An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of MigRaine (GLADIATOR)
Phase: PHASE3
Conditions: Migraine Disorders
Sponsor: Eli Lilly and Company

H8H-CD-LAHL(D)/COL MIG-305 v4  
 
 
An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute 
Treatment Of MigRaine (GLADIATOR)  
 
 
NCT02565186 
 
 
Approval Date: 09-Nov-2018 
 
 

LY573144
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Protocol COL MIG-305 (H8H-CD-LAHL)
An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and
200 mg) in the Acute Treatment Of MigRaine (GLADIATOR) 
EudraCT No. 2015-005674-37
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 (COL MIG-305 v1) Signed and Approved by CoLucid: 17 June 2015
Amendment (COL MIG-305 v1.1) Signed and Approved by CoLucid:  08 December 2015
Amendment (COL MIG-305 v2) Signed and Approved by CoLucid:  12 May 2017
Amendment H8H-CD-LAHL(C)/COL MIG-305 v3 Electronically Signed and Approved by Lilly:  
15 September 2017
Amendment H8H-CD-LAHL(D)/COL MIG-305 v4 Electronically Signed and Approved by Lilly on 
date provided below.
Approval Date: 09-Nov-2018 GMT

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INVESTIGATOR STATEMENT
Protocol Number:  H8H-CD-LAHL(D)/COL MIG-305 v4
Protocol Title:  
An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the
Acute Treatment Of MigRaine (GLADIATOR)
I understand that all information concerning lasmiditan in connection with this study and not 
previously published is confidential. This confidential information includes the Investigator’s 
Brochure, Clinical Study Protocol, Case Report Form, clinical methodology, and basic scientific 
data.
I will not initiate this study without approval from the Institutional Review Board/Ethics 
Committee and I understand that any changes in the protocol must be approved in writing by Eli
Lilly and Company (Lilly), and the Institutional Review Board/Ethics Committee before they can 
be implemented, except when necessary to eliminate immediate hazards to the subjects.
  
I confirm that I have read this protocol amendment H8H-CD-LAHL(D)/COL MIG-305 v4, I 
understand it, and I will work according to this protocol amendment. I will also work consistently 
with the ethical principles that have their origin in the Declaration of Helsinki and that are 
consistent with Good Clinical Practice (GCP) and the applicable laws and regulations. I will 
accept the monitor's overseeing of the trial. I will abide by the publication plan set forth in my 
agreement with Eli Lilly and Company (or subsidiary). I confirm that if I or any of my staff are 
members of the ethics review board, we will abstain from deliberation and voting on this protocol 
amendment.
Site Address 
Investigator’s Signature 
Date
Site Name
Investigator’s Printed Name

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1.
SYNOPSIS
Name of Sponsor Company: 
Eli Lilly and Company
Drug Under Study: 
Lasmiditan (COL-144; 
LY573144)
Title of Protocol: An Open-label, Long-term, Safety Study of Lasmiditan (200 mg and 100 mg) in the
Acute Treatment of Migraine
Protocol Number:
H8H-CD-LAHL/COL MIG-305
Phase: 3
Indication: Migraine -
Acute Treatment 
Primary Objective: To evaluate the safety and tolerability of long-term intermittent use of lasmiditan
100 mg and of lasmiditan 200 mg, as the first dose and as a second dose, for the acute treatment of
migraine.
Secondary Objectives: To explore the long-term efficacy of lasmiditan 100 mg and lasmiditan 200 mg
in terms of headache response over time.
Additional Objectives: To compare patient reported resource utilization during the study to patient 
reported information from COL MIG-301 or COL MIG-302 in terms of cardiovascular events and in terms 
of migraine episodes.
Study Endpoints
Primary Endpoint: The proportion of patients and the proportion of attacks associated with any adverse
event and with specific adverse events.
Secondary Endpoint:  The proportion of migraine attacks treated with lasmiditan 100 mg and with
lasmiditan 200 mg which respond at 2 hours, calculated for each 3 month period.
Study Design: 
This is a prospective, randomized, open-label study in subjects with migraine who have completed the 
Phase 3 studies, COL MIG-301 or COL MIG-302. Subjects will be stratified (yes or no) for use of 
concomitant medications that reduce the frequency of migraine episodes.
Subjects will be asked to treat all migraine attacks with study drug on an outpatient basis for up to 
12 months. Each patient’s study participation will consist of a screening visit (Visit 1) and a treatment 
period of up to 12 months during which the subject will treat all migraine attacks with either lasmiditan 
200 mg or lasmiditan 100 mg (with a second dose of study drug permitted between 2 and 24 hours (h)
for recurrence of migraine only for subjects randomized to lasmiditan 100 mg). During the treatment
period subjects will return to the clinic at 1, 3, 6, 9 and 12 months. There will be an early termination (ET) 
visit within two weeks (14 days) of treatment discontinuation for all subjects that discontinue between 
scheduled visits. The End-of-Study (EoS) visit will be at 12 months or at any scheduled visit when the 
subject’s participation in the study is ended. Participation in the study for 12 months will be defined as 
completing Month 12/Visit 6.
At Screening/Visit 1 subjects will provide written informed consent and authorize Health Insurance 
Portability and Accountability Act (HIPAA). Study eligibility will be assessed on the basis of completing 
study COL MIG-301 or COL MIG-302.  The EoS/Visit 2 of COL MIG-301 or COL MIG-302 can be the 
same day as Screening/Visit 1.  Assessments required for this visit can be the same assessments 
obtained at the EoS/Visit 2 of COL MIG-301 or COL MIG-302 as long as that visit occurred on the 
same day or no more than two weeks prior to signing informed consent and HIPAA for participation in 
COL MIG-305 as outlined in the Schedule of Assessments (Table 1). Regardless of the timing of 

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signing of informed consent for COL MIG-305, medical history, migraine history and concomitant 
medication use will be reviewed and any changes or updates since enrolling in COL MIG-301 or COL 
MIG-302 will be noted. All subjects will complete the MIDAS questionnaire.  If Screening/Visit 1 is not 
the same day as EoS/V2 of COL MIG-301 or COL MIG-302 but within 2 weeks, a complete physical 
examination, vital signs and urine pregnancy test will also be done. Subjects that are consented more 
than two weeks after EoS/Visit 2 of COL MIG-301 or COL MIG-302 will undergo the following 
assessments: a complete physical examination, vital signs, clinical laboratory tests (including urine 
pregnancy test on women of child-bearing potential (WOCBP)) and 12-lead ECG. A Columbia Suicide 
Severity Rating Scale (C-SSRS) will be completed.  All subjects will be randomized and dispensed 
study drug and instructed to use lasmiditan as the first treatment for each migraine attack. Subjects will 
be randomly assigned in a 1:1 ratio, to receive lasmiditan 100 mg (L100 mg) or lasmiditan 200 mg 
(L200 mg). Subjects randomized to lasmiditan 100 mg will be allowed to take a second dose of study 
drug if needed for recurrence of migraine.
Treatment Period: Subjects will be asked to use lasmiditan as the first treatment for each new 
migraine attack within 4 hours of onset providing that the headache severity is at least moderate at that 
time and not improving. Subjects should not exceed a total dose of 200 mg of lasmiditan in a 24-hour 
period. Subjects will record their response to the first dose over the next 48 hours using an electronic 
diary. If the migraine responds within 2 hours (headache becomes pain free) but then recurs after 
2 hours, a second dose of study drug may be taken up to 24 hours after the first dose only for subjects 
randomized to lasmiditan 100 mg. Subjects will record their response to a second dose, taken for 
recurrence, for 48 hours in the electronic diary. The total time for recording response to study drug is 
up to 72 hours depending on whether or not a second dose of study drug is used (for subjects 
randomized to lasmiditan 100 mg). Subjects using an alternate medication other than a second dose of 
study drug for the treatment of migraine rescue or recurrence will report the use of medication and 
continue to record their responses in the electronic diary up to the 48 hour timepoint.
Subjects will be asked to return to the clinic at months 1, 3, 6, 9 and 12 (Visits 2, 3, 4, 5 and 6). At each 
visit a brief physical examination based on adverse events (AEs), vital signs and a urine pregnancy test 
on all WOCBP will be obtained.
Blood and urine samples for clinical laboratory parameters 
(hematology, serum chemistry and urinalysis) will be obtained at Month 1/Visit 2, Month 6/Visit 4 and 
Month 12/Visit 6 (EoS/ET). A 12-lead ECG will be obtained at Month 6/Visit 4 and Month 12/Visit 6
(EoS/ET). C-SSRS will be completed at each visit. The MIDAS questionnaire will be completed at 
Month 3/Visit 3, Month 6/Visit 4, Month 9/Visit 5 and Month 12/Visit 6 (EoS/ET).  At each visit, 
resource utilization, AEs, use of concomitant medication, use of study drug and patient diary compliance 
will be assessed; subjects who are continuing will be dispensed study drug.  Subjects who decide to 
withdraw at a scheduled visit should confirm the date of the visit is 7 days (± 2 days) from their last 
migraine treated with study drug.  Subjects who decide to discontinue between scheduled visits are 
asked to contact the clinic to schedule an ET /Visit 6 within two weeks (14 days) after discontinuation of 
dosing.  The total time on study is up to 54 weeks (a maximum of 378 days).
Subject Population: Adult patients with a history of migraine who have completed COL MIG-301 or 
COL MIG-302.  
Number of Subjects:  Approximately 2580 subjects 
(combined from COL MIG-301 and COL MIG-302)
will be enrolled, with the goal of having at least 300 
patients dose an average of 2 migraines per month 
for 6 months and 100 patients dose an average of 2 
migraines per month for 12 months.  
Number of Centers: Up to 240 centers in US 
and ex-US  (all COL MIG-301 and COL 
MIG-302 centers will be included)
Test Product and Doses:
lasmiditan 100 mg and lasmiditan 200 mg 
Route of Administration:  Oral 

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Criteria for Inclusion/Exclusion:
     Inclusion: Subjects may be included in the study only if all the following criteria are met:
1. Able and willing to give written informed consent and authorize HIPAA.
2. Completed COL MIG-301 or COL MIG-302 within the last 12 weeks. Subjects that completed COL 
MIG-301 prior to COL MIG-305 being available will be allowed to enroll as long as enrollment occurs 
within 4 weeks of COL MIG-305 activation at their site. Subjects discontinued due to administrative 
hold will be allowed to re-enroll in the study.
3. Females of child-bearing potential must be using or willing to use a highly effective form of 
contraception (e.g. combined oral contraceptive, intrauterine device (IUD), abstinence or 
vasectomized partner).
4. Able and willing to complete an electronic diary to record details of all migraine attacks treated with 
study drug.
     Exclusion: Subjects are excluded from the study if any of the following criteria are met:
1.
Any medical condition or clinical laboratory test which in the judgment of the Investigator makes 
the subject unsuitable for the study.
2.
Pregnant or breast-feeding women.
3.
Women of child-bearing potential not using or not willing to use highly effective contraception.
4.
Subject is at imminent risk of suicide (positive response to question 4 or 5 on the C-SSRS).
6.
Initiation of or a change in concomitant medication to reduce the frequency of migraine episodes since 
completing COL MIG-301 or COL MIG-302.
6.
Participation in any clinical trial of an experimental drug or device since completing EoS/Visit 2 of 
COL MIG-301 or COL MIG-302.
7.
Subject did not dose a migraine during the allotted time while enrolled in COL MIG-301 or COL 
MIG-302 or was evaluated to be noncompliant with the e-diary requirements (particularly 
recording their migraine and post-dose assessments).
Criteria for Evaluation:
Safety:

Adverse events (spontaneously reported)

Physical examination

Vital signs

12-lead electrocardiograms

Clinical laboratory parameters
Efficacy/Pharmacodynamics (for each attack unless otherwise specified:

Headache pain (4 point scale: none (0), mild (1), moderate (2), severe (3))

Most bothersome symptom (MBS) (selected from a list of the associated symptoms of migraine
(nausea, phonophobia or photophobia) present at predose)

Nausea, phonophobia or photophobia (yes or no)

Headache response within 24 hours - time to headache relief and time to pain free

24 and 48 hour sustained pain free response

Presence of vomiting (yes or no)

Disability (5 point scale: none (0), mild (1), moderate (2), severe (3) or very severe (4)

Requirement for rescue medication between 2, 24, and 48 hours (yes or no)

Requirement for recurrence medication between 2, 24, and 48 hours (yes or no)

Patient global impression of change (7 point scale)

Headache pain after a second dose of lasmiditan for rescue or recurrence of migraine

Time to headache relief and time to pain free after a second dose of lasmiditan for rescue or
recurrence of migraine

MBS free after a second dose of lasmiditan for rescue or recurrence of migraine

Total number of migraine attacks and attacks treated with study medication over each 3 month

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period
Resource utilization:

Any CV events and/or related resource utilization such as visits to cardiologists, procedures, 
hospitalizations, new treatments or treatment adjustments for CV disease as collected in study 
COL MIG-301 or COL MIG-302 compared to on study Visit 1 through Visit 6/EoS/ET.

Any visits to an emergency room or physician’s office for treatment of migraine as collected in 
study COL MIG-301 or COL MIG-302 compared to on study Visit 1 through Visit 6/EoS/ET
excluding study specific visits.

Concomitant medications for the treatment of migraine and/or pain as collected in study COL 
MIG-301 or COL MIG-302 compared to concomitant medications for migraine and/or pain Visit 1
through Visit 6/EoS/ET.

Missed days of work and/or school or daily activities based on responses to MIDAS 
questionnaire.
Statistical Analysis:
Safety:
Adverse events will be summarized in terms of the proportion of patients and the proportion of attacks 
associated with any adverse event and with specific adverse events. Physical examinations, vital signs, 
clinical laboratory parameters (hematology, serum chemistry and urinalysis) and ECG parameters will be 
summarized in terms of change from baseline status at 1, 3, 6, 9 and 12 months or early termination.
Efficacy:
This is an open-label study with no control group. Efficacy data will be summarized using descriptive 
statistics. The proportion of attacks treated with study medication which respond at 2 hours will be 
calculated for each 3 month period.
Resource Utilization:
Resource utilization such as visits to cardiologists, procedures, hospitalizations, new treatments or 
treatment adjustments for CV disease as well as visits to the emergency room or a physician’s office for 
the treatment of migraine will be summarized by treatment arm in terms of patient reported information 
recorded in study COL MIG-301 or COL MIG-302 compared to information reported at Visits 2, 3, 4, 5, 
and EoS/ET/6. Concomitant medication use for migraine and/or pain and missed days of work and/or 
school or daily activities based on responses to MIDAS questionnaire will be summarized by treatment 
arm.
Sample Size Rationale  
The sample size was chosen to provide an appropriate long-term safety database. It is not based on 
statistical hypothesis.

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Schedule of Assessments
Assessment
Visit 1 
Screening
and Baseline
Visit 2, 3, 4
and 5
(Months 1, 3, 6 
and 9)
Visit 6/EoS/ ET1
Obtain informed consent/HIPAA
X
Review inclusion / exclusion criteria
X
Review migraine history, medical
history and concomitant medications
X
MIDAS questionnaire
X
X
X
Review resource utilization
(visits to specialists, ERs, etc.)
X
X
X
Complete physical examination
X
Vital signs (heart rate, blood pressure)
X2
X
X
Brief physical examination based on AE(s)
X2
X
X
Weight
X
X
12-lead ECG
X3
VISIT 4  ONLY
X
Clinical laboratory4
X3
VISIT 2 and 4
X
Urine pregnancy for women of child-bearing 
potential
X5,6
X6
X6
Columbia Suicide Severity Rating Scale
X3
X
X
Randomization
X
Dispense study drug, study diary, and
provide detailed instructions
X
X
Collect empty dosing card(s) 
and unused study drug. Review
dosing compliance and diary
X
X
Migraine attack (electronic
diary) documentation by
subject
X
Documentation of 
rescue/recurrence medication
X
X
Documentation of adverse
events and concomitant
medication
X
X
1. ET is for subjects that discontinue the study between scheduled visits. The patient should return to the clinic within 14 days of the 
decision to withdraw from the study.  EoS is the designation for any scheduled visit that the subject discontinues at or Visit 6 (month 
12).
2. Brief physical examination based on AE (s) and vital signs will be the values obtained from EoS/Visit 2 of COL MIG-301 or COL 
MIG-302   only if subject signs consent and enrolls in COL MIG-305 on the same day.
3. Laboratory tests, ECG and C-SSRS will be the values obtained from EoS/Visit 2 of COL MIG-301 or COL MIG-302, as long as 
the subject signs consent and enrolls in COL MIG-305 on the same day or within two weeks (14 days) of EoS/Visit 2. 
4. Clinical laboratory tests include hematology, biochemistry, lipid profile and urinalysis.  In the event of clinically significant 
laboratory findings, including but not limited to hepatic laboratory abnormalities, repeat or additional laboratory testing may be 
required outside of a scheduled clinic visit.
5. A urine pregnancy test for women of childbearing potential is required unless Visit 1 is same day as EoS/Visit 2 of COL MIG-301 
or COL MIG-302.     

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6. If urine pregnancy test is positive a confirmatory serum βHCG test must be performed. The confirmatory test may be run in the
local clinical laboratory.  The subject should be told not to dose with study drug until the confirmatory test results are obtained.  If 
serum test is positive the subject is to be discontinued from the study.

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2.
TABLE OF CONTENTS
1.
SYNOPSIS...............................................................................................................3
2.
TABLE OF CONTENTS............................................................................................9
3.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS....................................13
4.
INTRODUCTION....................................................................................................15
4.1
Background ............................................................................................................16
4.2
Clinical Studies to Date...........................................................................................16
4.3
Minimization of Risk................................................................................................18
4.4
Potential Benefit .....................................................................................................18
4.5
Dose Rationale.......................................................................................................19
4.6
Conduct of the Study..............................................................................................19
5.
TRIAL OBJECTIVES AND PURPOSE ...................................................................19
5.1
Primary objective....................................................................................................19
5.2
Secondary objectives .............................................................................................19
5.3
Additional Objectives..............................................................................................19
5.4
Overall Study Design and Plan: Description ...........................................................19
5.4.1       Schedule of Assessments ..........................................................................................21
5.5
Assessments by Study Visit....................................................................................22
5.5.1
Screening Visit /Visit 1............................................................................................22
5.5.2
Treatment...............................................................................................................22
5.5.3
Month 1/Visit 2........................................................................................................23
5.5.4
Month 3, 6 and 9/Visit 3, 4 and 5 ............................................................................24
5.5.5
EoS/ET/Visit 6 (Month 12) ......................................................................................24
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................25
6.1
Inclusion Criteria.....................................................................................................25
6.2
Exclusion Criteria....................................................................................................25
6.3
Protocol Exceptions and Deviations........................................................................25
6.4
Subject Withdrawal Criteria ....................................................................................26
7.
TREATMENT OF SUBJECTS ................................................................................27
7.1
Subject numbering and enrollment status...............................................................27
7.2
Description of Study Drug.......................................................................................27
7.3
Concomitant Medications .......................................................................................27
7.3.1
Rescue Medication.................................................................................................27
7.3.2
Recurrence Medication...........................................................................................27

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7.4
Prohibited Medications ...........................................................................................27
7.5
Treatment Compliance ...........................................................................................28
7.6
Randomization and Blinding...................................................................................28
7.7
Unblinding Procedures ...........................................................................................28
7.7.1
Emergency unblinding of treatment assignment .....................................................28
7.7.2
Unblinding for Regulatory Authorities......................................................................28
8. 
STUDY DRUG MATERIALS AND MANAGEMENT ................................................28
8.1
Study Drug .............................................................................................................28
8.2
Study Drug Packaging and Labeling.......................................................................29
8.3
Study Drug Storage................................................................................................29
8.4
Study Drug Preparation ..........................................................................................29
8.5
Administration.........................................................................................................29
8.6
Study Drug Accountability.......................................................................................30
9.
TREATMENT ASSESSMENTS..............................................................................30
9.1
Safety and Efficacy Parameters..............................................................................30
9.1.1
Medical History.......................................................................................................30
9.1.2
Physical Examination .............................................................................................31
9.1.3
Vital Signs ..............................................................................................................31
9.1.4
ECG .......................................................................................................................32
9.1.5
Clinical Laboratory..................................................................................................32
9.1.6
Columbia Suicide Severity Rating Scale.................................................................33
9.1.7
Dosing Instructions.................................................................................................34
9.1.8
Subject Diary..........................................................................................................34
9.2
Adverse Events and Serious Adverse Events.........................................................35
9.2.1
Adverse Events ......................................................................................................35
9.2.2
Treatment Emergent Adverse Events (TEAE) ........................................................37
9.2.3
Serious Adverse Events .........................................................................................37
9.2.4 
Unexpected Adverse Event ....................................................................................37
9.3
Reporting Serious Adverse Events .........................................................................37
9.4
Follow-up of adverse events...................................................................................38
9.5
Reporting safety information to the IRB/EC ............................................................38
9.6
Pregnancies ...........................................................................................................39
10.
STATISTICS...........................................................................................................39
10.1
Sample Size ...........................................................................................................40
10.2
Randomization .......................................................................................................40

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10.3
Analysis Populations ..............................................................................................40
10.3.1
Disposition..............................................................................................................40
10.3.2
Primary efficacy – FIRST dose ...............................................................................40
10.3.3
Second Dose Analysis Populations ........................................................................41
10.4
Accountability and Background Characteristics ......................................................42
10.4.1
Enrollment and Disposition.....................................................................................42
10.4.2
Subject Characteristics...........................................................................................42
10.4.3
Treatment Exposure...............................................................................................42
10.5
Safety Analyses......................................................................................................42
10.5.1
Adverse Events ......................................................................................................43
10.5.2
Physical Examinations, Vital Signs, ECG Parameters and Clinical 
Laboratory Test Values...........................................................................................43
10.5.3
C-SSRS..................................................................................................................43
10.6
Efficacy Analyses ...................................................................................................43
10.6.1
Headache Response..............................................................................................43
10.6.2
Sensitivity Analyses of the Primary and Key Secondary Endpoints.........................44
10.6.3
Other Efficacy Analyses..........................................................................................44
10.7
Analysis of Second dose ........................................................................................45
10.7.1
Analysis of second dose for rescue ........................................................................45
10.7.2
Analysis of second dose for recurrence..................................................................45
10.8
Resource Utilization................................................................................................45
11.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..........................................46
11.1.
Study Monitoring.....................................................................................................46
11.2
Data collection.......................................................................................................46
11.3
Audits and Inspections...........................................................................................46
12.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................................47
13.
ETHICS ..................................................................................................................48
13.1
Ethics Review.........................................................................................................48
13.1.1
IRB/EC opinion......................................................................................................48
13.2
Written Informed Consent.......................................................................................49
13.3
Amendments to the protocol...................................................................................49
13.4
Discontinuation of the study....................................................................................49
13.5
Study drug supply, storage and tracking.................................................................49
13.6
Confidentiality.........................................................................................................50
13.7
Publication policy....................................................................................................50

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14.
RETENTION OF RECORDS ..................................................................................51
15.
REFERENCES.......................................................................................................52
16.
APPENDIX 1.  WORLD HEALTH ORGANIZATION TOXICITY CRITERIA............54
17.
APPENDIX 2. MIGRAINE DISABILITY ASSESSMENT TEST................................58
18.
APPENDIX 3. COLUMBIA SUICIDE SEVERITY RATING SCALE- SINCE 
LAST VISIT ............................................................................................................59
19.
APPENDIX 4. PROCESS TO RE-START SUBJECTS AFFECTED BY 
ADMINISTRATIVE HOLD.......................................................................................64
20.
APPENDIX 5. LIVER SAFETY:  SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS...............................................................................................66
21.
APPENDIX 6. PROTOCOL AMENDMENT HISTORY ............................................67

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3.
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and specialist terms are used in this study protocol.
>
Greater than
≥
Greater than or equal to
<
Less than
5-HT
5-Hydroxytryptamine
βHCG
Beta human chorionic gonadotropin
AE(s)
Adverse event(s)
ALT
Alanine aminotransferase
AMPP
American Migraine Prevalence and Prevention 
ALP
Alkaline phosphatase
AST
Aspartate aminotransferase
BP
Blood pressure
bpm
Beats per minute
BPPV
Benign paroxysmal positional vertigo
BUN
Blood urea nitrogen
CAD
Coronary artery disease
CBC
Complete blood count
CD
Compact disc
CFR
Code of Federal Regulations
CPK
Creatine phosphokinase
CRF
Case Report Form
CRO
Contract research organization
CS
Clinically significant
C-SSRS
Columbia Suicide Severity Rating Scale
DBP
Diastolic blood pressure
DVD
Digital video disc
ECG
Electrocardiogram
EoS
End of study
ET
Early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
HEENT
Head, eyes, ears, nose, and throat
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICHD
International Headache Classification
Ig
Immunoglobulin
IHS
International Headache Society
INR
International Normalised Ratio
IRT
Interactive Response Technology
IUD
Intrauterine Device
IV
Intravenous
ITT
Intent-to-treat
L
Lasmiditan
MBS
Most Bothersome Symptom

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MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MIDAS
Migraine disability assessment
mITT
modified Intent-to-treat
mL
milliliter
mmHg
millimeters of mercury
NCS
Not clinically significant
P
Placebo
PP
Per protocol
RBC
Red blood cell
SAE
Serious adverse event
SBP
Systolic blood pressure
SD
Standard deviation
TBL
Total bilirubin
TEAE
Treatment emergent adverse events
ULN
Upper limit of normal
WBC
White blood cells
WHO
World Health Organization
WOCBP
Women of child-bearing potential
WNL
Within normal limits

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4.
INTRODUCTION
Migraine is a common neurological disorder and was ranked by the World Health Organization 
(WHO) in their 2010 Global Burden of Disease survey as one of 7 most debilitating conditions, 
and as the third most common disease in the world among both males and females.[1]
Although the introduction of triptans greatly improved the acute treatment of migraine, a large 
percentage of patients still lack adequate treatment. A recent study by the American Migraine 
Prevalence and Prevention (AMPP) concluded that 40% of episodic migraineurs have 
significant unmet needs; the most frequent complaints were headache-related disability (19%) 
and dissatisfaction with current medications (15%).[2] In addition, concerns about cardiovascular
safety are believed to limit the prescription of triptans to less than 50% of migraineurs in the US.
[3]
Hence, there is a significant unmet need for novel migraine therapies with a distinct 
mechanism of action from triptans. One such agent is lasmiditan (COL-144). Unlike any 
approved treatment for acute migraine, lasmiditan selectively targets 5-HT1F receptors on 
neurons in the central and peripheral trigeminal system to alleviate migraine, and lacks the 
vasoconstrictor activity inherent with triptans.  
Lasmiditan is being developed as a novel acute therapy for migraine and to fulfill significant 
unmet needs in migraine patients with risk factors for undiagnosed cardiovascular disease, and 
those who respond poorly to their current prescription medication for acute migraine. The 
current mainstay migraine therapies are chemical analogs of sumatriptan (‘triptans’), developed 
for their potent cranial vasoconstrictor properties.[4]  Triptans are selective 5-HT1B/1D receptor 
agonists and mediate their vasoconstrictor activity via 5-HT1B receptors expressed on vascular 
smooth muscle. [5]
As large numbers of patients were exposed to triptans, it was established 
through post-marketing surveillance that their vasoconstrictor mechanism of action also 
conferred a risk of serious cardiovascular adverse events, some fatal. [3] Consistent with their 
common pharmacology, sumatriptan, zolmitriptan, rizatriptan, eletriptan and naratriptan all 
induced comparable dose-dependent contraction of isolated human coronary arteries.[5,6,7]   
Because of the liability of triptans to cause coronary vasospasm, they are contraindicated in 
patients with known coronary artery disease (CAD), and it is strongly recommended that they 
are not prescribed to patients with risk factors for undiagnosed CAD (e.g., hypertension,
hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with
surgical or physiological menopause, male over 40 years of age) without first undergoing a
thorough cardiovascular evaluation. 
Treatment of migraineurs with known cardiovascular disease and cardiovascular 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.[8] Many migraineurs who were previously eligible for 
triptan therapy may become ineligible as they age and develop cardiovascular disease and/or 
associated risk factors. For these patients, there is a pressing need for an effective migraine 
therapy with a non-vascular mechanism of action.
This study is a Phase 3 multicenter study in subjects with acute migraine. The study is designed 
to evaluate the safety and tolerability of long-term intermittent use of lasmiditan 200 mg and 
lasmiditan 100 mg given as a first dose for the treatment of a migraine attack.  A second dose of 
study drug is allowed to investigate the safety of lasmiditan 200 mg and lasmiditan 100 mg 
when taken for rescue or when taken for recurrence of migraine. 
In addition to safety 
assessments, the efficacy of long term intermittent use of lasmiditan will be evaluated. Data 
from this study will be used to further investigate and confirm the safety and efficacy of 

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lasmiditan in the treatment of acute migraine in patients with risk factors for cardiovascular
disease.
4.1
Background
Lasmiditan is a highly selective and potent 5-HT1F receptor agonist with > 470-fold higher affinity 
(Ki 2.21 nM) for the 5-HT1F receptor than for 5-HT1B/1D receptors in radioligand binding assays.  
Based on activation of G proteins, the agonist efficacy of lasmiditan at the 5-HT1F receptor was 
~80% that of 5-HT.  Lasmiditan is a pyridinoylpiperidine derivative, structurally unrelated to 
existing migraine therapies.  Lasmiditan (1 µM) was examined for its binding affinity at more 
than 50 other GPCRs, ion channels, and transporter sites, and had no significant affinities 
except at the benzodiazepine binding site of the GABAA channel (Ki 0.29 µM).  Unlike
diazepam, lasmiditan did not potentiate GABA currents in a human cloned GABAA channel 
functional assay, and hence this binding affinity was not considered to be biologically relevant. 
In rodent models of migraine, selective 5-HT1F receptor agonists inhibited trigeminal nociceptive 
processing without affecting blood vessel tone.[9,10,11]  Unlike triptans, lasmiditan did not constrict 
rabbit saphenous vein,[9] an assay predictive of human coronary artery constriction.[12]  
Lasmiditan is under development as a neurally acting treatment for migraine without the 
vasoconstrictor liability of triptans.
4.2
Clinical Studies to Date
Five Phase 1 studies have been completed in Europe using intravenous (IV), sublingual, and 
oral formulations of lasmiditan.  Two European Phase 2 studies have been completed with 
lasmiditan in the acute treatment of migraine. 
Lasmiditan was well tolerated in healthy volunteers following 20 minute IV infusions at dose 
levels of 0.1 to 20 mg with few AEs reported (clinical study H8H-BD-LACA).  There was a clear 
increase in the number of AEs reported following 20 minute IV infusions of 30 and 60 mg of 
lasmiditan, although most were rated as mild.  The number of AEs reported following 60 mg of 
lasmiditan decreased significantly when the rate of infusion was reduced from 3 to 1 mL/min 
and the infusion time was increased to 60 minutes, although the number of subjects reporting 
AEs was similar.  All subjects receiving 60 minute IV infusions of 120 and 180 mg of lasmiditan 
reported AEs with a similar overall frequency at each dose level.  The majority of AEs were mild 
in severity at all dose levels although there was a dose-related increase in the number of 
moderate AEs reported, with the highest incidence recorded at the two highest dose levels (120 
and 180 mg of lasmiditan). The most frequently reported AEs considered to be related to the 
study drug were somnolence, paresthesia, dizziness and hot flushes.  These occurred with 
rapid onset, generally within 10 minutes of the start of the infusion at all dose levels.  Adverse 
events typical for the triptans such as chest pain, chest tightness, chest pressure, neck pain or 
stiffness were not reported, even after the highest dose of 180 mg was administered.
A Phase 2, placebo-controlled clinical study to assess the efficacy and safety of intravenous 
lasmiditan in the acute treatment of migraine has been completed (clinical study COL MIG-201).  
This study was blinded with regard to dose and treatment allocation and employed doses of 
lasmiditan from 2.5 to 45 mg IV infused over 20 minutes.  One hundred and thirty (130) patients 
were treated in the study and no serious adverse events (SAEs) were reported.  The only AE 
that was clearly dose related was paresthesia; however, most of these events were reported as 

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mild.  Lasmiditan given by the IV route was effective in the acute treatment of migraine in this 
study, showing a statistically significant dose-response relationship.
A Phase 1 placebo-controlled study assessed the safety and tolerability and pharmacokinetic 
(PK) profile of sublingual and oral lasmiditan (clinical study COL MIG-102).  The sublingual 
route of administration was investigated using ascending single doses from 1 to 32 mg 
lasmiditan versus placebo in healthy subjects in one study arm.  In a second study arm, single 
ascending oral doses of a solution formulation from 25 to 400 mg lasmiditan or placebo were 
administered to healthy subjects.  In a third arm of the study, the safety and tolerability of 100 
mg and 400 mg of the oral solution formulation were evaluated in an additional cohort of 
subjects.  The tolerability of both the oral and sublingual route of administration was good.  
However, the sublingual route did not show any advantage in comparison to the oral route of 
administration since there was no evidence of enhanced bioavailability in terms of exposure 
(Cmax, AUC0–t) or time to peak concentration (tmax).  The oral route of administration was 
therefore selected for further study.  Oral doses of the solution formulation were generally well 
tolerated up to the maximum dose tested of 400 mg lasmiditan.  There were no clinically 
significant changes in safety parameters or clinical laboratory results. 
The assessment of bioequivalence of the oral solution and tablet formulations of 200 mg 
lasmiditan and of dose linearity of ascending doses of 50, 200 and 400 mg lasmiditan of a tablet 
formulation were investigated in a further clinical Phase 1 study (clinical study COL MIG-103), 
including also the assessment of safety and tolerability.  In general, lasmiditan was well 
tolerated across all doses.  The most common AEs across all doses with a dose-related 
increase in frequency were fatigue and dizziness followed by somnolence and paresthesia.
In the Thorough QT study (clinical study COL MIG-105) which was designed, performed and 
analyzed in accordance with the ICH E14 guidance,[13] the primary objective was to assess the 
effect of 100 mg lasmiditan and 400 mg lasmiditan on cardiac de- and re-polarization. The 
statistical evaluation of the primary variable revealed that lasmiditan caused no significant QT 
prolongation either at 100 mg or at 400 mg.  The results met the criteria for a negative thorough 
QT/QTc study according to ICH E14. [13]
The bioavailability of lasmiditan 200 mg administered orally as a tablet formulation under fed 
and fasted conditions was investigated (clinical study COL MIG-104). A slight delay in the time 
to reach maximum plasma concentration was observed in the fed state. As in other Phase 1 
studies, lasmiditan was well tolerated. The most common AEs across both conditions were 
somnolence, dizziness, orthostatic hypotension (with and without dizziness) and paresthesia.
The efficacy of oral lasmiditan in the acute treatment of migraine was evaluated in a Phase 2 
double-blind, placebo-controlled, parallel-group dose-ranging study conducted in five European 
countries (clinical study COL MIG-202).  A total of 391 subjects treated a single migraine attack 
at home using one of four doses of lasmiditan (50, 100, 200 or 400 mg) or placebo.  The 
proportion of patients with headache relief (moderate or severe headache becoming mild or 
none) or who were pain free showed statistically significant dose responses at 2 hours after 
treatment. Associated symptoms such as nausea, phonophobia and photophobia also 
responded to lasmiditan.  There were no clinically significant changes in clinical laboratory 
parameters, ECGs or vital signs.
Treatment-emergent adverse events (TEAEs) were reported by 22% of the subjects receiving 
placebo and by 65, 73, 86 and 84% of subjects receiving 50, 100, 200 and 400 mg lasmiditan, 

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respectively.  The most common adverse events seen in the lasmiditan groups were related to 
the nervous system.  These included dizziness, fatigue, vertigo, somnolence and paresthesia.  
Chest symptoms characteristic of triptan use were rare and occurred with a similar frequency in 
the placebo and active groups.
During the clinical development of lasmiditan there were no deaths and no subjects were 
withdrawn due to adverse events.  One serious adverse event (SAE) of moderate dizziness 
leading to overnight hospitalization was reported in the oral dose-ranging study.  This occurred 
in a female patient given 200 mg lasmiditan, and resolved without sequelae.
More details on the preclinical and clinical experience with lasmiditan are given in the Clinical 
Investigator’s Brochure. [14]
4.3
Minimization of Risk
The dose levels of lasmiditan (100 mg and 200 mg) have previously been tested and shown to 
be safe and well tolerated in healthy subjects and in patients with acute migraine, including in 
Phase 3 studies COL MIG-301 and COL MIG-302.
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).
Rescue medication (other than study drug) will be permitted after completion of the 2 hour 
assessments if the migraine does not respond (subject is not headache pain free).  
For subjects randomized to lasmiditan 100 mg, if the migraine responds within 2 hours 
(headache becomes pain free) but then recurs after 2 hours, a second dose of study drug may 
be taken up to 24 hours after the first dose.
To insure standardization, all adverse events will be assessed using WHO Toxicity Criteria 
(Appendix 1).
4.4
Potential Benefit
Migraine is a common disorder with a prevalence of 11.7% (17.1% of women and 5.4% of men)
based on a large population survey of US households. Nearly a third of sufferers experience
three or more migraine attacks a month, and over half report that the attacks cause severe
disability or require bed rest. [15] Despite the functional impairment caused by the disease, it is 
estimated that less than half of all migraineurs use prescription medication to manage their 
disease, indicating a substantial unmet medical need. [16]
In the completed Phase 2 studies, lasmiditan was effective in alleviating migraine attacks when 
given by the IV or oral routes of administration. This study will recruit patients meeting the 
internationally recognized diagnostic criteria for migraine set by the International Headache 
Society (IHS) who complete Phase 3 studies COL MIG-301 or COL MIG-302.

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4.5
Dose Rationale
The dose levels of lasmiditan to be used in this study (100 mg and 200 mg) have been tested 
and shown to be safe and well tolerated in both healthy subjects and in patients with acute 
migraine, including in Phase 3 studies COL MIG-301 and COL MIG-302. This study will further 
evaluate the safety and efficacy of the long-term intermittent use of lasmiditan 100 mg and 
200 mg.  
The allowance of a second dose of either lasmiditan 100 mg or 200 mg for treatment of rescue 
or recurrence of migraine is to further evaluate the safety and efficacy of a second dose of 
lasmiditan and establish the dosing profile for the use of lasmiditan in the treatment of acute 
migraine.
4.6
Conduct of the Study
This study will be conducted according to the protocol and in compliance with current principles 
of Good Clinical Practices (GCP) and International Conference on Harmonization (ICH). Further 
information on the ethical conduct of the study is in Section 13.
5.
TRIAL OBJECTIVES AND PURPOSE
5.1
Primary objective
To evaluate the safety and tolerability of long-term intermittent use of lasmiditan 100 mg and of
lasmiditan 200 mg, as the first and as a second dose, in the acute treatment of migraine.
5.2
Secondary objectives
To explore the long-term efficacy of
lasmiditan 100 mg and lasmiditan 200 mg in terms of
headache response over time.
5.3
Additional Objectives
To compare patient reported resource utilization during the study to patient reported information 
from COL MIG-301 or COL MIG-302 in terms of cardiovascular events and in terms of migraine 
episodes.
5.4
Overall Study Design and Plan: Description
This is a prospective, randomized, open-label study in subjects with migraine who have
completed CoLucid Phase 3 study, COL MIG-301 or COL MIG-302. Subjects will be stratified (yes 
or no) for use of concomitant medications that reduce the frequency of migraine episodes.
Subjects will be asked to treat all migraine attacks with study drug on an outpatient basis for
up to 12 months. Each patient’s study participation will consist of a screening visit (Visit 1) and 
a treatment period of up to 12 months during which the subject will treat all migraine attacks
with either lasmiditan 200 mg or lasmiditan 100 mg (with a second dose of study drug
permitted
between
2
and
24 hours (h)
for
recurrence
of
migraine only for subjects 
randomized to lasmiditan 100 mg). During the treatment period subjects will return to the clinic 
at 1,3,6,9 and 12 months. There will be an early termination (ET) visit within two weeks 

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(14 days) of treatment discontinuation for all subjects that discontinue between scheduled visits. 
The End-of-Study (EoS) visit will be at 12 months or at any scheduled visit when the subject’s 
participation in the study is ended. Participation in the study for 12 months will be defined as 
completing Month 12/Visit 6.
At Screening/Visit 1 subjects will provide written informed consent and authorize Health
Insurance Portability and Accountability Act (HIPAA). Study eligibility will be assessed on the
basis of completing study COL MIG-301 or COL MIG-302.  The EoS/Visit 2 of COL MIG-301 
or COL MIG-302 can be the same day as Screening/Visit 1.  Assessments required for this
visit can be the same assessments obtained at the EoS/Visit 2 of COL MIG-301 or COL MIG-
302 as long as that visit occurred on the same day or no more than two weeks prior to
signing informed consent and HIPAA for participation in COL MIG-305 as outlined in the 
Schedule of Assessments (Table 1). Regardless of the timing of signing of informed consent for 
COL MIG-305, medical history, migraine history and concomitant medication use will be 
reviewed and any changes or updates since enrolling in COL MIG-301 or COL MIG-302 will be 
noted. All subjects will complete the MIDAS questionnaire.  If Screening/Visit 1 is not the same 
day as EoS/V2 of COL MIG-301 or COL MIG-302 but within 2 weeks, a complete physical 
examination, vital signs and urine pregnancy test will also be done.  Subjects that are 
consented more than two weeks after EoS/Visit 2 of COL MIG-301 or COL MIG-302 will 
undergo the following assessments: a complete physical examination, vital signs, clinical
laboratory tests (including urine pregnancy test on women of child-bearing potential (WOCBP))
and 12-lead ECG. A Columbia Suicide Severity Rating Scale (C-SSRS) will be completed.  All 
subjects will be randomized and dispensed study drug and instructed to use lasmiditan as
the first treatment for each new migraine attack. Subjects will be randomly assigned in a
1:1 ratio, to receive lasmiditan 100 mg (L100 mg) or lasmiditan 200 mg (L200 mg). Subjects
randomized to lasmiditan 100 mg will be allowed to take a second dose of study drug if
needed for recurrence of migraine.
Treatment Period: Subjects will be asked to use lasmiditan as the first treatment for each new 
migraine attack within 4 hours of onset providing that the headache severity is at least moderate
at that time and not improving. Subjects will record their response to the first dose over the next 
48 hours using an electronic diary. For subjects randomized to lasmiditan 100 mg, if the 
migraine does respond within 2 hours (headache becomes pain free) but then recurs after 2 
hours, a second dose of study drug may be taken up to 24 hours after the first dose. Subjects 
should not exceed a total dose of 200 mg of lasmiditan in a 24-hour period. Subjects will record 
their response to a second dose, taken for recurrence, for 48 hours in the electronic diary. The 
total time for recording response to study drug is up to 72 hours depending on whether or not a 
second dose of lasmiditan 100 mg is used. Subjects using an alternate medication other than a 
second dose of lasmiditan 100 mg for the treatment of migraine rescue or recurrence will report 
the use of medication and continue to record their responses in the electronic diary up to the 48 
hour timepoint.
Subjects will be asked to return to the clinic at months 1, 3, 6, 9 and 12 (Visits 2, 3, 4, 5 and 6). 
At each visit a brief physical examination based on adverse events (AEs), vital signs and a urine 
pregnancy test on all WOCBP will be obtained.  Blood and urine samples for clinical laboratory 
parameters (hematology, serum chemistry and urinalysis) will be obtained at Month 1/Visit 2, 
Month 6/Visit 4 and Month 12/Visit 6 (EoS/ET). A 12-lead ECG will be obtained at Month 
6/Visit 4 and Month 12/Visit 6 (EoS/ET). C-SSRS will be completed at each visit. The MIDAS 
questionnaire will be completed at Month 3/Visit 3, Month 6/Visit 4, Month 9/Visit 5 and 
Month 12/Visit 6 (EoS/ET).  At each visit, resource utilization, AEs, use of concomitant 
medication, use of study drug and patient diary compliance will be assessed; subjects who are 

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continuing will be dispensed study drug.  Subjects who decide to withdraw at a scheduled visit 
should confirm the date of the visit is 7 days (± 2 days) from their last migraine treated with 
study drug.  Subjects who decide to discontinue between scheduled visits are asked to contact 
the clinic to schedule an ET /Visit 6 within two weeks (14 days) after discontinuation of dosing. 
The total time on study is up to 54 weeks (a maximum of 378 days).
5.4.1       Schedule of Assessments

Screening/Visit 1: Screening examinations to determine subject eligibility
are performed. This visit can be the same as EoS/Visit 2 of COL MIG-301 or COL MIG-302
if occurring on the same day or within 2 weeks of completing EoS/Visit 2 and consenting to 
participate in this study. Subjects are randomized and provided with a dosing card.  

Visits 2, 3, 4 and 5 (Months 1, 3, 6 and 9):
The subject will return to the clinic for each visit for safety assessments. The timing of the 
visits should be at approximately the same time of day (± 1 hour). Study drug and e-diary 
compliance will be reviewed.  Empty dosing card(s) will be collected along with any unused 
study drug.  Study drug will be dispensed. 
Monthly visit increments are defined as follows:

Visit 2/Month 1 – is defined as 30 days ± 2d from Visit 1

Visit 3/Month 3 – is defined as 60 days ± 4d from Visit 2

Visit 4/Month 6 – is defined as 90 days ± 4d from Visit 3

Visit 5/Month 9 – is defined as 90 days ± 4d from Visit 4

Visit 6 (Month 12)/EoS/ET:  End of study visit or Early termination
The subject will return to the clinic for EoS visit at month 12 for final safety assessments. 
Empty dosing card(s) and unused study drug will be collected. This visit should be 
scheduled 90 days +/- 4d from Visit 5 and be one week (7 days ± 2 days) after the last 
migraine treated on study.  If a patient decides to discontinue from the study at any of the 
scheduled visits the Visit 6/EoS assessments will be conducted. 
        Visit 6/Month 12 (EoS) – is defined as 90 days +/- 4d from Visit 5 and  7 days 
(±2d) after last migraine treated with study drug whichever is later. 

If a subject decides to withdraw from the study at any scheduled visit, the visit 
should occur at the increments defined and be 7 days (± 2 days) from the last 
migraine treated on study.

For study consideration, 12 months is defined as completing Month 12/Visit 6.
Early termination is defined as the subject’s return to the clinic between scheduled 
study visits to discontinue from the study for any reason.  The visit should be 
scheduled within two weeks of the  decision to discontinue.  Safety assessment will 
be performed.  Empty dosing card(s) and unused study drug will be collected.
The overall Schedule of Assessments for the study is provided in Table 1.

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5.5
Assessments by Study Visit
5.5.1
Screening Visit /Visit 1
The following items must be completed and reviewed by the Investigator or sub-Investigator:

Explain the purpose of the study to prospective subjects and obtain written informed 
consent and HIPAA.

Review inclusion/exclusion criteria (See Sections 6.1 and 6.2.).

Review and update medical history including migraine history and prior treatment
and collect demographic information (See Section 9.1.1).

Review and update concomitant medications that the subject is taking.  

Review and update resource utilization (See Section 9.1.1.3).  

Have subject complete MIDAS questionnaire (See Section 9.1.1.2 and Appendix 2).

Collect weight (Height will be obtained from COL MIG-301 or COL MIG-302 to 
calculate BMI).  

Perform a complete physical examination. (See Section 9.1.2). IF not the same day 
as EoS/Visit 2 of COL MIG-301 or COL MIG-302.  

Obtain a brief physical examination (if indicated by an AE) from EoS/Visit 2 of COL 
MIG-301 or COL MIG-302 if the same day. 

Obtain vital signs (See and 9.1.3). IF not the same day as EoS/Visit 2 of COL MIG-
301 or COL MIG-302. (Or from EoS/Visit 2 of COL MIG-301 or COL MIG-302 if 
same day).  

Perform a 12-lead ECG (see Section 9.1.4). ONLY if more than two weeks from 
EoS/Visit 2 of COL MIG-301 or COL MIG-302. (Otherwise ECG from EoS/Visit 2 of 
COL MIG-301 or COL MIG-302 is used).  

Collect blood and urine samples for clinical laboratory tests (hematology, chemistry, 
and urinalysis; see Section 9.1.5). ONLY if more than two weeks from EoS/Visit 2 of 
COL MIG-301 or COL MIG-302 (Otherwise values from EoS/Visit 2 of COL MIG-301 
or COL MIG-302 is used).

Collect urine sample for urine pregnancy test for WOCPB (or from EoS/Visit 2 of 
COL MIG-301 or COL MIG-302 if same day).  If urine pregnancy test is positive a 
confirmatory serum βHCG test must be performed. The confirmatory test may be run 
in the local clinical laboratory.  The subject should be told not to dose with study drug 
until the confirmatory test results are obtained.  If serum test is positive the subject is 
to be discontinued from the study.

Obtain C-SSRS (See Section 9.1.6 and Appendix 3). ONLY if more than two weeks 
from EoS/Visit 2 of COL MIG-301 or COL MIG-302.

Review study requirements and instructions on dosing and completing electronic 
diary (See Section 9.1.7 and 9.1.8).

Randomize subject through the Interactive Response Technology (IRT) system.

Dispense study drug as assigned. 

Provide access to electronic diary.

Confirm timing of Visit 2.

Discharge subject.
5.5.2
Treatment
Subjects will be allowed to treat all acute migraine attacks with study drug. Study migraines 
should be of moderate or severe intensity that is not improving. The attack is to be treated within

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4 hours of onset.  Subjects should not exceed a total dose of 200 mg of lasmiditan in a 24-hour 
period.

Prior to dosing the subject will record:
o
Time of onset
o
Time migraine pain becomes moderate or severe and the severity ((2) moderate 
or (3) severe) of the pain.
o
Presence or absence (yes or no) of each of the following associated symptoms 
of migraine: nausea, phonophobia and photophobia.  

From the list of associated symptoms present the subject will identify 
which ONE is most bothersome to them as the MBS.
o
Presence or absence (yes or no) of vomiting.
o
Degree of interference with normal activities

Subject will dose with study drug and record time of dosing.

Subject will record their response to treatment for 48 hours after dosing with study 
drug. Total time to record response is up to 72 hours if a second dose of study drug
is taken for recurrence of migraine (for subjects randomized to lasmiditan 100 mg)
(See Section 9.1.8).

Subjects will report any unusual symptoms not felt before with a migraine during 
each migraine treated with study drug as well as any concomitant medication use by 
way of the e-diary. Sites will receive an alert and should contact the subject within 48 
hours to discuss the unusual symptoms and determine if the symptom(s) are an AE 
along with the duration and effect of the AE on the subject.
5.5.3
Month 1/Visit 2
This visit is to occur at approximately the same time of day (± 1 hour), 30 days (± 2d) from 
Screening/Visit 1. The following assessments will be performed:

Collect empty dosing card and/or any unused study drug and review dosing 
compliance.

Review patient diary compliance.

Collect resource utilization (See Section 9.1.1.3).

Have subject complete MIDAS questionnaire (See Section 9.1.1.2 and Appendix 2). 

Obtain C-SSRS (See Section 9.1.6 and Appendix 3).

Assess for AEs and use of concomitant medications.

Perform a brief symptom-related physical examination if indicated by an AE (See 
Section 9.1.2.).

Obtain vital sign readings (See Section 9.1.3).

Collect blood and urine samples for clinical laboratory tests (hematology, chemistry,
and urinalysis) (See Section 9.1.5). The laboratory tests will include a urine 
pregnancy test for WOCBP. A positive urine pregnancy test will be confirmed with a 
serum βHCG test. (The confirmatory test may be run in the local clinical laboratory).

Remind subject of study requirements.

Return any unused drug and dispense new patient card or carton of study drug.

Schedule next visit.

Discharge subject.

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5.5.4
Month 3, 6 and 9/Visit 3, 4 and 5

Visit 3/Month 3 – is defined as 60 days ± 4d from Visit 2

Visit 4/Month 6 – is defined as 90 days ± 4d from Visit 3

Visit 5/Month 9 – is defined as 90 days ± 4d from Visit 4
The visits should occur at approximately the same time of day (± 1 hour). The following 
assessments will be performed:

Collect empty dosing card and/or any unused study drug and review dosing 
compliance.

Review patient diary compliance.

Collect resource utilization (See Section 9.1.1.3).

Have subject complete MIDAS questionnaire (See Section 9.1.1.2 and Appendix 2).

Obtain C-SSRS (See Section 9.1.6 and Appendix 3).

Assess for AEs and use of concomitant medications.

Perform a brief symptom-related physical examination if indicated by an AE (See 
Section 9.1.2.).

Obtain vital sign readings (See Section 9.1.3).

Perform a 12-lead ECG (See Section 9.1.4) MONTH 6/VISIT 4 ONLY.

Collect blood and urine samples for clinical laboratory tests (hematology, chemistry, 
and urinalysis) (See Section 9.1.5). MONTH 6/VISIT 4 ONLY.

Collect urine sample for urine pregnancy test for WOCPB (or from EoS/Visit 2 of 
COL MIG-301 or COL MIG-302 if same day).  If urine pregnancy test is positive a 
confirmatory serum βHCG test must be performed. The confirmatory test may be run 
in the local clinical laboratory.  The subject should be told not to dose with study drug 
until the confirmatory test results are obtained.  If serum test is positive the subject is 
to be discontinued from the study.  Remind subject of study requirements.

Return any unused drug and dispense new patient carton of study drug if required. 

Schedule next visit.

Discharge subject.
5.5.5
EoS/ET/Visit 6 (Month 12)
The following assessments will be performed. This EoS visit is for all subjects completing 
study through month 12 OR any subject concluding their participation in the study at any 
scheduled visit.  The visit should occur at approximately the same time of day (± 1 hour) and 
90 days (± 4 d) from the last visit and be at least 7 days after the last migraine is dosed.
Patient completion through month 12 will be defined as completing Month 12/Visit 6.  The 
ET visit is for all subjects discontinuing from the study at any time between scheduled study 
visits for any reason.  The visit should occur within 14 days of the decision to discontinue.

Collect empty dosing card(s) and all unused study drug and review dosing 
compliance.

Review patient diary compliance.

Collect resource utilization (See Section 9.1.1.3).

Have patient complete MIDAS questionnaire (See Section 9.1.1.2 and Appendix 2).

Obtain C-SSRS (See Section 9.1.6 and Appendix 3.

Assess for AEs and use of concomitant medications.

Perform a brief symptom-related physical examination if indicated by an AE (See 
Section 9.1.2.).

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
Obtain vital sign readings (See Section 9.1.3).

Perform a 12-lead ECG (See Section 9.1.4).

Collect blood and urine samples for clinical laboratory tests (hematology, chemistry, 
and urinalysis) (See Section 9.1.5). The laboratory tests will include a urine 
pregnancy test for WOCBP.  A positive urine pregnancy test will be confirmed with a 
serum βHCG test. (The confirmatory test may be run in the local clinical laboratory).

Subject’s participation in study is complete.
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS
6.1
Inclusion Criteria
All subjects entered into this trial must meet the following criteria:
1. Able and willing to give written informed consent and authorize HIPAA.
2.
Completed COL MIG-301 or COL MIG-302 within the last 12 weeks. Subjects that completed COL 
MIG-301 prior to COL MIG-305 being available will be allowed to enroll as long as enrollment 
occurs within 4 weeks of COL MIG-305 activation at their site. Subjects discontinued due to 
administrative hold will be allowed to re-enroll in the study. (process outlined in Appendix 
4).
3. Females of child-bearing potential must be using or willing to use a highly effective form 
of contraception (e.g. combined oral contraceptive, IUD, abstinence, or vasectomized 
partner).
4. Able and willing to complete an electronic diary to record details of all migraine attacks
treated with study drug.
6.2
Exclusion Criteria
Subjects will be excluded from this trial if they meet any of the following criteria:
1. Any medical condition or clinical laboratory test which in the judgment of the Investigator
makes the subject unsuitable for the study.
2. Pregnant or breast-feeding women.
3. Women of child-bearing potential not using or not willing to use highly effective 
contraception.
4. Subject is at imminent risk of suicide (positive response to question 4 or 5 on the 
C-SSRS).
5. Initiation of or a change in concomitant medication to reduce the frequency of migraine 
episodes since completing COL MIG-301 or COL MIG-302.
6. Participation in any clinical trial of an experimental drug or device since completing 
EoS/Visit 2 of COL MIG-301 or COL MIG-302.
7. Subject did not dose a migraine during the allotted time while enrolled in COL MIG-301 
or COL MIG-302 or was evaluated to be noncompliant with the e-diary requirements 
(particularly recording their migraine and post-dose assessments).
6.3
Protocol Exceptions and Deviations
Exceptions to the above eligibility criteria will not be granted. It is expected that subjects will 
meet all eligibility criteria.  Departures from the protocol should be avoided, unless required for 

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the safety of the subject.  Protocol deviations will be documented by the study monitor and will 
be included in the final clinical study report. Protocol deviations should be submitted to the 
Institutional Review Board (IRB)/Ethics Committee (EC), in accordance with the site’s IRB/EC 
requirements.
6.4
Subject Withdrawal Criteria
Subjects may voluntarily withdraw from the study, or be removed from the study at the 
discretion of the Investigator or Sponsor, at any time.  The Investigator may withdraw a subject 
at any time if it is determined that continuing in the study would result in a significant safety risk 
to the subject. 
If such withdrawal occurs, or if the subject fails to return for Visit 6/EoS/ET the Investigator 
should determine the primary reason for a subject’s premature withdrawal from the study and 
record the reason in the subject’s study records.
Premature withdrawal may occur for any of the following reasons:

Non-compliance with the protocol requirements

Pregnancy

Death

Adverse event (AE) 

Subject request

Investigator request

Sponsor request
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the Investigator should 
show “due diligence” by documenting in the source documents all steps taken to contact the 
subject, e.g., dates of telephone calls, registered letters, etc.
All subjects discontinuing from the trial before a scheduled visit regardless of cause, must be 
seen for ET/Visit 6 for safety assessments and to return all unused study drug and the e-diary.  
Subjects that withdraw from the study prior to dosing a migraine attack should return to the clinic 
for ET/Visit 6 to return all unused study drug and the e-diary. Subjects that desire to withdraw 
from the study at one of the scheduled visits (Visit 2, 3, 4 or 5) should complete the EoS/Visit 6
study assessments and return all unused study drug and the e-diary.
Subjects who are withdrawn from the study for any reason will not be replaced.

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7.
TREATMENT OF SUBJECTS
7.1
Subject numbering and enrollment status
Each subject will use the same seven-digit subject number from the previous Phase 3 study 
(COL MIG-301 or COL MIG-302).  If a subject fails to be randomized, the reason for not being 
randomized should be documented in the source documents.
7.2
Description of Study Drug
For study purposes lasmiditan 100 mg and lasmiditan 200 mg are both referred to as study 
drug. 
7.3
Concomitant Medications
Concomitant medications (including devices) 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 
subject’s time on study must be recorded in the CRFs.
7.3.1
Rescue Medication
Rescue medication (other than study drug) will be permitted after completion of the 2 hour 
assessments if the migraine does not respond (subject is not headache pain free). The 
Investigator may advise each subject as to an alternative suitable rescue medication.  Triptans,
ergots, opioids and barbiturates MUST NOT be used for rescue medication within 24 hours of 
study drug administration.  The use of any rescue medication will be recorded in the subject 
diary.
7.3.2
Recurrence Medication
If the migraine responds within 2 hours (headache becomes pain free) but then recurs after 
2 hours, a second dose of study drug may be taken up to 24 hours after the first dose (only for 
subjects randomized to lasmiditan 100 mg). Triptans, ergots, opioids and barbiturates MUST 
NOT be used for treatment of migraine recurrence within 24 hours of study drug administration.
The use of any medication for the treatment of migraine recurrence will be recorded.
7.4
Prohibited Medications
Use of the following medications is prohibited for the duration of a subject’s participation in the 
study from Screening /Visit 1 through EoS/ET/Visit 6:

Any investigational treatment other than lasmiditan.

All other symptom modifying treatments (e.g. antiemetics) for migraine except rescue or 
recurrence medication as detailed in Section 7.3.1 and 7.3.2.

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.

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7.5
Treatment Compliance
Study drug will be taken by the subject on an outpatient basis throughout the study.  Prior to 
discharge from Screening/Visit 1 subjects will be given study drug to treat all migraine attacks
for the first month.  Information on the time and date of each dose (initial treatment along with 
treatment of recurrence with a second dose of study drug for subjects randomized to lasmiditan 
100 mg) will be recorded by the subject in the electronic diary.  Subjects will return empty 
dosing card(s) and any (all) unused study drug to the clinic at each visit.  Unused study drug 
may be returned to the subject and a new patient card or carton of study drug dispensed. 
Subject use of study drug will be monitored to control for medication overuse.
7.6
Randomization and Blinding
Subjects will be randomized through a central randomization process by IRT
during 
Screening/Visit 1. A randomization number and study drug card number will be assigned for 
dosing.  Lasmiditan will be provided in 8-tablet treatment packs.
7.7
Unblinding Procedures
7.7.1
Emergency unblinding of treatment assignment
The study is open label.
7.7.2
Unblinding for Regulatory Authorities
The study is open label.
8. STUDY DRUG MATERIALS AND MANAGEMENT
8.1
Study Drug
Study drug refers to lasmiditan 100 mg and lasmiditan 200 mg.
Lasmiditan drug product is a tablet containing 100 mg or 200 mg of lasmiditan (as free base).  
The tablet is white, film coated, and round with no markings.  Lasmiditan drug product is for oral 
administration.
 
 
 
Each dose of study drug will consist of one tablet for the treatment of a single migraine attack. 
For subjects randomized to lasmiditan 100 mg, a second dose may be used for treatment of 
recurrence of migraine between 2 and 24 hours after the first dose.  For subjects randomized to 
lasmiditan 200 mg, no additional study drug is to be taken within 24 hours of the dose, as the 
maximum dose of lasmiditan to be taken in a 24-hour period is 200 mg. 
CCI

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8.2
Study Drug Packaging and Labeling
All study drug will be provided as child resistant individual dosing cards containing 8 tablets. In 
the card, each tablet will be contained within an individual blister pack.  At the discretion of the 
investigator and depending on the visit and usage by the subject, subjects will receive a patient 
pack of two dosing cards, or a patient pack of three dosing cards.
Study drug labels will include protocol number, Sponsor’s name and address, and an 
Investigational New Drug statement.  
8.3
Study Drug Storage
All study drug should be stored at room temperature.  
8.4
Study Drug Preparation
No preparation will be required.
8.5
Administration
Subjects will be screened outside a migraine attack.  The study drug will be dispensed to the 
subject at each visit with instructions to treat all acute migraine attacks as follows:

Screening/Visit 1, subjects will receive a single blister card containing 8 tablets.  

Month 1/Visit 2 subjects continuing on study may receive a single blister card 
containing 8 tablets or a patient carton containing two dosing cards of 8 tablets each.  

At each subsequent visit (Visits 3, 4 and 5/Months 3, 6 and 9) subjects may receive a 
single blister card containing 8 tablets or a patient carton containing two dosing cards of 
8 tablets each or a patient carton containing 3 dosing cards of 8 tablets each.  
Subjects are to return all dosing cards (used and unused to each visit).  Additional single 
dosing cards of 8 tablets are available in the event more study drug is needed to treat 
migraines during the time between visits or if a subject loses a dosing card or needs a dosing 
card replaced. Subject use will be monitored to control for medication overuse.
Subjects will be instructed to take one tablet with approximately 4 ounces of water as the 
FIRST treatment for a new migraine attack providing that: any aura symptoms have resolved

the headache is either moderate or severe and has been so for less than 4 hours

no prior analgesic or acute migraine treatment has been taken to treat the current 
migraine attack.
Subjects will be instructed to take a second dose (one tablet) of study drug (only for those 
subjects randomized to lasmiditan 100 mg), if needed, with approximately 4 ounces of water for 
recurrence of migraine at least 2 hours after the first dose.  Subjects should not exceed a total
dose of 200 mg of lasmiditan in a 24-hour period.
Subjects will be instructed to treat all migraines with lasmiditan as the first treatment for each 
new migraine attack within 4 hours of onset.

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8.6
Study Drug Accountability
Under supervision of the Investigator, the study pharmacist or designee will be responsible for 
drug accountability. The pharmacist or designee will keep an accurate inventory of test article(s) 
and dispensing using a drug dispensing log. The pharmacist or designee must keep study drug 
inventory available for inspection by the Sponsor, an agent for the Sponsor, and regulatory 
authorities. 
Subjects will be required to return all unused study drug and all empty dosing cards. If any 
unused material is remaining at the site at study completion, the pharmacy will be instructed 
how to dispose of or return the material to the Sponsor after the Sponsor’s representative has 
performed accountability. The Sponsor’s representative will complete authorization forms for 
disposal or return with the responsible pharmacist or designee. Copies of these forms should be 
included with the returned material. The original form should be maintained in the pharmacy 
within the site study files.
9.
TREATMENT ASSESSMENTS
9.1
Safety and Efficacy Parameters
Safety will be monitored with physical examinations, vital signs, ECGs, clinical laboratory 
testing, and AE/SAE assessments. 
Efficacy will be evaluated using subject recorded response to relief from pain and from the MBS
(nausea, phonophobia or photophobia) based on the first dose, as well as use of rescue 
medication and/or recurrence of headache and use of medication for recurrence of migraine. 
Efficacy of a second dose will be evaluated using subject recorded response to relief from pain
and from the MBS (nausea, phonophobia or photophobia) by subjects who took a second dose 
for rescue or for recurrence. Standardization of data capture is provided in detail in the 
remainder of this section.  Assessments should be performed in relation to dosing as indicated.
9.1.1
Medical History
During Screening/Visit 1 general medical history recorded for participation in COL MIG-301 or 
COL MIG-302 will be reviewed. Information previously recorded will be carried over into the 
database for COL MIG-305.  Any changes or updates to a patient’s medical history from 
information recorded for participation in COL MIG-301 or COL MIG-302 will be recorded on the 
CRF and will include information relating to any prior or existing medical conditions involving the 
following disease types or systems: infectious diseases, allergic, metabolic/endocrine/nutritional, 
hematopoietic, musculoskeletal, dermatologic, head, eyes, ears, nose and throat (HEENT), 
breasts, respiratory, cardiovascular, gastrointestinal/hepatic, genitourinary/renal, neurological, 
and psychiatric/psychosocial. 
Concomitant medications or devices, for migraine or pain, and any other medication for other 
medical conditions will also be reviewed. Information previously recorded will be carried over 
into the database for COL MIG-305. Any changes from information recorded for and during 
participation in COL MIG-301 or COL MIG-302 will be recorded on the CRF. At each visit, the 
use of any concomitant medications will be reviewed and updated for any changes in frequency 
or dosing.

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In addition, any additional information since participation in COL MIG-301 or COL MIG-302
regarding the subject’s migraine history including prior treatment will be recorded.  
9.1.1.1
Demographics
During Screening/Visit 1, subject initials, age, and date of birth will be recorded on the CRF.  
Gender, race and ethnicity will be carried over into the database from the information recorded 
for COL MIG-301 or COL MIG-302.
9.1.1.2
MIDAS
MIDAS is a 5 item questionnaire (Appendix 2) evaluating the impact of migraine on a patient’s 
life over the past 3 months. The questionnaire is to be completed by each subject at 
Screening/Visit 1, Month 3/Visit 3, Month 6/Visit 4, Month 9/Visit 5 and Month 12/Visit 6/
EoS/ET.
Subjects should be given sufficient time to complete the questionnaire and it should be 
completed prior to any procedures (i.e. physical exam, blood draw).  The questionnaire is a 
self-reported measure and is to be reviewed with the subject for completeness only.  Subjects 
should not be questioned about any of the responses or given suggestions on how to answer 
any of the questions, however clarification of what a question is asking is allowed.
9.1.1.3
Resource Utilization
During Screening/Visit 1 subject information reported during participation in Phase 3 study 
COL MIG-301 or COL MIG-302 about any CV events and/or related resource utilization such as 
visits to cardiologists, procedures, hospitalizations, new treatments or treatment adjustments for 
CV disease will be reviewed and updated as appropriate. In addition the previously reported 
information regarding any ER visits or visit to physician’s office for migraine treatment will be 
reviewed and updated. The information recorded for COL MIG-301 or COL MIG-302 will be 
carried over into the database for the COL MIG-305. At each visit, Month 1/Visit 2, Month 
3/Visit 3, Month 6/Visit 4, Month 9/Visit 5 and Month 12/Visit 6/EoS/ET the subject will again 
be asked about resource utilization during their time on study.
9.1.2
Physical Examination
If EoS/Visit 2 of COL MIG-301 or COL MIG-302 is the same day as Screening/Visit 1, only a 
brief physical examination if indicated by an AE will be performed (as required by the earlier 
studies).  If the subject is not enrolling in COL MIG-305 the same day they are completing COL 
MIG-301 or COL MIG-302, a complete physical examination will be performed during 
Screening/Visit 1. 
A complete physical examination of all body systems will include the 
following: general appearance, skin, HEENT, heart, lymph nodes, lungs, abdomen, 
extremities/joints, neurological systems, and mental status. At each visit, Month 1/Visit 2, 
Month 3/Visit 3, Month 6/Visit 4, Month 9/Visit 5 and Month 12/Visit 6/EoS/ET, a brief 
symptom related physical examination will be performed if indicated by an AE.
Weight will be measured at Screening/Visit 1. BMI will be calculated by the database using the 
subject’s height recorded for COL MIG-301 or COL MIG-302.  Weight will also be measured at 
Month 12/Visit 6/EoS/ET.
9.1.3
Vital Signs
Vital signs, measured after at least 5 minutes rest, will include seated systolic blood pressure 
(SBP), diastolic blood pressure (DBP) and heart rate (HR). All vital sign measurements will be 

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performed by appropriately qualified and authorized study personnel, using appropriate 
equipment. 
Blood pressure (BP) will be measured after at least 5 minutes rest and if possible in the same 
arm at each visit by using an automated sphygmomanometer. The results will be recorded in 
millimeters of mercury (mmHg). HR will be measured in the radial artery in the dominant arm for 
30 seconds and will be recorded as beats per minute (bpm). 
Vital signs will be assessed at Screening/Visit 1 and at Month 1/Visit 2, Month 3/Visit 3, 
Month 6/Visit 4, Month 9/Visit 5 and Month 12/Visit 6/EoS/ET.  If Screening/Visit 1 is the 
same day as EoS/Visit 2 of COL MIG-301 or COL MIG-302 the vital signs obtained will be used 
for both studies.
9.1.4
ECG
A standard, digital 12-lead ECG will be obtained after at least 5 minutes rest at Screening/Visit
1 (ONLY if more than two weeks since EoS/Visit 2 of COL MIG-301 or COL MIG-302) and at 
visit Month 6/Visit 4, and Month 12/Visit 6/EoS/ET.  If Screening/Visit 1 is the same day or 
within 2 weeks of EoS/Visit 2 of COL MIG-301 or COL MIG-302, the data obtained will be used 
for both studies.
A trained ECG technician will perform the ECGs and all ECG results must be reviewed at the 
site by the Investigator or a medically qualified designee for clinical management of the subject. 
Abnormal findings will be identified as either clinically significant (CS), or not clinically significant 
(NCS). CS findings are to be reported as AEs by the Investigator. ECGs will be sent to a central 
reader for further evaluation.   
ECG reports from the central reader will include: rhythm, rate, axis, PR, QRS, and corrected (by 
both Fridericia and Bazett) and uncorrected QT intervals.
9.1.5
Clinical Laboratory
Samples of blood and urine will be collected for clinical laboratory tests during Screening/Visit
1 (ONLY if more than two weeks since EoS/Visit 2 of COL MIG-301 or COL MIG-302) and at 
visit Month 1/Visit 2, Month 6/Visit 4, and Month 12/Visit 6/EoS/ET. If Screening/Visit 1 is 
the same day the data will be used for both studies.  If Screening/Visit is within 2 weeks of 
EoS/Visit 2 of COL MIG-301 or COL MIG-302 the data obtained will be used for both studies 
except a urine pregnancy test for WOCBP will be performed. Tests will be conducted as 
designated below: 
9.1.5.1
Clinical Laboratory tests conducted
Clinical laboratory evaluations will include:
Hematology:  white blood cell (WBC) count with differential (neutrophils, lymphocytes, 
eosinophils, monocytes, basophils), hemoglobin, hematocrit, platelet count, and red blood cell 
(RBC) count.  
Serum Chemistry Profile:  albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), calcium, chloride, 
bicarbonate, creatinine, glucose, phosphate, potassium, sodium, total bilirubin, total protein, 
total cholesterol, HDL, and triglycerides.

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Urinalysis:  protein, glucose, nitrite, ketones, blood (hemoglobin), pH, specific gravity, 
microscopic bacteria, RBCs, WBCs, casts, crystals, and cells. Microscopic examination of 
sediment will be performed only if the results of the urinalysis dipstick evaluation are positive.
For WOCBP, a urine pregnancy test for β-HCG will be performed at the Screening/Visit 1
(test will count for EoS/Visit 2 for COL MIG-301 or COL MIG-302 if visit is same day).  A urine 
pregnancy test will be performed at each visit. If a urine pregnancy test is positive during the 
study the subject will be discontinued from the study after confirmation with a positive serum 
βHCG. A subject with a positive urine βHCG must not be dosed unless a negative serum βHCG 
is obtained. The confirmatory serum test may be performed at the local clinical laboratory.
9.1.5.2
Abnormal and Clinically Significant Results
The Investigator must categorize all abnormal hematology, chemistry, and urinalysis laboratory 
values as either CS or NCS. Clinical significance is defined as any variation in laboratory 
parameters, which has medical consequences that result in an alteration in the subject’s 
medical care. The Investigator will use the WHO Toxicity Criteria (see Appendix 1) as a guide 
when evaluating the clinical significance of all abnormal clinical laboratory results. In case of 
CS laboratory results, the Investigator will continue to monitor the subject with additional 
laboratory assessments until (1) values have reached normal range and/or baseline levels, or 
(2) the Investigator has judged that the abnormal values are not related to the administration of 
study drug or other protocol-specific procedures.
9.1.5.3
Hepatic Safety Monitoring
If a study subject experiences elevated ALT ≥3X ULN, AST ≥3X ULN, ALP ≥2X ULN, or 
elevated TBL ≥2X ULN, liver testing (Appendix 5) 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

Subject discontinued from treatment due to a hepatic event or abnormality of liver tests

Hepatic event considered to be a SAE
9.1.6
Columbia Suicide Severity Rating Scale 
C-SSRS is a suicidal ideation rating scale that rates an individual's degree of suicidal ideation 
on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and 
intent”. The scale intends to prospectively identify and classify suicidal ideation and behavior 
based on a semi-structured interview by the Investigator or designee trained in administering 
the questionnaire.  

If Screening/Visit 1 is the same day or within 2 weeks of EoS/Visit 2 of COL MIG-301 
or COL MIG-302 the data obtained will be used for both studies.

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
The “since last visit” version will be administered at Screening/Visit 1 (ONLY if more 
than two weeks since EoS/Visit 2 of COL MIG-301 or COL MIG-302) and at visit Month
1/Visit 2, Month 3/Visit 3, Month 6/Visit 4, Month 9/Visit 5 and Month 12/Visit 6/
EoS/ET.  (Appendix 3).  
If present, suicide ideation will be classified in  5 classes (1-5), the intensity of suicidal ideation 
will be classified in 5 dimensions, and any suicidal behavior will be classified in 6 classes (actual 
attempt, interrupted attempt, aborted attempt, preparatory acts towards and attempt, suicidal 
behavior, suicide).
9.1.7
Dosing Instructions
Study drug should be administered as the FIRST treatment for an acute migraine attack. If the 
subject has already taken any prior analgesic or acute migraine treatment, he/she is no longer 
eligible to treat the current migraine attack but may treat a later attack with the study drug.
Subjects should treat all migraines with study drug.
Subjects will be asked to treat each migraine attack within 4 hours of onset providing that the 
headache severity is at least moderate at that time and not improving. Subjects will record their 
response over the next 48 hours using an electronic diary. Subjects should not exceed a total 
dose of 200 mg of lasmiditan in a 24-hour period. Subjects will be instructed not to use rescue 
medication (other than study drug) until at least 2 hours after taking study drug. If the subject 
does not become headache pain free within 2 hours, rescue medication (other than study drug)
will be permitted after completion of the 2 hour assessments. The Investigator will advise each 
subject as to alternative suitable rescue medication. Triptans, ergots, opioids and barbiturates
MUST NOT be used for rescue medication within 24 hours of study drug administration. For 
subjects randomized to lasmiditan 100 mg, if the migraine responds within 2 hours (headache 
becomes pain free) but then recurs after 2 hours, a second dose of study drug may be taken for 
up to 24 hours from the first dose.
9.1.8
Subject Diary
Subjects will be trained on the use of the electronic diary at Screening/Visit 1. Efficacy data will 
be collected in an electronic diary for an attack.  Subjects will record the date and time at which 
each migraine headache starts and when it first becomes moderate or severe.  They will also 
record the date and time of taking the first dose of study drug.  All migraines treated with study 
drug will be recorded in the diary.
For each migraine, subjects will be asked to assess their headache severity at specified time
points: 0 (pre dose), 0.5, 1, 2, 4, and 24 and 48 hours post dose using the IHS four point
headache severity rating scale (0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe 
pain). The need for an alternative treatment as rescue medication will be assessed between 2 
and 24 hours and at 48 hours.  Recurrence of pain and second dosing of study drug (only for 
those randomized to lasmiditan 100 mg) will be assessed between 2 and 24 hours and at 48 
hours.
At the same time points, specified above, subjects will grade the degree of interference with 
normal activities and the presence or absence (yes or no) of accompanying symptoms: 
photophobia, phonophobia and nausea. At time 0 (pre dose) subjects will select from the
accompanying symptoms present (nausea, phonophobia or photophobia) which one is the most 
bothersome to them. Subjects will be asked to record the presence or absence (yes or no) of 
vomiting. Subjects will also be asked to record the exact time at which headache relief became 

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meaningful to them and the time at which they become headache pain free.  At 2 hours subjects 
will be asked to record their global impression of change using a 7-point scale (very much 
better, much better, a little better, no change, a little worse, much worse, and very much 
worse).
The diary will also be used to record any symptoms or side effects the subject is experiencing 
and the use of any concomitant medications.  The diary is to be completed for the duration of a 
subject’s participation in the study. 
9.1.8.1
Recording Use of Rescue Medication and Migraine Symptoms
Any use of a rescue medication (other than study drug) taken because headache pain freedom
is not achieved at 2 hours will be recorded. Subjects will document the date and time of dosing 
for rescue and any migraine symptoms they are experiencing at time of dosing and at time 
points specified above.  Migraine pain will be graded as none (0), mild (1), moderate (2) or 
severe (3) and other symptoms (nausea, phonophobia, or photophobia) will be recorded as yes 
or no. At time 0 (pre dose) subjects will select from the accompanying symptoms present 
(nausea, phonophobia or photophobia) which one is the most bothersome to them. Subjects 
will be asked to record the presence or absence (yes or no) of vomiting. Subjects will also be
asked to record the exact time at which headache relief became meaningful to them and the 
time at which they become headache pain free. 
9.1.8.2
Recording Recurrence and Migraine Symptoms
If migraine recurs within 48 hours of dosing, the subject will note the exact time when the
headache returns to mild, moderate, or severe intensity after being pain free. For subjects 
randomized to lasmiditan 100 mg, subjects will document the time they take the second 
dose of study drug and any migraine symptoms they are experiencing at the time of dosing 
and at time points specified above.
Migraine pain will be graded as none (0), mild (1), 
moderate (2), or severe (3) and other symptoms (nausea, phonophobia, or photophobia) will 
be recorded as yes or no.  At time 0 (pre dose) subjects will select from the accompanying 
symptoms present (nausea, phonophobia or photophobia) which one is the most bothersome 
to them. Subjects will be asked to record the presence or absence (yes or no) of vomiting. 
Subjects will also be asked to record the exact time at which headache relief became
meaningful to them and the time at which they become headache pain free. 
9.2
Adverse Events and Serious Adverse Events
9.2.1
Adverse Events
An AE is defined as any undesirable physical, psychological, or behavioral effect experienced 
by a subject during his/her participation in an investigational study, in conjunction with the use of 
the drug, whether or not product-related.
During the treatment of a migraine with study drug 
subjects will be asked if they are feeling anything unusual that they have not felt with a migraine 
before. A ‘yes’ response will trigger an alert to the site to contact the subject and assess the AE
in terms of what the subject is experiencing, how long the symptoms lasted and how much the 
symptom(s) impacted them. During the time between dosing, subjects will be asked how they 
are feeling. A response of ‘not well’ will trigger an alert to the site to contact the subject and 
assess the AE similarly to the assessment of AEs reported during treatment.  The occurrence of 
AEs should also be reviewed by non-directive questioning of the subject at each visit in the 
study.  AEs may include, but are not limited to:
•
Subjective or objective symptoms spontaneously offered by the subject and/or observed by 
the Investigator or medical staff, and

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•
Changes in laboratory abnormalities that are clinically relevant as assessed by the 
Investigator and for which a medical intervention was initiated. 
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use of 
the product are not considered AEs after treatment unless they reoccur after the subject has 
recovered from the pre-existing condition or, in the opinion of the Investigator; they represent a 
clinically significant exacerbation in intensity or frequency. AEs are collected from the time the 
subject signs the informed consent form until the completion of EoS/ ET/Visit 6.  AEs reported 
prior to dosing will be captured and considered non-treatment emergent AEs. AEs reported 48 
hours after dosing a migraine and between migraines will be captured and considered non-
treatment emergent AEs.   
All AEs must be recorded in the site’s study records and the AE CRF with the following 
information:
1. Relationship to Study Drug:  The Investigator must assess whether they consider an AE to 
be drug-related. In assessing this relationship, the Investigator must use information about 
the drug as outlined in the Investigator’s Brochure (IB), the subject’s pre-existent medical 
conditions/concurrent medication, and chronology of the event relative to drug 
administration. The following definitions will be used:

Reasonably or possibly related applies to those AEs that, after careful medical 
consideration at the time they are evaluated, are considered by the Investigator (or 
other qualified physician) to have at least a possible relationship to study drug.

Not reasonably or not possibly related applies to those AEs that, after careful 
medical consideration at the time they are evaluated, are considered by the 
Investigator (or other qualified physician) to have no relationship, or no reasonable 
possibility of a relationship, to study drug.
2. Event Severity:  The Investigator will be asked to assess the severity of the AE using the 
WHO Toxicity Criteria, as shown in Appendix 1. The WHO criteria assign a grade of 1 
through 4 to indicate the severity of AEs. For AEs that are not listed in the WHO criteria, the 
Investigator will use medical judgment to assess the severity of the AE.
The following are guidelines to be used by the Investigator to judge the event severity of an 
AE that is not in the WHO Toxicity Criteria:

Mild - awareness of sign or symptom, but easily tolerated
   Moderate - discomfort enough to cause interference with usual activity
   Severe - incapacitating with inability to work or perform usual activity
   Life Threatening
3. Duration: Start and end dates and times, or if continuing.

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4. Action taken.
5. Whether it constitutes a SAE, per definition below.
6. Outcome: resolved, resolved/ with sequelae, continuing, death, or unknown (only for 
subjects that are lost to follow-up).
The investigator (or designee) should attempt to establish a diagnosis of the AE based on the 
sign, symptoms and/or other clinical information.  In such cases, the diagnosis, and not the 
individual signs/symptoms or laboratory abnormalities should be documents in the subject’s 
source documentation and the CRF unless the etiology of the event is unknown.  An 
assessment should be made at each visit (or more frequently if necessary) of any changes in 
severity, the suspected relationship to study drug, the interventions required to treat it and the 
outcome.
9.2.2
Treatment Emergent Adverse Events (TEAE)
A TEAE will be an AE that occurred during the study after the first dose of study drug or that 
was present prior to dosing and exacerbates after the first dose of study drug. Based on the 
half-life of study drug (3.5-4 hours) and the varied time between dosing a migraine attack, the 
temporal relationship of an adverse event to time of dosing will be as assessed prior to 
considering the adverse event to be a TEAE. Any new AE recorded 48 hours after a dose of 
study drug will not be considered a TEAE.
9.2.3
Serious Adverse Events
An SAE is any AE that results in any of the following outcomes:
•
Death: This includes death unrelated to the study drug (e.g. car accident).  If a subject dies 
during the study and an autopsy is performed, autopsy results will become part of the 
subject’s study chart and a copy should be sent to the Sponsor.
•
Life-threatening experience
•
Required or prolonged inpatient hospitalization:
Exceptions will be hospitalizations for a) 
elective or preplanned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since the start of study drug or b) treatment on an 
emergency outpatient basis for an event not fulfilling any of the definitions of a SAE and not 
resulting in hospital admission 
•
Persistent or significant disability/incapacity
•
Congenital anomaly
•
Important medical events that may not result in death, be immediately life threatening, or 
require hospitalization may be considered a SAE when, based upon medical judgment, they 
may jeopardize the patient and may require intervention to prevent one of the outcomes 
listed above.
9.2.4 Unexpected Adverse Event
An unexpected adverse event is defined as an AE, the nature or severity of which is not 
consistent with the information in the Investigator’s Brochure for lasmiditan.
9.3
Reporting Serious Adverse Events
The Investigator is responsible for reporting all SAEs, regardless of causality, to the Sponsor 
or their designated representative by entering the information into the eCRF within 24 hours of 
learning of the occurrence.  The reporting timeframe starts when the subject signs the informed 

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consent form and ends following the last dose of study treatment at EoS/ET/Visit 6.  At a 
minimum, a description of the event and the Investigator’s judgment of causality must be 
provided at the time of the initial report. These preliminary reports will be followed by detailed 
descriptions that will include copies of de-identified hospital case reports, autopsy reports, and 
other documents when requested and applicable.
Complications or progression of an initial SAE must be reported as a follow-up SAE Report to 
the original SAE, regardless of when the follow-up information is received by the Investigator.  A 
follow-up SAE Report must be submitted within 24 hours of the Investigator receiving the 
follow-up information.  An SAE that is considered completely unrelated to a previously reported 
one should be reported separately as a new SAE.
Follow-up information should be communicated by updating the data in the SAE eCRF. The 
follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, and whether the subject continued or withdrew from study participation. 
If the SAE was not previously documented in the Investigator’s Brochure and is thought to be 
related to study drug, the Sponsor or their designee may urgently require further information 
from the Investigator for regulatory authority reporting. The Sponsor may need to issue an 
Investigator Notification to inform all investigators involved in any study with the same drug that 
this SAE has been reported.
The Investigator and study personnel should institute any supplemental investigations of SAEs 
based on their clinical judgment of likely causative factors. This may include clinical laboratory 
tests not specified in the protocol, histopathologic examinations, or consultations with 
specialists.
The Sponsor or their designee may also request the Investigator to conduct 
supplemental assessments.
The Investigator should notify Quintiles Pharmacovigilance of any death or SAE occurring after 
a subject has withdrawn from the study when such a death or SAE may reasonably be related 
to the study drug. However, the Investigator is not obligated to actively seek adverse events in 
former study participants.
9.4
Follow-up of adverse events
All SAEs and any non-serious adverse events or laboratory abnormalities resulting in premature 
discontinuation will be followed until they have resolved, returned to baseline, or are determined 
to be chronic or stable by the Investigator.  Other non-serious adverse events should be 
followed through the EoS/ET/Visit 6.  
9.5
Reporting safety information to the IRB/EC
The Investigator is responsible for following all local regulations for the reporting of safety 
information, including the reporting of SAEs to the IRB/ EC.
The Investigator must promptly report to his or her IRB/EC all unanticipated problems involving 
risks to subjects.  This includes death from any cause and all serious adverse events 
reasonably or possibly associated with the use of study drug.  It is recommended that all SAEs 
occurring at a site, regardless of causality, be reported to the site’s IRB/EC in accordance with 
the IRB/EC’s requirements.

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Lasmiditan has been filed under an Investigational New Drug (IND) application with the US 
FDA.  An SAE may require safety reports to be filed to regulatory agencies if the SAE is related 
to the study drug and is unexpected based upon the current Investigator’s Brochure.  In this 
case, the Investigator will receive a copy of the safety report as submitted to the regulatory 
agencies.  The Investigator is responsible for submitting the safety report (initial and follow-up) 
or other safety information (e.g., revised Investigator’s Brochure) to the IRB/EC in accordance 
with the IRB/EC’s requirements and keep a copy in their files.
9.6
Pregnancies
To ensure subject safety, each pregnancy in a subject on study drug must be reported to the 
medical monitor within 24 hours of learning of its occurrence.  Subjects who become pregnant 
will be withdrawn from the study.  The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy should be recorded on a subject’s source documents and a Pregnancy Notification 
and Outcome Form and reported by the Investigator to Quintiles Pharmacovigilance using the 
same procedure for reporting SAEs in Section 9.3. A pregnancy, by itself, is not a SAE.  
Pregnancy follow-up should also be recorded and should include an assessment of the possible 
relationship to the study drug of any pregnancy outcome. Any pregnancy-related SAE (e.g. 
spontaneous abortion) or any other SAE experienced during pregnancy must be recorded on a 
separate SAE Report Form and reported per SAE reporting procedures in Section 9.3.
10.
STATISTICS
Prior to locking the database, a detailed statistical analysis plan will be developed before any
receipt of study data and decisions will be made regarding the integrity of subject data for 
inclusion in the statistical analysis.  All safety analyses will be based on the Safety Population. 
The efficacy analyses and baseline characteristics will be based on the Intent-to-Treat (ITT) and 
mITT population. The Per Protocol Population will be used to support the ITT analyses.
The primary objective of this study is to evaluate the safety and tolerability of long-term
intermittent use of lasmiditan 100 mg and of lasmiditan 200 mg, as the first and as a second
dose, in the acute treatment of migraine.
The secondary objective of the study is to explore the long-term efficacy of lasmiditan 100 mg 
and lasmiditan 200 mg in terms of headache response over time.
Summary analysis of the safety and efficacy of the use of a second dose of lasmiditan for either 
rescue or recurrence will be performed only in the subjects that actually took a second dose of 
study drug within 24 hours of the first dose.  Analysis will be performed on the subset of 
subjects that dosed for rescue and on the subset that dosed for recurrence of migraine.
Data from all investigative sites will be pooled for all planned analyses.  Analysis of individual 
site findings will be considered if necessary.  For those measures that are summarized using 
change from baseline scores, observed scores may also be presented descriptively.

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Any changes in the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other changes to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the statistical analysis plan as well as the clinical study report.  Additional exploratory 
analyses will be conducted as deemed appropriate.  All data listings, summaries and analyses 
will be performed by Quintiles.
10.1 Sample Size
This Phase 3 study is designed to demonstrate that lasmiditan is safe in the long-term 
intermittent treatment of acute migraine in adult patients with and without aura. The sample size 
was chosen to provide an appropriate long-term safety database. It is not based on any
statistical hypothesis. In accordance with ICH guidelines, the goal is at least 300 patients will 
treat an average of 2 migraines per month for 6 months and at least 100 patients will treat an 
average of 2 migraines per month for 12 months.
10.2 Randomization 
This is a multicenter, randomized, open-label, parallel group study.  
Subjects will be centrally randomized to one of two treatments to receive lasmiditan 200 mg 
(L200 mg) or lasmiditan 100 mg (L100 mg) in a 1:1 ratio.  Subjects will be stratified (yes or no) 
for use of concomitant medications that reduce the frequency of migraine episodes.  Subject will 
be randomized and study drug will be dispensed at each study visit.
10.3 Analysis Populations
10.3.1 Disposition
The summary of disposition, the percentage of patients who received a dose of study drug, and 
subject data listings will be based on the randomized population:
Randomized 
population
All randomized subjects. Subjects are evaluated by the drug to 
which they are randomized. 
10.3.2 Primary efficacy – FIRST dose
The statistical analysis of the first dose will be based on the analysis populations as defined 
below:
Safety population
All randomized subjects who use at least one dose of study 
drug, regardless of whether or not they undergo any study 
assessments.  Subjects are evaluated by the drug they use, not 
by the drug to which they are randomized.

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ITT population
mITT population
All randomized subjects who use at least one dose of study drug
and have any post-dose assessments.  Subjects are evaluated 
by the drug to which they are randomized.
All randomized subjects who use at least one dose of study drug 
to treat a qualifying migraine attack and have any post-dose
assessments. Subjects are evaluated by the drug to which they 
are randomized.
PP population
All ITT subjects will be considered per protocol (PP) if they dose 
any migraine attacks and do not deviate from the protocol.
The following is a list of additional protocol violations which would exclude subjects from the PP 
population:  

Subject received excluded rescue medications or used rescue medication before 2 hour 
time point. 

Subject used recurrence medication before 2 hour time point.

Subject did not receive study drug as assigned.

Subject did not meet all inclusion/exclusion criteria.

Subject did not treat a migraine of at least moderate severity.
10.3.3
Second Dose Analysis Populations
The analysis populations for the second dose used for rescue or for recurrence will be as 
defined below. 
Subjects must have taken the second dose and have been considered 
evaluable for the first dose and primary analysis to be included in the second dose analysis. 
Safety population
All randomized subjects who were considered in the safety 
population after the first dose and used a second dose of study 
drug, regardless of whether or not they undergo any study 
assessments.  Subjects are evaluated by the drug they receive, 
not by the drug to which they are randomized.
ITT-2nd Dose
population
mITT-2nd Dose
population
All randomized subjects who were considered ITT after the first 
dose and used a second dose of study drug and have any 
post-dose assessments.  Subjects are evaluated by the drug to 
which they are randomized.
All randomized subjects who were considered mITT after the first 
dose and used a second dose of study drug and have any 
post-second dose assessments. Subjects are evaluated by the 
drug to which they are randomized.
PP-2nd Dose
population
All ITT subjects will be considered per protocol (PP) if they use a 
second dose for rescue or recurrence of a migraine attack and 
do not deviate from the protocol. 

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The 2nd dose ITT, mITT and PP analysis populations will be further qualified by reason for 
second dose. Subjects will be considered in the 2nd dose rescue populations or 2nd dose 
recurrence populations as defined:

Rescue population: All randomized subjects who did not achieve headache pain free at 
2 hours, completed the 2 hour assessments and took a second dose of study drug 
between 2 hours and 24 hours. 

Recurrence population: All randomized subjects who achieved headache pain free at 2 
hours, but then experienced recurrence of mild, moderate or severe migraine pain and 
took a second dose of study drug up to 24 hours from the first dose.
10.4 Accountability and Background Characteristics
10.4.1 Enrollment and Disposition
The number of subjects enrolled, by study population and Investigative site, will be presented by 
treatment.  The primary reasons for discontinuation will be summarized by treatment and based 
on the safety population.  The number and percentage of subjects with protocol deviations 
leading to exclusion from the PP population will be presented by reason for exclusion, stratified 
by treatment.  All deviations will be listed.
10.4.2 Subject Characteristics
Subject characteristics will be obtained at the Screening/Visit 1 prior to randomization and will 
be summarized by treatment arm and overall. Summaries will include descriptive statistics for 
continuous measures (sample size, mean, standard deviation, median, minimum, maximum) 
and for categorical measures (sample size, frequency and percentages).  
The results of these tests will be used in a descriptive way to highlight potential imbalances 
between the treatment groups.  Subject characteristics may include, but are not limited to: age, 
gender, race/ethnicity, height, weight, BMI, and migraine history.
Subject characteristics will be summarized on all study populations.
10.4.3 Treatment Exposure
Treatment exposure will be assessed in terms of the actual dose.  Summary statistics will be 
performed on the number of subjects who took a first dose for the treatment of their migraine 
and the number of subjects who took both a first and second dose.  The average dosage used 
per month in three month intervals and the cumulative doses taken over the course of the study 
will be summarized within each treatment arm using descriptive statistics (n, mean, SD, median, 
minimum, and maximum).
10.5 Safety Analyses
Values for all safety variables will be listed by subject and time point as appropriate.
Where appropriate, safety variables will be summarized by using descriptive statistics, 
separated by treatment arm and dose (the first dose and the second dose for recurrence or 
rescue or use of alternative rescue medication), and time of assessment. Descriptive statistics 
for quantitative variables will include: n, mean, median, minimum, maximum, and standard 
deviation.
Descriptive statistics for qualitative variables will include frequency counts and 

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percentages. Adverse events will be summarized in terms of the proportion of patients and the 
proportion of attacks associated with any adverse event and with specific adverse events.
10.5.1 Adverse Events 
AEs will be coded by the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms, 
and all summary tables for AEs will be organized by these categories. Frequency counts and 
percentages will be presented for subjects with AEs within each system organ class and 
preferred term, separated by treatment arm and dose (the first dose and the second dose for 
recurrence or rescue or alternative rescue medication).  Both subjects ever experiencing an 
event as well as total events will be presented.  Descriptive statistics will also be calculated for 
each treatment arm and dose (initial and second dose for recurrence or rescue medication) for
AE relationship and AE severity. If multiple intensities are reported for a given AE for a subject, 
the most severe intensity will be counted. A separate, similar analysis will be conducted for 
TEAEs.
An AE with the date of onset on or within 48 hours after a dose of study drug, or an event that 
worsens in intensity within 48 hours of a dose of study drug will be considered a TEAE.  An AE 
that occurs in the interval after 48 hours of dosing until the next migraine is dosed will not be 
considered a TEAE.
SAEs and TEAEs that resulted in termination of the study drug and withdrawal from the study 
will be presented.
10.5.2 Physical Examinations, Vital Signs, ECG Parameters and Clinical Laboratory Test 
Values
By-subject listings of physical examinations, vital signs, ECG parameters and clinical laboratory 
data will include indications of values that are outside the reference ranges, and values that are 
clinically significant.  Observed and change from baseline (Screening/Visit 1) values for vital 
signs, ECGs, and clinical laboratory test results will be summarized as appropriate by treatment 
arm and dose. Shift tables describing out-of-reference range shifts will be provided for vital 
signs, ECGs and clinical laboratory test results from the Screening/Visit 1 to EoS/Visit 6, as 
appropriate by treatment arm and dose.
10.5.3 C-SSRS
By-subject listings of any suicidal ideation or behavior will be listed.
10.6 Efficacy Analyses
This is an open-label study with no control group.  Efficacy data will be summarized using 
descriptive statistics. The proportion of attacks treated with lasmiditan 100 mg and with 
lasmiditan 200 mg which respond at 2 hours will be calculated for each 3 month period.
10.6.1 Headache Response
Headache pain free at 2 hours will be defined as a reduction in headache severity from 
moderate (2) or severe (3) at baseline to none (0) two hours after dosing with study drug.  MBS  
free at 2 hours will be defined as a ‘no’ response to the presence of the symptom (either 
nausea, phonophobia, or photophobia) that was identified as MBS at predose, 2 hours after 
dosing with study drug.
A qualifying migraine is defined as a migraine treated with study drug within 4 hours of onset

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Subjects taking rescue medication within the first two hours or who fail to record headache 
severity at 2 hours will be assumed to be non-responders in the mITT and the ITT analyses.  
A subject is defined to have used rescue medication within the first two hours post dosing if at 
least one medication is documented in the rescue medication log in the subject electronic diary 
for which:
0 (min) < 
date/ time rescue medication (diary) –
date/ time of dosing (diary) < 120 (min).
Subjects who do not provide a headache pain severity rating at baseline or who use other 
medication prior to the study drug for the study migraine attack will be assumed to be non-
responders for the mITT and ITT analysis.
10.6.2 Sensitivity Analyses of the Primary and Key Secondary Endpoints
The analyses of pain free at 2 hours and of MBS free at 2 hours are defined as proportions.  
The prespecified approach for handling missing data is to assume that subjects with missing 
data are nonresponders.  While this approach is appropriately conservative, a sensitivity 
analysis will be incorporated to exclude subjects with missing data.
10.6.3 Other Efficacy Analyses
10.6.3.1
Headache relief
The proportion of attacks treated with study medication with headache relief (moderate or
severe headache at baseline, which became mild or none, or mild headache which became
none) at 2 hours post dose will be evaluated. The time course to headache relief will be 
explored up to 48 hours. 
10.6.3.2
Headache recurrence
The proportion of attacks treated with study medication with headache recurrence (moderate or
severe headache at baseline, which became pain free at 2 hours post-dose and worsened
again up to 48 hours post-dose) will be evaluated based on first dose.  
10.6.3.3
Headache rescue
The requirement for rescue medication at 2 hours and between 2 and 24 hours and 24- 48 
hours (yes or no) will be evaluated based on first dose. The information on rescue medication 
use will be presented descriptively by time of use and treatment arm.
10.6.3.4
Associated Symptoms of Migraine
Descriptive analysis of the associated symptoms of migraine, nausea, phonophobia and 
photophobia, will be performed at 2 hours. Freedom from each symptom will be defined as a 
‘no’ response to the presence of the symptom 2 hours after dosing with study drug. Summary 
statistics will be presented by treatment arm and timepoint as appropriate.
10.6.3.5
Additional analyses
Summary statistics will be presented on presence of vomiting, disability (4 point scale: not at all 
(0), mild interference (1), moderate interference (2), completely, needs bed rest (3)), and patient 
global impression of change (7 point scale) by treatment arm and timepoint as appropriate.

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10.7 Analysis of Second dose
10.7.1 Analysis of second dose for rescue
A second dose of study drug will be considered rescue medication if taken by a subject that did 
not achieve headache pain free at 2 hours and completed the 2 hour assessments prior to 
taking the second dose.
Summary statistics will be presented by treatment arm on relief of migraine symptoms (pain free
and MBS free) along with the time course to headache relief explored up to 48 hours.  Subjects 
that use an alternative rescue medication will not be included in the summary statistics of 
response to treatment for rescue.
10.7.2 Analysis of second dose for recurrence
A second dose of study drug will be considered treatment for recurrence if taken by a subject 
that achieved headache pain free at 2 hours, completed the 2 hour assessments, and then 
experienced documented recurrence of mild, moderate, or severe migraine pain prior to taking 
the second dose.  
Summary statistics will be presented by treatment arm on the relief of migraine symptoms (pain
free and MBS free) along with the time course to headache relief explored up to 48 hours. Only 
subjects that used a second dose of study drug for recurrence of migraine will be included in the 
summary statistics of response to treatment for recurrence.
10.8 Resource Utilization
By-subject listings of any resource utilization will be listed and will be summarized using 
descriptive statistics, separated by treatment arm and visit.  Days missed from work and/or 
school or daily activities will be tabulated from information recorded on the MIDAS scale
separated by treatment arm and visit.

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11.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
11.1. Study Monitoring
The investigator will allow the Sponsor or a designee:

to inspect the site, the facilities, and the material used for the study;

to meet all members of the team involved in the study;

to consult all the documents relevant to the study;

to check that the eCRFs have been correctly completed;

to have direct access to source documents for comparison of data therein with the data in 
the eCRFs;

to check that AEs have been documented; and

to verify that the study is carried out in compliance with the protocol.
This study will be monitored at regular intervals, by agreement of the Investigator.
All information dealt with during these visits will be treated as strictly confidential.
The Investigator will provide the sponsor with the following:

Progress reports at regular intervals

Adequately completed eCRFs
11.2
Data collection
Investigational sites will be supplied with instructions on accessing the web-based Electronic 
Data Capture (EDC) system via secure web portal.  Representatives of Lilly (or designee) will 
train designated site staff on the EDC system.  Investigational site staff will not be given access 
to the EDC system until the required training is completed and documented.  Designated site 
staff will enter the data required by the protocol into the electronic CRFs.  Automatic validation 
programs check for data discrepancies in the CRFs and, by generating appropriate error 
messages, allow modification or verification of the entered data by the site staff.  After database 
lock, the Investigator will receive a CD or DVD of the subject data for archiving at the 
investigational site. 
11.3
Audits and Inspections
The Investigator will be informed that an audit will be carried out, at the request of the Sponsor, 
before, during, or after the study.
The Investigator will be informed that the Regulatory Agencies may also carry out an inspection. 
In this case, the Investigator must inform the sponsor as soon as he receives the notification of 
inspection.
The Investigator must allow the representatives of the Regulatory Agencies and persons 
responsible for the audit:

to inspect the site, facilities, and material used for the study;

meet all members of his team involved in the study;

have direct access to study data and source documents; and

to consult all the documents relevant to the study.

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12.
QUALITY CONTROL AND QUALITY ASSURANCE
The Investigator or the appointed persons agree to complete the subject's eCRFs, at each 
investigation. Only the Investigator or appointed persons in his/her team may fill out or correct 
the eCRFs. The eCRFs will display the subject number corresponding to the order of inclusion 
in the study (7 digits) and the initials of the subject (1 letter for forename, 1 letter for middle 
name and 1 letter for surname).
The Sponsor or their designee will review the eCRFs entered by investigational site staff for 
completeness and accuracy and instruct the investigational site staff to make any required 
corrections or additions.  Queries will be sent to the investigational site using an electronic data 
query within the EDC system.  Designated investigational site staff will be required to respond to 
the query and make any necessary changes to the data.  
All corrections and alterations of data on the eCRFs must be made by the Investigator or by the 
appointed persons as instructed in the eCRF guidelines.
If corrections or alterations are 
required of paper source documents, corrections may be made in the following manner: strike 
through the datum to be corrected using a single line so that the original remains legible; 
correction fluid must never be used. The correction should be written to the side or above the 
original entry and must be initialed and dated by the Investigator or one of his designated team.
It is the responsibility of the monitor to make certain that all data are completed on the eCRFs.
The Investigator and the monitor must sign and date the eCRF per the eCRF procedure in order 
to attest respectively to the:

authenticity of the data collected in the eCRF, and

coherence between the data in the eCRF and those in the source documents.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system.  
Adverse events and medical history will be coded using the Medical dictionary for regulatory 
activities (MedDRA) terminology.
ECGs will be evaluated for safety through central readers and the results will be sent 
electronically to the study database.  Clinical laboratory samples will be processed through a 
central laboratory and the results will be sent electronically to the study database.
Randomization codes and data about all study drugs dispensed to the subject will be tracked 
using a centralized randomization process.  The system will be supplied by a vendor, who will 
also manage the database.  The database will be sent electronically to the study database (or a 
designated CRO).      
After the above actions have been completed and the database has been declared to be 
complete and accurate, it will be locked for data analysis.  Any changes to the database after 
that time can only be made with the approval of Lilly.
At the end of the study, the Investigator will receive a CD or DVD of all data submitted for 
subjects at that site.  This CD or DVD will serve as the archival copy and must be retained per 
the record retention policy.

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The Investigator will keep a log of volunteers screened for study participation as appropriate and 
will indicate the reason why individual volunteers did not enter the study. The log will be 
submitted to the CRO or their designee as defined in the study manual.  The Investigator must 
submit to the Sponsor or its representatives a completed eCRF for each subject who receives 
any study drug.
If computerized medical files are used, and if the computer system allows, no change made in 
the medical files by the Investigator should obscure the original information. The record must 
clearly indicate that a change was made and clearly provide a means to locate and read the 
prior information. The Investigator will save data at regular intervals.
The Investigator must guarantee the safety of the study data in the medical files by 
implementing security measures to prevent unauthorized access to the data and to the 
computer system.
13.
ETHICS
The study will be carried out in accordance with:

the text of the Declaration of Helsinki adopted by the World Medical Assembly in June 1964; 
amended in Tokyo, October 1975; in Venice, October 1983; in Hong-Kong, September 1989; 
in Somerset West, October 1996; and in Edinburgh, October 2000; updated with the 
clarification note, Washington 2002, and Tokyo 2004;

the ICH recommendations: Good Clinical Practice (E6), applied since January 17, 1997;

and other applicable regulations.
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
13.1 Ethics Review
13.1.1
IRB/EC opinion
Before initiation of the study, the Investigator must obtain approval or favorable opinion of the 
study, informed consent, privacy authorization, and any advertisement for subject recruitment 
from a properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start.  A signed and dated statement that the protocol 
and informed consent and advertisement (as applicable) have been approved by the 
IRB/IEC/REB must be given to Lilly or its designated representative(s) before study initiation.  
Prior to study start, the investigator is required to sign the Investigator statement page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol.
The Investigator is responsible for obtaining continued review of the study at intervals not 
exceeding one year or otherwise specified by the IRB/IEC/REB.  The Investigator must supply 
CRO/Lilly with written documentation of continued review of the clinical study.

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The Investigator must promptly inform their IRB/IEC/REB of all SAEs or other safety information 
reported from CRO/Sponsor.
13.2 Written Informed Consent
Subjects will be informed of the nature of the study, its aim, its possible risks and restrictions, its 
duration and the fee, if any, they will receive. The protocol will be explained during a meeting 
prior to the study and each subject must be informed that participation in the study is voluntary 
and that he/she may withdraw from the study at any time. At this meeting, an information sheet 
will be given to each subject. The subject should read the form and obtain answers to any 
questions prior to signing and dating the informed consent form. The process of obtaining 
informed consent should be documented in the subject source documents.  Each Investigator 
must retain the original signed and dated informed consent form.  A copy of the signed and 
dated informed consent form will be given to the subject.  No subject can enter the study, or 
have study specific assessments performed before his/her informed consent has been obtained.  
Lilly or its designated representative(s) will provide to Investigators in a separate document a 
proposed informed consent form that complies with the ICH GCP guideline and regulatory 
requirements and is considered appropriate for this study.  Any changes to the proposed 
consent form suggested by the Investigator must be agreed to by Lilly or its designated 
representative(s) before submission to the IRB/IEC/REB and a copy of the approved version 
must be provided to the Lilly monitor or designated representative(s) after IRB/IEC/REB 
approval.
13.3 Amendments to the protocol
To alter the protocol, amendments must be written by Lilly, and approvals must be received 
from all parties that approved the original protocol (IRB/IEC/REB, and if applicable, the local 
regulatory authorities) before implementation.  However, in cases where an amendment is 
required for subject safety, an amendment may be implemented prior to IRB/IEC/REB approval.  
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol.  
Lilly may make administrative changes (i.e., changes that do not significantly affect subject 
safety, the study’s scope or scientific quality) without a formal protocol amendment.
13.4 Discontinuation of the study
Lilly reserves the right to discontinue this study under the conditions specified in the clinical trial 
agreement.
13.5 Study drug supply, storage and tracking
Study drugs must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
assistants have access.  Upon receipt, all study drugs should be stored according to the 
instructions specified on the drug labels.  Drug labels will be in the local language and comply 
with the legal requirements of each country.  Clinical supplies are to be dispensed only in 
accordance with the protocol.

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Subjects will be asked to return all unused study drug and packaging at each clinic visit, at the 
end of the study or at the time of study drug discontinuation.  All empty, partially used containers 
and unused supplies may be destroyed at the site, retrieved by the study monitor or shipped to 
a designated facility identified by Lilly according to governmental regulations at the conclusion of 
this study (or as appropriate during the course of the study), per the instructions of the Sponsor. 
The Investigator will keep an accurate accounting of all study drug dispensed, destroyed or 
returned.  Monitoring of drug accountability will be performed by the monitor during site visits 
and at the completion of the trial.
13.6 Confidentiality
All study findings and documents will be regarded as confidential.  The Investigator and other 
study personnel must not disclose such information without prior written approval from Lilly.
Subject confidentiality will be strictly maintained to the extent possible under the law.  Subject 
names must not be disclosed.  Subjects will be identified on the CRFs and other documents 
submitted to Lilly, or its designated representative, by their initials and/or assigned subject 
number.  Documents that identify the subject (e.g., the signed informed consent form) should 
not be submitted to Lilly or its designated representative, and must be maintained in confidence 
by the Investigator.
13.7 Publication policy
The publication policy for Study H8H-CD-LAHL/COL MIG-305 is described in the Clinical Trial 
Agreement.   

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14.
RETENTION OF RECORDS
Retention of records is outlined in the Clinical Trial Agreement for this study.

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15.
REFERENCES
1.
Steiner, TJ, Stovner, LJ, Birbeck GL, Migraine: The seventh disabler. Cephalalgia 2013;
0:1-2.
2.
Buse DC, Serrano D, Pearlman SH, Ng-Mak DS, Reed ML, Lipton RB, Examination of 
Unmet Treatment Needs Among Persons with Episodic Migraine: Results of the 
American Migraine Prevalence and Prevention Study (AMPP). Abstract 2011.
3. 
Dodick DW, Lipton RB, Martin V, et al. Triptan Cardiovascular Safety Expert Panel. 
Consensus statement: cardiovascular safety profile of triptans (5-HT agonists) in the 
acute treatment of migraine. Headache 2004; 44:414—25.
4.
Humphrey PPA, Feniuk W, Perren MJ, Beresford IJM, Skingle M, Whalley ET. Serotonin 
and migraine. Ann NY Acad Sci 1990; 600:587—598
.
5.
Nilsson T, Longmore J, Shaw D, et al. Characterisation of 5-HT receptors in human 
coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol 1999a; 
372:49—56.
6. 
Maasen VanDenBrink A, Reekers M, Bax WA, Ferrari MD, Saxena PR. Coronary side-
effect potential of current and prospective antimigraine drugs. 
Circulation 1998; 98:25—30.
7.
Van den Broek RWM, Maasen VanDenBrink A, de Vries R, et al. Pharmacological 
analysis of contractile effects of eletriptan and sumatriptan on human isolated blood 
vessels. Eur J Pharmacol 2000; 407:165—73.
8.
Bigal ME, Kurth T, Santanello N, et al. Migraine and cardiovascular disease: A 
population-based study. Neurology 2010; 74:628—635.
9.
Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, et 
al.,Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. 
Cephalalgia 2010; 30(10):1159-1169.
10.
Shepheard S, Edvinsson L, Cumberbatch M, Williamson D, Mason G, Webb J, et al.,                        
Possible antimigraine mechanisms of action of the 5HT1F receptor agonist LY334370. 
Cephalalgia 1999; 19(10):851-858.
11.
Goadsby PJ, Classey JD, Evidence for serotonin (5-HT)1B, 5-HT1D and 5-HT1F receptor 
inhibitory effects on trigeminal neurons with craniovascular input. Neuroscience
2003;122(2):491-498.
12.
Cohen ML, Johnson KW, Schenck KW, Phebus LA, Migraine therapy: relationship 
between serotonergic contractile receptors in canine and rabbit saphenous veins to 
human cerebral and coronary arteries. Cephalagia 1997:17 (6):631-638.
13.
E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for           
Non-antiarrhythmic Drugs: Guidance to Industry, 2005.
14.
CoLucid Pharmaceuticals, Inc. COL-144 Investigator Brochure v9.0 February 2017.

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15.
Lipton RB, Bigal ME, Diamond F, et al. Migraine prevalence, disease burden, and the 
need for preventive therapy. Neurology 2007; 68:343—49.
16.
Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WE. Migraine diagnosis and 
treatment; results from the American Migraine Study II. Headache 2001; 41:638-645.

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16.
APPENDIX 1.  WORLD HEALTH ORGANIZATION TOXICITY CRITERIA
World Health Organization (WHO) Toxicity Criteria by Grade
Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Hematology 
WBC (x103/L) 
4 
3.0 - 3.9 
2.0 - 2.9 
1.0 - 1.9 
< 1.0 
Platelets (x103/L) 
WNL 
75.0 - normal 
50.0 - 74.9 
25.0 - 49.9 
< 25.0 
Hemoglobin (g/dL) WNL 
10.0 - normal 
8.0 - 9.9 
6.5 - 7.9 
< 6.5 
Granulocytes/ 
Bands (x103/L) 
2 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Lymphocytes 
(x103/L) 
2 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Haemorrhage 
none 
mild, no transfusion
gross, 1 - 2 units 
transfusion per episode 
gross, 3 - 4 units 
transfusion per episode 
massive, > 4 units 
transfusion per episode 
Coagulation 
Fibrinogen 
WNL 
0.99 - 0.75 x N 
0.74 - 0.50 x N 
0.49 - 0.25 x N 
< 0.25 x N 
Prothrombin 
time(Quick) 
WNL 
1.01 - 1.25 x N 
1.26 - 1.50 x N 
1.51 - 2.00 x N 
> 2.00 x N 
Partial thrombo-
plastin time 
WNL 
1.01 - 1.66 x N 
1.67 - 2.33 x N 
2.34 - 3.00 x N 
> 3.00 x N 
Metabolic 
Hyperglycaemia 
(mg/dL) 
< 116 
116 - 160 
161 - 250 
251 - 500 
> 500 or ketoacidosis 
Hypoglycaemia 
(mg/dL) 
> 64 
55 - 64 
40 - 54 
30 - 39 
< 30 
Amylase 
WNL 
< 1.5 x N 
1.5 - 2.0 x N 
2.1 - 5.0 N 
> 5.0 x N 
Hypercalcaemia 
(mg/dL) 
< 10.6 
10.6 - 11.5 
11.6 - 12.5 
12.6 - 13.4 
13.5 
Hypocalcaemia 
(mg/dL) 
> 8.4 
8.4 - 7.8 
7.7 - 7.0 
6.9 - 6.1 
6 
Hypomagnesaemia 
(mg/dL) 
> 1.4 
1.4 - 1.2 
1.1 - 0.9 
0.8 - 0.6 
0.5 
Gastrointestinal 
Nausea 
none 
able to eat reasonable 
intake 
intake significantly 
decreased but can eat 
no significant intake 
__ 
Vomiting 
none 
1 episode in 24 hrs 
2 - 5 episodes in 24 hrs 6 - 10 episodes in 24 
hrs 
> 10 episodes in 24 hrs 
or requiring parenteral 
support 
Diarrhea 
none 
increase of 2 - 3 stools / 
day over pre-Rx 
increase of 4 - 6 stools / 
day, or nocturnal stools, 
or moderate cramping 
increase of 7 - 9 stools / 
day, or incontinence, or 
severe cramping 
increase of > 10 stools / 
day or grossly bloody 
diarrhea, or need for 
parenteral support 

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Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Stomatitis 
none 
painless ulcers, 
erythema, or mild 
soreness 
painful erythema, 
oedema, or ulcers but 
can eat solids 
painful erythema, 
oedema, or ulcers and 
cannot eat solids 
requires parenteral or 
enteral support for 
alimentation 
Liver 
Bilirubin (N = 17 
µmol/L) 
WNL 
-----
< 1.5 x N 
1.5 - 3.0 x N 
> 3.0 x N 
Transaminase 
(SGOT, SGPT) 
WNL 
2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Alk Phos or 5 
nucleotidase 
WNL 
≥ 2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Liver- clinical 
no change from 
baseline 
-----
-----
pre-coma 
hepatic coma 
Kidney, Bladder 
Creatinine 
WNL 
< 1.5 x N 
1.5 - 3.0 x N 
3.1 - 6.0 x N 
> 6.0 x N 
Proteinuria 
no change 
1 (+) or < 0.3 g% or 3 
g/L 
2 - 3 (+) or 0.3 - 1.0 g% 
or ≥3 - 10 g/L 
4 (+) or > 1.0 g% or > 
10g/L 
nephrotic syndrome 
Haematuria 
negative 
microscopic only 
gross, no clots no Rx 
needed 
gross and clots bladder 
irrigation 
requires transfusion or 
cystectomy 
Weight gain/loss 
< 5.0 % 
5.0 - 9.9 % 
10.0 - 19.9 % 
20.00% 
-----
Pulmonary 
Pulmonary 
none or no 
change 
asymptomatic, with 
abnormality in PFTs 
dyspnoea on significant 
exertion 
dyspnoea at normal 
level of activity 
dyspnoea at rest 
Cardiac 
Cardiac 
arrhythmias 
none 
asymptomatic, transient, 
requiring no therapy 
recurrent or persistent, 
no therapy required 
requires treatment 
requires monitoring; or 
hypotension, or 
ventricular tachycardia 
or fibrillation 
Cardiac function 
none 
asymptomatic, decline 
of resting ejection 
fraction by less than 20 
% of baseline value 
asymptomatic, decline 
of resting ejection 
fraction by more than 20 
% of baseline value 
mild CHF, responsive to 
therapy 
severe or refractory 
CHF 
Cardiac ischaemia none 
non-specific T- wave 
flattening 
asymptomatic, ST and T 
wave changes 
suggesting ischaemia 
angina without evidence 
of infarction 
acute myocardial 
infarction 
Cardiac- pericardial none 
asymptomatic effusion, 
no intervention required 
pericarditis (rub, chest 
pain, ECG changes) 
symptomatic effusion; 
drainage required 
tamponade; drainage 
urgently required 
Hypertension 
none or no 
change 
asymptomatic, transient 
increase by greater than 
20 mm Hg (D) or to 
> 150/100 if previously 
WNL. No treatment 
required. 
recurrent or persistent 
increase by greater than 
20 mm Hg (D) or to 
> 150/100 if previously 
WNL. No treatment 
required. 
requires therapy 
hypertensive crisis 

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Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Hypotension 
none or no 
change 
changes requiring no 
therapy (including 
transient orthostatic 
hypo- tension) 
requires fluid 
replacement or other 
therapy but not 
hospitalization 
requires therapy and 
hospitalization; resolves 
within 48 hours of 
stopping the agent 
requires therapy and 
hospitalization for > 48 
hrs after stopping the 
agent 
Neurologic 
Neuro: sensory 
none or no 
change 
mild paraesthesias; loss 
of deep tendon reflexes 
mild or moderate 
objective sensory loss; 
moderate paraesthesias 
severe objective 
sensory loss or 
paraesthesias that 
interfere with function 
-----
Neuro: motor 
none or no 
change 
subjective weakness; no 
objective findings 
mild objective weakness 
without significant 
impairment of function 
objective weakness with 
impairment of function 
paralysis 
Neuro: cortical 
none 
mild somnolence or 
agitation 
moderate somnolence 
or agitation 
severe somnolence, 
(>50 % waking hours), 
agitation, confusion, 
disorientation or 
hallucinations 
coma, seizures, toxic 
psychosis 
Neuro: cerebellar 
none 
slight incoordination, 
dysdiadochokinesia 
intention tremor, 
dysmetria, slurred 
speech, nystagmus 
locomotor ataxia 
cerebellar necrosis 
Neuro: mood 
no change 
mild anxiety or 
depression 
moderate anxiety or 
depression 
severe anxiety or 
depression 
suicidal ideation 
Neuro: headache 
none 
mild 
moderate or severe but 
transient 
unrelenting and severe -----
Neuro: constipation none or no 
change 
mild 
moderate 
severe 
ileus > 96 hrs 
Neuro: hearing 
none or no 
change 
asymptomatic, hearing 
loss on audiometry only tinnitus 
hearing loss interfering 
with function but 
correctable with hearing 
aid 
deafness not 
correctable 
Neuro: vision 
none or no 
change 
-----
-----
symptomatic subtotal 
loss of vision 
blindness 
Pain 
Pain 
none 
mild 
moderate 
severe 
reg. narcotics 
Skin 
Skin 
none or no 
change 
scattered macular or 
papular eruption or 
erythema that is 
asymptomatic 
scattered macular or 
papular eruption or 
erythema with pruritus 
or other associated 
symptoms 
generalized 
symptomatic macular, 
papular or vesicular 
eruption 
exfoliative dermatitis or 
ulcerating dermatitis 
Alopecia 
Alopecia 
no loss 
mild hair loss 
pronounced or total hair 
loss 
-----
-----
Allergy 
Allergy 
none 
transient rash, drug 
fever < 38oC (100.4oF) 
urticaria, drug fever 
38oC (100.4oF), mild 
bronchospasm 
serum sickness, 
bronchospasm requiring 
parenteral medication 
anaphylaxis 

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Category
Toxicity
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Local 
Local 
none 
pain 
pain and swelling with 
inflammation or phlebitis ulceration 
plastic surgery indicated 
Fever of unknown 
origin 
Fever of unknown 
origin 
none 
37.1 - 38.0oC 
(98.7o - 100.4oF) 
38.1 - 40.0oC 
(100.5 - 104oF) 
> 40.0oC (> 104.0oF) for 
less than 24hrs 
> 40.0oC (>104oF) for 
more than 24 hrs or 
accompanied by 
hypotension 
Infection 
Infection 
none 
mild 
moderate 
severe 
life-threatening 
Additional events 
Asthenia 
analogous to 
Karnofsky index 
(WHO grading) 
Chills 
analogous to 
fever 
Peripheral oedema analogous to 
weight gain 
Anorexia 
analogous to 
weight loss 

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17.
APPENDIX 2. MIGRAINE DISABILITY ASSESSMENT TEST
The MIDAS (Migraine Disability Assessment) questionnaire was put together to help you measure the
impact your headaches have on your life. The information on this questionnaire is also helpful for your
primary care provider to determine the level of pain and disability caused by your headaches and to find
the best treatment for you.
INSTRUCTIONS: Please answer the following questions about ALL of the headaches you have had over 
the last 3 months. Record your answer in the box next to each question.  Select zero if you did not have the 
activity in the last 3 months
__________ 1. On how many days in the last 3 months did you miss work or school
because of your headaches?
__________ 2. How many days in the last 3 months was your productivity at work or
school reduced by half or more because of your headaches? (Do not
include days you counted in question 1 where you missed work or
school.)
__________ 3. On how many days in the last 3 months did you not do household work
(such as housework, home repairs and maintenance, shopping, caring
for children and relatives) because of your headaches?
__________ 4. How many days in the last 3 months was your productivity in household
work reduced by half of more because of your headaches? (Do not
include days you counted in question 3 where you did not do household
work.)
__________ 5. On how many days in the last 3 months did you miss family, social or
leisure activities because of your headaches?
__________ Total (Questions 1-5)
__________ A. On how many days in the last 3 months did you have a headache? (If a
headache lasted more than 1 day, count each day.)
__________ B. On a scale of 0 - 10, on average how painful were these headaches?
(where 0 = no pain at all, and 10 = pain as bad as it can be.)
Scoring: After you have filled out this questionnaire, add the total number of days from questions 1 to 5 
(ignore A and B).
MIDAS Grade
Grade Definition
MIDAS Score
I
Little or no disability
0-5
II
Mild disability
6-10
III
Moderate disability
11-20
IV
Severe disability
21+
Please give the completed form to your clinician.
This survey was developed by Richard B. Lipton, MD, Professor of Neurology, Albert Einstein College of Medicine, New York, NY, 
and Walter F. Stewart, MPH, PhD, Associate Professor of Epidemiology, Johns Hopkins University, Baltimore, MD.

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CCI

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CCI

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CCI

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CCI

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CCI

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19.
APPENDIX 4. Process to Re-start subjects affected by 
administrative hold
The following outlines the procedures for discontinuing the subjects enrolled in GLADIATOR 
from October 7, 2015 to November 10, 2015 and to re-enroll those subjects that wish to 
continue on study. 
1)     For subjects that have NOT dosed:
a.      Please contact these subjects and request them to return to the clinic and return 
all IP and their eDiary.
b.     No other procedures are required since they did not dose (confirmed on 
returning the dosing card of 8-tablets).
d.     Discontinue the subject in Cenduit.
e.     Discontinue the subject in the eDiary (Refer to page 66 in the ERT Site Manual).
f.       Discontinue subject in EDC.
g. IF the subject does not wish to be re-enrolled, subject’s participation is complete.
h.   IF the subject wishes to be re-enrolled:

Consent subject as though subject is new to the study.

Complete all Visit 1 assessments as outlined in the protocol (Section 5.6.1).

Review the diary and re-start the subject in the diary.

Re-enroll the subject and dispense study drug.  Please NOTE: the subject 
may not be randomized to the same dose as they had been previously.
2)     For subjects who DOSED and already completed a Visit 2 as Visit 2 and not an ET visit:
a.      Please contact these subjects and request them to return to the clinic and return 
all IP   and their eDiary
b.     Discontinue subject in Cenduit
c.      Discontinue subject in the eDiary (Refer to page 66 in the ERT Site Manual)
d.     Discontinue subject in EDC
e.      IF the subject does NOT wish to be re-enrolled

AND at Visit 2, you did not collect an ECG and record weight (as required at 
an ET visit (V6/ET – Section 5.6.5) perform an ECG and record weight as 
part of this ET visit.

IF at Visit 2 you did collect an ECG and record weight the subject’s 
participation is complete.
f.       IF the subject wishes to be re-enrolled:

Consent subject as though subject is new to the study.

Complete all Visit 1 assessments as outlined in the protocol (Section 5.6.1).

Review the diary and re-start the subject in the diary.

Re-enroll the subject and dispense study drug.  Please NOTE: the subject 
may not be randomized to the same dose as they had been previously.
3)     For patients who dosed and who haven’t had a visit yet
a.      Please contact these subjects and request them to return to the clinic and return 
all IP   and their eDiary 
b. Discontinue the subject in Cenduit
c.     Discontinue the subject in eDiary (Refer to page 66 in the ERT Site Manual)
d.    Discontinue subject in EDC
e.       IF the subject does NOT wish to be re-enrolled

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
Complete ALL Visit 6/ET assessments as outlined in the protocol (Section 
5.6.5).

The subject’s participation is complete.
f.       IF the subject wishes to be re-enrolled:

Consent subject as though subject is new to the study.

Complete all Visit 1 assessments as outlined in the protocol (Section 5.6.1).

Review the diary and re-start the subject in the diary.

Re-enroll the subject and dispense study drug.  Please NOTE: the subject 
may not be randomized to the same dose as they had been previously
Note – all data collected from the subjects enrolled from October 7, 2015 to November 10, 2015 
and affected by this administrative hold will be reported. Dosing information as well as safety 
data (AEs, clinical laboratories, ECGs, physical examinations and vital signs) will be kept in the 
database, separated by date and included in the final study report. 

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20.
APPENDIX 5. Liver Safety:  Suggested Actions and Follow-Up 
Assessments 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and 
may be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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21.
APPENDIX 6. Protocol Amendment History
Protocol H8H-CD-LAHL/COL MIG-305 [An Open-label, Long-term, Safety Study of Lasmiditan
(200 mg and 100 mg) in the Acute Treatment of Migraine] has been amended.  The new 
protocol is indicated by amendment (D)/V4 and will be used to conduct the study in place of any 
preceding version of the protocol.
The rationale for the amendment include the following:

As part of the lasmiditan clinical development process, Lilly reviewed the totality of the 
lasmiditan data, including the recently concluded Study LAIF that assessed duration of 
driving impairment at a maximum lasmiditan dose of 200 mg.  In light of the lack of 
driving study data on potential impairment at doses above 200 mg, Lilly has determined 
that the maximum permitted dose in 24 hours will be 200 mg across the lasmiditan 
clinical development program.  Therefore, patients in this study will be instructed to no 
longer take a second dose of lasmiditan 200 mg in a 24-hour period.  

While a second dose of lasmiditan 100 mg will continue to be permitted, pooled results 
of prior studies do not provide clear evidence of clinical benefit when a second dose is 
taken for rescue.  However, there is some evidence that a second dose of 100 mg could 
be effective for headache recurrence (the pain goes away completely and later returns).  
Therefore the study is limiting second dose with lasmiditan 100 mg to use for recurrence 
only.

The re-dispensing of unused study drug is no longer allowed, and therefore language 
pertaining to re-dispensing has been deleted.

As lasmiditan was associated with driving impairment in a study of healthy volunteers on 
a computer-based driving simulator, language was updated to indicate patients should 
restrict their driving, operation of heavy machinery, or other similar activities after taking 
study drug as described in the ICF.

As the standard Lilly hepatic monitoring language and tests were omitted from the study 
when the protocol was previously updated, these have been included in order to 
effectively assess abnormalities pertaining to hepatic laboratory analytes.

Clarification to the schedule of activities footnote was made to indicate that repeat and/or 
additional laboratory testing may be necessary if clinically significant laboratory results 
are obtained.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:

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Amendment Summary for Protocol H8H-CD-LAHL(D)/COL MIG-305 V4
Section # and Name
Description of Change
Brief Rationale
3 List of Abbreviations
Added abbreviations for hepatic 
laboratory analytes.
Section on hepatic safety monitoring 
added.
1 Synopsis;
4.3 Minimization of Risk; 
5.4 Overall Study Design and Plan: 
Description ;
5.5.2 Treatment;
7.3.1 Rescue Medication;
7.3.2 Recurrence Medication;
7.5 Treatment Compliance;
8.1 Study Drug;
8.5 Administration;
9.1.7 Dosing Instructions
9.1.8 Subject Diary;
9.1.8.1 Recording Use of Rescue 
Medication and Migraine 
Symptoms;
9.1.8.2 Recording Recurrence and 
Migraine Symptoms
Updated wording to reflect that a 
second dose of study drug is only 
permitted for lasmiditan 100 mg and 
no longer for lasmiditan 200 mg, and 
that the second dose of lasmiditan is 
only to be taken for recurrence and 
not for rescue.
The maximum permitted dose of 
lasmiditan has been determined to be 
200 mg in a 24-hour period.
There is no clear evidence for the 
benefit of a second dose of 
lasmiditan 100 mg for rescue.
Schedule of Assessments
Added wording to footnote 
number 4 to state that repeat and/or 
additional laboratory testing may be 
necessary if clinically significant 
laboratory results are obtained.
Updated for clarification.
4.3 Minimization of Risk
Updated wording to indicate that 
patients are to restrict their 
driving/operation of heavy 
machinery.
Wording was updated to reflect the 
fact that lasmiditan was associated 
with driving impairment in a study 
of healthy volunteers on a driving 
simulator and to refer to the ICF for 
further instruction.
8.5 Administration
Deleted wording regarding the re-
dispensing of study drug.
Re-dispensing of study drug is no 
longer allowed.
9.1.5.3 Hepatic Safety Monitoring 
Section added.
To outline required hepatic 
monitoring.
20 Appendix 5  Liver Safety: 
Suggested Actions and Follow-Up 
Assessments
Section added.
To outline suggestions for action in 
case of clinically significant hepatic 
abnormalities.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1
Synopsis:
Study Design: 
…
Subjects will be asked to treat all migraine attacks with study drug on an outpatient basis for up 
to 12 months.  Each patient’s study participation will consist of a screening visit (Visit 1) and a 
treatment period of up to 12 months during which the subject will treat all migraine attacks with 
either lasmiditan 200 mg or lasmiditan 100 mg (with a second dose of study drug permitted 
between 2 and 24 hours (h) for rescue or recurrence of migraine only for subjects randomized to 
lasmiditan 100 mg). 
…
Subjects will be randomly assigned in a 1:1 ratio, to receive lasmiditan 100 mg (L100 mg) or 
lasmiditan 200 mg (L200 mg). Subjects randomized to lasmiditan 100 mg will be allowed to take 
a second dose of their assigned treatmentstudy drug if needed for rescue or recurrence of 
migraine.
Treatment Period: Subjects will be asked to use lasmiditan as the first treatment for each new 
migraine attack within 4 hours of onset providing that the headache severity is at least moderate 
at that time and not improving. Subjects should not exceed a total dose of 200 mg of lasmiditan 
in a 24-hour period. Subjects will record their response to the first dose over the next 48 hours 
using an electronic diary. Subjects will be asked not to use rescue medication until at least 2 
hours after dosing with study drug and completing the 2 hour assessments. If the migraine 
(headache pain) does not respond at 2 hours, a second dose of study drug may be taken up to 
24 hours after the first dose as long as no other rescue medication has been used. If the 
migraine does responds within 2 hours (headache becomes pain free) but then recurs after 2 
hours, a second dose of study drug may be taken up to 24 hours after the first dose only for 
subjects randomized to lasmiditan 100 mg. Subjects will record their response to a second 
dose, taken for either rescue or recurrence, for 48 hours in the electronic diary. The total time 
for recording response to study drug is up to 72 hours depending on whether or not a second 
dose of study drug is used (for subjects randomized to lasmiditan 100 mg). Subjects using an 
alternate medication other than a second dose of study drug for the treatment of migraine 
rescue or recurrence will report the use of medication and continue to record their responses in 
the electronic diary up to the 48 hour timepoint.
Schedule of Assessments - Footnotes:
…
4. Clinical laboratory tests include hematology, biochemistry, lipid profile and urinalysis.  In the 
event of clinically significant laboratory findings, including but not limited to hepatic laboratory 
abnormalities, repeat or additional laboratory testing may be required outside a scheduled clinic 
visit.
3
List of Abbreviations and Definitions
…
APALP
Alkaline phosphatase
CPK
Creatine phosphokinase

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…
GGT
Gamma glutamyl transferase
…
Ig
Immunoglobulin
...
INR
International Normalised Ratio
…
RBC
Red blood cell
…
TBL
Total bilirubin
…
ULN
Upper limit of normal
4.3 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 informed 
consent form (ICF).Since somnolence, dizziness and fatigue have been reported with study 
drug administration, patients participating in this study will be advised not to drive or operate 
machinery after taking treatment until they know how they will react to lasmiditan.
Rescue medication (other than study drug) will be permitted after completion of the 2 hour 
assessments if the migraine does not respond (subject is not headache pain free).  A second 
dose of randomized study drug may be taken up to 24 hours after the first dose as long as no 
other rescue medication has been used.
For subjects randomized to lasmiditan 100 mg, iIf the migraine responds within 2 hours 
(headache becomes pain free) but then recurs after 2 hours, a second dose of randomized 
study drug may be taken up to 24 hours after the first dose.
5.4 Overall Study Design and Plan: Description
…
Subjects will be asked to treat all migraine attacks with study drug on an outpatient basis for up 
to 12 months. Each patient’s study participation will consist of a screening visit (Visit 1) and a 
treatment period of up to 12 months during which the subject will treat all migraine attacks with 
either lasmiditan 200 mg or lasmiditan 100 mg (with a second dose of study drug permitted 
between 2 and 24 hours (h) for rescue or recurrence of migraine only for subjects randomized 
to lasmiditan 100 mg).
…
Subjects will be randomly assigned in a 1:1 ratio, to receive lasmiditan 100 mg (L100 mg) or
lasmiditan 200 mg (L200 mg). Subjects randomized to lasmiditan 100 mg will be allowed to 
take a second dose of their assigned treatmentstudy drug if needed for rescue or recurrence of 
migraine.
Treatment Period: Subjects will be asked to use lasmiditan as the first treatment for each new 
migraine attack within 4 hours of onset providing that the headache severity is at least moderate 
at that time and not improving.  Subjects will record their response to the first dose over the next 
48 hours using an electronic diary.  Subjects will be asked not to use rescue medication until at 
least 2 hours after dosing with study drug and completing the 2 hour assessments. If the 
migraine (headache pain) does not respond at 2 hours, a second dose of study drug may be 

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taken up to 24 hours after the first dose as long as no other rescue medication has been used. 
For subjects randomized to lasmiditan 100 mg, iIf the migraine does respond within 2 hours 
(headache becomes pain free) but then recurs after 2 hours, a second dose of study drug may 
be taken up to 24 hours after the first dose.  Subjects should not exceed a total dose of 200 mg 
of lasmiditan in a 24-hour period.  Subjects will record their response to a second dose, taken 
for either rescue or recurrence, for 48 hours in the electronic diary.  The total time for recording 
response to study drug is up to 72 hours depending on whether or not a second dose of study 
druglasmiditan 100 mg is used.  Subjects using an alternate medication other than a second 
dose of study druglasmiditan 100 mg for the treatment of migraine rescue or recurrence will 
report the use of medication and continue to record their responses in the electronic diary up to 
the 48 hour timepoint.
5.5.2
Treatment
Subjects will be allowed to treat all acute migraine attacks with study drug. Study migraines 
should be of moderate or severe intensity that is not improving. The attack is to be treated within 
4 hours of onset.  Subjects should not exceed a total dose of 200 mg of lasmiditan in a 24-hour 
period.
…

Subject will record their response to treatment for 48 hours after dosing with study 
drug. Total time to record response is up to 72 hours if a second dose of study drug
is taken for rescue or recurrence of migraine (for subjects randomized to lasmiditan 
100 mg) (See Section 9.1.8).
7.3.1
Rescue Medication
Rescue medication (other than study drug) will be permitted after completion of the 2 hour 
assessments if the migraine does not respond (subject is not headache pain free). If the 
migraine does not respond within 2 hours a second dose of randomized study drug may be 
taken up to 24 hours after the first dose as long as no other rescue medication has been used. 
7.3.2
Recurrence Medication
If the migraine responds within 2 hours (headache becomes pain free) but then recurs after 2 
hours, a second dose of randomized study drug may be taken up to 24 hours after the first dose
(only for subjects randomized to lasmiditan 100 mg). 
7.5 Treatment Compliance
Study drug will be taken by the subject on an outpatient basis throughout the study.  Prior to 
discharge from Screening/Visit 1 subjects will be given study drug to treat all migraine attacks 
for the first month. Information on the time and date of each dose (initial treatment along with 
the use of rescue medication or treatment of recurrence with a second dose of study drug for 
subjects randomized to lasmiditan 100 mg) will be recorded by the subject in the electronic 
diary.  
8.1 Study Drug
Each dose of study drug will consist of one tablet for the treatment of a single migraine attack. 
For subjects randomized to lasmiditan 100 mg, a second dose may beA subject can used a 
second tablet for use as rescue medication or as for treatment of recurrence of migraine
between 2 and 24 hours after the first dose.  For subjects randomized to lasmiditan 200 mg, no 
additional study drug is to be taken within 24 hours of the dose, as the maximum dose of 
lasmiditan to be taken in a 24-hour period is 200 mg.

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8.5 Administration
…
Subjects are to return all dosing cards (used and unused to each visit).  Remaining tablets can 
be re-dispensed along with the next assigned patient 8-tablet single card or carton as 
appropriate based on the individual subjects need.  
…
Subjects will be instructed to take a second dose (one tablet) of study drug (only for those 
subjects randomized to lasmiditan 100 mg), if needed, with approximately 4 ounces of water for 
rescue or for recurrence of migraine at least 2 hours after the first dose.  Subjects should not 
exceed a total dose of 200 mg of lasmiditan in a 24-hour period.
9.1.5.3
Hepatic Safety Monitoring
If a study subject experiences elevated ALT ≥3X ULN, AST ≥3X ULN, ALP ≥2X ULN, or 
elevated TBL ≥2X ULN, liver testing (Appendix 5; Section 20) 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

Subject discontinued from treatment due to a hepatic event or abnormality of liver tests

Hepatic event considered to be a SAE
9.1.7
Dosing Instructions
…
Subjects will be asked to treat each migraine attack within 4 hours of onset providing that the 
headache severity is at least moderate at that time and not improving. Subjects will record their 
response over the next 48 hours using an electronic diary.  Subjects should not exceed a total 
dose of 200 mg of lasmiditan in a 24-hour period.  Subjects will be instructed not to use rescue 
medication (other than study drug) until at least 2 hours after taking study drug.  If the subject 
does not become headache pain free within 2 hours, rescue medication (other than study drug)
will be permitted after completion of the 2 hour assessments.  A second dose of randomized 
study drug may be taken up to 24 hours after the first dose as long as no other rescue 
medication has been used.  The Investigator will advise each subject as to alternative suitable 
rescue medication. Triptans, ergots, opioids and barbiturates MUST NOT be used for rescue 
medication within 24 hours of study drug administration.  For subjects randomized to lasmiditan 
100 mg, Iif the migraine responds within 2 hours (headache becomes pain free) but then recurs 
after 2 hours, a second dose of randomized study drug may be taken for up to 24 hours from 
the first dose.

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9.1.8
Subject Diary
…
The need for an alternative treatment as rescue medication and second dosing of study drug or 
an alternative treatment will be assessed between 2 and 24 hours and at 48 hours.  
Recurrence of pain and second dosing of study drug (only for those randomized to lasmiditan 
100 mg) will be assessed between 2 and 24 hours and at 48 hours.
9.1.8.1
Recording Use of Rescue Medication and Migraine Symptoms
Any use of a second dose of study drug for rescue medication (other than study drug) taken 
because headache pain freedom is not achieved at 2 hours will be recorded.  
9.1.8.2
Recording Recurrence and Migraine Symptoms
If migraine recurs within 48 hours of dosing, the subject will note the exact time when the 
headache returns to mild, moderate, or severe intensity after being pain free. For subjects 
randomized to lasmiditan 100 mg, Ssubjects will document the time they take the second dose 
of study drug and any migraine symptoms they are experiencing at the time of dosing and at 
time points specified above.  

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20. APPENDIX 5. Liver Safety:  Suggested Actions and Follow-Up Assessments
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and 
may be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalised ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.