, study device, and/or study procedure and the AE.
The investigator will use AE follow-up forms to record additional details regarding AEs related 
to injection sites and hypersensitivity events.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s study drug is discontinued as a result of an AE, study site personnel must report this 
to Lilly or its designee via EDC, clarifying if possible the circumstances leading to 
discontinuation of treatment.
9.2.1. Adverse Event Monitoring with a Systematic Questionnaire
Nonleading AE collection should occur prior to the collection of the C-SSRS.
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form.
If an AE is serious or leads to discontinuation, it needs to be included on the AE form and the 
process for reporting SAEs is followed.
9.2.2. 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)

J1H-MC-LAJB(b) Clinical Protocol
Page 37
LY3451838

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.
The study site personnel must alert the Lilly, or its designee, of any SAE as soon as practically 
possible.
Additionally, study site personnel must alert Lilly, 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 patient 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 patients once they have 
discontinued from and/or completed the study (the patient disposition EDC has been completed). 
However, if the Investigator learns of any SAE, including a death, at any time after a patient 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.
9.2.2.1.
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 identifies as related to investigational product or procedure. 
Lilly has procedures that will be followed for the identification, recording and expedited 
reporting of SUSARs that are consistent with global regulations and the associated detailed 
guidances.

J1H-MC-LAJB(b) Clinical Protocol
Page 38
LY3451838
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will 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.
In case of overdose, use supportive therapy. There is no known antidote to LY3451838 overdose.
9.4.
Safety
Planned time points for all safety assessments are provided in the Schedule of Activities
(Section 2).
9.4.1.
Physical and Neurological Examinations

A complete physical examination will be performed at screening and at time of discharge 
(Section 2). Targeted physical examination of skin, lungs, and skeletomuscular system 
will be performed according to the Schedule of Activities (Section 2). Symptom-driven 
physical examinations will be performed if deemed clinically necessary. 

A complete neurological examination will be performed by a physician at the time points 
specified in the Schedule of Activities (Section 2). If abnormalities are noted at these 
time points, additional examinations should be repeated until the participant has returned 
to baseline. The examiner should be familiar with the participant’s baseline examination. 
Mandated elements of the examination include mental status, gait, balance, coordination, 
cranial nerves, sensory and motor systems, and reflexes. Work-up for participants with 
clinically significant changes in neurological examinations should be considered. 
Additional neurological examination will be performed as soon as possible, along with 
any other methodical follow-ups deemed necessary by the investigator.
9.4.2. Vital Signs
Vital signs will include body temperature, sitting blood pressure, and pulse. For each patient, 
vital signs measurements should be conducted according to the Schedule of Activities
(Section 2).
Predose vital signs should be taken approximately 1 hour prior to the scheduled dosing.
Any clinically significant findings from vital signs measurement that result in a diagnosis should 
be reported to Lilly, or its designee, as an AE via EDC.
9.4.3. Electrocardiograms
For each patient, a single 12-lead digital ECG should be collected according to the Schedule of 
Activities (Section 2). Electrocardiograms should be collected prior to blood draws and dosing. 

J1H-MC-LAJB(b) Clinical Protocol
Page 39
LY3451838
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection. 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 
patient is still present, to determine whether the patient meets entry criteria at the relevant visits 
and for immediate patient 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 patient for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the patient can continue in the study. The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation.
9.4.3.1.
Digital Electrocardiogram Storage
Digital ECGs collected from 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 should be reported to
Lilly, or its designee, as an AE via EDC. 
9.4.4. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2). 
With the exception of 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. Note 
that any result that may unblind a site would not be shared.
Any clinically significant findings from laboratory tests that result in a diagnosis should be 
reported to Lilly, or its designee, as an AE via EDC.
9.4.5. 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. Antibodies may be further characterized for their ability to neutralize the activity of 
the LY3451838. To interpret the results of immunogenicity, a venous blood sample will be 

J1H-MC-LAJB(b) Clinical Protocol
Page 40
LY3451838
collected at the same time points to determine the plasma concentrations of LY3451838. All 
samples for immunogenicity should be taken predose when applicable and possible.
Treatment-emergent antidrug antibodies (TE-ADAs) are defined in Section 10.3.6. If the 
immunogenicity sample at the last scheduled assessment or discontinuation visit is TE-ADA 
positive, additional samples may be taken until the signal returns to baseline (ie, no longer 
TE-ADA positive) or for up to 1 year after last dose.
Samples will be retained for a maximum of 15 years after the last patient 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.
9.4.6. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.6.1.
Hepatic Safety Monitoring
If a study patient experiences any of the following abnormal liver test results, liver testing 
(Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, TBL, direct 
bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the abnormality and to 
determine if it is increasing or decreasing:

elevated ALT ≥3X ULN

ALP ≥2X ULN

elevated TBL ≥2X ULN 
If the abnormality persists or worsens, clinical and laboratory monitoring should be initiated by 
the investigator and in consultation with the study medical monitor. Monitoring of ALT, AST, 
TBL, and ALP should continue until levels normalize or return to approximate baseline levels. 
Hepatic Safety Data Collection
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 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

patient discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be an SAE
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 41
LY3451838
9.4.6.3.
Hypersensitivity Reaction
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
EDC. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants 
who experience a systemic hypersensitivity reaction be treated per national and international 
guidelines. 
In the case of generalized urticaria or anaphylaxis, additional blood samples should be collected 
as described in Appendix 5. Laboratory results are provided to the sponsor via the central 
laboratory.
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, 
 
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 42
LY3451838
, and urine analysis) will be undertaken to assess for the development of 
 serum sickness and other manifestations of type 3 hypersensitivity reactions. 
Unscheduled stored serum samples for possible immune safety laboratory testing (including, but 
not limited to: β-tryptase, total IgE, immune-complex testing, and cytokine panel) should be 
collected approximately 60 to 120 minutes and 4 to 6 weeks after hypersensitivity reactions.
9.4.6.4.
Infusion Reaction
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. Signs and symptoms of a local infusion site reaction may 
include erythema, induration, pain, pruritus, and edema. In the event that an infusion reaction 
occurs during the infusion, please see Section 7.6.1 for guidance on administration of remaining 
study drug, if applicable. In the event that an infusion reaction occurs at any other time, 
appropriate supportive care and/or medication may be used as determined by the study 
investigator(s). These adverse events should be captured as specified in Section 9.2.
Unscheduled stored serum samples for possible immune safety laboratory testing (including, but 
not limited to: β-tryptase, total IgE, immune-complex testing, and cytokine panel) should be 
collected approximately 60 to 120 minutes and 4 to 6 weeks after moderate or severe infusion 
reactions.
The clinical information, including examination findings, laboratory testing and treatment for all 
adverse events, including infusion reactions, will be captured in the EDC.
9.4.6.5.
Suicidal Ideation and Behavior Risk Monitoring
Patients being treated with LY3451838/placebo should be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior, especially at 
the beginning and end of the course of treatment, or at the time of dose changes, either increases 
or decreases. Consideration should be given to discontinuing the study medication in patients 
who experience signs of suicidal ideation or behavior, following a risk assessment.
Columbia Suicide-Severity Rating Scale is a scale that captures the occurrence, severity, and 
frequency of suicidal ideation and behavior during the assessment period via a questionnaire. 
The scale was developed by the National Institute of Mental Health (NIMH) trial group (TASA) 
for the purpose of being counterpart to the Columbia Classification Algorithm of Suicide 
Assessment (C-CASA) categorization of suicidal events.
CCI
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 43
LY3451838
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 actual date and time of each sampling must be recorded.
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 patient number. These samples and any data generated can be 
linked back to the patient only by the investigative site personnel. 
Samples will be retained for a maximum of 15 years after the last patient 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.
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 44
LY3451838
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 45
LY3451838
9.9.
Health Economics
The health outcome measures will be collected according to the Schedule of Activities
(Section 2).
Migraine-Specific Quality of Life Questionnaire version 2.1: The Migraine-Specific Quality 
of Life Questionnaire version 2.1 (MSQ v2.1) is a self-administered health status instrument that 
was developed to address the physical and emotional impact on functioning that is of specific 
concern to individuals suffering from migraine headaches. The instrument consists of 14 items 
that address 3 domains: (1) Role Function-Restrictive; (2) Role Function-Preventive; and (3) 
Emotional Function (Jinghran et al. 1998b). The restrictive domain specifically measures 
disability as related to the impact on performance of normal activities, with the preventive 
domain addressing complete functional impairment and the emotional domain assessing the 
feelings related to disabling monthly migraine headache days. Responses are given using a 
6-point Likert-type scale, ranging from “none of the time” to “all of the time.” Raw scores for 
each domain are computed as a sum of item responses, with the collective sum providing a total 
raw score that is then converted to a 0 to 100 scale, with higher scores indicating a better health 
status, and a positive change in scores reflecting functional improvement (Jinghran et al. 1998a; 
Marting et al. 2000). The instrument was designed with a 4-week recall period and is considered 
reliable, valid, and sensitive to change in functional impairment due to migraine (Jinghran et al. 
1998b; Bagley et al. 2012).
Six-item Headache Impact Test (HIT-6): HIT-6 is a tool used to measure the impact headaches 
have on patient’s ability to function on the job, at school, at home and in social situations. The 
HIT-6 consists of six items: pain, social functioning, role functioning, vitality, cognitive 
functioning, and psychological distress. The patient answers each question using one of the 
following 5 responses: “never,” “rarely,” “sometimes,” “very often,” or “always.” These 
responses are summed to produce a total HIT-6 score that ranges from 36 to 78, where a higher 
score indicates a greater impact of headache on the daily life of the respondent (Shin et al. 2008). 
A validation study showed that the HIT-6 is a reliable and valid tool for measuring the impact of 
headache on daily life in both episodic and chronic migraine sufferers (Yang et al. 2011).
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 46
LY3451838
10. Statistical Considerations
10.1. Sample Size Determination
The study will screen an estimated 110 potential patients to ensure randomization of 
approximately 60 migraine patients. Enrollment will be stratified by type of migraine, episodic 
versus chronic, and patients will be randomly assigned to either LY3451838 or placebo in a 1:1 
allocation ratio within each stratum. Enrollment in the chronic migraine stratum will be capped 
so that no more than approximately 50% of the randomized population will be patients with 
chronic migraine. 
The analysis will be conducted using all randomized patients, and it is assumed that 
approximately 2% of the patient population will dropout during the 28 days treatment period. 
The study will be considered successful if there is at least a
 probability that the number of 
monthly migraine headache days with LY3451838 treatment is 
days less than the number of 
monthly migraine headache days with placebo treatment
 
Enrolling approximately 60 patients who are stratified by type of migraine, episodic versus 
chronic, and randomly assigned to either LY3451838 or placebo in a 1:1 allocation ratio within 
each stratum will provide approximately 
 
 
 
 
 
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All patients who sign informed consent
Randomized
All patients who are assigned a study treatment. Patients who had no post 
randomization efficacy measure for the parameter being analyzed will be 
excluded. 
Safety
All randomized patients who take at least 1 dose of double-blind study 
treatment. Patients will be included in the treatment group they were 
randomized to. In the event of a treatment error, patients will be analyzed 
according to the treatment they actually received.
CCI
CCI
CCI
CCI
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 47
LY3451838
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. Details of 
statistical analysis methods will be described in the SAP.
Efficacy analyses will be conducted on the randomized set. Safety analyses will be conducted on 
the safety population. When mean change from baseline is assessed, the patient will be included 
in the analysis only if the patient has a baseline and a postbaseline measurement. 
In general, for analyses of numeric outcome measures during the treatment phase, baseline value 
is defined as the last observation at or before Visit 3. Treatment effects will be evaluated based 
on a 2-sided significance level of 0.05. No adjustments for multiplicity will be applied to 
comparisons of baseline characteristics or safety parameters.  
A Bayesian analysis will be performed for the primary efficacy endpoint, and the corresponding 
frequentist analyses will be conducted as a sensitivity analysis. All other statistical inference will 
be performed using frequentist methods.
For continuous variables, descriptive statistics will include the number of patients, mean, 
median, standard deviation, minimum, and maximum. Categorical variables will be summarized 
using the number and percentage of patients.
Any change to the data analysis methods described in the protocol will require a protocol 
amendment ONLY if it changes a principal feature of the protocol. Any other change to the data 
analysis methods described in the protocol, and the justification for making the change, will be 
described in the clinical study report. Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
SAS® software version 9.4 or higher will be used to perform statistical analyses, unless 
otherwise specified.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study. All patients
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.
10.3.2.2. Patient Characteristics
The following patient characteristics at baseline will be summarized by treatment.

Demographic (age, sex, ethnic origin, height, weight, body mass index)

Migraine and/or headache-related measures from the ePRO diary per 1-month
baseline period

J1H-MC-LAJB(b) Clinical Protocol
Page 48
LY3451838

Number of prior migraine preventive treatment failures from the list in Section 6.1
(Inclusion Criterion #6):
o
Failed 2 medication categories
o
Failed 3 medication categories
o
Failed 4 medication categories

Medical history and pre-existing conditions
Medical history and pre-existing conditions will be summarized by preferred term within system 
organ class (SOC).
10.3.2.3. Concomitant Therapy
The proportion of patients who received concomitant medication and acute medications will be 
summarized.
10.3.2.4. Treatment Compliance
Any dose reduction, overdose, or dose delay will be summarized for all treated patients by 
cohort.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary analysis will be performed using an analysis of covariance (ANCOVA) model for 
the change from baseline in the monthly number of migraine headache days. The model will 
include randomized treatment and type of migraine as fixed effects and the baseline number of 
monthly migraine headache days as a covariate. The analysis will use a non-informative prior for 
the treatment effect. The treatment group means, treatment contrast, and their respective 95% 
credible regions as well as the success criterion will be based on the posterior treatment effect 
distributions.
10.3.3.2. Secondary Analyses
Frequentist analyses for change from baseline in the monthly number of migraine headache days 
and change from baseline in the monthly number of headache days will be performed using the 
ANCOVA model. Comparisons between the treatments in rate of responders will be conducted 
using Cochran Mantel Haenszel tests that are stratified by the type of migraine. 
10.3.3.3. Exploratory Analyses
Details on exploratory analysis will be provided in the SAP.
10.3.4. Safety Analyses
The safety and tolerability of treatment will be assessed by summarizing the following:

TEAEs

SAEs

AEs leading to discontinuation

J1H-MC-LAJB(b) Clinical Protocol
Page 49
LY3451838

Potential hypersensitivity events

AEs related to injection site reactions

Vital signs

Physical and neurological examinations

ECGs

Laboratory measurements

CBB
The parameters will be listed, and summarized using standard descriptive statistics. Additional 
analysis will be performed as required.
10.3.6. Evaluation of Immunogenicity
The frequency and percentage of patients with preexisting ADA and with TE-ADA+ to 
LY3451838 may 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 TE-ADA+ patients the distribution of maximum 
titers may be described. The frequency of neutralizing antibodies may also be tabulated in TE 
ADA+ patients, when available.
CCI

J1H-MC-LAJB(b) Clinical Protocol
Page 50
LY3451838
The relationship between the presence of antibodies and the PK parameters and PD response
including safety and efficacy to LY3451838 may be assessed.
10.3.7. Other Analyses
10.3.7.1. Health Economics
The change from baseline for the treatment phase for MSQ v2.1 and HIT-6 will be analyzed. In 
addition, categorical analyses will be performed. Additional details will be provided in the SAP.
10.3.7.2. Analysis of C-SSRS Data
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide.
Additional details will be provided in the SAP.
10.3.8. Interim Analyses
An interim analysis is planned when data from the majority of  randomized patients have 
completed the 1-month treatment period. The interim efficacy results may be used for internal 
decision-making to trigger planning activities associated with the investigational product. No 
adjustment of Type I error will be performed as the study will not be stopped for efficacy, and no 
modification of Study LAJB is expected based on these interim results. The assessment would be 
conducted by a sponsor assessment committee with a limited number of preidentified team 
members who do not have direct site contact or data entry/validation responsibilities. Unblinding 
details will be specified in the unblinding plan section of the SAP or in a separate unblinding 
plan document. Information that may unblind the study during the analyses will not be reported 
to study sites or to the blinded study team until the study has been unblinded.

J1H-MC-LAJB(b) Clinical Protocol
Page 51
LY3451838
11.
References
[ICHD-3] The International Classification of Headache Disorder, 3rd edition. Cephalgia. 
2018;38(1):1-211.
Abu Bakar N, Tanprawate S, Lambru G, et al. Quality of life in primary headache disorders: A 
review. Cephalgia. 2016;36(1):67-91.
Bagley CL, Rendas-Baum R, Maglinte GA, et al. Validating migraine-specific quality of life 
questionnaire v 2.1 in episodic and chronic migraine. Headache. 2012;52(3):409-21.
Begasse de Dhaem OAJ, French J, Morrison C, et al. Migraine comorbidity and cognitive 
performance in patients with focal epilepsy. Epilepsy Behav. 2019;97:29-33.
Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation 
of prophylactic medications for episodic migraine and chronic migraine: results from the 
second international burden of migraine study (IBMS-II). Headache. 2013;53(4) :644-55.
Blumenfeld AM, Varon SF, Wilcox TK, et al. Disability, HRQoL and resource use among 
chronic and episodic migraineurs: results from the International Burden of Migraine Study 
(IBMS). Cephalgia. 2011;31(3):301-15.
Buse DC, Manack An, Fanning KM, et al. Chronic migraine prevalence, disability, and 
sociodemographic factors: results from the American Migraine Prevalence and Prevention 
Study. Headache. 2012;52(10):1456-70.
Cogstate resources page. Cogstate web site. Available at: https://www.cogstate.com/clinical-
trials/computerized-cognitive-assessment/featured-batteries/. Accessed July 7, 2020. 
Darby DG, Pietrzak RH, Fredrickson J, et al. Intraindividual cognitive decline using a brief 
computerized cognitive screening test. Alzheimers Dement. 2012;8(2):95-104.
Ferrari MD, Diener HC, Ning X, et al. Fremanezumab versus placebo for migraine prevention in 
patients with demonstrated failure to up to four migraine preventive medication classess 
(FOCUS) : a randomised, double-blind, placebo-controlled, phase 3b trial. Lancet. 
2019:394(10203):1030-40.
Grau RG. Drug-induced vasculitis: new insights and a changing lineup of suspects. Curr 
Rheumatol Rep. 2015;17(12):1-10.
Jinghran P, Davis SM, LaVange LM, Miller DW, Helms RW. MSQ: Migraine-specific-quality-
of-life questionnarie. Further investigation of the factor structure. Pharmacoeconomics. 
1998;13(6):707-17.
Jinghran P, Osterhaus JT, Miller DW, Lee JT, Kirchdoerfer L. Development and validation of 
Migraine-specific quality of life questionnaire. Headache. 1998;36(4):295-302
Jolivel V, Basille M, Aubert N, de Jouffrey S, Ancian P, Le Bigot JF, et al. Distribution and 
functional characterization of pituitary adenylate cyclase-activating polypeptide receptors in 
the brain of non-human primates. Neuroscience. 2009;160(2):434-51.
Katsarava Z, Buce DC, Manack AN, Lipton RB. Defining the difference between episodic 
migraine and chronic migraine. Curr Pan Headache Rep. 2012;16(1):86-92.

J1H-MC-LAJB(b) Clinical Protocol
Page 52
LY3451838
Lanteri-Minet M, Duru G, Mudge M, Cottrell S. Quality of life impairment, disability and 
economic burden associated with chronic daily headache, focusing on chronic migraine with 
or without medication overuse: a systematic review. Cephalgia. 2011;31(7):837-50.
Lim YY, Ellis KA, Harrington K, et al. Use of the CogState Brief Battery in the assessment of 
Alzheimer’s disease related cognitive impairment in the Australian Imaging, Biomarkers and 
Lifestyle (AIBL) study. J Clin Exp Neuropsychol. 2012;34(4):345-358.
Lim,YY, Jaeger J, Harrington K, et al. Three-month stability of the CogState Brief Battery in 
healthy older adults, mild cognitive impairment, and Alzheimer’s disease: results from the 
Australian Imaging, Biomarkers, and Lifestyle-rate of change substudy (AIBL-ROCS). Arch 
Clin Neuropsychol. 2013;28(4):320-330.
Martin BC, Pathak DS, Sharfman MI, et al. Validity and reliability of the migrain-specific 
quality of life questionnaire (MSQ v2.1). Headache. 2000;40(3):204-15.
Maruff P, Thomas E, Cysique L, et al. Validity of the CogState Brief Battery: relationship to 
standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, 
schizophrenia, and AIDS dementia complex. Arch Clin Neuropsychol. 2009;24(2):165-178.
Pike J, Mutebi A, Shah N, et al. Factors associated with a history of failure and switching 
migraine prophylaxis treatment: an analysis of clinical practice data from the United States, 
Germany, France, and Japan. Value in Health. 2016;19(3):A68.
Reuter U, Godsby PJ, Lanteri-Minet M, et al. Efficacy and tolerability of erenumab in patients 
with episodic migraine in whom two-to-four preventive treatments were unsuccessful: 1 
randomised, double-blind, placebo-controlled, phase 3b study. Lancet. 
2018;392(10161):2280-7.
Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-
like attacks in patients with migraine without aura. Brain. 2009;132(Pt 1):16-25.
Shin HE, Park JW, Kim YI, Lee KS. Headache Impact Test-6 (HIT-6) scores for migraine 
patients: Their relation to disability as measured from a headache diary. J Clin Neurol. 
2008;4(4):158-163.
Tfelt-Hansen P, Pascual J, Ramadan N, Dahlof C, D'Amico D, Diener HC, et al. Guidelines for 
controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia. 
2012;32(1):6-38
Tuka B, Helyes Z, Markovics A, Bagoly T, Szolcsányi J, Szabó N, Tóth E, Kincses ZT, Vécsei 
L, Tajti J. Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and 
interictal periods of migraine patients. Cephalalgia. 2013;33(13):1085-1095.
Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, et al. Pituitary adenylate 
cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev. 
2009;61(3):283-357.
Vos T, Flaxman D, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 
289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease 
Study 2010. Lancet. 2012;380(9859):2163-96. 
Yang M, Rendas-Baum R, Varon SF, Kosinski M. Validation of the Headache Impact Test 
(HIT-6™) across episodic and chronic migraine. Cephalgia. 2011;31(3):357-67.

J1H-MC-LAJB(b) Clinical Protocol
Page 53
LY3451838
Zagami AS, Edvinsson L, Goadsby PJ. Pituitary adenylate cyclase activating polypeptide and 
migraine. Ann Clin Transl Neurol. 2014;1(12):1036-1040.

J1H-MC-LAJB(b) Clinical Protocol
Page 54
LY3451838
12.
Appendices

J1H-MC-LAJB(b) Clinical Protocol
Page 55
LY3451838
Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug 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 adverse event 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.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under concentration-time curve
blinding/masking
A double-blind study is one in which neither the [patient] nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
CAS
Cranial Autonomic Symptoms
CBB
Cogstate Brief Battery
CGRP
calcitonin gene-related peptide
Cmax
maximum observed drug concentration
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRP
C-reactive protein
C-SSRS
Columbia Suicide Severity Rating Scale
CV
coefficient of variance
dBM
digital biomarker
ECG
electrocardiogram
EDC
electronic data capture system
enroll
The act of assigning a patient to a treatment. Patients who are enrolled in the study are 
those who have been assigned to a treatment.

J1H-MC-LAJB(b) Clinical Protocol
Page 56
LY3451838
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ePRO
electronic patient-reported outcomes
ESR
erythrocyte sedimentation rate
GCP
good clinical practice
HIT-6
Headache Impact Test
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICHD-3
International Classification of Headache Disorders version 3
Ig
immunoglobulins
IHS
International Headache Society
Informed consent
A process by which a patient 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 patient’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form.
IV
intravenous
IVRS/IWRS
interactive voice-response system/interactive web-response system
MOH
medication overuse headache
MSQ
Migraine Specific Quality of Life Questionnaire
NOAEL
no-observed-adverse-effect-level
PACAP
pituitary adenylate cyclase-activating peptide
PK/PD
pharmacokinetics/pharmacodynamics
QTc
corrected QT interval
SAE
serious adverse event
SAP
statistical analysis plan
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. 

J1H-MC-LAJB(b) Clinical Protocol
Page 57
LY3451838
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
TE-ADA
treatment-emergent antidrug antibody
TEAE
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
ULN
upper limit of normal
VIP
Vasoactive intestinal peptide
WOCBP
Women of child-bearing potential

J1H-MC-LAJB(b) Clinical Protocol
Page 58
LY3451838
Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Erythrocyte sedimentation rate (ESR)
Fasting Glucose
Glycosylated hemoglobin (HbA1c)
Urinalysis
Albumin
Specific gravity
Cholesterol
pH
Creatine kinase (Total CK)
Protein
Estimated glomerular filtration rate (eGFR)b
Glucose
C-reactive protein (CRP)
Ketones
Complement component 3 (C3)
Complement component 3a (C3a)
Blood
Complement component 4a (C4a)
Urine leukocyte esterasea
Pregnancy Test (serumc/urined/follicle-stimulating hormonee)
Hepatitis B surface antigenf
Hepatitis C antibodyf
Human immunodeficiency virusf
Urine drug screenf
Abbreviations: CKD = chronic kidney disease; EPI = epidemiology collaboration; RBC = red blood cells; WBC = 
white blood cells.
a
A positive urine leukocyte esterase result will require a follow-up sample with microscopic analysis and possibly 
a urine culture.
b
eGFR for serum creatinine calculated by the central laboratory using the CKD EPI method
c
To be performed for women of child-bearing potential at screening only.
d
In case of a positive result, the pregnancy must be confirmed by a serum test.
e
To be performed for women of non-child-bearing potential with 6-12 months of spontaneous amenorrhea at 
screening only.
f
To be performed at screening only.

J1H-MC-LAJB(b) Clinical Protocol
Page 59
LY3451838
Appendix 3.
Study Governance Considerations

J1H-MC-LAJB(b) Clinical Protocol
Page 60
LY3451838
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient 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 patient or legal 
representative. This includes obtaining the appropriate signatures and dates 
on the informed consent form (ICF) prior to the performance of any protocol
procedures and prior to the administration of investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the patient and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the patient was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients. Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council 
for Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s). Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s). All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator 
Brochure (IB) and updates during the course of the study

informed consent form

other relevant documents (for example, curricula vitae, advertisements)

J1H-MC-LAJB(b) Clinical Protocol
Page 61
LY3451838
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

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

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Investigators in this clinical trial should be neurologists, headache specialists, or other specialists 
with experience in headache clinical trials and treating migraine patients.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The study team will select the CSR coordinating investigator. If this investigator is unable to 
fulfill this function, another investigator will be chosen by Lilly to serve as the CSR coordinating 
investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the CRFs, and 
study procedures.

make periodic visits to the study site

J1H-MC-LAJB(b) Clinical Protocol
Page 62
LY3451838

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and 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 patient data 
recorded against source documents at the study site. The study may be audited by Lilly or its 
representatives, 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 original source 
documents.
Appendix 3.2.1.
Data Capture System
An EDC system will be used in this study. The site maintains a separate source for the data 
entered by the site into the sponsor-provided EDC system, if collected external to the EDC 
system.
Electronic patient-reported outcome (ePRO) measures (for example, a diary) or other data 
reported directly by the patient (for example, a rating scale) may be entered in an ePRO 
instrument (for example, personal digital assistant [PDA]), or by means of an interactive 
response technology (IRT) at the time the information is obtained. In these instances where there 
is no prior written or electronic source data at the site, the ePRO instrument record will serve as 
the source.
If ePRO records are stored at a third party site, investigator sites will have continuous access to 
the source documents during the study and will receive an archival copy at the end of the study 
for retention.
Any data for which the ePRO instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
Electronic case report form data will be encoded and stored in a clinical trial database. Data 
managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central vendor’s database system. Data will subsequently be transferred 
from the central vendor to the sponsor designated warehouse.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file. Paper 
documentation provided by the patient in this study may include, for example, a headache 
medication log on which patients will record their acute headache medication use during the 
study.

J1H-MC-LAJB(b) Clinical Protocol
Page 63
LY3451838
Data from complaint forms submitted to Lilly.
will be encoded and stored in the global product complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site patients may be discontinued if Lilly, the investigator, or the ERB of the study site
judges it necessary for medical, safety, regulatory, or other reasons consistent with applicable 
laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study J1H-MC-LAJB is described in the Clinical Trial Agreement.

J1H-MC-LAJB(b) Clinical Protocol
Page 64
LY3451838
Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations: ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised 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.

J 1 H -M C -L A J B( b) Cli ni c al Pr ot o c ol
P a g e 6 5
L Y 3 4 5 1 8 3 8
A p p e n di x 5.
R e c o m m e n d e d L a b or at or y  Te sti n g f or 
H y p er s e n siti vit y  E v e nt s
La b testi n g s h o uld be perf or m e d at t he ti me of  a S y ste mic H y perse nsit i vity E v e nt. I mp orta nt 
i nf or mat i on a b o ut w h y, w he n, a n d w hat t o t est f or are pr o vi de d bel o w. T he ma na ge me nt of  the 
a d verse e ve nt ma y warra nt lab testi n g be y o n d t hat descri be d b el o w a n d s h o uld be p erf or me d as 
cli nicall y i n dicate d.
La b orat or y  testin g d uri n g a S y ste mic H y perse nsit i vity E ve nt is n ot perf or me d f or dia g n ostic 
p ur p oses. Its i nte nt is se veral f o l d:

T o hel p c haracteri ze a n d classif y s yste mic h y perse nsiti vity reactio ns

T o m eet re g ulat or y e x pectatio ns

T o i m pr o ve s u bse q ue nt cli nical ma na ge me nt b y  hel pi n g t o disti n g uis h bet wee n t he vari o us 
me c ha nist ic bases of a na p h yla xis
W he n s h o ul d la bs be o btai ne d?

I n t he prese nce of ge neralize d urticaria or if a na p h ylaxis is s us pecte d

After t he s u bject has bee n sta bilize d, o btai n a sa m ple wit hi n 1 -2 h o urs of t he e ve nt, h o we ver, 
sa m ples ma y be o btai ne d as late as 1 2 h o urs after t he e ve nt as a nal ytes ca n re mai n altere d f or 
a n e xte n de d peri o d of ti me . Rec or d t he ti me at w hic h t he sa m ple was c o llecte d.

O btai n a f o ll ow u p sa m ple at t he ne xt re g ularl y sc he d ule d visit or after 4 wee ks, w hic he ver is 
later.
W hat l a bs * s h o uld be o btai ne d?

Tr y ptase * *

A D A a n d L Y c o nce ntrati o n ( P K)
o
A D A testi n g s h o ul d i ncl u de dr u g s pecific I g E or t he bas o p hil act i vati on test ( B A T) #. 
T hese tests are n ot r o uti nel y  a vaila ble a n d nee d t o be de vel o pe d f or i n di vi d ual m olec ules 
base d o n t he ir e v o l vi n g safety pr ofile. Sa m ples are c ollecte d, a n d testi n g c o n d ucte d o nce 
t he assa y is a vaila ble, as a p pr o priate. Pl ease c o ns ult a n i m m u n ol o gist wit hi n G P S f or 
f urt her g ui da nce.

C o m ple me nt
o
C 3a a n d C 5a

C y t o ki nes
o
I L-6, I L -1 β, I L -1 0 ( or a n y c yt o ki ne pa nel t h at i ncl u des t hese 3 c yt o ki nes)
* t hese la bs are b u n dle d i n t he Cli nical La b orat or y O peratio ns H y perse nsit i vity La b Testi n g Kit 
* * If a tr y ptase sa m ple is o btai ne d m ore t ha n 2 h o urs after t he e ve nt (ie , wi t hi n 2 t o 1 2 h o urs), or 
is n ot o btai ne d beca use m o re t ha n 1 2 h o urs ha ve la pse d si nce t he e ve nt, o btai n uri ne f or 

J1H-MC-LAJB(b) Clinical Protocol
Page 66
LY3451838
N-methylhistamine (NMH) testing. Note that for tryptase serum samples obtained within 2-12 
hours of the event, urine NMH testing is performed in addition to tryptase testing. Collect the 
first void urine following the event. Obtain a follow up urine for NMH testing at the next 
regularly scheduled visit or after 4 weeks, whichever is later.
# The BAT is an in vitro cell based assay that only requires a serum sample. It is a surrogate assay 
for drug specific IgE but is not specific for IgE.

J1H-MC-LAJB(b) Clinical Protocol
Page 67
LY3451838
Appendix 6.
Migraine and Headache Endpoint 
Definitions
Diagnosis
Definition/Criteria
Migraine headache
A headache, with or without aura, of ≥30 minutes duration, with both of the 
following required features (A and B):
A. At least 2 of the following headache characteristics:

Unilateral location

Pulsating quality

Moderate or severe pain intensity

Aggravation by or causing avoidance of routine physical activity
AND
B. During headache at least one of the following:

Nausea and/or vomiting

Photophobia and phonophobia
(Definition adapted from the standard IHS ICHD-3 definition)
Probable migraine headache
A headache of ≥30 minutes duration, with or without aura, but missing one of 
the migraine features in the IHS ICHD-3 definition. To be exact, it meets either 
at least two A criteria and zero B criteria, or one A criteria and at least one B 
criteria.
Migraine headache day 
(primary objective)
A calendar day on which a migraine headache or probable migraine headache 
occurs.
ICHD migraine headache day
A calendar day on which a migraine headache occurs.
Migraine headache attack
Beginning on any day a migraine headache or probable migraine headache is 
recorded and ends when a migraine-free day occurs.
Non-migraine headache
All headaches of ≥30 minutes duration not fulfilling the definition of migraine 
or probable migraine.  
Non-migraine headache day
A calendar day on which a non-migraine headache occurs.
Headache day
A calendar day on which any type of headache occurs (including migraine, 
probable migraine, and non-migraine headache).
Episodic migraine
Four to 14 migraine headache days and <15 headache days per 30-day period 
in the prospective baseline period.
Chronic migraine
At least 15 headache days per 30-day period in the prospective baseline period, 
of which at least 8 are migraine.
Abbreviations: ICHD = International Classification of Headache Disorders; IHS = International Headache Society.

J1H-MC-LAJB(b) Clinical Protocol
Page 68
LY3451838
Appendix 7.
Protocol Amendment J1H-MC-LAJB(b)
Summary
Overview
Protocol J1H-MC-LAJB, A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
LY3451838 in Adults with Treatment-Resistant Migraine, has been amended. 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 described in the 
following table. Other general editorial corrections and formatting changes not affecting content 
have been made in the document, and these changes are not identified in the amendment 
summary table or with strikethrough/underscore.
Amendment Summary for Protocol J1H-MC-LAJB Amendment (b)
Section # and Name
Description of Change
Brief Rationale
1. Synopsis
Number of patients updated.
Statistical calculations 
confirmed that CSF could 
be achieved with less
patients
5.2  Number of Participants
Number of patients updated.
Statistical calculations 
confirmed that CSF could 
be achieved with less
patients
6.1 Inclusion Criteria
Criterion 6 added

Nortriptyline

Rimegepant and atogepant

For clarification.

Approved post 
protocol approval
7.8  Concomitant Therapy
Added short term use of steroids to Table 7.1.
To allow short term use 
of steroids
10.1  Sample Size Determination

Number of patients updated

Sample size calculation assumptions 
updated
Statistical calculations 
confirmed that CSF could 
be achieved with less
patients
10.3.2.2  Patient Characteristics
Removed bullet, “Alcohol, tobacco, caffeine, 
and nicotine consumption”.
Said data is not being 
collected and thus, will 
not be statistically 
summarized
10.3.8  Interim Analysis
Replaced “all” with “majority of” patients to 
be included in the interim analysis.
To clarify what patients 
will be included

J1H-MC-LAJB(b) Clinical Protocol
Page 69
LY3451838
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.
1.
Synopsis
Number of Patients:
The study will screen an estimated 215 110 potential patients to ensure randomization of 
approximately 120 60 migraine patients, of which approximately 60 30 patients with chronic
migraine.
5.2
Number of Participants
The study will screen an estimated 215 110 potential patients to ensure randomization of 
approximately 120 60 migraine patients, of which approximately 60 30 patients have episodic 
migraine (defined as 4 to 14 migraine headache days and <15 headache days per 1-month period 
in the prospective baseline period). To ensure an appropriate balance of patients with episodic 
and chronic migraine, the sponsor will stop enrollment of patients with chronic migraine if the 
number of patients exceeds approximately 50%. Chronic migraine will be defined as at least 
15 headache days per 1-month period in the prospective baseline period, of which at least 8 are 
migraine. Similar frequency of headache days must also be present during the 2 months previous 
to baseline for both episodic and chronic categories, according to investigator’s assessment.
6.1
Inclusion Criteria
6.   Prior to Visit 1, have documentation (by medical or pharmacy record or by physician’s 
confirmation) of previous failure of 2 to 4 standard-of-care migraine preventive medication 
categories from the following list and in the past 10 years due to inadequate efficacy (that is, 
maximum tolerated dose for at least 2 months, (3 months in case of Botulinium toxin A or B) 
and/or safety/tolerability reasons:
a.
Propranolol or metoprolol
b. Topiramate
c.
Valproate or divalproex
d. Amitriptyline or nortriptyline
e.
Flunarizine
f.
Candesartan
g. Anti-CGRP antibodies (either ligand or receptor)

J1H-MC-LAJB(b) Clinical Protocol
Page 70
LY3451838
h. Botulinium toxin A or B (if documented that botulinium toxin was taken for chronic 
migraine)
i.
Rimegepant ODT
j.
Atogepant
7.8
Concomitant Therapy
Table LAJB 12.1
Treatments Allowed and Treatments Not Allowed as Concomitant 
Therapy
A. Medications allowed for the ACUTE treatment of migraine headaches or other pain 
or injury:
Acetaminophen (paracetamol) up to 3000 mg/day, NSAIDs; Triptans; Ergotamine and derivatives; Isometheptene
mucate, dichloralphenazone and acetaminophen combination (Midrin); or combinations thereof; ubrogepant;
The following medications are allowed with restrictions:
1.
Opioid and barbiturates no more than 4 days/month.
2.
Single dose of injectable steroids allowed only once during the study, in an emergency setting (SP II, III, 
IV).
3.
Short term use of steroids, < 7days,  for medical circumstances that may arise.
B. Medications, Procedures or Devices not allowed for any reason/indication in Study 
Period II (Baseline), III (Double-Blind Treatment), and IV (Follow-up):
ACE inhibitors 
Acetazolamide
Acupuncture
Anticonvulsants/Antiepileptics
Antipsychotics
Angiotensin receptor blockers (ARBs)
Beta-blockers 
Botulinum toxin applied to head/neck area for therapeutic use 
Cannabis / Cannabinoids / Cannabidiol
Chiropractic procedures, physiotherapy, TENS or other electric devices on head and neck
Corticosteroids for oral use
Flunarizine
Gabapentin
Herbals with anti-inflammatory effect (feverfew, willow bark, petasites/butterbur)  
Monoamine oxidase inhibitors (MAOIs)
Memantine
Methysergide
Nerve block in head/neck area
Oxetorone
Pizotifen
Pregabalin
Serotonin 5HT2a/2c antagonists, eg, trazodone, nefazodone  
Stimulants (prescription strength), eg, methylphenidate, dextroamphetamine, mixed amphetamine salts
Tizanidine
Tricyclic antidepressants (TCAs)
Triptans for prophylaxis of menstrual related migraine 
Venlafaxine
Verapamil

J1H-MC-LAJB(b) Clinical Protocol
Page 71
LY3451838
C. Restricted medication during Study Period III (Double-Blind Treatment) and Study 
Period IV (Follow-up): Use of the following medications for indications other than 
migraine prevention is allowed providing the dose is stable 2 months prior to Visit 2 and 
is expected to remain stable during the Treatment Phase. 
Benzodiazepines
Bupropion 
Calcium-channel blockers (except verapamil, flunarizine, and lomerizine)
Clonidine 
Guanfacine 
Mirtazapine 
SSRIs/NRIs/SNRIs (other than venlafaxine) 
Use of electric devices (ie, TENS), physiotherapy, chiropractic procedures on low back and extremities
D. Restricted medication during Study Period IV (Follow-up):
Medications from List B.
Medications or treatments for migraine prevention of.
Medications in List C may now be started, stopped, or have dose modification as long as not being used for 
migraine prevention.
Abbreviations: 5HT = 5-hydroxytryptamine; ACE = angiotensin-converting enzyme; NRI = norepinephrine 
reuptake inhibitor; NSAID = nonsteroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake 
inhibitor; SP = Study Period; SSRI = selective serotonin reuptake inhibitor; TENS = transcutaneous electrical 
nerve stimulation.
10.1
Sample Size Determination
The study will screen an estimated 215 110 potential patients to ensure randomization of 
approximately 120 60 migraine patients. Enrollment will be stratified by type of migraine, 
episodic versus chronic, and patients will be randomly assigned to either LY3451838 or placebo 
in a 1:1 allocation ratio within each stratum. Enrollment in the chronic migraine stratum will be 
capped so that no more than approximately 50% of the randomized population will be patients 
with chronic migraine. 
The analysis will be conducted using all randomized patients, and it is assumed that 
approximately 2% of the patient population will dropout during the 28 days treatment period. 
The study will be considered successful if there is at least a 60% probability that the number of 
monthly migraine headache days with LY3451838 treatment is 1.5 days less than the number of 
monthly migraine headache days with placebo treatment (i.e., the success criterion is 
P(LY3451838 - Placebo <-1.5) ≥0.60).
Enrolling approximately 120 60 patients who are stratified by type of migraine, episodic versus 
chronic, and randomly assigned to either LY3451838 or placebo in a 1:1 allocation ratio within 
each stratum will provide approximately 77 94% probability for meeting the success criterion if 
the mean monthly number of migraine headache days with LY3451838 is 2.35 2.57 days less 
than the mean monthly number of migraine headache days with placebo for both the episodic 
migraine population and 3.70 days less for the chronic migraine population.
Assumptions in this sample size calculation were based on data from previous Phase 2 and 
Phase 3 studies with galcanezumab in patients with episodic and chronic migraine. It is assumed 

J1H-MC-LAJB(b) Clinical Protocol
Page 72
LY3451838
that the baseline mean (± standard deviation) monthly migraine headache days will be 9.34
(±2.82) days for the episodic population and 18.65 (±4.68) days for the chronic population. It is 
also assumed that the change from baseline mean (± standard deviation) monthly migraine 
headache days for placebo will be -0.31 (± 32.50) days for the episodic migraine population and 
-2.21 (± 5.273.75) days for the chronic migraine population. 
10.3.2.2
Patient Characteristics
The following patient characteristics at baseline will be summarized by treatment.

Demographic (age, sex, ethnic origin, height, weight, body mass index)

Migraine and/or headache-related measures from the ePRO diary per 1-month 
baseline period

Number of prior migraine preventive treatment failures from the list in Section 6.1
(Inclusion Criterion #6):
o
Failed 2 medication categories
o
Failed 3 medication categories
o
Failed 4 medication categories

Alcohol, tobacco, caffeine, and nicotine consumption

Medical history and pre-existing conditions
10.3.8 Interim Analyses
An interim analysis is planned when data from the majority of all randomized patients have 
completed the 1-month treatment period. The interim efficacy results may be used for internal 
decision-making to trigger planning activities associated with the investigational product. No 
adjustment of Type I error will be performed as the study will not be stopped for efficacy, and no 
modification of Study LAJB is expected based on these interim results. The assessment would be 
conducted by a sponsor assessment committee with a limited number of preidentified team 
members who do not have direct site contact or data entry/validation responsibilities. Unblinding 
details will be specified in the unblinding plan section of the SAP or in a separate unblinding 
plan document. Information that may unblind the study during the analyses will not be reported 
to study sites or to the blinded study team until the study has been unblinded.

Leo Document ID = 8b336ee6-89e8-406f-82d1-a8f32dfbd810
Approver: 
Approval Date & Time: 19-Nov-2021 20:56:50 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 19-Nov-2021 21:03:03 GMT
Signature meaning: Approved
PPD
PPD