Randomized Controlled Trial of Lasmiditan Over Four Migraine Attacks
Phase: PHASE3
Conditions: Migraine
Sponsor: Eli Lilly and Company

H8H-MC-LAIJ Protocol (b) 
 
 
Randomized Controlled Trial of Lasmiditan Over Four Migraine Attacks  
 
 
NCT03670810 
 
Approval Date 30-Mar-2020 

H8H-MC-LAIJ(b) Clinical Protocol
Page 1
LY573144
Protocol H8H-MC-LAIJ(b)
Randomized Controlled Trial of Lasmiditan Over Four
Migraine Attacks (CENTURION)
EU Trial Number:  2018-001661-17 
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 
lasmiditan (LY573144), 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.
Lasmiditan (LY573144)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 07 May 2018
Amendment (a) Electronically Signed and Approved by Lilly on 20 Nov 2018
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 30-Mar-2020 GMT

H8H-MC-LAIJ(b) Clinical Protocol
Page 2
LY573144
Table of Contents
Section
Page
Protocol H8H-MC-LAIJ(b) Randomized Controlled Trial of Lasmiditan 
Over Four Migraine Attacks (CENTURION)......................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................17
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................20
5.
Study Design.....................................................................................................................23
5.1.
Overall Design .............................................................................................................23
5.1.1.
Screening (Visit 1) ...............................................................................................24
5.1.2.
Randomization (Visit 2).......................................................................................25
5.1.3.
Treatment Period..................................................................................................25
5.2.
Number of Patients.......................................................................................................26
5.3.
End of Study Definition ...............................................................................................26
5.4.
Scientific Rationale for Study Design...........................................................................26
5.5.
Justification for Dose ...................................................................................................27
6.
Study Population...............................................................................................................28
6.1.
Inclusion Criteria..........................................................................................................28
6.2.
Exclusion Criteria ........................................................................................................29
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................31
6.3.
Lifestyle Restrictions....................................................................................................31
6.4.
Screen Failures.............................................................................................................31
7.
Treatments........................................................................................................................32
7.1.
Treatments Administered .............................................................................................32
7.1.1.
Packaging and Labelling ......................................................................................33
7.2.
Method of Treatment Assignment ................................................................................33
7.2.1.
Selection and Timing of Doses:  Study Treatment and Other 
Migraine Treatments ............................................................................................33
7.3.
Blinding .......................................................................................................................34
7.4.
Dosage Modification....................................................................................................34
7.5.
Preparation/Handling/Storage/Accountability...............................................................34

H8H-MC-LAIJ(b) Clinical Protocol
Page 3
LY573144
7.6.
Treatment Compliance .................................................................................................35
7.7.
Concomitant Therapy...................................................................................................35
7.8.
Treatment after the End of the Study............................................................................35
7.8.1.
Treatment after Study Completion........................................................................35
7.8.2.
Special Treatment Considerations and Minimization of Risk................................36
8.
Discontinuation Criteria ....................................................................................................37
8.1.
Discontinuation from Study Treatment.........................................................................37
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................37
8.1.2.
Temporary Discontinuation from Study Treatment...............................................37
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................37
8.2.
Discontinuation from the Study....................................................................................38
8.3.
Lost to Follow-Up........................................................................................................39
9.
Study Assessments and Procedures ...................................................................................40
9.1.
Efficacy Assessments...................................................................................................40
9.1.1.
Primary Efficacy Assessments .............................................................................40
9.1.2.
Secondary Efficacy Assessments..........................................................................40
9.1.3.
Appropriateness of Assessments ..........................................................................42
9.2.
Adverse Events ............................................................................................................43
9.2.1.
Serious Adverse Events........................................................................................43
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................45
9.2.2.
Complaint Handling.............................................................................................45
9.3.
Treatment of Overdose.................................................................................................45
9.4.
Safety...........................................................................................................................45
9.4.1.
Electrocardiograms ..............................................................................................45
9.4.2.
Vital Signs ...........................................................................................................45
9.4.3.
Laboratory Tests ..................................................................................................46
9.4.4.
Other Tests...........................................................................................................46
9.4.5.
Safety Monitoring ................................................................................................47
9.4.5.1.
Hepatic Safety Monitoring..............................................................................47
9.5.
Pharmacokinetics .........................................................................................................47
9.6.
Pharmacodynamics ......................................................................................................47
9.7.
Genetics .......................................................................................................................47
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................47
9.8.
Biomarkers...................................................................................................................48
9.9.
Medical Resource Utilization and Health Economics ...................................................48
10.
Statistical Considerations ..................................................................................................49
10.1. Sample Size Determination ..........................................................................................49
10.2. Populations for Analyses..............................................................................................49

H8H-MC-LAIJ(b) Clinical Protocol
Page 4
LY573144
10.3. Statistical Analyses ......................................................................................................50
10.3.1.
General Statistical Considerations ........................................................................50
10.3.2.
Treatment Group Comparability...........................................................................51
10.3.2.1.
Patient Disposition..........................................................................................51
10.3.2.2.
Patient Characteristics ....................................................................................51
10.3.2.3.
Concomitant Therapy .....................................................................................51
10.3.2.4.
Compliance ....................................................................................................52
10.3.3.
Efficacy Analyses ................................................................................................52
10.3.3.1.
Primary Analyses ...........................................................................................52
10.3.3.2.
Secondary Analyses........................................................................................52
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................53
10.3.4.
Safety Analyses....................................................................................................53
10.3.4.1.
Treatment-Emergent Adverse Events..............................................................53
10.3.4.2.
Columbia-Suicide Severity Rating Scale.........................................................54
10.3.4.3.
Vital Signs......................................................................................................54
10.3.4.4.
Labs ...............................................................................................................54
10.3.4.5.
Assessment of Driving Accidents ...................................................................54
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................54
10.3.6.
Evaluation of Immunogenicity .............................................................................54
10.3.7.
Other Analyses.....................................................................................................54
10.3.7.1.
Health Economics...........................................................................................54
10.3.7.2.
Subgroup Analyses.........................................................................................54
10.3.8.
Interim Analyses..................................................................................................55
11.
References ........................................................................................................................56
12.
Appendices .......................................................................................................................59

H8H-MC-LAIJ(b) Clinical Protocol
Page 5
LY573144
List of Tables
Table
Page
Table LAIJ.2.1. Schedule of Activities....................................................................................13
Table LAIJ.4.1. Objectives and Endpoints...............................................................................20
Table LAIJ.5.1. Treatment Group Sequences ..........................................................................24
Table LAIJ.7.1. Treatment Regimens......................................................................................32

H8H-MC-LAIJ(b) Clinical Protocol
Page 6
LY573144
List of Figures
Figure
Page
Figure LAIJ.5.1. Illustration of patient flow design for Protocol H8H-MC-LAIJ. .....................24

H8H-MC-LAIJ(b) Clinical Protocol
Page 7
LY573144
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................60
Appendix 2.
Clinical Laboratory Tests...............................................................................63
Appendix 3.
Study Governance Considerations..................................................................64
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................68
Appendix 5.
Diagnostic Criteria for Selected Migraine Types............................................69
Appendix 6.
Medication Overuse Headache Diagnostic Criteria ........................................72
Appendix 7.
eDiary Assessments.......................................................................................73
Appendix 8.
Protocol Amendment H8H-MC-LAIJ(b) Summary........................................74

H8H-MC-LAIJ(b) Clinical Protocol
Page 8
LY573144
1.
Synopsis
Title of Study:
Protocol H8H-MC-LAIJ Randomized Controlled Trial of Lasmiditan Over Four Migraine 
Attacks (CENTURION)
Rationale: 
In 2 Phase 3 single migraine attack studies, lasmiditan demonstrated statistically significant 
superiority versus placebo in the proportion of patients who were headache pain-free as well as 
the proportion of patients who were free of their migraine-associated most bothersome symptom 
(MBS) at 2 hours postdose.  This global, multicenter, placebo-controlled, double-blind study will 
assess the efficacy, consistency of response, and safety of lasmiditan in acute treatment of 4 
migraine attacks with or without aura.  
Objectives/Endpoints:
Objectives
Endpoints
Primary

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on migraine headache pain 
freedom compared to placebo

The proportion of patients in each group that are pain-free
(defined as mild, moderate, or severe headache pain 
becoming none) at 2 hours postdose during the first attack 

To evaluate the consistency of response to 
lasmiditan 200 mg and 100 mg compared to 
placebo

The proportion of patients in each group that are pain-free 
(defined as mild, moderate, or severe headache pain 
becoming none) at 2 hours postdose in at least 2 out of 
3 attacks
Secondary
     Efficacy

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on freedom from MBS compared 
to placebo

The proportion of patients in each group that are free of 
MBS associated with migraine at 2 hours postdose during 
the first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on pain relief compared to 
placebo

The proportion of patients with pain relief (defined as 
moderate or severe headache pain becoming mild or none 
and mild pain becoming none) in each group at 2 hours 
post dose during the first attack.

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on sustained freedom from pain 
compared to placebo

The proportion of patients in each group with 24-hour and 
with 48-hour sustained pain freedom during the first 
attack defined as pain-free at 2 and 24 hours, and 2 and 48 
hours, respectively, with no rescue medication

To evaluate the need for rescue medication in 
patients treated with lasmiditan 200 mg and 
100 mg compared to placebo

The proportion of patients in each group requiring rescue 
medication for migraine within 24 hours of treatment 
during the first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg at 2 hours on freedom from 
symptoms associated with migraine compared 
to placebo

The proportion of patients in each group that are free of 
symptoms associated with migraine at 2 hours postdose 
during the first attack, including each of the following:  
phonophobia, photophobia, nausea, and vomiting

H8H-MC-LAIJ(b) Clinical Protocol
Page 9
LY573144
Objectives
Endpoints
Secondary, Efficacy, continued

To assess the probability of migraine relapse 
in patients treated with lasmiditan 200 mg and 
100 mg compared to placebo

The proportion of patients in each group with migraine 
recurrence at 24 and 48 hours during the first attack 
defined as return of any headache in patients who were 
pain-free at 2 hours.

To explore the time course of lasmiditan 200 
mg and 100 mg efficacy compared to placebo

The proportion of patients in each group at each time 
point with pain freedom, pain relief, freedom from MBS, 
and no disability postdose during first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on migraine-related disability 
compared to placebo

Mean change from baseline in total score and individual 
items as measured by the MIDAS scale, in each group at 
end of study

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on disability during migraine 
attacks compared to placebo

The proportion of patients in each group with no 
disability as measured by the disability item, at 2 hours 
postdose during the first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on PGIC compared to placebo

The proportion of patients in each group very much or 
much better as measured by PGIC, at 2 hours postdose 
during the first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on HRQoL during an acute 
migraine attack compared to placebo

Mean HRQoL score for domains of social functioning, 
migraine symptoms, and feelings/concerns, as measured 
by the 24-hour MQoLQ, in each group at 24 hours 
postdose during first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on treatment satisfaction 
compared to control

The proportion of patients in each group who are satisfied 
with their treatment at EoS as measured by a 4-item 
questionnaire

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on health utility compared to 
placebo

Mean change from baseline in utility in each group as 
measured by the EQ-5D-5L, at 24 hours postdose during 
first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg in triptan nonresponders

The proportions of patients in the subpopulation of triptan 
nonresponders that achieve primary and secondary 
objectives in each group during the first attack

The proportions of patients in the subpopulation of triptan 
nonresponders versus other patients that achieve primary 
and secondary objectives in each group during the first 
attack
     Consistency

To evaluate the consistency of lasmiditan 200 
mg and 100 mg on migraine headache pain 
relief in 2 out of 3 attacks compared to 
placebo

The proportion of patients with pain relief (defined as 
moderate or severe headache pain becoming mild or none 
and mild pain becoming none) in each group at 2 hours 
postdose in at least 2 out of 3 attacks

To evaluate the consistency of response to 
lasmiditan 200 mg and 100 mg in 3 out of 4 
attacks compared to control

The proportion of patients in each group that are pain-free 
(defined as mild, moderate, or severe headache pain
becoming none) at 2 hours postdose in at least 3 out of 
4 attacks

To evaluate the consistency of lasmiditan 200 
mg and 100 mg on migraine headache pain 
relief in 3 out of 4 attacks compared to control

The proportion of patients with pain relief (defined as 
moderate or severe headache pain becoming mild or none 
and mild pain becoming none) in each group at 2 hours 
postdose in at least 3 out of 4 attacks

H8H-MC-LAIJ(b) Clinical Protocol
Page 10
LY573144
Objectives
Endpoints
Secondary, Consistency, continued

To evaluate the consistency of lasmiditan 200 
mg and 100 mg in triptan nonresponders.

The proportions of patients in the subpopulation of triptan 
nonresponders versus other patients that achieve 
consistency in each group defined as pain freedom during 
2 out of 3 attacks
Abbreviations:  24-hour MQoLQ = 24-Hour Migraine Quality of Life Questionnaire; EQ-5D-5L = EuroQol 
5-dimension 5-level scale; HRQoL = Health-Related Quality of Life; MBS = most bothersome symptom; 
MIDAS = Migraine Disability Assessment Test; PGIC = Patient Global Impression of Change.
Summary of Study Design:  
Study H8H-MC-LAIJ is a prospective, multicenter, randomized, double-blind, modified-parallel, 
placebo-controlled Phase 3 study of adult patients suffering from migraine with or without aura.  
Treatment Arms and Duration:  
One treatment group will receive lasmiditan 200 mg for 4 attacks, 1 treatment group will receive 
lasmiditan 100 mg for 4 attacks, and a control group will receive placebo for 3 attacks and 
lasmiditan 50 mg for 1 attack.  The control group will consist of 2 treatment sequence groups 
(1:1) where 1 group will receive lasmiditan for attack 3 and the other group will receive 
lasmiditan for attack 4.
For rescue (pain freedom not achieved) or recurrence (pain freedom achieved but then pain 
recurs), patients may take their own unexcluded medications beginning at least 2 hours postdose; 
patients MUST NOT take triptan, ergot, opioid, or barbiturate medications within 24 hours of 
taking study drug (that is, 24 hours before or after).
To avoid differential drop out which could compromise the validity of the study, patients should 
not be informed about the treatment groups; instead, patients should be informed that no patient 
will receive placebo for all attacks.
Number of Patients:
Approximately 2100 patients will be screened to achieve approximately 1600 patients 
randomized, approximately 1150 patients with data for first attack, and approximately 800 
patients with data for consistency assessment.  An additional 200 patients may be randomized if 
there is an insufficient number of patients with complete data for consistency assessment.
Statistical Analysis:
Efficacy analyses will be conducted on the intent-to-treat (ITT) population.  This set includes all 
randomized patients who use at least 1 dose of study drug for an ITT-evaluable attack, defined as
a treated attack of at least mild pain severity with any postdose pain severity assessments at or 
before 2 hours postdose. The primary efficacy analysis will compare the proportion of patients 
with 2-hour pain freedom during the first attack in the lasmiditan 200-mg group with placebo 
and compare the proportions of patients with 2-hour pain freedom during the first attack in the 
lasmiditan 100-mg group with placebo.

H8H-MC-LAIJ(b) Clinical Protocol
Page 11
LY573144
The consistency analyses will be conducted on the ITT consistency population, a subset of the 
ITT population with sufficient evaluable attacks.  To evaluate the primary consistency endpoint, 
the proportions of patients with 2-hour pain freedom during 2 out of the first 3 evaluable attacks
in the lasmiditan 200-mg and 100-mg groups will be compared to the results of the evaluable 
attacks treated with placebo in the control group. 
Primary and gated secondary endpoints will be analyzed in a multiple comparisons procedure 
that preserves overall type I error at the 1-sided significance level of 0.025. Tests of all other 
endpoints will be conducted at a 2-sided significance level of 0.05.
Safety analyses will be conducted on the safety population.  This set includes all randomized 
patients who take at least 1 dose of study drug, regardless of whether or not they undergo any 
study assessments. Patients will be evaluated by the drug they used, not by the drug to which 
they were randomized.

H8H-MC-LAIJ(b) Clinical Protocol
Page 12
LY573144
2.
Schedule of Activities

H8H-MC-LAIJ(b) Clinical Protocol
Page 13
LY573144
Table LAIJ.2.1.
Schedule of Activities
Visit 1a
Screening
Visit 2
Baseline
(at site)
Treatment Attack 1-4b
All attacks:  Mod/sev within 4 hrs of onset
Attack 2:  ≥48 hrs after dosing Attack 1
Attack 3:  ≥48 hrs after dosing Attack 2
Attack 4:  ≥48 hrs after dosing Attack 3
Visit 6 EoS 
(at site)
or EDCc
Notes
V1+3-30
days
(pending 
lab 
results)
Visit 3 
Phone Call 
1 after 
Attack 1 or
at 1 mod±1 
wk after V2
Visit 4 
Site Visit
at +2 mos±1 
wk after V2 
Visit 5 
Phone Call 2 
at 3 mos±1 
wk after V2
≥7 days after 
last treated 
attack (=last 
dose) OR at 4
mos±2 wks after 
V2
Obtain informed consent
X
Inclusion and exclusion
X
Introduce eDiary (V1)
including assess patient 
capability to use eDiary
X
Demographics
X
Vital signs
X
X
X
Temperature, BP, pulse. 
BP/pulse measured sitting
before blood draws, dosing.  
Use local BP equipment.
Weight 
X
X
Height
X
Menstrual cycle status
X
X
X
X
X
Females asked to provide dates 
and durations of menstrual 
period; table included in paper 
journal to record between visits.
Review migraine history 
including prior treatment
X
Review medical history and 
concomitant medication
X
Physical examination 
X
X
Neurological exam
X
X

H8H-MC-LAIJ(b) Clinical Protocol
Page 14
LY573144
Document migraine 
characteristics per IHS criteria 
X
Complete MIDAS 
X
X
C-SSRS - BL/screening 
version e
X
C-SSRS - since last visit 
version e
X
X
X
   Self-Harm Supplement Form
X
X
X
X
   Self-Harm Follow-up Form f
X
X
X
X
12-lead ECG 
X
Patients must be supine for 5 to 
10 min before ECG collection 
and remain supine but awake 
during collection.
Clinical laboratory 
(hematology, serum chemistry, 
urinalysis)
X
X
X
Hepatic algorithm triggered in 
cases of hepatic abnormalities 
identified by laboratory testing.
Serum pregnancy test or FSH
X
X
X
Pregnancy tests assessed in 
WOCBP (serum as indicated; 
urine more frequently if 
mandated by local regulations); 
FSH assessed as appropriate 
(details in Inclusion Criterion 
#7)
Urine drug screen
X
Can be repeated once if result is 
positive.
Pharmacogenetic sample 
(genetic sample/DNA)
X
Confirm eligibility 
X
Patient training video
X
Randomization 
X
Dispense study drug
X
Provide study eDiary and 
provide detailed instructions
and complete EQ-5D-5L
X

H8H-MC-LAIJ(b) Clinical Protocol
Page 15
LY573144
Migraine attack (eDiary)
documentation by patient
X
X
Patients enter data in eDiary 
during attacks (Appendix 7)
and from V2 to EoS, will be 
reminded daily to record AEs 
and new conmeds in paper 
journal.
mTOQ-6
X
HCRU
X
X
Employment status
X
X
Assessment of driving 
accidents/violations
X
X
X
Treatment Satisfaction
X
Verify any eDiary or study
drug issues, assess compliance 
all procedures, provide 
instructions if needed
X
X
X
Determine compliance study 
drug
X
X
Documentation of 
rescue/recurrence medication 
X
X
X
X
Documentation of AEs and 
concomitant medication
X
X
X
X
X
X
Collect unused/empty study 
drug pack and eDiary
X

H8H-MC-LAIJ(b) Clinical Protocol
Page 16
LY573144
Abbreviations:  24-hour MQoLQ = 24-Hour Migraine Quality of Life Questionnaire; AE = adverse event; BP = blood pressure; conmed = concomitant 
medication; C-SSRS = Columbia Suicide Severity Rating Scale; DNA = deoxyribonucleic acid; ECG = electrocardiogram; EDC = early discontinuation; eDiary
= electronic diary; EoS = end of study; EQ-5D-5L = EuroQol 5 Dimension 5 Level; FSH = follicle-stimulating hormone; HCRU = Health Care Resource 
Utilization; hrs = hours; IHS = International Headache Society; MIDAS = Migraine Disability Assessment Test; min = minutes; mo/mos = month/months; mod = 
moderate; mTOQ-6 = Migraine Treatment Optimization Questionnaire; PGIC = Patient Global Impression of Change; QoL = quality of life; sev = severe; V = 
visit; WOCBP = women of child-bearing potential (see Inclusion Criterion #7 for details); wks = weeks.
a
V1 activities to be collected outside migraine attack.
b
Attacks treated do not need to be consecutive. Minimum amount of time between attacks is 48 hours (determined by timing of dosing, i.e., the next attack 
may not be treated with study drug within 48 hours of taking study drug).  During the treatment period, unscheduled visits may be completed at the discretion 
of the investigator.  In the event of abnormal laboratory findings, including but not limited to tests that may indicate abnormal liver function, repeat or 
additional laboratory testing may be required outside a scheduled clinic visit.
c
Patients that do not treat a migraine with study drug for any reason during the study should attend an EoS visit to return unused study drug and the eDiary. 
No other assessments are required.
d
Phone call after attack 1 or after 1 month of treatment, whichever comes first.
e
Adapted for the assessment of the ideation and behavior categories only (the Intensity of Ideation and Lethality of Behavior sections are removed).
f
Required if triggered by the Self-Harm Supplement Form per instructions.

H8H-MC-LAIJ(b) Clinical Protocol
Page 17
LY573144
3.
Introduction
3.1.
Study Rationale
Pivotal trials of acute treatments for migraine should address both the efficacy in single migraine 
attacks and the consistency of the therapeutic response over multiple attacks. In 2 Phase 3 single 
migraine attack studies, lasmiditan demonstrated statistically significant superiority versus 
placebo in the proportion of patients who were headache pain-free at 2 hours postdose as well as 
the proportion of patients who were free of their migraine-associated most bothersome symptoms 
(MBS) at 2 hours postdose.  
This global, multicenter, placebo-controlled, double-blind study will assess the efficacy, 
consistency of response, and safety of lasmiditan in acute treatment of 4 migraine attacks with or 
without aura. The primary hypotheses of the study are that lasmiditan is superior to placebo as 
measured by the proportion of participants who have pain freedom at 2 hours postdose during the
first attack, and that lasmiditan shows consistency of effect as defined by pain freedom at 2 hours 
in at least 2 out of 3 attacks.
3.2.
Background
Migraine is a common neurological disorder and was ranked by the World Health Organization 
(WHO) in their 2010 Global Burden of Disease survey as 1 of 7 most debilitating conditions, and 
as the third most common disease in the world among both males and females (Steiner et al. 
2013).  Migraine prevalence was estimated to be 11.6% (Woldeamanuel and Cowan, 2017). 
Regional crude migraine prevalence was 16.4% in Central and South America, 11.4% in Europe, 
10.4% in Africa, 10.1% in Asia, and 9.7% in North America.  
Although the introduction of triptans improved the acute treatment of migraine, some patients 
still lack adequate treatment. A recent analysis of the American Migraine Prevalence and 
Prevention study concluded that 40% of patients with episodic migraine have significant unmet 
needs; the most frequent complaints were headache-related disability (19%) and dissatisfaction
with current medications (15%) (Buse et al. 2012).
Treatment of patients with migraine and known cardiovascular (CV) disease or CV risk factors is 
particularly challenging because the incidence of myocardial infarction, stroke, claudication, 
diabetes, hypertension, and hypercholesterolemia are all higher in individuals with migraine 
compared with the general population (Bigal et al. 2010; Adelborg et al. 2018). While triptans 
are often used as first-line therapy, not all patients with migraine respond to or tolerate triptans.  
In addition, concerns about CV safety are believed to limit the prescription of triptans in some 
patients with migraine in the United States (Dodick et al. 2004).  Hence, there is a significant 
unmet need for novel migraine therapies with a distinct mechanism of action from that of 
triptans.  
Other therapies including nonsteroidal anti-inflammatory drugs, opioids, and barbiturates are not 
specifically targeted to treat migraine and have limitations.  Nonsteroidal anti-inflammatory 
drugs have limited effectiveness and some side effects including labeled warnings concerning

H8H-MC-LAIJ(b) Clinical Protocol
Page 18
LY573144
CV risk.  Opioids and barbiturates also have limited efficacy and carry well known risks
including overuse, dependency, and adverse effects. For these reasons, there is substantial unmet 
medical need for new medications for acute treatment of migraine (Lipton et al. 2013; Tfelt-
Hansen & Diener 2012).
Lasmiditan is a high-affinity, centrally-penetrant, highly selective 5-hydroxytryptamine (5-HT 
[serotonin]) 1F receptor agonist without significant pharmacological activity at 5-HT1B or 5-
HT1D receptors.  It has a chemical structure and pharmacologic profile that is distinct from the 
triptans, the current standard of care for acute migraine treatment, which were developed for 
their vasoconstrictor properties (Humphrey et al. 1990; Goadsby 2009; Mitsikostas and Tfelt-
Hansen 2012).  Evidence suggests that lasmiditan exerts its therapeutic effects in the treatment of 
migraine by decreasing neuropeptide release and inhibiting pain pathways including the 
trigeminal nerve (Labastida-Ramírez et al. 2017) without causing vasoconstriction in human 
coronary arteries (Ramadan et al. 2003).
Two Phase 3 multicenter, double-blind, placebo-controlled lasmiditan studies, including LAHJ
with 100-mg and 200-mg dose arms and LAHK with 50-mg, 100-mg, and 200-mg dose arms to 
treat a single migraine attack have been completed (Lilly 2018 [IB]). The primary endpoint in 
each study was the proportion of patients who were headache pain-free at 2 hours postdose 
(defined as mild, moderate, or severe headache pain reduced to none). In both studies, this 
endpoint was significant for all doses of lasmiditan versus placebo. The key secondary endpoint 
was the proportion of patients who were free of their migraine-associated MBS at 2 hours 
postdose (defined as the associated symptom present and identified as MBS prior to dosing and 
then absent at 2 hours). In both studies, this endpoint was significant for all doses of lasmiditan 
versus placebo.
Study LAHL (an open-label, 12-month safety study of lasmiditan (100 mg and 200 mg) in the 
acute treatment of migraine) is a Phase 3, prospective, randomized study in adults with migraine.  
Patients who completed either Study LAHJ or Study LAHK were given the opportunity to enroll 
in Study LAHL, which is designed to assess the safety and tolerability of long-term intermittent 
use of lasmiditan 100 mg and lasmiditan 200 mg for the acute treatment of migraine. Study 
LAHL was initiated on 13 November 2015 and is currently ongoing.  
Lasmiditan is generally well tolerated.  In the Phase 3 studies, a treatment-emergent adverse 
event (TEAE) was defined as an event that first occurred or worsened in severity after baseline 
and within 48 hours of a first or second dose (if applicable) of study drug.  The most common 
TEAEs reported in Study LAHJ/301 and Study LAHK/302 were dizziness, paresthesia,
somnolence, fatigue, and nausea. A majority of the TEAEs were mild or moderate in severity
and self-limiting in nature.
Trials to assess the consistency of response are recommended by the International Headache 
Society (IHS 2012) and by the European Medicines Agency (EMA 2007). Also, in studies of 
patients with migraine, consistency of response is one of the most important attributes of 
migraine medications (Lipton et al. 2005).
  

H8H-MC-LAIJ(b) Clinical Protocol
Page 19
LY573144
3.3.
Benefit/Risk Assessment
Lasmiditan has been shown to be effective for the treatment of acute migraine with or without 
aura in adults.  In Phase 3 trials, lasmiditan showed statistically significant superiority over
placebo on the primary endpoints including pain freedom and MBS freedom at 2 hours after 
taking study drug.  Lasmiditan was generally well tolerated with the most common TEAEs
including dizziness, paresthesia, somnolence, fatigue, and nausea.  Generally, these TEAEs were 
mild or moderate in severity and self-limiting.  All doses of lasmiditan were associated with 
driving impairment in a study of healthy volunteers on a computer-based driving simulator. 
Patients should restrict their driving, operation of heavy machinery, or other similar activities 
after taking study drug as described in the informed consent form (ICF).  Based on the 
statistically significant and clinically relevant effects of lasmiditan for treatment of acute 
migraine in adults with identified safety issues only including generally mild-to-moderate and 
transient tolerability issues, the positive benefit to risk profile of lasmiditan supports the conduct 
of this study to further evaluate and understand the efficacy, consistency, and safety of 
lasmiditan across 4 migraine attacks.  
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of lasmiditan are to be found in the 
Investigator’s Brochure (IB).

H8H-MC-LAIJ(b) Clinical Protocol
Page 20
LY573144
4.
Objectives and Endpoints
Table LAIJ.4.1 shows the objectives and endpoints of the study.
Table LAIJ.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on migraine headache pain 
freedom compared to placebo

The proportion of patients in each group that are pain-free
(defined as mild, moderate, or severe headache pain 
becoming none) at 2 hours postdose during the first attack 

To evaluate the consistency of response to 
lasmiditan 200 mg and 100 mg compared to 
placebo

The proportion of patients in each group that are pain-free 
(defined as mild, moderate, or severe headache pain 
becoming none) at 2 hours postdose in at least 2 out of 
3 attacks
Secondary
     Efficacy

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on freedom from MBS compared 
to placebo

The proportion of patients in each group that are free of 
MBS associated with migraine at 2 hours postdose during 
the first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on pain relief compared to 
placebo

The proportion of patients with pain relief (defined as 
moderate or severe headache pain becoming mild or none 
and mild pain becoming none) in each group at 2 hours 
postdose during the first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on sustained freedom from pain 
compared to placebo

The proportion of patients in each group with 24-hour and 
with 48-hour sustained pain freedom during the first 
attack defined as pain-free at 2 and 24 hours, and 2 and 48 
hours, respectively, with no rescue medication

To evaluate the need for rescue medication in 
patients treated with lasmiditan 200 mg and 
100 mg compared to placebo

The proportion of patients in each group requiring rescue 
medication for migraine within 24 hours of treatment 
during the first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg at 2 hours on freedom from 
symptoms associated with migraine compared 
to placebo

The proportion of patients in each group that are free of 
symptoms associated with migraine at 2 hours postdose 
during the first attack, including each of the following:  
phonophobia, photophobia, nausea, and vomiting

To assess the probability of migraine relapse 
in patients treated with lasmiditan 200 mg and 
100 mg compared to placebo

The proportion of patients in each group with migraine 
recurrence at 24 and 48 hours during the first attack 
defined as return of any headache in patients who were 
pain-free at 2 hours

To explore the time course of lasmiditan 200 
mg and 100 mg efficacy compared to placebo

The proportion of patients in each group at each time 
point with pain freedom, pain relief, freedom from MBS, 
and no disability postdose during first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on migraine-related disability 
compared to placebo

Mean change from baseline in total score and individual 
items as measured by the MIDAS scale, in each group at 
end of study

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on disability during migraine 
attacks compared to placebo

The proportion of patients in each group with no 
disability as measured by the disability item, at 2 hours 
postdose during the first attack

H8H-MC-LAIJ(b) Clinical Protocol
Page 21
LY573144
Objectives
Endpoints
Secondary, Efficacy, continued

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on PGIC compared to placebo

The proportion of patients in each group very much or 
much better as measured by PGIC, at 2 hours postdose 
during the first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on HRQoL during an acute 
migraine attack compared to placebo

Mean HRQoL score for domains of social functioning, 
migraine symptoms, and feelings/concerns, as measured 
by the 24-hour MQoLQ, in each group at 24 hours 
postdose during first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on treatment satisfaction 
compared to control

The proportion of patients in each group who are satisfied 
with their treatment at EoS as measured by a 4-item 
questionnaire

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg on health utility compared to 
placebo

Mean change from baseline in utility in each group as 
measured by the EQ-5D-5L, at 24 hours postdose during 
first attack

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg in triptan nonresponders

The proportions of patients in the subpopulation of triptan 
nonresponders that achieve primary and secondary 
objectives in each group during the first attack 

The proportions of patients in the subpopulation of triptan 
nonresponders versus other patients that achieve primary 
and secondary objectives in each group during the first 
attack
     Consistency

To evaluate the consistency of lasmiditan 200 
mg and 100 mg on migraine headache pain 
relief in 2 out of 3 attacks compared to 
placebo

The proportion of patients with pain relief (defined as
moderate or severe headache pain becoming mild or none 
and mild pain becoming none) in each group at 2 hours 
postdose in at least 2 out of 3 attacks

To evaluate the consistency of response to 
lasmiditan 200 mg and 100 mg in 3 out of 4 
attacks compared to control

The proportion of patients in each group that are pain-free 
(defined as mild, moderate, or severe headache pain
becoming none) at 2 hours postdose in at least 3 out of 
4 attacks

To evaluate the consistency of lasmiditan 200 
mg and 100 mg on migraine headache pain 
relief in 3 out of 4 attacks compared to control

The proportion of patients with pain relief (defined as 
moderate or severe headache pain becoming mild or none 
and mild pain becoming none) in each group at 2 hours 
postdose in at least 3 out of 4 attacks

To evaluate the consistency of lasmiditan 200 
mg and 100 mg in triptan nonresponders

The proportions of patients in the subpopulation of triptan 
nonresponders versus other patients that achieve 
consistency in each group defined as pain freedom during 
2 out of 3 attacks 
Exploratory

To evaluate in females the efficacy, as 
measured by migraine pain and associated 
symptoms, of lasmiditan compared to placebo 
on migraine attacks occurring in proximity to 
menses

During a 5-day window starting 2 days before the onset of 
menstruation, the proportion of migraine attacks in 
menstruating females with migraine pain freedom, pain 
relief, and MBS freedom at 2 hours after dosing in each 
group 

To evaluate the efficacy of lasmiditan on total 
migraine freedom

Proportion of patients in each group who have total 
migraine freedom, defined as no pain and no migraine-
associated symptoms, at 2 hours postdose during the first 
attack

H8H-MC-LAIJ(b) Clinical Protocol
Page 22
LY573144
Objectives
Endpoints
Exploratory, continued

To explore the effect of lasmiditan on the 
consistency of 2-hour freedom from MBS 
during 2 out of 3 attacks

The proportion of patients in each group that are free of 
MBS associated with migraine at 2 hours postdose during 
2 out of 3 attacks

To evaluate the efficacy of lasmiditan on 
HRQoL with respect to domains of work 
functioning and energy/vitality during an acute 
migraine attack

Mean HRQoL score for domains of work functioning and 
energy/vitality, as measured by the 24-hour MQoLQ, in 
each group at 24 hours postdose during first attack

To evaluate the efficacy of lasmiditan on 
HCRU

Mean change from baseline in HCRU in each group

To evaluate the efficacy of lasmiditan 50 mg

The proportions of patients with pain freedom, pain relief, 
MBS freedom, no disability, and very much or much 
better as measured by PGIC, at 2 hours postdose in 
patients treated with lasmiditan 50 mg during attacks 3 
and 4 versus placebo during attacks 3 and 4

To explore the efficacy of lasmiditan on time 
to meaningful relief and the time to pain 
freedom

The time to meaningful relief and time to pain freedom in 
each group during each attack
Abbreviations:  24-hour MQoLQ = 24-Hour Migraine Quality of Life Questionnaire; EQ-5D-5L = EuroQol 
5-dimension 5-level scale; HCRU = Health Care Resource Utilization; HRQoL = Health-Related Quality of Life; 
MBS = most bothersome symptom; MIDAS = Migraine Disability Assessment Test; PGIC = Patient Global 
Impression of Change.

H8H-MC-LAIJ(b) Clinical Protocol
Page 23
LY573144
5. Study Design
5.1.
Overall Design
Study H8H-MC-LAIJ is a prospective, multicenter, randomized, double-blind, modified parallel, 
placebo-controlled Phase 3 study of adult patients suffering from migraine with or without aura.  
Patients will have a history of migraine for at least 1 year, 3 to 8 migraine attacks per month, and 
disabling migraine as defined by a Migraine Disability Assessment Test (MIDAS) score ≥11.
The treatment group sequences are summarized in Table LAIJ.5.1 and will include 1 treatment 
group that receives lasmiditan 200 mg for 4 attacks, 1 treatment group that receives lasmiditan 
100 mg for 4 attacks, and a control group that receives placebo for 3 attacks and lasmiditan 
50 mg for 1 attack.  The control group will consist of 2 treatment sequence groups (1:1) where 1
group will receive lasmiditan for attack 3 and the other group will receive lasmiditan for attack 4.  
Patients will be asked to treat 4 migraine attacks with study drug on an outpatient basis. Patients 
will be provided with doses for treatment of all 4 attacks. Each patient’s study participation will 
consist of a screening visit (Visit 1) followed by a randomization visit (Visit 2) 3-to-30 days after 
screening, a Treatment Period of up to 16 weeks including phone visits and 1 site visit, and an 
end-of-study visit (EoS) at least 7 days after treating the last migraine attack (or at 4 months ±2
weeks after Visit 2). 
Figure LAIJ.5.1 illustrates the patient flow design.

H8H-MC-LAIJ(b) Clinical Protocol
Page 24
LY573144
Abbreviations:  EDC = early discontinuation; EoS = end of study; hrs = hours; min = 
minimum.
a
Preventive treatment allowed (if stable 3 months prior to V1).
b
At each attack patient will take 3 tablets to maintain blinding.
c
Attacks treated do not need to be consecutive.
d
Phone call/Visits will only occur if all 4 attacks are not completed by that time.
e
Patient will wait to take study drug until migraine pain is moderate/severe; must 
be the FIRST treatment for the migraine taken within 4 hours of onset.
Figure LAIJ.5.1.
Illustration of patient flow design for Protocol H8H-MC-LAIJ.
Table LAIJ.5.1.
Treatment Group Sequences
Treatment Group 
Sequences
Attack 1
Attack 2
Attack 3
Attack 4
Lasmiditan 200 mg
LTN200
LTN200
LTN200
LTN200
Lasmiditan 100 mg
LTN100
LTN100
LTN100
LTN100
Control 1
placebo
placebo
LTN50
placebo
Control 2
placebo
placebo
placebo
LTN50
Abbreviations:  LTN200 = lasmiditan 200 mg; LTN100 = lasmiditan 100 mg; LTN50 = lasmiditan 50 mg.
To avoid differential drop out which could bias and compromise the study, patients should not be 
informed about the treatment group sequences described in Table LAIJ.5.1.  Instead, patients 
should be informed that no patient will receive placebo for all attacks.
5.1.1. Screening (Visit 1)
At the screening visit (Visit 1) patients will provide written informed consent and will be 
screened to review the inclusion and exclusion criteria.  Study eligibility will be assessed on the 
basis of medical history including detailed migraine history meeting the International 
Classification of Headache Disorders (ICHD)-3 classification 1.1 or 1.2.1 for migraine, onset of 
migraine prior to age 50, 3 to 8 migraine attacks per month but <15 headache days per month
during the past 3 months, baseline physical examination, vital signs, clinical laboratory tests, 12-
lead electrocardiogram (ECG) and responses to the MIDAS questionnaire indicating disabling 

H8H-MC-LAIJ(b) Clinical Protocol
Page 25
LY573144
migraine. Patients will be asked about any concomitant medication use as well as any CV events 
in the last 6 months and/or related resource utilization such as visits to cardiologists, procedures, 
hospitalizations, new treatments or treatment adjustments for CV disease. A Columbia-Suicide 
Severity Rating Scale (C-SSRS) will be completed. Patients will receive some initial 
introduction to the electronic diary (eDiary) and the site will assess whether the patient is willing 
and able to use the eDiary to record data during their migraine attacks. 
See Table LAIJ.2.1 for a complete list of assessments performed at Visit 1.
For patients not meeting study requirements at the screening visit or found to not qualify based 
on laboratory assessments, there will be no additional site visits. 
5.1.2. Randomization (Visit 2)
At Visit 2, patients will be randomly assigned treatment as described in Section 5.1, will have 
additional assessments (see Table LAIJ.2.1), will be dispensed study drug, and will begin the 
Treatment Period.  If available and where local regulations and ethical review boards (ERBs) 
allow, patients will also watch a training video designed to address patient expectations with 
regard to participation in a placebo-controlled trial and the difference between medical treatment 
and research. The patient will receive detailed instruction on the use of the eDiary and on dosing 
their migraine attacks with study drug.  
5.1.3. Treatment Period
During the treatment period, patients will participate in phone visits after attack 1 or at 1 month
(whichever comes first) and at 3 months of study participation, and a site visit at 2 months of 
study participation. Patients completing their 4 migraine attacks sooner than these time points 
will move directly to their EoS visit.
For each of 4 attacks, patients will be instructed to treat their migraine within 4 hours of onset 
providing that the headache severity is at least moderate or severe at the time, is not improving, 
and no other migraine treatment has been taken.  Patients will record their response to study drug
over the next 48 hours using the eDiary set up to remind the patient to complete assessments at 
specific postdose time points:  0.5, 1, 2, 4, 6, 24, and 48 hours. There must be at least a 48-hour 
gap after taking study drug for the treated attack, before treating the next migraine with study 
drug.  
For migraine attacks which do not meet the criteria above or when the patient is unable to treat 
with study drug and complete all study procedures during a particular migraine, they may use 
their usual migraine medication for that migraine and then treat the next appropriate migraine 
with study drug.  In summary, patients are requested to treat 4 consecutive appropriate migraine
attacks with study drug, but this is not required if it is not possible.  
As described in detail in Section 7.2.1, patients requiring medication for rescue or for migraine 
recurrence may take their own unexcluded medication. 
Study governance considerations are described in detail in Appendix 3.

H8H-MC-LAIJ(b) Clinical Protocol
Page 26
LY573144
5.2.
Number of Patients
Approximately 2100 patients will be screened to achieve approximately 1600 patients 
randomized, approximately 1150 patients with data for first attack, and approximately 800
patients with data for consistency assessment.  An additional 200 patients may be randomized if 
there is an insufficient number of patients with complete data for consistency assessment.  
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure for the last visit for the 
last patient. 
5.4.
Scientific Rationale for Study Design
The patient population for this study will closely align to the study population studied in the 
lasmiditan Phase 3 program to date.
A modified parallel design was chosen after consideration of multiple design options.  The 
modified parallel design was previously used successfully to assess the consistency of 
telcagepant over 4 attacks (Ho et al. 2010).  This design was chosen over a parallel 
placebo-controlled design because of reduced risk of unblinding leading to differential drop-out 
rates.  
A frequently used approach, termed random-insertion-of-placebo, is for each patient to receive 
placebo for 1 of their attacks.  However, relative to this approach, the modified parallel approach 
in this study has beneficial features, including the opportunity to study the consistency of 
response to 2 doses of lasmiditan (100 mg and 200 mg) with a relatively simple study design.  
Finally, while random-insertion-of-placebo provides the consistency of treatment, it does not
provide an opportunity for comparing the consistency of effect in patients treated with drug 
versus placebo.
The efficacy of lasmiditan 100 mg and 200 mg will be assessed during the first attack by 
comparing the results in those groups with the results with placebo in the control group.
The number of attacks is 4 and the duration of the treatment phase of the study is up to 16 weeks. 
Patients with 3 to 8 migraine attacks per month will be recruited to increase the probability that 
patients will achieve 1 or more evaluable migraine attacks per month as recommended in the IHS 
guideline (IHS Clinical Trials Subcommittee 2012).
Inclusion of the control group
The inclusion of the control group provides the opportunity to compare the efficacy and 
consistency of response to lasmiditan 100 mg and 200 mg to placebo, improved maintenance of 
blinding since patients in the control group will receive lasmiditan 50 mg for 1 attack, more 
patient acceptability since they will not receive placebo for all attacks, and the opportunity to 
assess the efficacy of lasmiditan 50 mg during 1 attack. Placebo effect in acute treatment of 
migraine varies from 6% to 47%, highlighting the importance of comparing active study drug to 
placebo. Because rescue medication is permitted after 2 hours, the use of placebo in the design 
is ethically appropriate (Lipton et al. 2005). 

H8H-MC-LAIJ(b) Clinical Protocol
Page 27
LY573144
5.5.
Justification for Dose
Two single-attack Phase 3 studies of lasmiditan have been completed, and these studies show 
dose-dependent efficacy of lasmiditan versus placebo to increase freedom from both pain and 
MBS with lasmiditan.  All doses (50 mg, 100 mg, and 200 mg) showed statistically significant 
superiority versus placebo on pain freedom, MBS freedom, and pain relief versus placebo.  In 
general, the efficacy of lasmiditan was dose dependent, with lasmiditan 50 mg showing the least 
efficacy and lasmiditan 200 mg showing the most efficacy.  Safety analysis showed TEAEs were 
increased with lasmiditan compared to placebo, including dizziness, paresthesia, somnolence, 
fatigue, nausea, and lethargy.  In general, these TEAEs were observed to increase in a dose-
dependent manner (ie, they were lowest with lasmiditan 50 mg and highest with lasmiditan 
200 mg).  These TEAEs were usually mild to moderate in severity and self-limiting.  Because of 
the relatively greater efficacy of lasmiditan 100 mg and 200 mg, the main study arms will be 
lasmiditan 100 mg, lasmiditan 200 mg, and control.  To further understand the effects of
lasmiditan 50 mg, the control group will receive lasmiditan 50 mg for 1 attack.

H8H-MC-LAIJ(b) Clinical Protocol
Page 28
LY573144
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 
screening:
Type of Patient and Disease Characteristics
[1]
are of an acceptable age to provide informed consent according to the local regulations 
and are at least 18 years of age at time of screening (Visit 1) with migraine with or 
without aura fulfilling the IHS diagnostic criteria 1.1 or 1.2.1 (ICHD-3; see Appendix 5)
[2]
history of disabling migraine for at least 1 year
[3]
migraine onset before the age of 50 years
[4]
history of 3 to 8 migraine attacks per month (<15 headache days per month) during the 
past 3 months
[5]
MIDAS score ≥11
[6]
able and willing to complete an eDiary to record the details of each migraine attack 
treated with study drug
Patient Characteristics
[7]
are men or women; if women, must agree to abide by the following guidance:
women of child-bearing potential must agree to use a highly effective method of 
contraception (that is, one with less than 1% failure rate) such as combination oral 
contraceptives, implanted/injected contraceptives, intrauterine devices, or sterile partner
until 30 days after the last dose of study medication
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 stay in a same-sex 
relationship without sexual relationships with males. Periodic abstinence (for example, 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence 
just for the duration of a trial, and withdrawal are not acceptable methods of 
contraception 
women not of child-bearing potential may participate and include those who are:  

infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as mullerian agenesis; or  

post-menopausal – defined as either  

H8H-MC-LAIJ(b) Clinical Protocol
Page 29
LY573144
o
a woman between 40-50 years of age with an intact uterus, not on 
hormone therapy, who has had 

cessation of menses for at least 1 year, and   

a follicle-stimulating hormone >40 mIU/mL;
o
a woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either  

cessation of menses for at least 1 year, or  

at least 6 months of spontaneous amenorrhea with a follicle-
stimulating hormone >40 mIU/mL; or 
o
a woman 55 or older not on hormone therapy, who has had at least 6 
months of spontaneous amenorrhea; or  
o
a woman at least 55 years of age with a diagnosis of menopause prior 
to starting hormone replacement therapy   
Informed Consent
[8]
are able and willing to give signed informed consent
[9]
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, Google+, 
etc.) until the entire trial has completed
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions/ Prior and Concomitant Therapy
[10] known hypersensitivity to lasmiditan, or to any excipient of lasmiditan oral tablets 
[11] history or evidence of hemorrhagic stroke, epilepsy, or any other condition placing the 
patient at increased risk of seizures
[12] history of recurrent dizziness and/or vertigo including benign paroxysmal positional 
vertigo, Meniere’s disease, vestibular migraine, and other vestibular disorders  
[13] history of diabetes mellitus with complications (diabetic retinopathy, nephropathy, or 
neuropathy)
[14] history of orthostatic hypotension with syncope
[15] significant renal or hepatic impairment in the opinion of the investigator or if they meet 
hepatic monitoring criteria (see Section 9.4.5.1)
[16] patients who, in the investigator’s judgment, are actively suicidal and therefore deemed to 
be at significant risk for suicide, or those who have answered “yes” to either Question 4 
(Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 

H8H-MC-LAIJ(b) Clinical Protocol
Page 30
LY573144
(Active Suicidal Ideation with Specific Plan and Intent) on the “Suicidal Ideation” 
portion of the C–SSRS, or answer “yes” to any of the suicide-related behaviors (actual 
attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the 
“Suicidal Behavior” portion of the C–SSRS; and the ideation or behavior occurred within 
the past month of Visit 1 or 2
[17] Exclusion criterion [17] has been deleted.
[18] history, within past 12 months, of chronic migraine or other forms of primary or 
secondary chronic headache disorder (eg, hemicranias continua, medication overuse 
headache where headache frequency is ≥15 headache days per month [Appendix 5 and 
Appendix 6])
[19] use of more than 3 doses per month of either opioids or barbiturates
[20] initiation of or a change in concomitant medication to reduce the frequency of migraine
episodes within 3 months prior to Screening/Visit 1
[21] female patients who are pregnant or breast-feeding
[22] women of child-bearing potential who test positive for pregnancy based on a serum 
pregnancy test collected at Visit 1
[23] 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 potential abuse or any prescribed or over-the-counter medication in a 
manner that the investigator considers indicative of abuse/dependence
[24] have a positive urine drug screen for any substances of abuse at Visit 1
Note:  A retest is allowed if the urine drug screen is positive for any prescribed 
substance or if, in the judgment of the investigator, there is a medically acceptable 
explanation for the positive result.  The results of the retest must be negative at or 
prior to Visit 2
[25] have an acute, serious or unstable medical condition, or a history or presence of 
any other medical illness including but not limited to any autoimmune disease, 
CV, hepatic, respiratory, hematological, endocrine, psychiatric, or neurological 
disease, or any clinically significant laboratory abnormality, that, in the judgment 
of the investigator, indicates a medical problem that would preclude study 
participation
[26] known hypersensitivity to multiple drugs
Prior/Concurrent Clinical Trial Experience
[27] 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
[28] if patient recently took an investigational product, 5 half-lives or 30 days or requirements 
based on local regulations (whichever is longer) should have passed

H8H-MC-LAIJ(b) Clinical Protocol
Page 31
LY573144
[29] have previously completed or withdrawn from this study or any other study 
investigating lasmiditan
Other Exclusions
[30]
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
[31]
are Lilly employees 
Patients with test results which did not meet the inclusion/exclusion criteria may have the 
relevant test repeated once if it was thought to represent a laboratory error; a reversible, clinically 
insignificant intermittent condition; or was not consistent with the patient’s historical values.  If 
inclusion/exclusion criteria were not met after the repeat test, the patient should not be enrolled 
in the study.
6.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria 10 through 18, 21, 22, 25, and 26 are for excluding patients with significant 
illnesses or conditions that may affect their safety or confound study results. Exclusion Criteria
19 and 20 exclude patients with current or prior therapies that could negatively impact the safety 
of the patient or influence the analysis of the results. Exclusion Criteria 23 and 24 exclude 
treatments or illicit substances that may impact study results.  Exclusion Criteria 27, 28, and 29
exclude patients using drugs that cannot be mapped to a standard drug dictionary, or for which 
little data are known to analyze the potential relationship of AEs or drug interactions. Exclusion 
Criteria 30 and 31 prevent conflict of interest in study patients.
6.3.
Lifestyle Restrictions
Not applicable.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be
considered for rescreening once with approval from Lilly Medical for only the criteria shown 
below.  The interval between screening and rescreening must be at least 45 days or longer if 
required for the specified timeframes in the inclusion/exclusion criteria or concomitant 
medication list.  If rescreening is performed, the individual must sign a new ICF and will be 
assigned a new identification number.

Inclusion Criterion [1]:  If patients are less than age 18 at time of informed consent, they 
may be rescreened if they reach age 18 during the study enrollment period

Exclusion Criterion [22]:  false positive pregnancy test
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. 

H8H-MC-LAIJ(b) Clinical Protocol
Page 32
LY573144
7. Treatments
7.1.
Treatments Administered
This study involves treatment with lasmiditan 200 mg, 100 mg, and 50 mg or placebo
administered by mouth for migraine headaches of moderate to severe intensity.  Table LAIJ.7.1
shows the treatment regimens.  
Each dose will consist of 3 tablets for the treatment of a single migraine attack.

lasmiditan 50-mg dose – 1 lasmiditan 50-mg tablet and 2 lasmiditan 100 mg 
matching placebo

lasmiditan 100-mg dose – 1 lasmiditan 100-mg tablet, 1 lasmiditan 50 mg 
matching placebo, and 1 lasmiditan 100 mg matching placebo

lasmiditan 200-mg dose – 2 lasmiditan 100-mg tablets and 1 lasmiditan 50 mg 
matching placebo

placebo – 1 lasmiditan 50 mg matching placebo and 2 lasmiditan 100 mg 
matching placebo
Table LAIJ.7.1.
Treatment Regimens
Regimen
Attack 1
Attack 2
Attack 3
Attack 4
LTN200 mg 
Dose Group
LTN200 mg
2100-mg lasmiditan 
tablets 
150 mg lasmiditan
matching placebo
LTN200 mg
2100-mg lasmiditan
tablets
150 mg lasmiditan
matching placebo
LTN200 mg 
2100-mg lasmiditan 
tablets 
150 mg lasmiditan
matching placebo
LTN200 mg 
2100-mg lasmiditan 
tablets 
150 mg lasmiditan
matching placebo
LTN100 mg 
Dose Group
LTN100 mg
1100-mg lasmiditan 
tablet
150 mg lasmiditan
matching placebo
1100 mg lasmiditan 
matching placebo
LTN100 mg
1100-mg lasmiditan 
tablet  
150 mg lasmiditan 
matching placebo 
1100 mg lasmiditan 
matching placebo
LTN100 mg
1100-mg lasmiditan 
tablet
150 mg lasmiditan 
matching placebo
1100 mg lasmiditan 
matching placebo
LTN100 mg
1100-mg lasmiditan 
tablet
150 mg lasmiditan
matching placebo
1100 mg lasmiditan 
matching placebo
Control 1
Placebo
150 mg lasmiditan 
matching placebo
2100 mg lasmiditan
matching placebo
Placebo
150 mg lasmiditan 
matching placebo
2100 mg lasmiditan
matching placebo
LTN50 mg
150-mg lasmiditan 
tablet
2100 mg lasmiditan 
matching placebo 
Placebo
150 mg lasmiditan 
matching placebo 
2100 mg lasmiditan
matching placebo
Control 2
Placebo
150 mg lasmiditan 
matching placebo
2100 mg lasmiditan
matching placebo
Placebo
150 mg lasmiditan 
matching placebo 
2100 mg lasmiditan
matching placebo
Placebo
150 mg lasmiditan 
matching placebo 
2100 mg lasmiditan
matching placebo
LTN50 mg
150-mg lasmiditan 
tablet 
2100 mg lasmiditan
matching placebo
Abbreviations:  LTN200 = lasmiditan 200 mg; LTN100 = lasmiditan 100 mg; LTN50 = lasmiditan 50 mg.

H8H-MC-LAIJ(b) Clinical Protocol
Page 33
LY573144
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent 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
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 2.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  Patients will be randomized 1:1:1 
to the lasmiditan 200-mg, lasmiditan 100-mg, and control groups.
The IWRS will be used to assign double-blind investigational product to each patient. At Visit 2, 
patients will be provided with sufficient study drug to treat 4 migraine attacks. Site personnel 
will confirm that they have located the correct investigational product by entering a confirmation 
number found on the investigational product into the IWRS.
To achieve between-group comparability, the randomization will be stratified by country.
7.2.1. Selection and Timing of Doses:  Study Treatment and Other 
Migraine Treatments
Patients will be randomized 1:1:1 to the lasmiditan 200-mg, lasmiditan 100-mg, and control 
groups.  The doses will be administered for migraine attacks of moderate to severe intensity.  
The actual time of all dose administrations will be recorded in the eDiary. Patients will be 
instructed to take 3 tablets as the FIRST treatment for a new migraine attack.

The migraine is at least of moderate or severe severity.

Migraine should be treated within 4 hours of onset.

No prior analgesic or acute migraine treatment or symptom-modifying medication 
(for example, antiemetic) has been taken to treat the current migraine attack.

Patients should not take study drug within 24 hours after taking triptans, ergots, 
opioids, and barbiturates.
Rescue or Recurrence Medication.  Between 2 and 24 hours after dosing, patients may take their 
own unexcluded medication for rescue treatment (headache pain freedom is not achieved at 2 

H8H-MC-LAIJ(b) Clinical Protocol
Page 34
LY573144
hours) or for treatment of recurrent headache (headache pain freedom is achieved at 2 hours but 
recurs after 2 hours).  Patients should not take any medications until 2 hours after taking a dose 
of study drug and completing the 2-hour assessments.  After that, they may take unexcluded 
alternative medications for rescue or recurrence.  The investigator should advise patients of 
appropriate medications to be taken for rescue or recurrence, and inform patients that triptans, 
ergots, opioids, and barbiturates MUST NOT be taken within 24 hours of study drug 
administration (that is, 24 hours before or after).  The use of rescue or recurrence medication 
should be recorded in the patient’s paper journal.    
7.3.
Blinding
This is a double-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.
Emergency unblinding for AEs will 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 are recorded and reported by the IWRS.
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 clinical research 
physician (CRP) for the patient to continue in the study.
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 a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.  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.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dosage Modification
Dosage modification is not allowed.
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

H8H-MC-LAIJ(b) Clinical Protocol
Page 35
LY573144

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with provided instructions, 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)
7.6.
Treatment Compliance
Patient compliance with study drug will be assessed.  Compliance will be assessed by direct 
questioning, counting returned tablets, and so on.  Deviation(s) from the prescribed dosage 
regimen should be recorded in the case report form (CRF).
Study drug will be taken by the patient on an outpatient basis. Upon review of eligibility at Visit 
2, study drug to treat all 4 attacks will be provided. Information on date and time of each dose 
will be recorded by patient in the eDiary. Patients will return all unused study drug to the site at 
the end of study visit. The site will document which tablets are returned.  A patient will be 
considered significantly noncompliant if he or she is judged by the investigator to have 
intentionally or repeatedly taken more than the prescribed amount of medication.
7.7.
Concomitant Therapy
Concomitant medications (including devices) for migraine or pain prior to study enrollment and 
concomitant medication used to treat other medical conditions prior to study enrollment will be 
recorded during Screening/Visit 1.
Any changes in dosage or new medications added as a result of intercurrent illness during the 
patient’s time on study must be recorded in the CRFs.
Use of the following medications is prohibited for the duration of a patient’s participation in the 
study from Screening/Visit 1 through EoS: 

any investigational treatment other than lasmiditan 

if a patient requires the initiation of migraine prophylaxis (concomitant 
medication to reduce the frequency of migraine episodes) or a change in 
ongoing migraine prophylaxis after the Screening/Visit 1 they should be 
withdrawn from the study 
7.8.
Treatment after the End of the Study
7.8.1. Treatment after Study Completion 
Lasmiditan will not be made available after conclusion of the study to patients because other 
effective therapies for migraine are available.

H8H-MC-LAIJ(b) Clinical Protocol
Page 36
LY573144
7.8.2. Special Treatment Considerations and Minimization of Risk
All doses of lasmiditan were associated with driving impairment in a study of healthy volunteers 
on a computer-based driving simulator. Patients should restrict their driving, operation of heavy 
machinery, or other similar activities after taking study drug as described in the ICF.
Because of the potential of lasmiditan to cause central nervous system (CNS)-related side effects
(see Section 3.2 and IB), advise patients to use caution if taking study medication in combination 
with alcohol or other CNS depressants.

H8H-MC-LAIJ(b) Clinical Protocol
Page 37
LY573144
8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of investigational product:

Subject Decision
o
the patient requests to discontinue investigational product.

Discontinuation due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from investigational product due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via eCRF.
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets 1 of the following conditions after 
consultation with the Lilly designated medical monitor:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X 
upper limit of normal (ULN)

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (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%)

alkaline phosphatase (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%)
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE 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. Temporary Discontinuation from Study Treatment 
Not applicable for this as needed medication.
8.1.3. 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 and safety 

H8H-MC-LAIJ(b) Clinical Protocol
Page 38
LY573144
follow up should be performed as outlined in Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of the main 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
o
the investigator decides that the patient should be discontinued from the 
study

patient decision
o
the patient requests to discontinue study drug or to be withdrawn from the 
study

patient becomes pregnant or is breastfeeding

if a patient requires the initiation of migraine prophylaxis (concomitant medication to 
reduce the frequency of migraine episodes) or a change in ongoing migraine 
prophylaxis after the Screening/Visit 1 they should be withdrawn from the study 
Discontinuation due to suicidality.  It is recommended that a patient be assessed by a 
psychiatrist or appropriately trained professional to assist in deciding whether the patient should 
be discontinued from study drug if, during the study, a patient 

is, in the investigator’s judgment, actively suicidal and therefore deemed to be 
at significant risk for suicide

answers “yes” to either Question 4 (Active Suicidal Ideation with Some Intent 
to Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with 
Specific Plan and Intent) on the “Suicidal Ideation” portion of the C–SSRS, or 
answers “yes” to any of the suicide-related behaviors (actual attempt, 
interrupted attempt, aborted attempt, preparatory act or behavior) on the 
“Suicidal Behavior” portion of the C–SSRS; and the ideation or behavior 
occurred within the past month of the assessment
When a patient discontinues from a study due to suicidal ideation and/or behavior, the 
same follow-up procedures will be used as would be done for discontinuation due to any 
other AEs leading to discontinuation.
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.

H8H-MC-LAIJ(b) Clinical Protocol
Page 39
LY573144
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.
Site personnel, or an independent third party, will attempt to collect the vital status of the patient 
within legal and ethical boundaries for all patients randomized, including those who did not get 
investigational product.  Public sources may be searched for vital status information.  If vital 
status is determined, this will be documented and the patient will not be considered lost to 
follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.

H8H-MC-LAIJ(b) Clinical Protocol
Page 40
LY573144
9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities (Table LAIJ.2.1), 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
Patient Diary
Patients will be introduced to the eDiary at Visit 1 and trained on the use of the eDiary at Visit 2. 
Efficacy data for each attack will be collected in the eDiary. Patients will record the date and 
time at which their migraine headache starts and when it first becomes moderate or severe. They 
will also record the date and time of taking study drug.  Patients will be asked to assess their 
headache severity at specified time points:  0 (predose), 0.5, 1, 2, 4, 6, 24, and 48 hours postdose 
using the IHS 4-point headache severity rating scale (0 = no pain, 1 = mild pain, 2 = moderate 
pain, and 3 = severe pain) (see Appendix 7).  
9.1.2. Secondary Efficacy Assessments
Patient Diary
Secondary efficacy data will also be collected in the eDiary. 
At the time points 0 (pre dose), 0.5, 1, 2, 4, 6, 24, and 48 hours, patients will assess the presence 
or absence (yes or no) of accompanying symptoms: photophobia, phonophobia, nausea, and 
vomiting. At time 0 (pre dose) patients will select from the accompanying symptoms present 
(from nausea, phonophobia, or photophobia only) which one is the most bothersome to them (see 
Appendix 7). 
Patients will also be asked to record the time at which headache relief became meaningful to 
them and the time at which they become headache pain-free. At 2 and 24 hours after dosing with
study drug, patients will be asked to record their global impression of change (PGIC) using a 7-
point scale (very much better, much better, a little better, no change, a little worse, much worse, 
and very much worse) (see Appendix 7).
Patients should record details of AEs, concomitant medication use, and any other relevant 
information in the patient’s paper journal and these will be reviewed at the next visit.

H8H-MC-LAIJ(b) Clinical Protocol
Page 41
LY573144
Recording Use of Rescue/Recurrence Medication
Between 2 and 24 hours after dosing, patients may take their own unexcluded medication for 
rescue treatment (headache pain freedom is not achieved at 2 hours) or for treatment of recurrent 
headache.  The use of rescue or recurrence medication should be recorded in the patient’s paper 
journal.
Migraine Quality of Life Questionnaire (MQoLQ):  The 24-hour Migraine Quality of Life 
Questionnaire (24-hr MQoLQ) has been specifically developed to measure the HRQoL of 
patients with migraine within a 24-hour period after having taken migraine medication.  The 
24-hour MQoLQ is a 15-item, self-administered questionnaire.  The items cover 5 domains 
(work functioning, social functioning, energy and vitality, feelings and concerns, and migraine 
symptoms) (Hartmaier et al. 1995; Santanello et al. 1995, 1997). Each domain consists of 3 
questions answered on a 7-point scale where 1 indicates maximum impairment and 7 indicating 
no impairment.  A domain score is calculated by summing the responses to the 3 questions and 
the domain score ranges from 3 to 21.  The questionnaire will be administered 24 hours after
dosing with study drug during each migraine.
MIDAS:  The MIDAS is a patient-rated scale which was designed to quantify headache-related 
disability over a 3-month period.  This instrument consists of 5 items that reflect the number of 
days reported as missed, or with reduced productivity at work or home and social events.  Each 
question is answered as the number of days during the past 3 months of assessment, ranging 
from 0 to 90, with the total score being the summation of the 5 numeric responses.  A higher 
value is indicative of more disability (Stewart et al. 1999, 2001).  This instrument is considered 
reliable and valid, and is correlated with clinical judgment regarding the need for medical care 
(Stewart et al. 1999, 2001).  For clinical interpretability, 4 categorical grades were developed 
based on the total score:  Grade I (0 to 5) is for little or no disability, Grade II (6 to 10) is for 
mild disability, Grade III (11 to 20) is for moderate disability, and Grade IV (21+) is for severe 
disability.  The severe disability category has subsequently been subdivided into Grade IV-A 
(severe [21 to 40]) and Grade IV-B (very severe [41 to 270]) because a high proportion of 
patients with chronic migraine are in Grade IV (Blumenfeld et al. 2011).  Two additional 
questions (A and B) collect information on the frequency of headaches and the intensity of the 
headache pain.  These are not scored in the MIDAS Questionnaire but are included to provide 
clinically relevant information that may aid in treatment and management decisions.  The 
MIDAS will be captured at screening as part of the inclusion criteria and again at EoS with the 
recall period adjusted to capture disability since the patient enrolled in the study (depending on 
how quickly the patient completes the 4 migraine attacks, this could be from approximately 1 to 
4 months). 
mTOQ-6:  The mTOQ is a validated, self-administered questionnaire that assesses the efficacy 
of current acute migraine treatment (Lipton et al. 2009) and is demonstrated to measure an 
autonomous outcome domain related to, but distinct from, functioning and HRQoL over a 4-
week period (Lipton et al. 2009). The items assess the domains of functioning, rapid relief, 

H8H-MC-LAIJ(b) Clinical Protocol
Page 42
LY573144
consistency, recurrence, and side effects (Serrano et al 2015).  This study will use the 6-item 
version (mTOQ-6) at baseline/first visit with Likert type response options of Never (0 points); 
Rarely (0 points); Less than half the time (1 points); and Half the time or more (2 points). A 
total score from 0 to 8 is calculated by summing the points from 4 of the items (2-hour pain 
freedom, sustained 24-hour pain relief, comfortable to make plans, and perceived control) which
define categories of acute treatment response:  very poor (0), poor (1-5), moderate (6-7), and 
maximum (8) treatment efficacy (Lipton et al. 2015).  This questionnaire will be administered at 
Visit 2.
EQ-5D-5L:  5-Dimensions 5-Levels (EQ-5D-5L) questionnaire is a widely used, generic 
questionnaire that assesses health status (The EuroQol Group 1990; Herdman et al. 2011).  This 
is a patient-rated scale.  The questionnaire consists of 2 parts.  The first part assesses 
5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that 
have 5 possible levels of response (no problems, slight problems, moderate problems, severe 
problems, extreme problems).  This part of the EQ-5D can be used to generate a health state 
index score, which is used to compute quality-adjusted life years for utilization in health 
economic analyses.  The health state index score is calculated based on the responses to the 
5 dimensions, providing a single value on a scale from less than 0 (where 0 is a health state 
equivalent to death; negative values are valued as worse than death) to 1 (perfect health), with 
higher scores indicating better health utility.  The second part of the questionnaire consists of a 
visual analog scale on which the patient rates their perceived health state from 0 (the worst health 
you can imagine) to 100 (the best health you can imagine).  The EQ-5D-5L will be captured at 
Visit 2 and at 0 and 24 hours postdose during each migraine.
Disability:  Disability will be measured by determining the level of interference with normal 
activities with 4 response options including not at all; mild interference, marked interference; and 
need complete bed rest. This will be evaluated at 0, 0.5, 1, 2, 4, 6, and 24 hours postdose during 
each migraine. 
Patient Global Impression of Change (PGIC):  Patient global impression of change will be 
measured at 2 and 24 hours postdose with a 7-point scale ranging from very much better to very 
much worse during each migraine.
Treatment Satisfaction:  Treatment satisfaction will be evaluated at the EoS visit by 
determining the patient’s level of satisfaction (ranging from extremely dissatisfied to extremely 
satisfied); their willingness to take this treatment again (ranging from strongly disagree to 
strongly agree) and if they would they recommend this treatment to another patient (ranging 
from strongly disagree to strongly agree).
9.1.3. Appropriateness of Assessments
The assessments collected during this study are standard and generally recognized as reliable, 
accurate, and relevant.  The study has 2 primary endpoints.  Pain freedom at 2 hours postdose is 
a recommended primary endpoint to assess efficacy of a migraine treatment.  Based on 
regulatory guidance for consistency studies, the other primary endpoint is consistency of effect.  

H8H-MC-LAIJ(b) Clinical Protocol
Page 43
LY573144
The other assessments are also consistent with regulatory guidance and are commonly used in 
studies of medications for acute treatment of migraine.
9.2.
Adverse Events
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.  Such events should be recorded on the AE 
page of the eCRF.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
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 or until the event
stabilizes with appropriate diagnostic evaluation.  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.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record the following via eCRF 
for each AE:  time of onset, time of termination, severity, and their assessment of the potential 
relatedness of each AE to protocol procedure and investigational product.
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 or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
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 investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

H8H-MC-LAIJ(b) Clinical Protocol
Page 44
LY573144

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via initiation of the SAE eCRF. Once the SAE eCRF form is initiated, an 
email is automatically triggered to the Sponsor’s global patient safety department. Investigators 
can contact the sponsor via telephone at any time using the qualified medical personnel or Lilly 
affiliate medical contact details which are provided in the site study file. If alerts are issued via 
telephone, they are to be immediately followed with official notification via completion of the 
SAE eCRF. If the eCRF is unavailable (for example, for system maintenance) for a period of 
time that would compromise the sites’ ability to report an event within 24-hrs of awareness, a 
paper version of the form should be downloaded from the InvestigatorSpace portal, completed by 
the investigator, and submitted via fax to the Sponsor’s global patient safety department. This 
form includes a fax cover page that is pre-populated with the appropriate fax number. Serious 
adverse events submitted via the paper method are entered into the eCRF once the database is 
available. The 24-hour notification requirement refers to the initial SAE information and all 
follow-up SAE information. Patients with a serious hepatic AE should have additional data 
collected using the eCRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 

H8H-MC-LAIJ(b) Clinical Protocol
Page 45
LY573144
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.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  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.
9.2.2. 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 investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB.
9.4.
Safety
The safety assessments are described below.
9.4.1. Electrocardiograms
For each patient, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2) as a baseline.  There will be no central reading of ECGs.
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.  
Investigators may repeat an ECG collection as medically needed.  Any clinically significant 
findings from ECGs that result in a diagnosis and that occur after the patient receives the first 
dose of study treatment should be reported to Lilly or its designee as an AE via eCRF.
9.4.2. Vital Signs
Vital signs will include body temperature, blood pressure, and pulse.  Blood pressure and pulse 
will be measured in the sitting position prior to blood draws, according to the Schedule of 
Activities (Section 2) and following the study-specific recommendations included in the Manual 
of Operations for the study.

H8H-MC-LAIJ(b) Clinical Protocol
Page 46
LY573144
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via eCRF.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2). 
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor, if a central vendor is used for the clinical trial.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of study treatment should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.4. Other Tests
Columbia Suicide-Severity Rating Scale (C-SSRS):  A scale that captures the occurrence, 
severity, and frequency of suicide-related thoughts and behaviors during the assessment period
(Posner et al. 2011).  The scale includes suggested questions to solicit the type of information 
needed to determine if a suicide-related thought or behavior occurred.  The C-SSRS is 
administered by an appropriately trained healthcare professional with at least 1 year of patient 
care/clinical experience according to the Schedule of Activities (Section 2).  The tool was 
developed by the National Institute of Mental Health (NIMH) trial group (Treatment of 
Adolescent Suicide Attempters Study) for the purpose of being a counterpart to the Columbia 
Classification Algorithm of Suicide Assessment (C-CASA) categorization of suicidal events. 
Two versions of the C-SSRS will be used:

The screening version will be administered at Screening/Visit 1

The “since last visit” version will be administered at Visit 2 and Visit 4 (at 
2 months) and at V6 (EoS)
For this study, the C-SSRS is adapted for the assessment of the ideation and behavior categories 
only. The Intensity of Ideation and Lethality of Behavior sections are removed.
The nonleading AE collection should occur prior to the collection of the C-SSRS. If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. If an adverse event is serious or 
leads to discontinuation, this is an exception where the SAE and/or AE leading to 
discontinuation should be included on the AE form and the process for reporting SAEs should be 
followed.
Assessment of driving accidents/violations:  In order to further evaluate the impact of 
lasmiditan on driving, an assessment of driving accidents/violations will be conducted by 
site personnel according to the Schedule of Activities (Section 2).  

H8H-MC-LAIJ(b) Clinical Protocol
Page 47
LY573144
9.4.5. Safety Monitoring 
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.5.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3X ULN, AST ≥3X ULN, ALP ≥2X ULN, or 
elevated TBL ≥2X ULN, 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.  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

elevation of serum AST 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 a SAE
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Genetics
9.7.1. Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to lasmiditan and to 
investigate genetic variants thought to play a role in migraine.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.  

H8H-MC-LAIJ(b) Clinical Protocol
Page 48
LY573144
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 investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and/or ethical 
review boards (ERBs)/investigational review boards (IRBs) impose shorter time limits.  This 
retention period enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
lasmiditan or after lasmiditan become(s) commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section. 
9.8.
Biomarkers
Not applicable.
9.9.
Medical Resource Utilization and Health Economics
Health Care Resource Utilization and Employment Status:  The Health Care Resource 
Utilization questionnaire (HCRU) will be solicited by study personnel while documenting patient 
responses.  The HCRU consists of 3 questions, asking about the number of hospital emergency 
room visits, overnight stays in a hospital, and any other visits with a healthcare professional that 
occurred since the patient started in the study, outside of visits associated with their participation 
in the clinical trial.  Patients are also specifically asked about the number of healthcare events 
that are related to migraine attacks. The baseline visit will include the same questions but with 
the past 6 months as the recall period. 
A question on employment status will also be solicited according to the Schedule of Activities, 
given the correlation and potential confounding with health outcome measures.

H8H-MC-LAIJ(b) Clinical Protocol
Page 49
LY573144
10. Statistical Considerations
10.1. Sample Size Determination
Approximately 2100 patients will be screened to achieve approximately 1600 randomized, 
approximately 1150 with data for first attack, and approximately 800 with complete data for 
consistency assessment.  An additional 200 patients may be randomized if there is an insufficient 
number of patients with complete data for consistency assessment.  
Eligible patients will be randomized in blinded fashion in a 1:1:1 ratio to lasmiditan 200 mg, 
lasmiditan 100 mg, or control.  The control group will consist of 2 treatment sequence groups 
where all patients receive placebo for 3 attacks and are randomized 1:1 where 1 group will 
receive lasmiditan 50 mg for attack 3 and the other group will receive lasmiditan 50 mg for 
attack 4.
Using a 1-sided, 2-sample comparison of proportions at a 1-sided alpha of 0.025, a sample size 
of 380 patients per treatment arm for the first attack provides >90% power to detect a difference 
in headache pain-free response at 2 hours for assumed true rates of 29% for lasmiditan 100 mg 
and 19% for placebo for the first attack.  The power is expected to be higher for the comparison 
of lasmiditan 200 mg to placebo given the larger effect of lasmiditan 200 mg versus lasmiditan 
100 mg observed in previous studies. 
For the consistency primary endpoints, assuming 0.3 and 0.2 correlation coefficients among 
multiple attacks for lasmiditan and placebo respectively, and assuming a consistent response rate 
at each attack for lasmiditan and placebo, a sample size of 260 patients per treatment arm 
provides >90% power for 2-hour headache pain-free consistency for the 200-mg dose arm and 
nearly 90% power for consistency in the 100-mg dose arm. 
10.2. Populations for Analyses
For purposes of analysis, the populations are defined below.  For efficacy analyses, patients are 
evaluated by attack and by the group to which they are randomized. For safety analyses, patients 
will be analyzed according to the treatment group they actually received, which will generally be 
the same as randomized treatment unless there is an error.  

H8H-MC-LAIJ(b) Clinical Protocol
Page 50
LY573144
Population
Description
Entered
All participants who sign informed consent
ITT
All randomized patients who use at least 1 dose of study drug for an ITT-
evaluable attack, defined as a treated attack of at least mild pain severity with
any postdose pain severity asssessments at or before 2 hours postdose.
mITT
All randomized patients who use at least 1 dose of study drug for an mITT-
evaluable attack, defined as a treated attack of at least moderate pain severity
with any postdose pain severity assessments at or before 2 hours postdose.
ITT consistency
All randomized patients who experience a sufficient number of successes or  
failures (defined in Section 10.3.1) during ITT-evaluable attacks for any of the 
consistency analyses. 
mITT consistency
All randomized patients who experience a sufficient number of successes or  
failures (defined in Section 10.3.1) during mITT-evaluable attacks for any of the 
consistency analyses .
Safety
All randomized patients who take at least 1 dose of study drug, regardless of 
whether or not they undergo any study assessments. 
Abbreviations:  ITT = intent-to-treat; mITT = modified intent-to-treat.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. The statistical 
analysis plan (SAP) will be finalized and approved prior to unblinding of treatment at database 
lock.
Efficacy analyses will be conducted on the ITT population.  This set includes all randomized 
patients who use at least 1 dose of study drug for an ITT-evaluable attack, defined as a treated 
attack of at least mild pain severity with any postdose pain severity asssessments at or before 2 
hours postdose.  Patients will be evaluated by the attack and group to which they were 
randomized.  
Consistency analyses will be conducted on the ITT consistency population.  This set includes all 
randomized patients who experienced a sufficient number of successes or failures during ITT-
evaluable attacks for any of the consistency analyses. The “sufficient number” is defined 
differently for the 2 endpoints related to consistency (that is, 2 out of 3 attacks and 3 out of 4
attacks):  

Two of 3:  To evaluate the 2 out of 3 primary consistency endpoint, the results of ITT-
evaluable attacks in the lasmiditan 100-mg and 200-mg groups will be assessed, and the 
ITT-evaluable attacks treated with placebo in the control group will be used for 
comparison. For patients with more than 3 ITT-evaluable attacks, only the first 3 will be 
considered.
The population for the 2 out of 3 consistency endpoint with sufficient number of 
successes or failures is defined as all patients who experienced at least 2 successes or 2 
failures during their first 2 or 3 ITT-evaluable attacks.

H8H-MC-LAIJ(b) Clinical Protocol
Page 51
LY573144

Three of 4:  To evaluate the 3 out of 4 consistency endpoint, all ITT-evaluable attacks 
will be used. For the control group, the results of all ITT-evaluable attacks treated with 
lasmiditan 50 mg or placebo will be included.  The control group is used for comparison.
The population for the 3 out of 4 consistency endpoint with sufficient number of 
successes or failures is defined as all patients who experienced at least 3 successes or 2
failures during ITT-evaluable attacks.  
For analyses where mITT populations are specified, the definitions are the same as for ITT 
populations, except based on mITT-evaluable attacks.
Tests of the primary and gated secondary endpoints, as specified in the SAP, will be conducted at 
a 1-sided significance level of 0.025; tests of all other endpoints will be conducted at a 2-sided 
significance level of 0.05.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate as described in the Statistical Analysis Plan (SAP).
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
Patient disposition will be summarized by treatment group.  Reasons for discontinuation for all 
patients will be tabulated for treatment groups, and comparisons between treatment groups will 
be assessed by Fisher’s exact test.
10.3.2.2. Patient Characteristics
Patient characteristics will be summarized by treatment group and overall. Summaries will 
include descriptive statistics for continuous measures and for categorical measures (sample size, 
frequency, and percentages). Treatments will be compared by using analysis of variance 
techniques for continuous data and Pearson’s chi-square or Fisher’s exact test for categorical 
data. 
The results of these tests will be used in a descriptive way to highlight potential imbalances 
between the treatment groups. Patient characteristics may include, but are not limited to:  age, 
gender, race/ethnicity, height, weight, body mass index, and migraine history. 
Patient characteristics will be summarized on all study populations.
10.3.2.3. Concomitant Therapy 
Frequency and percentages will be calculated by treatment for concomitant medication. 
Treatments will be compared using Fisher’s exact test. 

H8H-MC-LAIJ(b) Clinical Protocol
Page 52
LY573144
10.3.2.4. Compliance 
Treatment compliance will be assessed in terms of the actual dose. Treatment compliance will 
be used to characterize the patients and determine clinical evaluability for some analyses. 
Treatment compliance will be summarized within each treatment group and each attack by 
means of descriptive statistics (n, mean, SD, median, minimum and maximum).
Ediary compliance will be summarized within each treatment group and each attack group.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The first primary objective of this study is to assess the efficacy of lasmiditan 200 mg and 
lasmiditan 100 mg on migraine headache pain freedom.  The primary measurement is the 
proportion of patients having pain freedom (defined as mild, moderate, or severe headache pain
becoming none) at 2 hours postdose during the first attack.  This analysis will be performed on 
the ITT population.
The second primary objective of this study is to assess the consistency of efficacy of lasmiditan 
200 mg and lasmiditan 100 mg on migraine headache pain freedom.  The primary measurement 
is the proportion of patients having pain freedom (defined as mild, moderate, or severe headache 
pain becoming none) at 2 hours postdose in at least 2 out of 3 attacks. This analysis will be 
performed using the ITT consistency population.
The primary objective for the study is met if the result from at least 1 of the 4 hypothesis tests 
specified above (lasmiditan 200 mg or 100 mg compared with placebo on migraine headache 
pain freedom, lasmiditan 200 mg or 100 mg compared with placebo on consistency of efficacy) 
is statistically significant. 
Logistic regression with categorical terms for treatment and geographic region will be used to 
statistically evaluate the proportions of patients achieving migraine headache pain freedom in 
first attack for lasmiditan treatment groups versus placebo and also in the consistency analyses 
comparing lasmiditan treatment groups versus placebo.  In order to control for overall type I 
error, the primary analyses will be tested using a multiple comparisons procedure that preserves 
overall type I error at 1-sided alpha level of 0.025.  This multiple comparisons procedure will be 
defined in the SAP, which contains the graphic scheme and weights for alpha propagation. 
As a sensitivity analysis, the primary and gated secondary efficacy endpoints will be repeated on 
the mITT population. Additionally, the consistency endpoints will be repeated in the mITT 
consistency population.
10.3.3.2. Secondary Analyses
The secondary measures will be analyzed using the ITT and ITT consistency populations.
Logistic regression will be used to statistically evaluate the proportions of response among 
lasmiditan groups and placebo. The model contains categorical terms for treatment and
geographic region. The comparisons will be between lasmiditan groups versus placebo at first 
attack and 2 out of 3 consistency endpoints.  The comparisons will be between lasmiditan groups 

H8H-MC-LAIJ(b) Clinical Protocol
Page 53
LY573144
versus control group for the 3 out of 4 attacks consistency endpoints.  For continuous endpoints, 
analysis of variance (ANOVA) or analysis of covariance (ANCOVA) will be used to assess the 
effect of lasmiditan.  The raw total score or change from baseline of total score are dependent 
variables.  The model includes fixed categorical effect of treatment and geographic region and 
baseline as covariate.  The primary comparison will be between the lasmiditan groups versus 
placebo.
In order to control for overall type I error, the primary and a subset of secondary objectives will 
be gated as described in the SAP.  The gated secondary analyses will be tested using a multiple 
comparisons procedure that preserves overall type I error at 1-sided alpha level of 0.025.  If any 
of the null hypotheses are rejected for the primary endpoints, the gated secondary endpoints will 
be tested according to the multiple comparisons procedure defined in the SAP. 
10.3.3.3. Tertiary/Exploratory Analyses 
Logistic regression will be used to statistically evaluate the proportions among lasmiditan groups 
and placebo group for exploratory endpoints.  The primary comparison will be between 
lasmiditan groups versus placebo at first attack and 2 out of 3 attacks.
Analysis of variance or ANCOVA will be used to assess the effect of lasmiditan over placebo or 
control for continuous endpoints. The model includes fixed categorical effect of treatment and 
geographic region and baseline as covariate.
10.3.4. Safety Analyses
10.3.4.1. Treatment-Emergent Adverse Events
Treatment-emergent adverse events are defined as the reported AEs that first occurred or 
worsened during the postbaseline phase compared with the baseline phase. For each TEAE, the 
reported severity level of the event (mild, moderate, or severe) will be determined by patient or
physician opinion. The Medical Dictionary for Regulatory Activities (MedDRA) Lowest Level
Term (LLT) will be used in the treatment-emergent computation. For each patient and TEAE, 
the maximum severity for the MedDRA level being displayed (preferred term, High Level Term, 
or system organ class [SOC]) is the maximum postbaseline severity observed from all associated 
LLTs mapping to that MedDRA level. An AE with time of onset within 48 hours after a dose of 
study drug, or an event that worsens in intensity within 48 hours after a dose of study drug will 
be considered a TEAE.  An AE that occurs in the interval after 48 hours of dosing until 
EoS/Visit 6 will not be considered a TEAE.  For events that are sex-specific, the denominator 
and computation of the percentage will include only patients from the specific sex.
Frequency counts and percentages will be presented for subjects with TEAEs within each SOC
and preferred term, separated by treatment arm.  Both subjects ever experiencing an event as 
well as total events will be presented.  Descriptive statistics will also be calculated for each 
treatment arm for AE relationship and AE severity.  If multiple intensities are reported for a 
given TEAE for a subject, the most severe intensity will be counted.  Analyses will be performed 
by treatment groups across all attacks and for each attack.  For the control arm, placebo and 
lasmiditan 50 mg will be evaluated separately. Other details can be found in the SAP.

H8H-MC-LAIJ(b) Clinical Protocol
Page 54
LY573144
10.3.4.2. Columbia-Suicide Severity Rating Scale 
Suicide-related thoughts and behaviors and self-injurious behavior with no suicidal intent, based 
on the C-SSRS, will be listed by patient.
10.3.4.3. Vital Signs
The number and percentage of patients meeting criteria for treatment-emergent abnormalities in
vital signs and weight at any time during study will be summarized by treatment group. 
10.3.4.4. Labs
By-patient listings of clinical laboratory data will include indications of values that are outside 
the reference ranges, and values that are clinically significant.  Shift tables describing 
out-of-reference range shifts will be provided for clinical laboratory test results from 
Screening/Visit 1 to EoS/Visit 6, as appropriate by treatment arm and dose.
10.3.4.5. Assessment of Driving Accidents
Assessment of accidents/violations will be listed by patient and treatment group.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
10.3.6. Evaluation of Immunogenicity 
Not applicable.
10.3.7. Other Analyses
10.3.7.1. Health Economics 
Mean HRQoL score in each group for 24-hour MQoLQ and change from baseline for MIDAS 
(item scores and total score), EQ-5D-5L, and the disability item will be analyzed. In addition, 
categorical analyses will be performed for disability and PGIC. Changes in health care resource 
utilization and employment status will also be evaluated.  Details are summarized in the SAP.
10.3.7.2. Subgroup Analyses 
Subgroup analyses for the primary efficacy and consistency endpoints and pain relief at 2 hours 
will include the following subgroup variables:

age

sex

weight

racial origin

previous response to triptan 

geographical region

cardiovascular risk factors

migraine headaches treated more than 4 hours after onset 
Additional details are available in the SAP.

H8H-MC-LAIJ(b) Clinical Protocol
Page 55
LY573144
10.3.8. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.

H8H-MC-LAIJ(b) Clinical Protocol
Page 56
LY573144
11.
References
Adelborg K, Szépligeti SK, Holland-Bill L, Ehrenstein V, Horváth-Puhó E, Henderson VW, 
Sørensen HT. Migraine and risk of cardiovascular diseases: danish population based matched 
cohort study. BMJ. 2018;360(10):k96. 
Bigal ME, Kurth T, Santanello N, Buse D, Golden W, Robbins M, Lipton RB. Migraine and 
cardiovascular disease: a population-based study. Neurology. 2010;74(8):628-635.
Blumenfeld AM, Varon SF, Wilcox TK, Buse DC, Kawata AK, Manack A, Goadsby PJ, Lipton 
RB. Disability, HRQoL and resource use among chronic and episodic migraineurs: results 
from the International Burden of Migraine Study (IBMS). Cephalalgia. 2011;31(3):301-315.
Buse D, Manack A, Serrano D, Reed M, Varon S, Turkel C, Lipton R. Headache impact of 
chronic and episodic migraine: results from the American Migraine Prevalence and Prevention 
study. Headache. 2012;52(1):3-17. 
Dodick D, Lipton RB, Martin V, Papademetriou V, Rosamond W, MaassenVanDenBrink A, 
Loutfi H, Welch KM, Goadsby PJ, Hahn S, Hutchinson S, Matchar D, Silberstein S, Smith 
TR, Purdy RA, Saiers J. Triptan Cardiovascular Safety Expert Panel. Consensus statement: 
cardiovascular safety profile of triptans (5-HT1B/1D agonists) in the acute treatment of 
migraine. Headache. 2004;44(5):414-425.
Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation 
of medicinal products for the treatment of migraine (Document) Document London, 24 
January 2007 European Medicines Agency (EMA)
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC50
0003481.pdf.
[EuroQol] The EuroQol Group. EuroQol--a new facility for the measurement of health-related
quality of life. Health Policy. 1990;16(3):199-208.
Goadsby PJ. The vascular theory of migraine—a great story wrecked by the facts. Brain.
2009;132(Pt 1):6-7.
Hartmaier SL, Santanello NC, Epstein RS, Silberstein SD. Development of a brief 24-hour 
migraine-specific quality of life questionnaire. Headache. 1995;35(6):320-9. 
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, Bonsel G, Badia X.
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).
Qual Life Res. 2011;20(10):1727-1736.
Ho AP, Dahlof CG, Silberstein SD, Saper JR, Ashina M, Kost JT, Froman S, Leibensperger H, 
Lines CR, Ho TW. Randomized, controlled trial of telcagepant over 4 migraine attacks. 
Cephalalgia. 2010;30(12):1443-1457.
Humphrey PPA, Feniuk W, Perren MJ, Beresford IJM, Skingle M, Whalley ET. Serotonin and 
migraine. Ann NY Acad Sci. 1990; 600(1):587-598. 
[IHS] International Headache Society, Headache Classification Subcommittee. The International 
Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211.

H8H-MC-LAIJ(b) Clinical Protocol
Page 57
LY573144
[IHS] International Headache Society, Clinical Trials Subcommittee, Tfelt-Hansen P, Pascual J, 
Ramadan N, Dahlöf C, D'Amico D, Diener HC, Hansen JM, Lanteri-Minet M, Loder E, 
McCrory D, Plancade S, Schwedt T. Guidelines for controlled trials of drugs in migraine: 
Third edition. A guide for investigators. Cephalalgia. 2012; 32(1): 6–38.
Labastida-Ramirez A, Rubio-Beltran E, Garrelds IM, Haanes KA, Chan KY, Kovalchin 
J, Johnson KW, Danser AHJ, Villalon CM, MaassenVanDenBrink A. Lasmiditan inhibits 
CGRP Release in the mouse trigeminovascular system, abstract PO-02-172. Cephalalgia. 
2017;37(1 Suppl):362-363.
[Lilly] Eli Lilly and Company. April 2018. Investigator’s Brochure for LY573144.
Lipton RB, Buse DC, Serrano D, Holland S, Reed ML. Examination of unmet treatment needs 
among persons with episodic migraine: results of the american migraine prevalence and 
prevention (AMPP) study. Headache. 2013;53(8):1300-1311. 
Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of 
episodic migraine is associated with new-onset chronic migraine. Neurology.
2015;84(7):688-695.
Lipton RB, Kolodner K, Bigal ME, Valade D, Láinez MJ, Pascual J, Gendolla A, Bussone G, 
Islam N, Albert K, Parsons B. Validity and reliability of the Migraine-Treatment Optimization 
Questionnaire. Cephalalgia. 2009;29(7):751-759.
Lipton RB, Bigal ME, Stewart, WF. Clinical trials of acute treatments for migraine including 
multiple attack studies of pain, disability, and health-related quality of life. Neurology.
2005;65(12 suppl 4):S50-S58.
Mitsikostas DD, Tfelt-Hansen P. Targeting to 5-HT1F receptor subtype for migraine treatment: 
lessons from the past, implications for the future. Cent Nerv Syst Agents Med Chem. 
2012;12(14):241-249.
Posner K, Brown G, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277.
Ramadan NM, Skljarevski V, Phebus LA, Johnson KW. 5-HT1F receptor agonists in acute 
migraine treatment: a hypothesis. Cephalalgia. 2003;23(8):776-785.
Santanello NC, Polis AB, Hartmaier SL, Kramer MS, Block GA, Silberstein SD. Improvement 
in migraine-specific quality of life in a clinical trial of rizatriptan. Cephalalgia.
1997;17(8):867-72; discussion 800.
Santanello NC, Hartmaier SL, Epstein RS, Silberstein SD. Validation of a new quality of life 
questionnaire for acute migraine headache. Headache. 1995;35(6):330-337.
Serrano D, Buse DC, Manack Adams A, Reed ML, Lipton RB. Acute treatment optimization in 
episodic and chronic migraine: results of the American Migraine Prevalence and Prevention 
(AMPP) Study. Headache. 2015;55(4):502-518..
Steiner TJ, Stovner LJ, Birbeck GL. Migraine: the seventh disabler. Cephalalgia.
2013;33(5):289-290.

H8H-MC-LAIJ(b) Clinical Protocol
Page 58
LY573144
Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine 
Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. 
Neurology. 2001;56(Suppl 1):S20–S28.
Stewart WF, Lipton RB, Kolodner K, Liberman J, Sawyer J. Reliability of the migraine 
disability assessment score in a population-based sample of headache sufferers. Cephalalgia.
1999;19(2):107-114.
Tfelt-Hansen PC, Diener, HC. Why should American headache and migraine patients still be
treated with butalbital-containing medicine? Headache. 2012;52(4):672-674.
Woldeamanuel YW, Cowan RP. Migraine affects 1 in 10 people worldwide featuring recent rise: 
A systematic review and meta-analysis of community-based studies involving 6 million 
participants. J Neurol Sci. 2017;372:307-315.

H8H-MC-LAIJ(b) Clinical Protocol
Page 59
LY573144
12.
Appendices

H8H-MC-LAIJ(b) Clinical Protocol
Page 60
LY573144
Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
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.
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRF
case report form
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CV
cardiovascular
ECG
electrocardiogram
EDC
early discontinuation

H8H-MC-LAIJ(b) Clinical Protocol
Page 61
LY573144
eDiary
electronic diary
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.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EoS
end of study
EQ-5D-5L
EuroQol 5-dimension 5-level scale
ERB
ethical review board
FSH
follicle-stimulating hormone
GCP
good clinical practice
HCRU
Health Care Resource Utilization
HRQoL
Health-Related Quality of Life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
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.
INR
international normalised ratio
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
institutional review board
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IVRS/IWRS
interactive voice-response system/interactive web-response system

H8H-MC-LAIJ(b) Clinical Protocol
Page 62
LY573144
LLT
lower level term
LTN
lasmiditan
MBS
most bothersome symptom
MedDRA
Medical Dictionary for Regulatory Activities
MIDAS
Migraine Disability Assessment Test
mITT
modified intention to treat 
MQoLQ
24-Hour Migraine Quality of Life Questionnaire
mTOQ-6
Migraine Treatment Optimization Questionnaire
PGIC
Patient Global Impression of Change
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
QoL
quality of life
SAE
serious adverse event
SAP
Statistical Analysis Plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin level
TEAE
Treatment-emergent adverse event:  An AE with time and date of onset on or within 48 
hours after a dose of study drug, or an event that worsened in intensity within 48 hours 
of a dose of study drug.
ULN
upper limit of normal
WOCBP
women of child-bearing potential

H8H-MC-LAIJ(b) Clinical Protocol
Page 63
LY573144
Appendix 2.
Clinical Laboratory Tests 
Clinical Laboratory Tests
Hematologya,b
Clinical Chemistrya,b
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
Glucose, nonfasting
Urinalysisa,b
Albumin
Specific gravity
Cholesterol
pH
Creatine kinase (CK)
Protein
Glucose
Pregnancy Test (females only) c
Ketones
Serum pregnancy
Blood
Urine pregnancy test (local)
Urine leukocyte esterase
Serum follicle-stimulating hormone (FSH) c
Urine drug screen
Stored Samples 
Pharmacogenetic sample (genetic sample/DNA)
Abbreviations:  DNA = deoxyribonucleic acid; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Results will be confirmed by the Central Lab at the time of initial testing.
c
Pregnancy tests to be assessed in women of child-bearing potential; FSH to be assessed as appropriate according 
to details in Inclusion Criterion #7.

H8H-MC-LAIJ(b) Clinical Protocol
Page 64
LY573144
Appendix 3.
Study Governance Considerations
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 participant or the 
participant’s legal representative and is kept on file

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant 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:

H8H-MC-LAIJ(b) Clinical Protocol
Page 65
LY573144

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)
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 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.
An investigator selected by the study team will serve as 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

H8H-MC-LAIJ(b) Clinical Protocol
Page 66
LY573144

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

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 electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
In this study, patient data will be collected directly via an electronic patient-reported outcome 
(ePRO) eDiary as part of an ePRO/Clinical Outcome Assessment (COA) system. This will 
include questions on headache pain, migraine associated symptoms, dosing, and use of rescue or 
recurrence medication.  Patient-rated scales/questionnaires will also be collected directly via the 
ePRO eDiary (see Appendix 7).  Data entered into the ePRO/COA system will serve as the 
source data.
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, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the Lilly data 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 

H8H-MC-LAIJ(b) Clinical Protocol
Page 67
LY573144
documentation provided by the patient will include, for example, The Migraine Disability 
Assessment Test, Treatment Satisfaction and Employment Status questionnaires, C-SSRS, and 
Driving assessment.
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 participation 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 H8H-MC-LAIJ is described in the Clinical Trial Agreement.

H8H-MC-LAIJ(b) Clinical Protocol
Page 68
LY573144
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 antibody
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.

H8H-MC-LAIJ(b) Clinical Protocol
Page 69
LY573144
Appendix 5.
Diagnostic Criteria for Selected Migraine 
Types 
International Classification of Headache Disorders-3 Diagnosis and Diagnostic Criteria per 
International Headache Society 2018
1.1 Migraine without aura
Previously used terms:  Common migraine; hemicranias simplex
Description: Recurrent headache disorder manifesting in attacks lasting 4–72 hours Typical 
characteristics of the headache are unilateral location, pulsating quality, moderate or severe 
intensity, aggravation by routine physical activity and association with nausea and/or 
photophobia and phonophobia.
Diagnostic criteria:
A. At least five attacks fulfilling criteria B–D
B. Headache attacks lasting 4–72 hours (when untreated or unsuccessfully treated)
C. Headache has at least two of the following four characteristics:
1. unilateral location
2. pulsating quality
3. moderate or severe pain intensity
4. aggravation by or causing avoidance of routine physical activity (e.g. walking 
or climbing stairs)
D. During headache at least one of the following:
1. nausea and/or vomiting
2. photophobia and phonophobia
E. Not better accounted for by another ICHD-3 diagnosis
1.2 Migraine with aura
Previously used terms: Classic or classical migraine; ophthalmic, hemiparaesthetic, hemiplegic 
or aphasic migraine; migraine accompagnée; complicated migraine
Description: Recurrent attacks, lasting minutes, of unilateralfully reversible visual, sensory or 
other central nervous system symptoms that usually develop gradually and are usually followed 
by headache and associated migraine symptoms.
Diagnostic criteria:
A. At least two attacks fulfilling criteria B and C

H8H-MC-LAIJ(b) Clinical Protocol
Page 70
LY573144
B. One or more of the following fully reversible aura symptoms:
1. visual
2. sensory
3. speech and/or language
4. motor
5. brainstem
6. retinal
C. At least three of the following six characteristics:
1. at least one aura symptom spreads gradually over ≥5 minutes
2. two or more aura symptoms occur in succession
3. each individual aura symptom lasts 5–60 minutes
4. at least one aura symptom is unilateral
5. at least one aura symptom is positive
6. the aura is accompanied, or followed within 60 minutes, by headache
D. Not better accounted for by another ICHD-3 diagnosis
1.2.1 Migraine with typical aura
Description:  Migraine with aura, in which aura consists of visual and/or sensory and/or 
speech/language symptoms, but no motor weakness, and is characterized by gradual 
development, duration of each symptom no longer than 1 hour, a mix of positive and negative 
features and complete reversibility
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2 Migraine with aura and criterion B below
B. Aura with both of the following: 
1. fully reversible visual, sensory and/or speech/language symptoms 
2. no motor, brainstem or retinal symptoms.
1.2.1.1  Typical aura with headache
Description:  Migraine with typical aura in which aura is accompanied or followed within 60 
minutes by headache with or without migraine characteristics.
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2.1 Migraine with typical aura and criterion B below

H8H-MC-LAIJ(b) Clinical Protocol
Page 71
LY573144
B. Headache, with or without migraine characteristics, accompanies or follows the aura 
within 60 minutes.
1.2.1.2  Typical aura without headache
Description:  Migraine with typical aura in which aura is neither accompanied nor followed by 
headache of any sort.
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2.1 Migraine with typical aura and criterion B below 
B. No headache accompanies or follows the aura within 60 minutes.
1.3 Chronic migraine
Description: Headache occurring on ≥15 or more days/month for more than three months, 
which, on at least eight days/month, has the features of migraine headache.
Diagnostic criteria:
A. Headache (migraine-like or tension-type-like) on 15 days/month for >3 months, and 
fulfilling criteria B and C
B. Occurring in a patient who has had at least five attacks fulfilling criteria B–D for 1.1 
Migraine without aura and/or criteria B and C for 1.2 Migraine with aura
C. On ≥8 days/month for >3 months, fulfilling any of the following:
1. criteria C and D for 1.1 Migraine without aura
2. criteria B and C for 1.2 Migraine with aura
3. believed by the patient to be migraine at onset and relieved by a triptan or ergot 
derivative
D. Not better accounted for by another ICHD-3 diagnosis
The reason for singling out 1.3 Chronic migraine from types of episodic migraine is that it is 
impossible to distinguish the individual episodes of headache in patients with such frequent or 
continuous headaches. In fact, the characteristics of the headache may change not only from day 
to day but even within the same day. Such patients are extremely difficult to keep 
medication-free in order to observe the natural history of the headache. In this situation, attacks 
with and those without aura are both counted, as are both migraine-like and tension-type-like 
headaches (but not secondary headaches).

H8H-MC-LAIJ(b) Clinical Protocol
Page 72
LY573144
Appendix 6.
Medication Overuse Headache Diagnostic 
Criteria
International Classification of Headache Disorders-3 Diagnosis and Diagnostic Criteria per 
International Headache Society 2018:
[A] Headache occurring on ≥15 days/month in a patient with a pre-existing 
headache disorder
[B] Regular overuse for >3 months of one or more drugs that can be taken for 
acute and/or symptomatic treatment of headache (see notes 1 to 3 below)
[C] Not better accounted for by another ICHD-3 diagnosis.
Notes:
[1]
Patients should be coded for one or more subtypes of 8.2 Medication-overuse 
headache according to the specific medication(s) overused and the criteria for 
each below. For example, a patient who fulfils the criteria for 8.2.2 Triptan-
overuse headache and the criteria for one of the subforms of 8.2.3 Non-opioid 
analgesic-overuse headache should receive both these codes. The exception 
occurs when patients overuse combination-analgesic medications, who are 
coded 8.2.5 Combination-analgesic-overuse headache and not according to 
each constituent of the combination-analgesic medication.
[2]
Patients who use multiple drugs for acute or symptomatic treatment of 
headache may do so in a manner that constitutes overuse even though no 
individual drug or class of drug is overused; such patients should be coded 
8.2.6 Medication-overuse headache attributed to multiple drug classes not 
individually overused.
[3]
Patients who are clearly overusing multiple drugs for acute or symptomatic 
treatment of headache but cannot give an adequate account of their names 
and/or quantities are coded 8.2.7 Medication-overuse headache attributed to 
unspecified or unverified overuse of multiple drug classes until better 
information is available.  In almost all cases, this necessitates diary follow-up.

H8H-MC-LAIJ(b) Clinical Protocol
Page 73
LY573144
Appendix 7.
eDiary Assessments
eDiary Assessment for all attacks treated with study 
drug
0h
0.5h
1h
2h
4h
6h
24h
48h
Headache severity
(0 = no pain, 1 = mild pain, 2 = moderate pain, and 
3 = severe pain)
X
X
X
X
X
X
X
X
Presence or absence (yes or no) of accompanying 
symptoms: photophobia, phonophobia, nausea, and 
vomiting
X
X
X
X
X
X
X
X
Select from the accompanying symptoms present (nausea, 
phonophobia or photophobia only) which one is the most 
bothersome 
X
Time at which headache relief became meaningful  
X
Time at which they become headache pain-free
X
MQoLQ
X
EQ-5D-5L
X
X
Disability
X
X
X
X
X
X
X
PGIC
X
X
Abbreviations:  eDiary = electronic diary; EQ-5D-5L = EuroQol 5 Dimension 5 Level; h = hours; MQoLQ = 24-
Hour Migraine Quality of Life Questionnaire; PGIC = Patient Global Impression of Change.

H8H-MC-LAIJ(b) Clinical Protocol
Page 74
LY573144
Appendix 8.
Protocol Amendment H8H-MC-LAIJ(b)
Summary
Overview
Protocol H8H-MC-LAIJ (Randomized Controlled Trial of Lasmiditan Over Four Migraine 
Attacks [CENTURION]) 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 summarized in 
the following bullets and in more detail in the subsequent table:

Updated protocol title to include the name “CENTURION.”

Modified description of endpoints associated with analyses of first attack for 
the subpopulation of triptan nonresponders in objectives section.

Clarified information about C-SSRS, specifically noting that a short form of 
the scale is being used and clarifying administration of the self-harm 
supplement and self-harm follow-up forms in the Schedule of Activities.

Clarified that driving assessments are conducted by site personnel.

Clarified that repeat laboratory testing outside a scheduled visit may be 
conducted in the event of abnormal laboratory findings.

Updated names and definitions of analysis populations for consistency with 
statistical analysis plan approved before first patient visit (ITT populations) or 
for consistency with studies this study may be compared with (mITT 
populations).  Updated related descriptions of analyses for clarity.

In addition, some minor points were clarified throughout, and grammatical 
errors and typographical errors were corrected. 

H8H-MC-LAIJ(b) Clinical Protocol
Page 75
LY573144
Amendment Summary for Protocol H8H-MC-LAIJ Amendment (b)
Section # and Name
Description of Change
Brief Rationale
Title Page, and
Section 1, Synopsis, Title of Study
CENTURION added to protocol title.
Added to provide easy study identification for 
publications.
Section 1, Synopsis, Objectives/Endpoints
(and Section 4, Objectives and Endpoints)
Modified description of endpoints associated with 
analyses of first attack for the subpopulation of 
triptan nonresponders. 
To align with gating strategy described in statistical 
analysis plan.
Section 1, Synopsis, Statistical Analysis subsection
Definition of ITT population was updated.  
Aligned with Version 1 of statistical analysis plan, 
which was approved before first-patient-visit.
Description of consistency analyses was updated.  
Clarified.
Section 2, Schedule of Activities
Rows/footnotes added regarding C-SSRS 
Updated to align with recommendations of Lilly 
Psychobehavioral Working Group; no changes to 
actual procedure.
Note about additional lab testing occurring outside 
scheduled visits added to footnote b.
Added to make existing procedure more apparent 
to sites.
Section 6.2, Exclusion Criteria
In exclusion [18], added cross-reference to
Appendix 6. 
Added so that cross-references to both applicable 
appendices were included.
Section 9.4.4, Other Tests
Added text to specify use of shortened version of 
the C-SSRS.
Updated to align with recommendations of Lilly 
Psychobehavioral Working Group; no changes to 
actual procedure.
Added text to indicate that driving assessments are 
conducted by site personnel.
Clarified existing procedures.
Section 10.2, Populations for Analysis 
Updated names and definitions of analysis 
populations; added mITT consistency population.  
Updated for consistency with statistical analysis 
plan approved before first patient visit (ITT 
populations); or with studies this study may be 
compared with (mITT populations).
Section 10.3.1, General Statistical Considerations
Updated descriptions of efficacy populations, 
particularly definition of sufficient attacks to be 
included in consistency analyses.
Updated for clarity and for consistency with 
changes in Section 10.2
Section 10.3.3.1, Primary Analyses
Simplified description of sensitivity analyses by 
deleting population definition. Added analysis of 
consistency endpoints in mITT consistency 
population.
Modified to meet submission needs.

H8H-MC-LAIJ(b) Clinical Protocol
Page 76
LY573144
Amendment Summary, continued
Section # and Name
Description of Change
Brief Rationale
Section 10.3.3.1, Primary Analyses
Section 10.3.3.2, Secondary Analyses
Section 10.3.3.3, Tertiary/Exploratory Analyses
Clarified that geographic region will be included in 
analysis models (not country).
Aligned with statistical analysis plan.
Appendix 1, Abbreviations
Updated TEAE definition to note that treatment-
emergent is limited to the 48 hours after dosing. 
Updated for consistency with statistical analyis 
plan.
Appendix 6, Medication Overuse Headache 
Diagnostic Criteria
Added source for criteria.
Clarification; no change to criteria.

H8H-MC-LAIJ(b) Clinical Protocol
Page 77
LY573144
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
For most sections, only the sentences or paragraphs with deletions or additions have been 
included; ellipses may be used to take the place of material that did not change.
Title page, title
Protocol H8H-MC-LAIJ(ab)
Randomized Controlled Trial of Lasmiditan Over Four
Migraine Attacks (CENTURION)
1. Synopsis, Title of Study
Protocol H8H-MC-LAIJ Randomized Controlled Trial of Lasmiditan Over Four Migraine 
Attacks (CENTURION)
1. Synopsis, Objectives/Endpoints
Only rows with additions or deletions are included below.
Objectives
Endpoints
Secondary
     Efficacy

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg in triptan nonresponders

The proportions of patients in the subpopulation of triptan 
nonresponders that achieve primary and secondary 
objectives in each group during the first attack

The proportions of patients in the subpopulation of triptan 
nonresponders versus other patients that achieve primary 
and secondary objectives in each group during the first 
attack
1. Synopsis, Statistical Analysis
Efficacy analyses will be conducted on the intent-to-treat (ITT) efficacy population. This set 
includes all randomized patients who used at least 1 dose of study drug for an ITT-evaluable 
attack, defined as a treated attack of at least mild pain severity with any postdose pain severity 
assessments at or before 2 hours postdose and had any postdose efficacy assessments.  The 
primary efficacy analysis will compare the proportion of patients with 2-hour pain freedom 
during the first attack in the lasmiditan 200-mg group with placebo and compare the proportions 
of patients with 2-hour pain freedom during the first attack in the lasmiditan 100-mg group with 
placebo.

H8H-MC-LAIJ(b) Clinical Protocol
Page 78
LY573144
The consistency analyses will be conducted on the ITT consistency population, a subset of the 
ITT population with sufficient evaluable attacks.  This set includes all randomized patients who 
experienced 2 successes or 2 failures on 2-hour pain freedom, regardless of whether or not they 
had data for all attacks.  To evaluate the 2 out of 3 primary consistency endpoint, the proportions 
of patients with 2-hour pain freedom during 2 out of the first 3 evaluable attacks in the 
lasmiditan 200-mg and 100-mg groups will be compared to the results of the evaluable attacks 
treated with placebo in the control groups. An attack will be defined as evaluable if there is non-
missing information on 2-hour pain freedom.
2. Schedule of Activities  
Only rows with additions or deletions are included below.

H8H-MC-LAIJ(b) Clinical Protocol
Page 79
LY573144
Table LAIJ.2.1.
Schedule of Activities
Visit 1a
Screening
Visit 2
Baseline 
(at site)
Treatment Attack 1-4b
All attacks:  Mod/sev within 4 hrs of onset
Attack 2:  ≥48 hrs after dosing Attack 1
Attack 3:  ≥48 hrs after dosing Attack 2
Attack 4:  ≥48 hrs after dosing Attack 3
Visit 6 EoS 
(at site)
or EDCc
Notes
V1+3-30 
days
(pending 
lab 
results)
Visit 3 
Phone Call 
1 after 
Attack 1 or
at 1 mod±1 
wk after V2
Visit 4 
Site Visit
at +2 mos±1 
wk after V2 
Visit 5 
Phone Call 2 
at 3 mos±1 
wk after V2
≥7 days after 
last treated 
attack (=last 
dose) OR at 4 
mos±2 wks after 
V2
C-SSRS - BL/screening 
version e
X
C-SSRS - since last visit 
version e
X
X
X
   Self-Harm Supplement Form
X
X
X
X
   Self-Harm Follow-up Form f
X
X
X
X
b
Attacks treated do not need to be consecutive.  Minimum amount of time between attacks is 48 hours (determined by timing of dosing, i.e., the next attack 
may not be treated with study drug within 48 hours of taking study drug).  During the treatment period, unscheduled visits may be completed at the discretion 
of the investigator.  In the event of abnormal laboratory findings, including but not limited to tests that may indicate abnormal liver function, repeat or 
additional laboratory testing may be required outside a scheduled clinic visit.
e
Adapted for the assessment of the ideation and behavior categories only (the Intensity of Ideation and Lethality of Behavior sections are removed).
f
Required if triggered by the Self-Harm Supplement Form per instructions.

H8H-MC-LAIJ(b) Clinical Protocol
Page 80
LY573144
4. Objectives and Endpoints
Only rows with additions or deletions are included below.
Objectives
Endpoints
Secondary
     Efficacy

To evaluate the efficacy of lasmiditan 200 mg 
and 100 mg in triptan nonresponders

The proportions of patients in the subpopulation of triptan 
nonresponders that achieve primary and secondary 
objectives in each group during the first attack

The proportions of patients in the subpopulation of triptan 
nonresponders versus other patients that achieve primary 
and secondary objectives in each group during the first 
attack
6.2. Exclusion Criteria  
[18] history, within past 12 months, of chronic migraine or other forms of primary or 
secondary chronic headache disorder (eg, hemicranias continua, medication overuse 
headache where headache frequency is ≥15 headache days per month [Appendix 5 and 
Appendix 6])
9.4.4 Other Tests
Columbia Suicide-Severity Rating Scale (C-SSRS):  A scale that captures the occurrence, 
severity, and frequency of suicide-related thoughts and behaviors during the assessment period
(Posner et al. 2011).  The scale includes suggested questions to solicit the type of information 
needed to determine if a suicide-related thought or behavior occurred.  The C-SSRS is 
administered by an appropriately trained healthcare professional with at least 1 year of patient 
care/clinical experience according to the Schedule of Activities (Section 2).  The tool was 
developed by the National Institute of Mental Health (NIMH) trial group (Treatment of 
Adolescent Suicide Attempters Study) for the purpose of being a counterpart to the Columbia 
Classification Algorithm of Suicide Assessment (C-CASA) categorization of suicidal events. 
Two versions of the C-SSRS will be used:

The screening version will be administered at Screening/Visit 1

The “since last visit” version will be administered at Visit 2 and Visit 4 (at 
2 months) and at V6 (EoS)
For this study, the C-SSRS is adapted for the assessment of the ideation and behavior categories 
only. The Intensity of Ideation and Lethality of Behavior sections are removed.
The nonleading AE collection should occur prior to the collection of the C-SSRS. If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. If an adverse event is serious or 
leads to discontinuation, this is an exception where the SAE and/or AE leading to 

H8H-MC-LAIJ(b) Clinical Protocol
Page 81
LY573144
discontinuation should be included on the AE form and the process for reporting SAEs should be 
followed.
Assessment of driving accidents/violations:  In order to further evaluate the impact of 
lasmiditan on driving, patients will be asked to respond to questions related to motor 
vehicle accidents and moving violations an assessment of driving accidents/violations 
will be conducted by site personnel according to the Schedule of Activities (Section 2).  

H8H-MC-LAIJ(b) Clinical Protocol
Page 82
LY573144
10.2. Populations for Analyses
Population
Description
Entered Enrolled 
All participants who sign informed consent
ITT efficacy
All randomized patients who use at least 1 dose of study drug for an ITT-
evaluable attack, defined as a treated attack of at least mild pain severity with
any postdose pain severity asssessments at or before 2 hours postdose and have 
any postdose efficacy assessments.  
mITT efficacy
All randomized patients who use at least 1 dose of study drug for an mITT-
evaluable attack, defined as a treated attack of at least moderate pain severity 
with any postdose pain severity assessments at or before 2 hours postdose to 
treat a migraine within 4 hours of migraine onset and have any postdose efficacy 
assessments.  
ITT consistency
All randomized patients who experience a sufficient number of successes or  
failures (defined in Section 10.3.1) during ITT-evaluable attacks for any of the 
consistency analyses participants from ITT efficacy population with sufficient 
information on consistency of 2-hour headache pain freedom as defined in 
Section 10.3.1.
mITT consistency
All randomized patients who experience a sufficient number of successes or  
failures (defined in Section 10.3.1) during mITT-evaluable attacks for any of the 
consistency analyses.
Safety
All randomized patients who take at least 1 dose of study drug, regardless of 
whether or not they undergo any study assessments.  
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. The statistical 
analysis plan (SAP) will be finalized and approved prior to unblinding of treatment at database 
lock.
Efficacy analyses will be conducted on the ITT efficacy population.  This set includes all 
randomized patients who used at least 1 dose of study drug for an ITT-evaluable attack, defined 
as a treated attack of at least mild pain severity with any postdose pain severity asssessments at 
or before 2 hours postdoseand had any postdose efficacy assessments.  Patients will be evaluated 
by the attack and group to which they were randomized.  
Consistency analyses will be conducted on the ITT consistency population.  This set includes all 
randomized patients who experienced a sufficient number of successes or failures during ITT-
evaluable attacks for any of the consistency analyses.  The “sufficient number” is defined 
differently for the There are 2 endpoints related to consistency (iethat is, 2 out of 3 attacks and 3 
out of 4 attacks).:  

Two of 3:  To evaluate the 2 out of 3 primary consistency endpoint, the results of the first 
3 ITT-evaluable attacks in the lasmiditan 100-mg and 200-mg groups will be assessed, 
and the ITT-evaluable attacks treated with placebo in the control group will be used for 
comparison. For patients with more than 3 ITT-evaluable attacks, only the first 3 will be 
considered. An attack is defined as evaluable if there is non-missing pain data at baseline 
and at 2 hours. 
The population for the 2 out of 3 consistency endpoint with sufficient number of 
successes or failures is defined as all patients who experienced at least either 2 successes 

H8H-MC-LAIJ(b) Clinical Protocol
Page 83
LY573144
or 2 failures during their first 2 or 3 ITT-evaluable attacks, regardless of whether or not 
they had data for all attacks.  Attacks treated with placebo are used for comparison.

Three of 4:  To evaluate the 3 out of 4 consistency endpoint, all ITT-evaluable attacks 
will be used. For the control group, the results of all ITT-evaluable attacks treated with 
lasmiditan 50 mg or placebo will be included.  The control group is used for comparison.
The population for the 3 out of 4 consistency endpoint with sufficient number of 
successes or failures is defined as all patients who experienced at least either 3 successes 
or 2 failures during ITT-evaluable attacks, regardless of whether or not they had data for 
all attacks.  For the control group, the results of all evaluable attacks treated with 
lasmiditan 50 mg or placebo will be included.  The control group is used for comparison. 
For analyses where mITT populations are specified, the definitions are the same as for ITT 
populations, except based on mITT-evaluable attacks.
…
10.3.3.1. Primary Analyses
The first primary objective of this study is to assess the efficacy of lasmiditan 200 mg and 
lasmiditan 100 mg on migraine headache pain freedom.  The primary measurement is the 
proportion of patients having pain freedom (defined as mild, moderate, or severe headache pain
becoming none) at 2 hours postdose during the first attack.  This analysis will be performed on 
the ITT efficacy population.
…
Logistic regression with categorical terms for treatment and either country or geographic region 
will be used to statistically evaluate the proportions of patients achieving migraine headache pain 
freedom in first attack for lasmiditan treatment groups versus placebo and also in the consistency 
analyses comparing lasmiditan treatment groups versus placebo.  In order to control for overall 
type I error, the primary analyses will be tested using a multiple comparisons procedure that 
preserves overall type I error at 1-sided alpha level of 0.025.  This multiple comparisons 
procedure will be defined in the SAP, which contains the graphic scheme and weights for alpha 
propagation. 
As a sensitivity analysis, the primary and gated secondary efficacy endpoints along with the 
MBS analysis will be repeated on the mITT population which includes those patients who treat a 
migraine with study drug within 4 hours of migraine onset and have any postbaseline efficacy 
data. Additionally, the consistency endpoints will be repeated in the mITT consistency 
population.
10.3.3.2. Secondary Analyses
The secondary measures will be analyzed using the ITT efficacy and ITT consistency 
populations.

H8H-MC-LAIJ(b) Clinical Protocol
Page 84
LY573144
Logistic regression will be used to statistically evaluate the proportions of response among 
lasmiditan groups and placebo.  The model contains categorical terms for treatment and, country 
or geographic region.  The comparisons will be between lasmiditan groups versus placebo at first 
attack and 2 out of 3 consistency endpoints.  The comparisons will be between lasmiditan groups 
versus control group for the 3 out of 4 attacks consistency endpoints.  For continuous endpoints, 
analysis of variance (ANOVA) or analysis of covariance (ANCOVA) will be used to assess the 
effect of lasmiditan.  The raw total score or change from baseline of total score are dependent 
variables. The model includes fixed categorical effect of treatment and geographic region 
country and baseline as covariate.  The primary comparison will be between the lasmiditan 
groups versus placebo.
…
10.3.3.3. Tertiary/Exploratory Analyses 
…
Analysis of variance or ANCOVA will be used to assess the effect of lasmiditan over placebo or 
control for continuous endpoints.  The model includes fixed categorical effect of treatment and 
geographic region country and baseline as covariate.
Appendix 1. Abbreviations and Definitions
TEAE
Treatment-emergent adverse event:  An AE with time and date of onset on or within 48 
hours after a dose of study drug, or an event that worsened in intensity within 48 hours 
of a dose of study drug.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.
Appendix 6. Medication Overuse Headache Diagnostic Criteria
International Classification of Headache Disorders-3 Diagnosis and Diagnostic Criteria per 
International Headache Society 2018Diagnostic criteria:

Leo Document ID = 505af348-4de2-4fed-aa47-a2f8d997e1b7
Approver: 
Approval Date & Time: 30-Mar-2020 15:47:16 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Mar-2020 20:09:21 GMT
Signature meaning: Approved
PPD
PPD