Clinical trial NCT02605174
Conditions: Migraine With or Without Aura
Sponsor: Eli Lilly and Company
Start date: 2016-05-01; Completion date: 2017-06-30
Enrollment: 3005 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a prospective randomized, double-blind, placebo-controlled study in participants with disabling migraine (Migraine Disability Assessment (MIDAS) score ≥ 11).

Detailed description:
Participants will be asked to treat a migraine attack with study drug on an outpatient basis. Participants will be provided with a dosing card containing a dose for initial treatment and a second dose to be used for rescue or recurrence of migraine. Each participant's study participation will consist of screening (Visit 1) with a telephone contact within 7 days to confirm eligibility, a Treatment Period of up to 8 weeks, and End-of-Study (EoS) (Visit 2) within one week (7 days) of treating a single migraine attack. The total time on study is approximately up to 11 weeks.

Arms: arm 1: Oral tablet. Lasmiditan 50 mg plus placebo (to match a lasmiditan dose). One dose for acute treatment of migraine. Second dose for rescue or recurrence of migraine allowed between 2 and 24 hours. arm 2: Oral tablet. Lasmiditan 100 mg plus placebo (to match a lasmiditan dose). One dose for acute treatment of migraine. Second dose for rescue or recurrence of migraine allowed between 2 and 24 hours. arm 3: Oral tablet. Lasmiditan 200 mg plus placebo (to match a lasmiditan dose). One dose for acute treatment of migraine. Second dose for rescue or recurrence of migraine allowed between 2 and 24 hours. arm 4: Oral tablet. Placebo tablets match each of the lasmiditan doses (50 mg, 100 mg and 200 mg). One dose for acute treatment of migraine. Second dose for rescue or recurrence of migraine allowed between 2 and 24 hours.
Interventions: intervention 1: Lasmiditan 50 mg intervention 2: Lasmiditan 100 mg intervention 3: Lasmiditan 200 mg intervention 4: Placebo
Intervention descriptions: intervention 1: One tablet lasmiditan 50 mg plus one placebo tablet (matching one of the lasmiditan doses) intervention 2: One tablet lasmiditan 100 mg plus one placebo tablet (matching one of the lasmiditan doses) intervention 3: One tablet lasmiditan 200 mg plus one placebo tablet (matching one of the lasmiditan doses) intervention 4: Two placebo tablets to match lasmiditan doses.

Protocol documents:
Prot_000.pdf: 
H8H-CD-LAHK 
 
 
A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the 
Acute TReaTment of MigrAiNe: A randomized, double-blind, placebo-controlled parallel group 
study (SPARTAN) 
 
NCT02605174 
 
Approval Date: November 30, 2015 
 


16.1 Study Information 
16.1.1 
Protocol and protocol amendments 
Document 
Date 
Original clinical study protocol 
30 November 2015 
 


 
 
 
Clinical Protocol  
 
 
A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared 
to Placebo in the Acute TReaTment of MigrAiNe: A randomized, double-blind, 
placebo-controlled parallel group study (SPARTAN) 
 
 
 
Protocol No. COL MIG-302 
 
 
FINAL V1.0 
November 30, 2015 
 
 
 
EudraCT No. 2015-005689-40 
 
 
 
 
CoLucid Pharmaceuticals, Inc. 
222 Third Street 
Cambridge, MA  02142 
 
 
 
 
 
 
Confidentiality Statement 
This confidential document is the property of CoLucid Pharmaceuticals, Inc.  No unpublished 
information contained herein may be disclosed without prior written approval from CoLucid 
Pharmaceuticals, Inc.  Access to this document must be restricted to relevant parties. 
 
 


CoLucid Pharmaceuticals, Inc.                                
     
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 STUDY PERSONNEL 
 
 
Protocol Author: 
   
 
   CoLucid Pharmaceuticals, Inc. 
   Head Clinical/Regulatory Operations 
 
 
 
 
 
 
 
 
 
30Nov2015 
 
Si
 
Date 
 
 
 
 
 
 
  
CoLucid Pharmaceuticals, Inc. 
CEO 
 
 
 
 
 
11-30-15 
 
 
Signature 
 
Date 
PPDPPD
PPD
PPD
PPD


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Investigator statement 
 
Protocol Number:  COL MIG-302 
 
Protocol Title:   
A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute 
TReaTment of MigrAiNe: A randomized, double-blind, placebo-controlled parallel group study 
(SPARTAN) 
 
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 CoLucid Pharmaceuticals, 
Inc., and the Institutional Review Board/Ethics Committee before they can be implemented, except 
when necessary to eliminate immediate hazards to the subjects. 
 
By my signature below, I attest that I have read, understand, and agree to abide by all the conditions, 
instructions, and restrictions contained in Protocol Number COL MIG-302, and will conduct the trial in 
accordance with Good Clinical Practice (GCP) and applicable regulatory requirements.   
 
 
 
 
 
 
 
 
 
 
 
Site Address  
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s Signature  
 
Date 
 
 
 
Site Name 
Investigator’s Printed Name 


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1. 
SYNOPSIS 
 
Name of Sponsor Company:  
CoLucid Pharmaceuticals, Inc. 
 
Drug Under Study: Lasmiditan (COL-144)  
Title of Protocol: A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to 
Placebo in the Acute TReaTment of MigrAiNe: A randomized, double-blind, placebo-controlled 
parallel group study (SPARTAN) 
Protocol Number: 
COL MIG-302 
 
Phase: 3 
 
Indication: Migraine - Acute Treatment  
 
Primary Objective:  To evaluate the efficacy at 2 hours of lasmiditan 50 mg, of lasmiditan 100 mg and of 
lasmiditan 200 mg compared to placebo on migraine headache pain and the Most Bothersome Symptom (MBS), 
as identified by the individual from the associated symptoms of nausea, phonophobia and photophobia. 
 
Secondary Objectives:  To explore the time course and effect of lasmiditan 50 mg, of lasmiditan 100 mg and of 
lasmiditan 200 mg on relief of pain and on the MBS. 
 
Additional Objectives: To explore the effect and time course of a second dose of lasmiditan 50 mg, of 
lasmiditan 100 mg and of lasmiditan 200 mg compared to placebo on relief of pain and MBS when used for 
rescue and for recurrence of migraine.  To explore resource utilization during the study compared to pre-study in 
terms of cardiovascular events and in terms of migraine episodes. 
 
Safety Objective:  To explore the safety and tolerability of lasmiditan 50 mg, of lasmiditan 100 mg and  of 
lasmiditan 200 mg, as the first dose and as a second dose, in terms of adverse events (AEs), physical 
examinations, vital signs, clinical laboratory evaluations, and 12-lead electrocardiograms (ECGs).  
 
Study Endpoints 
 
Primary Endpoint: The proportion of subjects headache pain free at 2 hours post dose (defined as moderate or 
severe headache pain becoming none)  
 
Key Secondary Endpoint: The proportion of subjects who are MBS free at 2 hours post dose (defined as the 
associated symptom present and identified as MBS prior to dosing being absent at 2 hours).  
 
Study Design:  
This is a prospective randomized, double-blind, placebo-controlled study in subjects with disabling migraine 
(Migraine Disability Assessment (MIDAS) score ≥ 11). 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 a migraine attack with study drug on an outpatient basis. Subjects will be provided 
with a dosing card containing a dose for initial treatment and a second dose to be used for rescue or recurrence 
of migraine.  Each subject’s study participation will consist of a screening visit (Visit 1) with a telephone contact 
within 7 days to confirm eligibility, a Treatment Period of up to 8 weeks, and an End-of-Study (EoS) visit (Visit 
2) within one week (7 days) of treating a single migraine attack.   The total time on study is approximately 11 
weeks. 
 
At the Screening visit (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 medical history 
including migraine history, baseline physical examination (including height and weight), vital signs, clinical 
laboratory tests, 12-lead ECG and responses to the MIDAS questionnaire. Subjects will be asked about any 
concomitant medication use as well as any cardiovascular (CV) events in the last 6 months and/or related 
resource utilization such as visits to cardiologists, procedures, hospitalizations, new treatments or treatment 


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adjustments for CV disease.  A Columbia Suicide Severity Rating Scale (C-SSRS) will be completed. Subjects 
will be given an electronic diary and be trained on its use to record information about their migraine, dosing their 
migraine and post-dose assessments.  Subjects will be randomized, dispensed study drug and instructed not to 
treat an attack until their eligibility has been confirmed by telephone once all screening evaluations are complete.  
Subjects will be randomly assigned to one of 7 treatment sequences to receive lasmiditan 50 mg (L50 mg),  
lasmiditan 100 mg (L100 mg) or lasmiditan 200 mg (L200 mg) or placebo (P) for  the first dose (in a 1:1:1:1 ratio 
) and the second dose, if needed for rescue or recurrence of migraine as follows: 
 
 
First dose for treatment 
of migraine  
Second dose for rescue or 
recurrence of migraine (if needed) 
L50 mg 
L 50 mg 
L 50 mg 
placebo 
L100 mg 
L100 mg 
L100 mg 
placebo 
L200 mg 
 
L200 mg 
L200 mg 
placebo 
placebo 
placebo 
 
Telephone Contact:  Within 7 days of Visit 1 a phone contact must be made by study staff to the subject 
confirming eligibility in the trial.  The subject will be reminded on the use of the diary and on dosing a migraine 
with study drug.  Once eligibility is confirmed, subjects will begin the Treatment Period. Subjects considered not 
eligible will be advised not to take the study drug and an appointment for an EoS/Visit 2 and the collection of 
study drug and the diary will be scheduled within one week (7 days) of the confirmation of eligibility phone call. 
• Treatment Period: Subjects will be asked to treat their next 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 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 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 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 is used.  Subjects are to contact the clinic to 
schedule EoS/Visit 2 within one week (7 days) after 1 attack has been treated, or after 8 weeks have passed 
without treating an attack. The total time on study is approximately 11 weeks. 
 
Subject Population: Adult patients with a history of migraine with or without aura.  
Number of Subjects:  Approximately 2968 subjects 
screened and randomized (742 per treatment arm 
based on the first dose) to ensure that at least 2280 
subjects (570 per treatment arm based on the first 
dose) complete the Treatment Period  
Number of Centers:  Up to 150 centers in the US and 
rest of world (Western EU, ) 
Test Product and Doses: lasmiditan 50 mg,  
lasmiditan 100 mg; lasmiditan 200 mg and matching 
placebo 
Route of Administration:  Oral  
 
 
 


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Study schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Within 7 days 
Telephone call/Eligibility confirmed 
 
Treatment Period:  
(Up to 8 weeks) 
 
First dose - Treat an acute migraine attack  
• At time of attack prior to dosing -  subject records severity 
of pain, associated symptoms (yes or no) and declares 
MBS 
Subject records response to treatment for up to 48 hours. 
 
Second dose – rescue or recurrence 
• If the migraine does not respond within 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 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. 
 
 
•   Subject records response to treatment with second dose 
for up to  48 hours 
• Total time recording response to treatment is up to 72 
hours. 
 
 
EoS/ Visit 2 
Within one week (7 days) after treating one attack  
 
 
OR 
 
After 8 weeks and no attack treated 
YES 
NO 
EoS/ Visit 2  
 
Within one week (7 days) after phone contact 
to collect study drug and subject diary 
Screening/Visit 1 
Randomization to Treatment 
First dose: 
L50  
              L100                      L200                    P 
Rescue or  
                
                
  
         
 
 
       
Recurrence      L50   L50    P      L100   L100     P      L200   L200    P           P    
 dose 


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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. Patients with migraine with or without aura fulfilling the International Headache Society (IHS) diagnostic 
criteria 1.1 (migraine without aura) or 1.2.1 (migraine with aura) (International Headache Classification 
(ICHD)-2004). 
3. History of disabling migraine for at least 1 year. 
4. MIDAS score ≥11. 
5. Migraine onset before the age of 50 years. 
6. History of 3 – 8 migraine attacks per month (< 15 headache days per month). 
7. Male or female, aged 18 years or above. 
8. 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). 
9. Able and willing to complete an electronic diary to record details of the migraine attack 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. Known hypersensitivity to lasmiditan or to any excipient of lasmiditan oral tablets or any sensitivity to a 
ditan. 
5. History or evidence of hemorrhagic stroke, epilepsy or any other condition placing the subject at 
increased risk of seizures. 
6. History of recurrent dizziness and/or vertigo including benign paroxysmal positional vertigo (BPPV), 
Meniere’s disease, vestibular migraine, and other vestibular disorders. 
7. History of diabetes mellitus with complications (diabetic retinopathy, nephropathy or neuropathy). 
8. History within the previous three years or current evidence of abuse of any drug, prescription or illicit, or 
alcohol. 
9. History of orthostatic hypotension with syncope. 
10. Significant renal or hepatic impairment.  
11. Subject is at imminent risk of suicide (positive response to question 4 or 5 on the C-SSRS) or had a 
suicide attempt within six months prior to the screening visit. 
12. Previous participation in this clinical trial. 
13. Participation in any clinical trial of an experimental drug or device in the previous 30 days. 
14. Known Hepatitis B or C or HIV infection. 
15. History, within past 12 months, of chronic migraine or other forms of primary or secondary chronic 
headache disorder (e.g. hemicranias continua, medication overuse headache) where headache 
frequency is ≥15 headache days per month. 
16. Use of more than 3 doses per month of either opiates or barbiturates. 
17. Initiation of or a change in concomitant medication to reduce the frequency of migraine episodes within 
three (3) months prior to Screening/Visit 1.  
18. Subjects who are employees of the sponsor.  
19. Relatives of, or staff directly reporting to, the Investigator. 
 
 
 


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Criteria for Evaluation: 
Efficacy/Pharmacodynamics: 
• 
Headache pain (4 point scale: none (0), mild (1), moderate (2), severe (3)) 
• 
Most bothersome symptom (selected from a list of associated symptoms 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 (4 point scale: not at all (0), mild interference (1), marked interference (2), completely, needs 
bed rest (3)) 
• 
Requirement for rescue medication between at 2 hours and between 2- 24, and 24-48 hours (yes or no) 
• 
Requirement for recurrence medication between  2- 24, and 24-48 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 
 
Safety:  
• 
Adverse events (spontaneously reported) 
• 
Physical examination  
• 
Vital signs 
• 
12-lead electrocardiograms 
• 
Clinical laboratory parameters 
 
Resource utilization: 
• 
Any CV events in the 6 months prior to screening and/or related resource utilization such as visits to 
cardiologists, procedures, hospitalizations, new treatments or treatment adjustments for CV disease 
compared to on study Visit 1 through Visit 2. 
• 
Any visits to an emergency room or physician’s office for treatment of migraine in the 3 months prior to 
screening compared to on study Visit 1 through Visit 2, excluding study specific visits. 
• 
Concomitant medications for the treatment of migraine and/or pain for 3 months prior to screening 
compared to concomitant medications for migraine and/or pain Visit 1 through Visit 2. 
• 
Missed days of work and/or school. 
 
Statistical Analysis: 
Efficacy: 
This multi-center, randomized, double-blind, parallel-group, placebo-controlled clinical study is designed to 
evaluate the efficacy and safety of lasmiditan 50 mg, of lasmiditan 100 mg and of lasmiditan 200 mg vs. placebo 
in the acute treatment of migraine based on the first dose. Subjects will be stratified (yes or no) for use of 
concomitant medications that reduce the frequency of migraine episodes. 
 
Efficacy will be assessed using the primary endpoint of the proportion of subjects headache pain free at 2 hours, 
defined as moderate or severe headache pain becoming none and the key secondary endpoint of the proportion 
of subjects MBS free at 2 hours defined as the associated symptoms (nausea, phonophobia or photophobia) 
present prior to dosing and identified by the subject to be MBS becoming absent. 
 
The primary analyses will compare the proportion of subjects who are headache pain free and the proportion of 
subjects who are MBS free at 2 hours in the lasmiditan 200 mg and placebo groups in the modified 
Intent-to-Treat (mITT) population.  Each of these two analyses will be carried out using logistic regression Wald 
Chi-square test with region included in the model and will be conducted using a one-sided test at the 
alpha=0.025 level of significance. 
 
If both primary analyses are statistically significant (one-sided, p<0.025), additional confirmatory hypotheses will 


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      November 30, 2015 
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be tested in the mITT population in the following sequential order: 
 
• 
Proportion of subjects who are headache pain free at 2 hours in the lasmiditan 100 mg and placebo group. 
• 
Proportion of subjects who are MBS free at 2 hours in the lasmiditan 100 mg and placebo group. 
• 
Proportion of subjects who are headache pain free at 2 hours in the lasmiditan 50 mg and placebo group. 
• 
Proportion of subjects who are MBS free at 2 hours in the lasmiditan 50 mg and placebo group. 
 
All of the above analyses will be completed using one-sided tests at the alpha=0.025 level of significance.  If an 
analysis is not statistically significant, then all subsequent analyses will be conducted but are designated as 
exploratory rather than confirmatory. 
  
Additional analyses will explore the time course and effect of the first dose of lasmiditan 200 mg and of 
lasmiditan 100 mg and of lasmiditan 50 mg on features of migraine including: headache response (a reduction in 
headache pain from moderate or severe to mild or none), vomiting, disability, headache recurrence and the use 
of recurrence medication, the use of rescue medication, patient global impression of change, time to headache 
relief, and time to headache pain free. Descriptive analyses will be performed on the proportion of subjects who 
are nausea free at 2 hours, the proportion who are phonophobia free 2 hours and the proportion who are 
photophobia free at 2 hours.  Exploratory second dose (for rescue or recurrence of migraine) comparisons 
between treatment groups will be performed. 
 
 
 
Sample Size Rationale   
This Phase 3 study is designed to demonstrate that lasmiditan is effective in the treatment of acute migraine in 
adult patients with and without aura. The sample size was estimated based on the 2 hour headache pain free 
and associated symptoms (nausea, phonophobia, or photophobia) free response rates observed in the Phase 2 
study COL MIG-202. 
 
Dose 
Pain free 
Nausea free 
Phonophobia free 
Photophobia free 
Placebo 
7.4% 
59.3% 
51.9% 
34.6% 
50 mg  
13.9% 
68.4% 
58.2% 
53.2% 
100 mg 
13.6% 
74.1% 
75.3% 
67.9% 
200 mg 
18.8% 
63.8% 
59.4% 
58.0% 
 
For the primary endpoint of the proportion of patients pain free at 2 hours a sample size of 570 evaluable 
subjects per arm provides power of >90% for the 50 mg dose, the 100 mg dose and the 200 mg dose. 
 
In order to estimate sample size for the key secondary endpoint of proportion of patients MBS free at 2 hours, 
simulation was performed in SAS on the conditional probability of being free from any one symptom defined as 
MBS under 4 different scenarios. For each symptom or combination of symptoms, the likelihood of an individual 
symptom being the MBS was estimated. In the most conservative scenario (scenario 1) it was assumed that 
nausea would always be declared the MBS if it was present, regardless of the presence of other symptoms 
(phonophobia or photophobia).  The other 3 scenarios assumed lower likelihoods of nausea to be considered 
the MBS and allowed for the other symptoms (either phonophobia or photophobia) to be considered the MBS at 
a higher rate.  This resulted in power estimates of > 95% for MBS at a sample size of 570 for the lasmiditan 50 
mg  dose and >99% for MBS at  sample sizes of 450 to 570 per arm for the 100 mg dose across all 4 scenarios. 
For the 200 mg dose, an average power of 71% was estimated across five seeds under the most conservative 
scenario 1. In contrast, the 3 scenarios that did not declare nausea to be the default MBS if it was present 
estimated a greater average power of 82.6% to 91%. 
 
 
 
 
 
 


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Group 
 
Scenario 
 
Variable 
Seed 
55405 
74951 
82002 
82377 
90075 
Placebo 
vs D50 
1 
Power (MBS) 
96.90% 
95.90% 
96.10% 
95.60% 
96.80% 
Sample Size 
570 
570 
570 
570 
570 
2 
Power 
93.70% 
94.30% 
94.80% 
93.90% 
93.90% 
Sample Size 
450 
450 
450 
450 
450 
3 
Power 
90.40% 
90.40% 
90.10% 
91.00% 
91.40% 
Sample Size 
575 
575 
575 
575 
575 
4 
Power 
93.70% 
94.30% 
94.80% 
93.90% 
93.90% 
Sample Size 
450 
450 
450 
450 
450 
Placebo 
vs D100 
1 
Power (MBS) 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
Sample Size 
570 
570 
570 
570 
570 
2 
Power 
99.90% 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
Sample Size 
450 
450 
450 
450 
450 
3 
Power 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
Sample Size 
575 
575 
575 
575 
575 
4 
Power 
99.90% 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
Sample Size 
450 
450 
450 
450 
450 
Placebo 
vs D200 
1 
Power 
70.87% 
70.87% 
72.97% 
71.17% 
68.47% 
Sample Size 
570 
570 
570 
570 
570 
2 
Power 
84.40% 
85.00% 
85.80% 
85.90% 
85.80% 
Sample Size 
450 
450 
450 
450 
450 
3 
Power 
83.50% 
83.20% 
81.30% 
83.40% 
81.80% 
Sample Size 
575 
575 
575 
575 
575 
4 
Power 
90.20% 
90.50% 
92.50% 
91.40% 
90.40% 
Sample Size 
450 
450 
450 
450 
450 
1 Mean rate is the freedom from MBS at 2 hours post dose. 
P=placebo, L = lasmiditan 
 
 
It is expected for a one-sided, two-sample comparison of proportions at the 2.5% level of significance, a sample 
size of 570 subjects per treatment arm (as defined by the first dose) provides >90% power to detect a difference 
in headache pain free response rates for assumed true rates of 7.4% and 18.8% (placebo and 200 mg), 7.4% 
and 13.6% (placebo and 100 mg) and 7.4% and 13.9% (placebo and 50 mg) >90 % power for MBS for both the 
50 mg dose arm and the 100 mg dose arm and very near or higher than 80% power for MBS in the 200 mg dose 
arm. 
 
Safety:  
Adverse events will be summarized, and event rates will be presented by treatment arm and dose (initial dose 
and second dose for rescue or recurrence or use of alternative rescue medication).  Physical examinations, vital 
signs, ECG parameters and clinical laboratory data, will be summarized by treatment arm and dose in terms of 
change from baseline status.  
 
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 information reported at Screening/Visit 1 compared 
to information reported at EoS/Visit 2. Concomitant medication use for migraine and/or pain and missed days of 
work and/or school will be summarized by treatment arm. 
 
 
 
 


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11 of 74 
 
 
Schedule of Assessments 
 
Assessment 
Visit 1 
Screening 
and Baseline 
Telephone 
Contact 
Within 7 days 
after Visit 1 
Treatment  
Treatment of an 
attack within 8 
weeks 
EoS/Visit 2  
Within 7 days after 
treatment  
OR  
After 8 weeks and no 
attack treated1 
Obtain informed consent/HIPAA 
X 
 
 
 
Document migraine characteristics per IHS 
criteria 
X 
 
 
 
Review inclusion / exclusion criteria 
X 
 
 
 
Complete MIDAS 
X 
 
 
 
Review migraine history including prior 
treatment  
X 
 
 
 
Review medical history and concomitant 
medication 
X 
 
 
 
Review resource utilization (visits to 
specialists, emergency rooms, etc) 
X 
 
 
X 
Physical examination and vital signs (heart 
rate, blood pressure) 
X 
 
 
X 
Weight and height 
X 
 
 
 
12-lead ECG 
X 
 
 
X 
Clinical laboratory2  
X 
 
 
X 
Columbia Suicide Severity Rating Scale 
X 
 
 
X 
Randomization 
X  
 
 
 
Dispense study drug, study diary, and provide 
detailed instructions 
X 
 
 
 
Confirm eligibility3 
 
X 
 
 
Migraine attack (electronic diary) 
documentation by subject  
 
 
X 
 
Documentation of rescue/recurrence 
medication 
 
 
X 
 
Documentation of adverse events and 
concomitant medication  
X 
X 
X 
X 
Collect unused/empty study drug pack.  
 
 
 
X1 
1 Subjects that do not treat a migraine for any reason during the 8 weeks should attend an EoS visit to return unused study drug and the 
e-diary. No other assessments are required. 
2 Clinical laboratory tests include hematology, biochemistry, lipid profile, urinalysis, and pregnancy test for women of childbearing potential. 
3 The confirmation of eligibility is made by telephone contact by the site study staff to the subject. Final eligibility is based on the laboratory 
results. If a subject is considered not eligible, he/she will be advised not to take the study drug and an appointment for a follow-up visit (Visit 
2/EoS) for collection of study drug and diary will be scheduled. No assessments are required. 


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2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS ............................................................................................................... 4 
2. 
TABLE OF CONTENTS .......................................................................................... 12 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................... 16 
4. 
INTRODUCTION .................................................................................................... 18 
4.1 
Background ............................................................................................................ 19 
4.2 
Clinical Studies to Date........................................................................................... 19 
4.3 
Minimization of Risk ................................................................................................ 21 
4.4 
Potential Benefit ..................................................................................................... 21 
4.5 
Dose Rationale ....................................................................................................... 22 
4.6 
Conduct of the Study .............................................................................................. 22 
5. 
TRIAL OBJECTIVES AND PURPOSE ................................................................... 22 
5.1 
Primary objective .................................................................................................... 22 
5.2 
Secondary objectives ............................................................................................. 22 
5.3 
Additional Objectives .............................................................................................. 22 
5.4 
Safety objectives .................................................................................................... 23 
5.5 
Overall Study Design and Plan: Description ........................................................... 23 
5.5.1 
Treatment Arms ...................................................................................................... 24 
5.5.2 
Schedule of Assessments ...................................................................................... 24 
5.6 
Assessments by Study Visit .................................................................................... 25 
5.6.1 
Screening Visit /Visit 1 ............................................................................................ 25 
5.6.2 
Phone Call .............................................................................................................. 25 
5.6.3 
Treatment ............................................................................................................... 26 
5.6.4 
 End of Study/Visit 2 ............................................................................................... 26 
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................ 27 
6.1 
Inclusion Criteria ..................................................................................................... 27 
6.2 
Exclusion Criteria .................................................................................................... 27 
6.3 
Protocol Exceptions and Deviations........................................................................ 28 
6.4 
Subject Withdrawal Criteria .................................................................................... 28 
7. 
TREATMENT OF SUBJECTS ................................................................................ 29 
7.1 
Subject numbering and enrollment status ............................................................... 29 
7.2 
Description of Study Drug ....................................................................................... 29 
7.3 
Concomitant Medications ....................................................................................... 29 
7.3.1 
Rescue Medication ................................................................................................. 29 


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7.3.2 
Recurrence Medication ........................................................................................... 29 
7.4 
Prohibited Medications ........................................................................................... 30 
7.5 
Treatment Compliance ........................................................................................... 30 
7.6 
Randomization and Blinding ................................................................................... 30 
7.7 
Unblinding Procedures ........................................................................................... 30 
7.7.1 
Emergency unblinding of treatment assignment ..................................................... 30 
7.7.2 
Unblinding for Regulatory Authorities ...................................................................... 30 
8. 
STUDY DRUG MATERIALS AND MANAGEMENT ................................................ 31 
8.1 
Study Drug ............................................................................................................. 31 
8.2 
Study Drug Packaging and Labeling ....................................................................... 31 
8.3 
Study Drug Storage ................................................................................................ 32 
8.4 
Study Drug Preparation .......................................................................................... 32 
8.5 
Administration ......................................................................................................... 32 
8.6 
Study Drug Accountability ....................................................................................... 32 
9. 
TREATMENT ASSESSMENTS .............................................................................. 33 
9.1 
Efficacy and Safety Parameters .............................................................................. 33 
9.1.1 
Medical History ....................................................................................................... 33 
9.1.2 
Physical Examination ............................................................................................. 34 
9.1.3 
Vital Signs .............................................................................................................. 34 
9.1.4 
ECG ....................................................................................................................... 34 
9.1.5 
Clinical Laboratory .................................................................................................. 34 
9.1.6 
Columbia Suicide Severity Rating Scale ................................................................. 35 
9.1.7 
Dosing Instructions ................................................................................................. 36 
9.1.8 
Subject Diary .......................................................................................................... 36 
9.2 
Adverse Events and Serious Adverse Events ......................................................... 37 
9.2.1 
Adverse Events ...................................................................................................... 37 
9.2.2 
Treatment Emergent Adverse Events (TEAE) ........................................................ 38 
9.2.3 
Serious Adverse Events ......................................................................................... 38 
9.2.4  
 Unexpected Adverse Event ................................................................................... 39 
9.3 
Reporting Serious Adverse Events ......................................................................... 39 
9.4 
Follow-up of adverse events ................................................................................... 40 
9.5 
Reporting safety information to the IRB/EC ............................................................ 40 
9.6 
Pregnancies ........................................................................................................... 40 
10. 
STATISTICS ........................................................................................................... 41 
10.1 
Sample Size ........................................................................................................... 41 


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10.2 
Randomization ....................................................................................................... 43 
10.3 
Analysis Populations .............................................................................................. 43 
10.3.1 
Primary efficacy – FIRST dose ............................................................................... 43 
10.3.2 
Second Dose Analysis Populations ........................................................................ 44 
10.4 
Accountability and Background Characteristics ...................................................... 45 
10.4.1 
Enrollment and Disposition ..................................................................................... 45 
10.4.2 
Subject Characteristics ........................................................................................... 45 
10.4.3 
Treatment Compliance ........................................................................................... 45 
10.5 
Efficacy Analyses ................................................................................................... 45 
10.5.1 
Primary Analysis ..................................................................................................... 45 
10.5.2
Sensitivity Analyses of the Primary and Key Secondary Endpoints ....................... 46 
10.5.3 
Multiplicity Adjustment for Hypothesis Testing ........................................................ 46 
10.5.4 
Other Efficacy Analyses .......................................................................................... 47 
10.6 
Analysis of Second dose ........................................................................................ 47 
10.6.1 
Analysis of second dose for rescue ........................................................................ 47 
10.6.2 
Analysis of second dose for recurrence .................................................................. 48 
10.7 
Missing Values ....................................................................................................... 48 
10.8 
Safety Analyses ...................................................................................................... 48 
10.8.1 
Adverse Events ...................................................................................................... 48 
10.8.2 
Physical Examinations, Vital Signs, ECG Parameters and Clinical 
Laboratory Test Values, .......................................................................................... 49 
10.8.3 
C-SSRS .................................................................................................................. 49 
10.9 
Resource Utilization ................................................................................................ 49 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................... 50 
11.1. 
Study Monitoring..................................................................................................... 50 
11.2 
 Data collection ....................................................................................................... 50 
11.3 
 Audits and Inspections........................................................................................... 50 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 51 
13. 
ETHICS .................................................................................................................. 52 
13.1 
Ethics Review ......................................................................................................... 52 
13.1.1 
 IRB/EC opinion ...................................................................................................... 52 
13.2 
Written Informed Consent ....................................................................................... 53 
13.3 
Amendments to the protocol ................................................................................... 53 
13.4 
Discontinuation of the study .................................................................................... 53 
13.5 
Study drug supply, storage and tracking ................................................................. 53 


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13.6 
Confidentiality ......................................................................................................... 54 
13.7 
Publication policy .................................................................................................... 54 
14. 
RETENTION OF RECORDS .................................................................................. 55 
15. 
REFERENCES ....................................................................................................... 56 
16. 
APPENDIX 1.  WORLD HEALTH ORGANIZATION TOXICITY CRITERIA ............. 58 
17. 
APPENDIX 2. INTERNATIONAL HEADACHE SOCIETY DIAGNOSTIC 
CRITERIA............................................................................................................... 62 
18. 
APPENDIX 3.  THE MIGRAINE DISABILITY ASSESSMENT TEST ....................... 65 
19. 
APPENDIX 4. COLUMBIA SUICIDE SEVERITY RATING SCALE-
SCREENING VISIT ................................................................................................ 66 
20. 
APPENDIX 5. COLUMBIA SUICIDE SEVERITY RATING SCALE- SINCE 
LAST VISIT ............................................................................................................ 70 
 
 
 
 


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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  
AP  
 
 
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 
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 
FDA 
 
 
Food and Drug Administration 
GCP 
 
 
Good Clinical Practice 
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 
IHS 
 
 
International Headache Society 
IRT 
 
 
Interactive Response Technology 
IUD 
 
 
Intrauterine Device 
IV  
 
 
Intravenous 
ITT  
 
 
Intent-to-treat 
L 
Lasmiditan 
MBS 
Most Bothersome Symptom 
MedDRA  
Medical Dictionary for Regulatory Activities 
mg  
 
 
milligram 
MIDAS  
 
Migraine disability assessment 
mITT  
 
modified Intent-to-treat 
mL  
 
 
milliliter 


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mmHg  
 
millimeters of mercury 
NCS 
 
 
Not clinically significant 
P  
 
 
Placebo 
PP  
 
 
Per protocol 
SAE 
 
 
Serious adverse event 
SBP 
 
 
Systolic blood pressure 
SD  
 
 
Standard deviation 
TEAE  
 
Treatment emergent adverse events 
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 determine the efficacy and safety of lasmiditan 200 mg compared to placebo and lasmiditan 
100 mg compared to placebo given as a first dose for the treatment of a migraine attack.  A 
second dose of study drug is included in the study design to investigate the safety and efficacy 
of lasmiditan 200 mg compared to placebo and lasmiditan 100 mg compared to placebo when 
taken for rescue or when taken for recurrence of migraine.   In addition to safety assessments, 
information will be obtained on the different dose levels of lasmiditan. Patients with 
cardiovascular risk factors will be eligible to participate in this clinical trial.  Data from this study 


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will be used to further investigate and confirm the safety and efficacy of 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 (50 mg, 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. 
 
Lasmiditan given orally at doses up to 400 mg has been well tolerated, with no clinically 
significant effects on vital signs, ECG or clinical laboratory parameters. The most frequent 
adverse events have been somnolence, dizziness, fatigue, and paresthesia. These were 
transient and usually of mild or moderate severity. 
 
Since somnolence, dizziness and fatigue have been seen, patients participating in this study will 
be advised not to drive or operate machinery for 12 hours after treatment. 
 
Rescue medication 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. 
 
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. 
 
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 substantial 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 


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Society (IHS).  Patients that complete COL MIG-302 will be eligible to be enrolled and 
randomized into the open-label, long-term, safety study of lasmiditan 100 mg and lasmiditan 
200 mg (COL MIG-305). 
 
4.5 
Dose Rationale 
The dose levels of lasmiditan to be used in this study (50 mg, 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. In a Phase 2 study, both doses were effective in alleviating the symptoms of 
migraine. In preclinical toxicology studies, adequate margins of safety have been established for 
lasmiditan 50 mg, 100 mg and 200 mg and its major human metabolites. This study will further 
evaluate the safety and efficacy of lasmiditan 50 mg, 100 mg and 200 mg with the primary 
analysis performed on the first dose taken for treatment of a new acute migraine attack.   
 
The inclusion of a second dose of either lasmiditan 50 mg or 100 mg or 200 mg or placebo as 
randomly assigned for treatment of rescue or recurrence of migraine is to evaluate the safety 
and efficacy of a second dose of lasmiditan and further 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 efficacy at 2 hours of lasmiditan 50 mg, of lasmiditan 100 mg and of lasmiditan 
200 mg compared to placebo on migraine headache pain and the Most Bothersome Symptom 
(MBS), as identified by the individual from the associated symptoms of nausea, phonophobia 
and photophobia. 
 
5.2 
Secondary objectives 
To explore the time course and effect of lasmiditan 50 mg, of lasmiditan 100 mg and of 
lasmiditan 200 mg on relief of pain and on the MBS. 
 
5.3 
Additional Objectives 
To explore the effect and time course of a second dose of lasmiditan 50 mg, of lasmiditan 100 
mg and of lasmiditan 200 mg compared to placebo on relief of pain and MBS when used for 
rescue and for recurrence of migraine.  To explore resource utilization during the study 
compared to  
pre-study in terms of cardiovascular events and in terms of migraine episodes. 
 


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5.4 
Safety objectives 
To explore the safety and tolerability of lasmiditan 50 mg, of lasmiditan 100 mg and  of 
lasmiditan 200 mg, as the first dose and as a second dose, in terms of adverse events (AEs), 
physical 
examinations, 
vital 
signs, 
clinical 
laboratory 
evaluations, 
and 
12-lead 
electrocardiograms (ECGs).  
 
5.5 
Overall Study Design and Plan: Description 
This is a prospective randomized, double-blind, placebo-controlled study in patients with 
disabling migraine (MIDAS score ≥11).  Approximately 2968 subjects will be screened and 
randomized (742 per treatment arm based on the first dose) to ensure that approximately 2280 
subjects (570 per treatment arm based on the first dose) treat a migraine attack and complete 
the Treatment Period.  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 a migraine attack with study drug on an outpatient basis. 
Subjects will be provided with a dosing card containing a dose for initial treatment and a second 
dose to be used for rescue or recurrence of migraine.  Each subject’s study participation will 
consist of a screening visit (Visit 1) with a telephone contact within 7 days to confirm eligibility, a 
Treatment Period of up to 8 weeks, and an EoS visit (Visit 2) within two weeks (14 days) of 
treating a migraine attack.  The total time on study is approximately 12 weeks. 
 
At the Screening visit (Visit 1) subjects will provide written informed consent and authorize 
HIPAA. Study eligibility will be assessed on the basis of medical history including migraine 
history, baseline physical examination (including height and weight), vital signs, clinical 
laboratory tests, 12-lead ECG and responses to the MIDAS questionnaire. Subjects will be 
asked about any concomitant medication use as well as any cardiovascular (CV) events in the 
last 6 months and/or related resource utilization such as visits to cardiologists, procedures, 
hospitalizations, new treatments or treatment adjustments for CV disease.  A C-SSRS will be 
completed. Subjects will be given an electronic diary and be trained on its use to record 
information about their migraine, dosing of their migraine and post-dose assessments. Subjects 
will be randomized, dispensed study drug and instructed not to treat an attack until their 
eligibility has been confirmed by phone once all screening evaluations are complete.  Subjects 
will be randomly assigned treatment as described in Section 5.5.1.  
 
Telephone contact. Within 7 days of Visit 1 a phone contact must be made by study staff to 
the subject confirming eligibility in the trial. At this point, ineligible subjects are instructed to 
return to the clinic to be discontinued and eligible subjects begin the Treatment Period. During 
the call, the subject will be reminded on the use of the diary and on dosing a migraine with study 
drug. 
 
Treatment Period: Subjects will be asked to treat their next 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 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 respond within 2 hours 


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(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 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 is used.  Subjects are to contact the clinic to schedule EoS/Visit 2 within one week (7 
days) after 1 attack has been treated, or after 8 weeks have passed without treating an attack. 
The total time on study is approximately 11 weeks. 
 
5.5.1 Treatment Arms 
Subjects will be centrally randomized to one of 7 treatment sequences to receive lasmiditan 50 
mg (L50 mg), lasmiditan 100 mg (L100 mg) or lasmiditan 200 mg (L200 mg) or placebo (P) for 
the initial dose (in a 1:1:1:1 ratio)  and the second dose, if needed for rescue or recurrence of 
migraine as follows:  
 
 
First dose for treatment 
of migraine  
Second dose for rescue or 
recurrence of migraine (if needed) 
L50 mg 
L 50 mg 
L 50 mg 
placebo 
L100 mg 
L100 mg 
L100 mg 
placebo 
L200 mg 
 
L200 mg 
L200 mg 
placebo 
placebo 
placebo 
 
 
5.5.2  Schedule of Assessments 
• 
Screening/Visit 1: The screening examinations to determine subject eligibility 
are performed. Subjects are randomized and provided with a dosing card. 
 
• 
Telephone call, confirmation of eligibility: Within 7 days after screening, a telephone 
contact must be made between the site study staff and subject to confirm study eligibility 
based on clinical laboratory results. If a subject is considered not eligible, he/she will be 
advised not to take the study drug. An appointment for a follow-up visit (EoS/Visit 2) and 
collection of study drug and diary will be scheduled. 
 
• 
EoS/Visit 2:  The end of study visit 
• 
The subject will return to the clinic for post-treatment follow-up one week (7 days) after a 
subject completes treatment (treats one migraine attack within 8 weeks)  
 
• 
If a subject has not treated a migraine attack within 8 weeks after Screening/Visit 1 the 
subject will be contacted to return to the clinic.  In this case, this visit will only be used to 
return the study drug and e-diary. 
 
The overall Schedule of Assessments for the study is provided in Table 1.  


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5.6 
Assessments by Study Visit 
5.6.1 Screening Visit /Visit 1 
The following items must be completed and reviewed by the Investigator or sub-Investigator 
within 14 days: 
• 
Explain the purpose of the study to prospective subjects and obtain written informed 
consent and HIPAA. 
• 
Document migraine characteristics per IHS criteria (See Appendix 2). 
• 
Review inclusion/exclusion criteria (See Sections 6.1 and 6.2.). 
• 
Document medical history including migraine history and prior treatment and collect 
demographic information (See Section 9.1.1). 
• 
Have subject complete MIDAS (See Section 9.1.1.2 and Appendix 3). 
• 
Record concomitant medications that the subject is taking. 
• 
Document resource utilization (See Section 9.1.1.3). 
• 
Perform a complete physical examination (including height, weight, and vital signs) 
(See Sections 9.1.2 and 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 serum βHCG for 
women of childbearing potential (WOCPB). Any woman with a positive pregnancy 
test will be ineligible for the study. Have subject complete C-SSRS (See Section 
9.1.6 and Appendix 4). 
• 
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.  
o For subjects who meet initial screening criteria and are randomized, advise as to 
when to expect the confirmatory telephone call.  Remind subject not to treat a 
migraine attack with study drug prior to this call. 
• 
Dispense study drug as assigned.  
• 
Provide access to electronic diary.  
o Starting at Visit 1 and continuing to EoS/Visit 2, subjects will be asked daily, 
how they are feeling and about the use of any concomitant medications. 
• 
Confirm timing of EoS/Visit 2. 
• 
Discharge subject. 
• 
A subject may be rescreened only once. 
 
5.6.2 Phone Call 
 
Within 7 days after screening, a phone contact must be made between site study staff and 
subject to confirm study eligibility based on the clinical laboratory results.  
 
• 
If a subject is eligible, a review of study requirements will be performed. Subjects will 
update their status in the e-diary to allow them to report a migraine and record 
dosing and post-dose assessments. Each subject will be reminded of when to treat a 
migraine attack with study drug, the use of rescue medication, the treatment of 
recurrence and diary completion along with the need to return to the clinic for EoS/ 
Visit 2. Subjects will be asked to treat their next migraine attack providing headache 
severity is at least moderate and not improving. 


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• 
If a subject is considered not eligible, she/he will be instructed not to take the study 
drug and an appointment to return the study drug and diary must be scheduled and 
should occur within one week (7 days). 
 
5.6.3 Treatment 
Subjects will be allowed up to 8 weeks to treat an acute migraine attack of moderate or 
severe intensity that is not improving. The attack is to be treated within 4 hours of onset. 
• 
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 (See Section 9.1.8). 
• 
Subjects will be asked about any adverse events (if they are feeling anything 
unusual) and about the use of any concomitant medications. 
 
5.6.4 End of Study/Visit 2 
The following assessments will be performed: 
• 
Collect any unused study drug and review dosing compliance. 
• 
Collect resource utilization (See Section 9.1.1.3). 
• 
Collect information on missed days of work and/or school due to migraine. 
• 
Have subject complete C-SSRS (See Section 9.1.6 and Appendix 5). 
• 
Review any information reported since Visit 1 regarding AEs and use of concomitant 
medication and confirm/assess for AEs and use of concomitant medications not 
already reported. 
• 
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). 
• 
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. 
 
 


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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. Patients with migraine with or without aura fulfilling the IHS diagnostic criteria 1.1 and            
1.2.1 (ICHD-2004, Appendix 2). 
3. History of disabling migraine for at least 1 year. 
4. MIDAS score ≥11 (Appendix 3). 
5. Migraine onset before the age of 50 years. 
6. History of 3 – 8 migraine attacks per month (< 15 headache days per month). 
7. Male or female, aged 18 years or above. 
8. 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). 
9. Able and willing to complete an electronic diary to record details of the migraine attack 
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. 
Known hypersensitivity to lasmiditan, or to any excipient of lasmiditan oral tablets, or 
any sensitivity to a ditan. 
5. 
History or evidence of hemorrhagic stroke, epilepsy or any other condition placing the 
subject at increased risk of seizures. 
6. 
History of recurrent dizziness and/or vertigo including BPPV, Meniere’s disease, 
vestibular migraine, and other vestibular disorders. 
7. 
History of diabetes mellitus with complications (diabetic retinopathy, nephropathy or 
neuropathy). 
8. 
History within the previous three years or current evidence of abuse of any drug, 
prescription or illicit, or alcohol. 
9. 
History of orthostatic hypotension with syncope. 
10. Significant renal or hepatic impairment.  
11. Subject is at imminent risk of suicide (positive response to question 4 or 5 on the 
C-SSRS) or had a suicide attempt within six months prior to the screening visit. 
12. Previous participation in this clinical trial. 
13. Participation in any clinical trial of an experimental drug or device in the previous 30 
days. 
14. Known Hepatitis B or C or HIV infection. 
15. History, within past 12 months, of chronic migraine or other forms of primary or 
secondary chronic headache disorder (e.g. hemicranias continua, medication overuse 
headache [Appendix 2]) where headache frequency is ≥15 headache days per month. 
16. Use of more than 3 doses per month of either opiates or barbiturates. 
17. Initiation of or a change in concomitant medication to reduce the frequency of migraine 


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episodes within three (3) months prior to Screening/Visit 1.  
18. Subjects who are employees of the sponsor.  
19. Relatives of, or staff directly reporting to, the Investigator. 
 
Subjects with test results which do not meet the above inclusion/exclusion criteria may have the 
underlying test repeated once if it is thought to represent a laboratory error, a reversible, 
clinically insignificant intermittent condition, or is not consistent with the subject’s historical 
values.  If inclusion/exclusion criteria are not met after the repeat test, the subject should not be 
enrolled in the study. 
 
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 
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 EoS/Visit 2, 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 prematurely discontinuing from the trial (prior to EoS/Visit 2), regardless of cause, 
must be seen for EoS/Visit 2.  Subjects that withdraw from the study prior to dosing a single 
attack should return to the clinic for EoS/Visit 2 to 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 
At screening, each subject will be assigned a unique seven-digit subject number.  The first three 
characters will be numbers that identify the study site, and will be assigned by the Sponsor.  
The remaining four characters identify the subject.  The latter four numbers will be assigned by 
the study site personnel in ascending sequential order to each unique subject screened at that 
site.  For example, the subject number for the first subject screened at Study Site 001 would be 
001-2001.  If a subject is rescreened, the reason for rescreening will be noted and the subject 
will keep the same number assigned at initial screening.   If a subject fails to be randomized, the 
reason for not being randomized should be documented in the source documents. The subject 
will be considered a screen failure. If a subject is randomized but is then deemed ineligible at 
the telephone confirmation the subject will be considered a randomization failure. This subject 
will return to the clinic to be discontinued. Study drug and the patient e-diary will be collected. A 
subject deemed to be a randomization failure may be rescreened if the reason for ineligibility is 
thought to represent a laboratory error, a reversible, clinically insignificant intermittent condition, 
or is not consistent with the subject’s historical values.  The subject will be given a new 
screening number.  In this case the subject should not be re-randomized until eligibility is 
confirmed.  If the subject is not re-randomized he/she will be considered a screen failure. 
 
7.2 
Description of Study Drug 
For study purposes lasmiditan and matching placebo are all referred to as study drug.  
 
7.3 
Concomitant Medications 
Concomitant medications (including devices), for migraine or pain during the 90 days (3 months) 
prior to study enrollment and concomitant medication used to treat other medical conditions 
during the 30 days (1 month) 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 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. 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 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 randomized study drug may be taken up to 24 hours after the first 
dose. 
 


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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/Visit 2:  
• 
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. 
 
7.5 
Treatment Compliance 
Study drug will be taken by the subject at home throughout the study.  Prior to discharge from 
Screening/Visit 1 subjects will be given study drug to treat a single migraine attack and a 
second dose for rescue or recurrence.   Information on the time and date of each dose (initial 
treatment along with the use of rescue medication or treatment of recurrence) will be recorded 
by the subject in the electronic diary.  Subjects will be instructed to return all unused study drug 
to the clinic at EoS/Visit 2.   
 
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 and matching placebo will be provided in double-blinded treatment packs. 
 
7.7 
Unblinding Procedures 
7.7.1 
Emergency unblinding of treatment assignment 
Emergency unblinding should only be performed when necessary in order to treat the subject.  
There is no known antidote to lasmiditan, so symptomatic and supportive management of any 
suspected and treatment related adverse event, if necessary, is clinically indicated. 
Unblinding will result in the subject being discontinued from the study, irrespective of whether 
the Investigator ultimately agrees with the event being related to study drug (lasmiditan).  Most 
often, study drug discontinuation and knowledge of the possible treatment assignments are 
sufficient to treat a study subject who presents with an emergency condition. The Investigator 
will have the ability to break the blind for any subject through the centralized randomization 
system (IRT). However, the Investigator should make every effort to contact the Sponsor’s 
medical monitor or their designee to discuss the subject’s emergency situation and the need to 
unblind prior to unblinding any subject, but must contact the Sponsor or designee within one 
working day after the event occurs. The Sponsor’s medical monitor or their designee will also 
have the ability to break the blind for the Investigator while remaining blinded via the centralized 
randomization system if the treating Investigator requests this  The blind may be broken in the 
case of a pregnancy should the subject desire this information. Any subject for whom the blind 
is broken is to be discontinued from future study treatment.  The date, time and reason for 
breaking the blind are to be recorded in the subject’s source documents. 
 
7.7.2 Unblinding for Regulatory Authorities 
In cases where unblinding is required for the purposes of reporting expedited safety events to 
country specific regulatory agencies or Ethics Committees, the unblinding will be performed by 


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an  authorized  member  of the Quintiles Pharmacovigilance team.   A  blinded  version  of  any 
documents to be submitted to the authorities will be shared as appropriate with study staff and 
site  personnel.  Only  the  authorized  person(s) within the Quintiles Pharmacovigilance and 
Regulatory Affairs will have access to the unblinded version of any documents. The procedures 
for requesting and obtaining unblinded information and for maintaining the integrity of the data 
and clinical trial are outlined in the Pharmacovigilance Plan for this study.  
8.  
STUDY DRUG MATERIALS AND MANAGEMENT 
8.1 Study Drug 
Study drug refers to lasmiditan and matching placebo. 
 
Lasmiditan drug product is a tablet containing 50 mg, 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. 
 
Lasmiditan hemisuccinate active pharmaceutical ingredient (API) was manufactured by Produits 
Chimiques  Auxillaires  et  de  Synthèse  (PCAS),  19  route  de  Meulan,  F-78520  Limay  (France).    
The  drug  product  was  manufactured  by  Aptuit  
(Verona)  Srl  Via  A.  Fleming,  4  37135  Verona, 
Italy  and  contains  the  following  inactive  excipients: 
 
 
  
 
The placebo tablets were also manufactured by Aptuit (Verona) and contain the following 
inactive excipients: 
  
he placebo tablets match the active tablets in size, 
shape and appearance. 
 
Each dose will consist of two tablets for the treatment of a single migraine attack and two tablets 
for use as rescue medication or as treatment of recurrence of migraine.  
  
• Lasmiditan 50 mg dose – one 50 mg lasmiditan tablet and either one lasmiditan 100 mg 
matching placebo, or one lasmiditan 200 mg matching placebo. 
•  Lasmiditan 100 mg dose – one  100 mg lasmiditan  
tablet and  either  one  
lasmiditan 50 
mg matching placebo, or one lasmiditan 200 mg matching placebo. 
•  Lasmiditan  200  mg dose – one  200 mg  
lasmiditan  
tablet and  either one  
lasmiditan 50 
mg matching placebo, or one lasmiditan 100 mg matching placebo 
• Placebo – one 50 mg lasmiditan matching placebo and one 100 mg matching placebo, 
or  one  50  mg  
lasmiditan  matching  placebo  and  one  200  mg  matching  placebo  or  one 
100 mg lasmiditan matching placebo and one 200 mg matching placebo. 
8.2 Study Drug Packaging and Labeling 
All study drug will be provided as individual dosing cards containing 2 doses. In the card, each 
tablet  will  be  contained  within  an  
individual  blister  pack.  
 There  will  be  a  
total  of  4  blisters  per 
card. The doses  will  be separately  designated  either for  initial  treatment or for rescue  or 
recurrence. 
CCI
 
CCI


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All study drug will be labeled with:  
 
• 
Protocol number 
• 
Sponsor’s name and address 
• 
Investigational New Drug statement 
• 
Subject’s initials and study ID number 
• 
Instructions for use and storage 
 
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 during Screening/Visit 1 with instructions to treat an acute migraine attack only after 
their eligibility has been confirmed by the site. Each subject will be informed of their eligibility via 
a telephone call within 7 days of the screening visit. 
 
Subjects will be instructed to take both tablets 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 the second dose (two tablets) if needed with approximately 4 
ounces of water for rescue or for recurrence of migraine. 
 
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. 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. 
 
 


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9. 
TREATMENT ASSESSMENTS 
9.1 
Efficacy and Safety Parameters 
Primary 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 recurrence medication. 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. Safety will be monitored with physical examinations, vital signs, ECGs, clinical 
laboratory testing, and AE/SAE assessments.  
 
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 
General relevant medical history 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.  
 
The Investigator will exclude subjects with ongoing significant major organ disease.   
 
Smoking history and family history of cardiovascular disease will be recorded on the CRF. 
 
Concomitant medications or devices, for migraine or pain during the 90 days (3 months) prior to 
study enrollment and concomitant medication used to treat other medical conditions during the 
30 days (1 month) prior to enrollment will be recorded on the CRF.  
 
In addition, information regarding the subject’s migraine history including prior treatment will be 
recorded. 
 
9.1.1.1  
Demographics 
During Screening/Visit 1, subject initials, age, gender, race and ethnicity will be recorded on 
the CRF.   
 
9.1.1.2  
MIDAS 
MIDAS is a 5 item questionnaire (Appendix 3) 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.  A score of ≥ 11 is required for inclusion in the study. 
 
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. 
 
 


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9.1.1.3  
Resource Utilization 
During Screening/Visit 1 subjects will be asked specifically about any CV events in the last 6 
months and/or related resource utilization such as visits to cardiologists, procedures, 
hospitalizations, new treatments or treatment adjustments for CV disease. In addition 
information regarding any ER visits or visit to physician’s office for migraine treatment will be 
recorded.    At EoS/Visit 2 the subject will again be asked about resource utilization during their 
time on study.  
 
The subject will also be asked about the number of days missed from work and/or school during 
the migraine treated with study drug.  
 
9.1.2 Physical Examination 
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. For EoS/Visit 2, a brief symptom related physical examination will be performed 
if indicated by an AE. 
 
Height and weight will be measured at Screening/Visit 1. BMI will be calculated by the 
database. 
 
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 
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).  
 
9.1.4 ECG 
A standard, digital 12-lead ECG will be obtained after at least 5 minutes rest at Screening/Visit 
1and EoS/Visit 2.   
 
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 and EoS/Visit 2.  Tests will be conducted as designated below:  
 


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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 (AP), 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. 
 
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 serum pregnancy test for β-HCG will be performed at the Screening/Visit 1.  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. At EoS/Visit 2, a urine pregnancy test will be 
performed. If positive, a confirmatory serum pregnancy test will be done. 
 
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. 
 
9.1.6 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.  Two versions of the C-SSRS will be used. 
 
• 
The screening version will be administered at Screening/Visit 1 (Appendix 4). 
 
• 
The “since last visit” version will be administered at EoS/Visit 2 (Appendix 5). 
 
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). 
 


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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 will be asked to treat their 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 will be instructed not to use 
rescue medication until at least 2 hours after taking study drug. If the subject does not become 
headache pain free within 2 hours, rescue medication 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. 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 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 
their 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. 
 
Subjects will be asked to assess their headache severity at specified time points: 0 (pre dose), 
0.5, 1, 1.5, 2, 3, 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 
rescue medication and second dosing of study drug or an alternative treatment will be assessed 
between 2 and 24 hour and at 48 hours.  Recurrence of pain and second dosing of study drug 
will be assessed between 2 and 24 hours and at 48 hours. 
 
At the  same  time points, 0 (pre dose), 0.5, 1, 1.5, 2, 3, 4, 24 and 48 hours, 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 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 from Visit 1 through to EoS/Visit 2 
 
9.1.8.1 
Recording Use of Rescue Medication and Migraine Symptoms 
The use of rescue medication 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 0.5, 1, 2, 4, 24 and 48 
hours post dosing.  Migraine pain will be graded as none (0), mild (1), moderate (2) or severe 


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(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. 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 0.5, 1, 2, 4, 24 and 48 hours post 
dosing. 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 be sought 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 
• 
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/ Visit 2.  AEs reported prior 
to dosing will be captured and considered non-treatment emergent AEs. AE reported 48 hours 
after dosing until the completion of EoS/Visit 2 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: 


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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. 
 
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.  
 
9.2.3 Serious Adverse Events 
An SAE is any AE that results in any of the following outcomes: 


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• 
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 
consent form and ends following the last dose of study treatment at EoS/Visit 2.  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 


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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/Visit 2.   
 
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. 
 
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. 
 


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10. 
STATISTICS 
Prior to locking and unblinding 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.  The efficacy analyses and baseline 
characteristics will be based on the Intent-to-Treat (ITT) and mITT population.  The primary 
analysis will be tested in the mITT population.   All safety analyses will be based on the Safety 
Population.  The Per Protocol Population will be used to support the ITT analyses. 
 
All tests of treatment effects will be conducted at a one-sided alpha level of 0.025. 
 
The primary objective of the study is to evaluate the efficacy of lasmiditan versus placebo at 2 
hours on migraine headache pain and the MBS as identified by the individual subject based on 
the first dose. 
 
Summary analysis of the efficacy and safety of the use of a second dose of lasmiditan versus 
placebo 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 analyzed using 
change from baseline scores, observed scores may also be presented descriptively. 
 
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 effective in the treatment of 
acute migraine in adult patients with and without aura. The sample size was estimated based on 
the 2 hour headache pain free and associated symptoms (nausea, phonophobia, and 
photophobia) free response rates observed in the Phase 2 study COL MIG-202. 
  
Dose 
Pain free 
Nausea free Phonophobia 
free 
Photophobia 
free 
Placebo 
7.4% 
59.3% 
51.9% 
34.6% 
50 mg  
13.9% 
68.4% 
58.2% 
53.2% 
100 mg 
13.6% 
74.1% 
75.3% 
67.9% 
200 mg 
18.8% 
63.8% 
59.4% 
58.0% 
 
For the primary endpoint of the proportion of patients pain free at 2 hours a sample size of 570 
evaluable subjects per arm provides power of >90% for the 50 mg dose, the 100 mg dose and 
the 200 mg dose. 
 


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In order to estimate sample size for the key secondary endpoint of proportion of patients MBS 
free at 2 hours, simulation was performed in SAS on the conditional probability of being free 
from any one symptom defined as MBS under 4 different scenarios. For each symptom or 
combination of symptoms, the likelihood of an individual symptom being the MBS was 
estimated. In the most conservative scenario (scenario 1) it was assumed that nausea would 
always be declared the MBS if it was present, regardless of the presence of other symptoms 
(phonophobia or photophobia).  The other 3 scenarios assumed lower likelihoods of nausea to 
be considered the MBS and allowed for the other symptoms (either phonophobia or 
photophobia) to be considered the MBS at a higher rate.  This resulted in power estimates of > 
95% for MBS at a sample size of 570 for the lasmiditan 50 mg  dose and >99% for MBS at  
sample sizes of 450 to 570 per arm for the 100 mg dose across all 4 scenarios. For the 200 mg 
dose, an average power of 71% was estimated across five seeds under the most conservative 
scenario 1. In contrast, the 3 scenarios that did not declare nausea to be the default MBS if it 
was present estimated a greater average power of 82.6% to 91%. 
 
 
 
Group 
 
Scenario 
 
Variable 
Seed 
55405 
74951 
82002 
82377 
90075 
Placebo 
vs D50 
1 
Power (MBS) 
96.90% 
95.90% 
96.10% 
95.60% 
96.80% 
Sample Size 
570 
570 
570 
570 
570 
2 
Power 
93.70% 
94.30% 
94.80% 
93.90% 
93.90% 
Sample Size 
450 
450 
450 
450 
450 
3 
Power 
90.40% 
90.40% 
90.10% 
91.00% 
91.40% 
Sample Size 
575 
575 
575 
575 
575 
4 
Power 
93.70% 
94.30% 
94.80% 
93.90% 
93.90% 
Sample Size 
450 
450 
450 
450 
450 
Placebo 
vs D100 
1 
Power (MBS) 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
Sample Size 
570 
570 
570 
570 
570 
2 
Power 
99.90% 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
Sample Size 
450 
450 
450 
450 
450 
3 
Power 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
Sample Size 
575 
575 
575 
575 
575 
4 
Power 
99.90% 
>99.99% 
>99.99% 
>99.99% 
>99.99% 
Sample Size 
450 
450 
450 
450 
450 
Placebo 
vs D200 
1 
Power 
70.87% 
70.87% 
72.97% 
71.17% 
68.47% 
Sample Size 
570 
570 
570 
570 
570 
2 
Power 
84.40% 
85.00% 
85.80% 
85.90% 
85.80% 
Sample Size 
450 
450 
450 
450 
450 
3 
Power 
83.50% 
83.20% 
81.30% 
83.40% 
81.80% 
Sample Size 
575 
575 
575 
575 
575 
4 
Power 
90.20% 
90.50% 
92.50% 
91.40% 
90.40% 
Sample Size 
450 
450 
450 
450 
450 
1 Mean rate is the freedom from MBS at 2 hours post dose. 
P=placebo, L = lasmiditan 
 
 
It is expected for a one-sided, two-sample comparison of proportions at the 2.5% level of 
significance, a sample size of 570 subjects per treatment arm (as defined by the first dose) 
provides >90% power to detect a difference in headache pain free response rates for assumed 
true rates of 7.4% and 18.8% (placebo and 200 mg), 7.4% and 13.6% (placebo and 100 mg) 
and 7.4% and 13.9% (placebo and 50 mg) >90 % power for MBS for both the 50 mg dose arm 


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and the 100 mg dose arm and very near or higher than 80% power for MBS in the 200 mg dose 
arm. 
 
 
10.2 Randomization  
This is a multicenter, randomized, double-blind, placebo controlled parallel group study.   
Subjects will be centrally randomized to one of 7 treatment sequences to receive lasmiditan 50 
mg,  lasmiditan 100 mg (L100 mg) or lasmiditan 200 mg (L200 mg) or placebo (P) for the first 
dose (in a 1:1:1:1 ratio) and the second dose for rescue or recurrence of migraine (if needed).  
Subjects will be stratified (yes or no) for use of concomitant medications that reduce the 
frequency of migraine episodes.  Study drug will be randomized and dispensed at Visit 1 as 
follows: 
First dose for treatment 
of migraine  
Second dose for rescue or 
recurrence of migraine (if needed) 
L50 mg 
L 50 mg 
L 50 mg 
placebo 
L100 mg 
L100 mg 
L100 mg 
placebo 
L200 mg 
 
L200 mg 
L200 mg 
placebo 
placebo 
placebo 
 
10.3 Analysis Populations 
10.3.1  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. 
 
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. 


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PP population 
All ITT subjects will be considered per protocol (PP) if they dose 
a migraine attack 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. 
 
10.3.2 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.  
 
 
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.  
 


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• 
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 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).  Treatments will be 
compared descriptively by using analysis of variance techniques for continuous data and 
Pearson’s chi-square or Fisher’s exact test for categorical data.  
 
The results of these tests will be used in a descriptive way to highlight potential imbalances 
between the treatment groups.  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 Compliance  
Treatment compliance will be assessed in terms of the actual dose.  Treatment compliance will 
be used to characterize the patients and determine clinical evaluability for some analyses.  
Treatment compliance will be summarized within each treatment group by means of descriptive 
statistics (n, mean, SD, median, minimum and maximum). 
 
10.5 Efficacy Analyses 
All of the efficacy analyses will be performed on the ITT or mITT population.  The primary 
analysis population is the mITT population.  The PP population will be used as supportive 
analyses. 
 
10.5.1 Primary Analysis 
The treatment effect between lasmiditan and placebo will be tested first for the primary endpoint 
of the proportion of subjects who are headache pain free and the key secondary endpoint of the 
proportion of subjects who are MBS free at 2 hours in the mITT population between the 
lasmiditan 200 mg and placebo dose group based on the first dose. The primary analysis will be 
completed using logistic regression Wald Chi-square test with a basic model including treatment 
group and region, using a one-sided test at the alpha=0.025 level of significance.   
 
If the primary analysis is statistically significant (one-sided, p<0.025), additional confirmatory 
hypotheses will be tested on the proportion of subjects who are headache pain free and the 
proportion of subjects who are MBS free at 2 hours in the lasmiditan 100 mg and placebo 


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groups followed by the lasmiditan 50 mg and placebo groups. 
 
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. 
 
Subjects taking rescue medication within the first two hours or who fail to record headache 
severity at 2 hours will be assumed to have no headache response 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 have no 
headache response for the ITT analysis. 
 
 
10.5.2 Sensitivity Analyses of the Primary and Key Secondary Endpoints 
The primary endpoint of pain free at 2 hours and the key secondary endpoint of MBS free 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. 
 
10.5.3 Multiplicity Adjustment for Hypothesis Testing 
The gatekeeping procedure will be implemented to prevent Type I error inflation for multiple 
comparisons among the primary and secondary analyses. The treatment effect between 
lasmiditan 200 mg and placebo will be tested first for the primary endpoint of the proportion of 
subjects who are headache pain free and the key secondary endpoint of the proportion of 
subjects who are MBS free at 2 hours in the mITT population.  
 
If the primary analysis is statistically significant (one-sided, p<0.025), additional confirmatory 
hypotheses will be tested in the mITT population in the following sequential order: 
 
1. Proportion of subjects who are headache pain free at 2 hours in the lasmiditan 
100 mg and placebo group. 
2. Proportion of subjects who are MBS free at 2 hours in the lasmiditan 100 mg and 
placebo group. 
3. Proportion of subjects who are headache pain free at 2 hours in the lasmiditan 50 
mg and placebo group. 
4. Proportion of subjects who are MBS free at 2 hours in the lasmiditan 50 mg and 
placebo group. 
 
 


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All of the above analyses will be completed using one-sided tests at the alpha=0.025 level of 
significance.  If one of the analyses is not statistically significant, then all subsequent analyses 
will be exploratory rather than confirmatory. 
 
10.5.4 Other Efficacy Analyses 
 
10.5.4.1 
Headache relief 
The proportion of subjects with headache relief (moderate or severe headache at baseline, 
which became mild or none) at 2 hours post dose will be evaluated. The time course to 
headache relief will be explored up to 48 hours. Kaplan-Meier analysis will be performed to 
compare time course to headache relief between lasmiditan 200 mg and placebo, lasmiditan 
100 mg and placebo and lasmiditan 50 mg and placebo.  
 
10.5.4.2 
Headache recurrence 
The proportion of subjects 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. The frequency of recurrence will be compared 
by the same logistic regression model used for the primary endpoint analysis.  The significance 
level of this exploratory analysis will be a nominal one-sided 0.05. 
 
10.5.4.3 
Headache rescue 
The requirement for rescue medication at 2 hours and between 2 and 24 hours and 24- 8 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 group. 
 
10.5.4.4 
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.   
 
10.5.4.5 
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). 
 
10.6 Analysis of Second dose 
All of the efficacy analyses will be performed on the ITT-2nd dose or mITT- 2nd dose population.  
The primary analysis population is the mITT-2nd dose population.  The PP-2nd dose population 
will be used as supportive analyses. 
 
10.6.1 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 sequence 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. 


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10.6.2 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 sequence 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. 
 
10.7 Missing Values 
The primary and key secondary endpoints are defined as proportions. If a subject has a missing 
value for a proportion endpoint, the subject will be classified as a nonresponder for this 
endpoint. Subjects who have more than one symptom (nausea, phonophobia or photophobia) 
but do not select one as the MBS prior to dosing, will be considered inevaluable for the MBS 
endpoint as there is no MBS selected to evaluate.  In the case of subjects that have only one 
symptom (nausea, phonophobia, or photophobia) at predose but do not select a MBS, the one 
symptom will be considered the MBS for analysis. 
 
For subjects who do not record a symptom rating, that symptom (pain, photophobia, 
phonophobia or nausea) will be assumed to be present at all time points where data are 
missing. Subjects who do not provide a headache severity rating at baseline will be assumed to 
have all four symptoms (pain, nausea, photophobia and phonophobia) at all time points.  If 
recurrence medication is taken within 24 hours post dosing, or from 24 hours to 48 hours post 
dosing, even if no headache is reported, headache recurrence will be assumed for the first dose 
analysis. 
 
The sensitivity analysis for handling missing data is described in detail in the SAP. 
 
10.8 Safety Analyses 
Values for all safety variables will be listed by subject and time point. 
 
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 
percentages. 
 
10.8.1 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 treatment sequence 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 


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also be calculated for each treatment arm and treatment sequence 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 EoS/Visit 2 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. 
 
10.8.2 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.  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 2, 
as appropriate by treatment arm and dose. 
 
10.8.3 C-SSRS 
By-subject listings of any suicidal ideation or behavior will be listed. 
 
10.9 Resource Utilization 
By-subject listings of any resource utilization will be listed and will be summarized using 
descriptive statistics, separated by treatment arm, and dose. 
 
 


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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 CoLucid 
Pharmaceuticals, Inc. (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 CoLucid Pharmaceuticals, Inc. 
 
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 CoLucid Pharmaceuticals, Inc. 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 


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CRO/CoLucid Pharmaceuticals, Inc. with written documentation of continued review of the 
clinical study. 
 
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. 
CoLucid Pharmaceuticals, Inc. 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 
CoLucid or its designated representative(s) before submission to the IRB/IEC/REB, and a copy 
of the approved version must be provided to the CoLucid 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 CoLucid Pharmaceuticals, Inc., 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.   
CoLucid 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 
CoLucid 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 


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with the legal requirements of each country.  Clinical supplies are to be dispensed only in 
accordance with the protocol. 
 
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 CoLucid 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 CoLucid. 
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 CoLucid, 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 CoLucid or its designated representative, and must be maintained in 
confidence by the Investigator. 
 
13.7 Publication policy 
As 
is 
customary 
for 
multicenter 
trials, 
publication 
by 
individual 
study 
sites 
or 
Investigator/Institution will not be allowed without the explicit written permission of the Sponsor.  
The Sponsor will determine authorship of the principal study manuscript(s) in conjunction with 
the Investigators, in abiding with current guidelines and requirements of medical journals. For 
such manuscript(s), masthead roles for Investigators will be determined based on subject 
enrollment and scientific contributions to the Study.   
 


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14. 
RETENTION OF RECORDS 
After the study, the Investigator will keep all information relevant to the study for 15 years. 


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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 v7.0 March 2015. 


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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  


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Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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  
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  


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Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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  
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  


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Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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  
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. INTERNATIONAL HEADACHE SOCIETY 
DIAGNOSTIC CRITERIA 
 
1. MIGRAINE 
 
1.1. Migraine without aura   
 
Description: 
Recurrent headache disorder manifesting in attacks lasting 4-72 hours. Typical characteristics 
of the headache are unilateral location, pulsating quality, moderate or severe intensity, 
aggravation by routine physical activity and association with nausea and/or photophobia and 
phonophobia 
Diagnostic criteria: 
A. At least 5 attacks1 fulfilling criteria B-D 
B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)2;3;4  
C. Headache has at least two of the following characteristics:  
1. unilateral location5;6  
2. pulsating quality7  
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (eg, walking or 
climbing stairs) 
D. During headache at least one of the following:  
1. nausea and/or vomiting 
2. photophobia and phonophobia8  
E. Not attributed to another disorder9  
 
Notes: 
1. Differentiating between 1.1 Migraine without aura and 2.1 Infrequent episodic tension-type 
headache may be difficult. Therefore at least 5 attacks are required. Individuals who otherwise meet 
criteria for 1.1 Migraine without aura but have had fewer than 5 attacks should be coded 1.6.1 
Probable migraine without aura.  
2. When the patient falls asleep during migraine and wakes up without it, duration of the attack is 
reckoned until the time of awakening. 
3. In children, attacks may last 1-72 hours (although the evidence for untreated durations of less than 2 
hours in children requires corroboration by prospective diary studies). 
4. When attacks occur on ≥15 days/month for >3 months, code as 1.1 Migraine without aura and as 
1.5.1 Chronic migraine.  
5. Migraine headache is commonly bilateral in young children; an adult pattern of unilateral pain 
usually emerges in late adolescence or early adult life. 
6. Migraine headache is usually frontal temporal. Occipital headache in children, whether unilateral or 
bilateral, is rare and calls for diagnostic caution; many cases are attributable to structural lesions. 
7. Pulsating means throbbing or varying with the heartbeat. 


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8. In young children, photophobia and phonophobia may be inferred from their behavior. 
9. History and physical and neurological examinations do not suggest any of the disorders listed in 
groups 5-12, or history and/or physical and/or neurological examinations do suggest such disorder 
but it is ruled out by appropriate investigations, or such disorder is present but attacks do not occur 
for the first time in close temporal relation to the disorder. 
 
 
1.2  Migraine with aura 
 
Description: 
Recurrent disorder manifesting in attacks of reversible focal neurological symptoms that usually 
develop gradually over 5-20 minutes and last for less than 60 minutes. Headache with the 
features of migraine without aura usually follows the aura symptoms. Less commonly, headache 
lacks migrainous features or is completely absent. 
Diagnostic criteria: 
A. At least 2 attacks fulfilling criterion B 
B. Migraine aura fulfilling criteria B and C for one of the sub-forms 1.2.1-1.2.6 
C. Not attributed to another disorder1  
 
 Notes: 
1. History and physical and neurological examinations do not suggest any of the disorders listed in 
groups 5-12, or history and/or physical and/or neurological examinations do suggest such disorder 
but it is ruled out by appropriate investigations, or such disorder is present but attacks do not occur 
for the first time in close temporal relation to the disorder. 
 
 
 
 
 


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Medication Overuse Headache 
Diagnostic criteria: 
A. Headache1 present on ≥15 days/month fulfilling criteria C and D 
B. Regular overuse2 for ≥3 months of one or more drugs that can be taken for acute and/or 
symptomatic treatment of headache3  
C. Headache has developed or markedly worsened during medication overuse 
D. Headache resolves or reverts to its previous pattern within 2 months after discontinuation 
of overused medication4  
 
Notes: 
1. The headache associated with medication overuse is variable and often has a peculiar pattern with 
characteristics shifting, even within the same day, from migraine-like to those of tension-type 
headache. 
2. Overuse is defined in terms of duration and treatment days per week. What is crucial is that 
treatment occurs both frequently and regularly, ie, on 2 or more days each week. Bunching of 
treatment days with long periods without medication intake, practiced by some patients, is much 
less likely to cause medication-overuse headache and does not fulfil criterion B. 
3. MOH can occur in headache-prone patients when acute headache medications are taken for other 
indications. 
4. A period of 2 months after cessation of overuse is stipulated in which improvement (resolution of 
headache, or reversion to its previous pattern) must occur if the diagnosis is to be definite. Prior to 
cessation, or pending improvement within 2 months after cessation, the diagnosis 8.2.8 Probable 
medication-overuse headache should be applied. If such improvement does not then occur within 
2 months, this diagnosis must be discarded. 
 
 
Medication overuse headache (MOH) as defined by ICHD II: 
o Opioids ≥ 10 days a month during the 90 days prior to screening 
o Combination medications (e.g., Fiorinal®) ≥ 10 days a month  
o NSAIDS or other simple medications > 14 days a month during the 90 days prior to 
screening 
o Triptans or ergots ≥ 10 days a month during the 90 days prior to screening 
 
 
 
 


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18. 
APPENDIX 3.  THE 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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19. 
APPENDIX 4. COLUMBIA SUICIDE SEVERITY RATING SCALE-
SCREENING VISIT 
 
 
COLUMBIA-SUICIDE SEVERITY  
RATING SCALE  
(C-SSRS)  
Screening Version 1/14/09  
 
 
 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; Burke, 
A.; Oquendo, M.; Mann, J.  
Disclaimer:  
This scale is intended to be used by individuals who have received training in its administration. The 
questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the 
determination of the presence of suicidal ideation or behavior depends on the judgment of the individual 
administering the scale.  
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental 
Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. 
A., Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In 
M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)  
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, 
New York, New York, 10032; inquiries and training requirements contact posnerk@childpsych.columbia.edu 
 
 
© 2008 The Research Foundation for Mental Hygiene, Inc 
 
 


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SUICIDAL IDEATION  
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the 
answer to question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is 
“yes”, complete “Intensity of Ideation” section below.  
Past  
X Months  
1. Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
describe:  
Yes No  
□ □  
2. Non-Specific Active Suicidal Thoughts  
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) 
without thoughts of ways to kill oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself?  
If yes, describe:  
Yes No  
□ □  
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is 
different than a specific plan with time, place or method details worked out (e.g., thought of method to kill self but not a 
specific plan). Includes person who would say, “I thought about taking an overdose but I never made a specific plan as 
to when, where or how I would actually do it…..and I would never go through with it.”  
Have you been thinking about how you might do this?  
describe:  
Yes No  
□ □  
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed 
to “I have the thoughts but I definitely will not do anything about them.”  
Have you had these thoughts and had some intention of acting on them?  
describe:  
Yes No  
□ □  
5. Active Suicidal Ideation with Specific Plan and Intent  
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.  
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this 
plan?  
describe:  
Yes No  
□ □  
INTENSITY OF IDEATION  
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 
from above, with 1 being the least severe and 5 being the most severe). Ask about time he/she was 
feeling the most suicidal.  
_____ _________________________________________________  
Most Severe Ideation:  
Type # (1-5) Description of Ideation  
Most Severe  
Frequency  
How many times have you had these thoughts?  
(1) Less than once a week (2) Once a week (3) 2-5 times in week (4) Daily or almost daily (5) Many times each day  
____  
Duration  
When you have the thoughts, how long do they last?  
(1) Fleeting - few seconds or minutes                        (4) 4-8 hours/most of day  
(2) Less than 1 hour/some of the time                        (5) More than 8 hours/persistent or continuous  
(3) 1-4 hours/a lot of time  
____  
Controllability  
Could/can you stop thinking about killing yourself or wanting to die if you want to?  
(1) Easily able to control thoughts                           (4) Can control thoughts with a lot of difficulty  
(2) Can control thoughts with little difficulty             (5) Unable to control thoughts  
(3) Can control thoughts with some difficulty          (0) Does not attempt to control thoughts  
____  
Deterrents  
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you 
from wanting to die or acting on thoughts of committing suicide?  
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                   (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                           (0) Does not apply  
____  


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Reasons for Ideation  
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was 
it to end the pain or stop the way you were feeling (in other words you couldn’t go on living 
with this pain or how you were feeling) or was it to get attention, revenge or a reaction from 
others? Or both?  
(1) Completely to get attention, revenge or a reaction from others (4) Mostly to end or stop the pain (you couldn’t go   
(2) Mostly to get attention, revenge or a reaction from others              on living with the pain or how you were feeling)  
(3) Equally to get attention, revenge or a reaction from others        (5) Completely to end or stop the pain (you couldn’t    
go on and end/stop the pain living with the 
pain or how you were feeling) 
                                                                                                       (0) Does not apply  
____  
SUICIDAL BEHAVIOR  
(Check all that apply, so long as these are separate events; must ask about all types)  
Past X Years or  
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part 
thought of as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated 
with the act, then it can be considered an actual suicide attempt. There does not have to be any injury or 
harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury 
results, this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, but 
they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt?  
Have you done anything to harm yourself?  
Have you done anything dangerous where you could have died?  
What did you do?  
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____?  
Or did you think it was possible you could have died from_____?  
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to 
relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious 
Behavior without suicidal intent)  
describe:  
Has subject engaged in Non-Suicidal Self-Injurious Behavior?  
Yes No  
□ □  
Total # of  
Attempts  
______  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes No  
□ □  
Interrupted Attempt:  
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for 
that, actual attempt would have occurred).  
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an attempt 
rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone 
else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an 
attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose 
around neck but has not yet started to hang - is stopped from doing so.  
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything?  
If yes, describe:  
Yes No  
□ □  
Total # of interrupted  
______  
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have 
engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the individual 
stops him/herself, instead of being stopped by something else.  
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything?  
describe:  
Yes No  
□ □  
Total # of  
aborted  
______  
Preparatory Acts or Behavior:  
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or 
thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by 
suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself 
(such as collecting pills, getting a gun, giving valuables away or writing a suicide note)?  
describe:  
Yes No  
□ □  
Suicidal Behavior:  
Suicidal behavior was present during the assessment period?  
Yes No  


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□ □  
Answer for Actual Attempts Only  
Most 
Recent  
Attempt  
Date:  
Most Lethal  
Attempt  
Date:  
Initial/First  
Attempt  
Date:  
Actual Lethality/Medical Damage:  
0. No physical damage or very minor physical damage (e.g., surface 
scratches).  
1. Minor physical damage (e.g., lethargic speech; first-degree burns; 
mild bleeding; sprains).  
2. Moderate physical damage; medical attention needed (e.g., 
conscious but sleepy, somewhat responsive; second-degree burns; 
bleeding of major vessel).  
3. Moderately severe physical damage; medical hospitalization and 
likely intensive care required (e.g., comatose with reflexes intact; third-
degree burns less than 20% of body; extensive blood loss but can 
recover; major fractures).  
4. Severe physical damage; medical hospitalization with intensive care 
required (e.g., comatose without reflexes; third-degree burns over 20% 
of body; extensive blood loss with unstable vital signs; major damage 
to a vital area).  
5. Death  
Enter 
Code  
______  
Enter Code  
______  
Enter Code  
______  
Potential Lethality: Only Answer if Actual 
Lethality=0  
Likely lethality of actual attempt if no medical damage (the following 
examples, while having no actual medical damage, had potential for 
very serious lethality: put gun in mouth and pulled the trigger but gun 
fails to fire so no medical damage; laying on train tracks with oncoming 
train but pulled away before run over).  
0 = Behavior not likely to result in injury  
1 = Behavior likely to result in injury but not likely to cause death  
Behavior likely to result in death despite available medical care  
Enter 
Code  
______  
Enter Code  
______  
Enter Code  
______  
 
 


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20. 
APPENDIX 5. COLUMBIA SUICIDE SEVERITY RATING SCALE- 
SINCE LAST VISIT 
 
COLUMBIA-SUICIDE SEVERITY 
 
RATING SCALE (C-SSRS) 
Since Last Visit 
 
Version 1/14/09 
 
 
 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J. 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration.  The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
 
 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in  The Columbia Suicide History Form, 
developed by John Mann,  MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD),  New York State Psychiatric Institute, 1051  Riverside Drive, New York, NY, 10032.  (Oquendo M. A., 
Halberstam  B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. 
 In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 
 
 
 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 
 
 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” 
section. If the answer to question 2 is “yes”, ask questions 3, 4 and 5. If the 
answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section 
below. 
Since Last 
Visit 


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1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not 
wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe: 
Yes       No 
□   □ 
2. Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about 
killing myself”) without thoughts of ways to kill oneself/associated methods, intent, or plan during the 
assessment period. 
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
Yes     No 
□   □ 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment 
period. This is different than a specific plan with time, place or method details worked out (e.g., thought of 
method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would 
never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
Yes     No 
□   □ 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as 
opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
If yes, describe: 
Yes       No 
□   □ 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to 
carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to 
carry out this plan? 
If yes, describe: 
Yes     No 
□   □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 
from above, with 1 being the least severe and 5 being the most severe). 
Most Severe Ideation:                        
Type # (1-5)                                        Description of Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3) 2-5 times in week    (4) Daily or almost daily   (5) Many 
times each day 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or 
continuous 
(3) 1-4 hours/a lot of time 


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Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                  (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                (0) Does not attempt to control thoughts 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that 
stopped you from wanting to die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide       (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you                                              (5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you                                      (0) Does not apply 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? 
Was it to end the pain or stop the way you were feeling (in other words you couldn’t go 
on living with this pain or how you were feeling) or was it to get attention, revenge or a 
reaction from others? Or both? 
 (1) Completely to get attention, revenge or a reaction from others   (4) Mostly to end or stop the pain (you couldn’t 
(2) Mostly to get attention, revenge or a reaction from others           go on living with the pain or how you were  
(3) Equally to get attention, revenge or a reaction from others           feeling)          
 (5) Completely to end or stop the pain (you  
couldn’t go on living with the pain or how 
you were feeling) 
(0) Does not apply 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. 
Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it 
can be considered an actual suicide attempt. There does not have to be any injury or 
harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun 
is broken so no injury results, this is considered an attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically 
from the behavior or circumstances. For example, a highly lethal act that is clearly not an 
accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from 
window of a high floor/story). Also, if someone denies intent to die, but they thought that 
what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you_          as a way to end your life? 
Did you want to die (even a little) when you_       ? 
Were you trying to end your life when you          ? 
Or did you think it was possible you could have died from          ? 
Or did you do it purely for other reasons / without ANY intention of 
killing yourself (like to relieve stress, feel better, g et sympathy, or 
get something else to happen)? (Self-Injurious Behavior without suicidal 
intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes      No 
□   □ 
Total # of 
Attempts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially 
self-injurious act (if not for that, actual attempt would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, 
this becomes an attempt rather than an interrupted attempt. Shooting: Person has gun pointed 
toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. 
Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and 
taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your 
life but someone or something stopped you before you actually did 
anything? 
Yes      No 
□   □ 
Total # of interrupted 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before
they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead
of being stopped by something else. 
Has there been a time when you started to do something to try 
to end your life but you stopped yourself before you actually 
did anything? 
Yes      No 
□   □ 
Total # of aborted 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything 
beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide 
(e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing 
to kill yourself (such as collecting pills, getting a gun, giving valuables 
away or writing a suicide note)? 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 


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Suicide: 
Yes   No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage: 
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat 
responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care 
required (e.g., comatose with reflexes intact; third-degree burns less than 20% of 
body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose 
without reflexes; third-degree burns over 20% of body; 
Enter Code 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no 
actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; 
laying on train tracks with oncoming train but pulled away before run over). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
 

SAP_001.pdf: 
H8H-CD-LAHK 
 
 
A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the 
Acute TReaTment of MigrAiNe: A randomized, double-blind, placebo-controlled parallel group 
study (SPARTAN) 
 
NCT02605174 
 
Approval Date: July 18, 2017 
 




Output Templates Signature Page 
 
Output Templates V2.0 (Dated 18JUL2017) for Protocol COL MIG-302 
 
 
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Company: 
Quintiles 
 
Upon review of this document, the undersigned approves this version of the Output 
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