Clinical trial NCT03076970
Conditions: Migraine
Sponsor: Eli Lilly and Company
Start date: 2017-03-21; Completion date: 2017-04-13
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a randomized, double-blind, three-period, cross-over study to investigate the effect of sumatriptan (Imitrex) 100 mg on the pharmacodynamics and pharmacokinetics of lasmiditan 200 mg.

Detailed description:
This is a randomized, double-blind, three-period, cross-over study to investigate the effect of single doses of sumatriptan (Imitrex) 100 mg on the pharmacodynamics of single doses of lasmiditan 200 mg. The study will last approximately 6 weeks including up to 3 weeks for screening and 22 days on study. Screening will be conducted within approximately 21 days of the first dose of study medication. Each dosing period will last 3 days (Day 1, Day 1, and Day 2). A wash-out period of 6 days will take place between each dose. The End of Study Visit (EoS) will take place 5 (+/- 2) days after the third dosing period is completed.

Arms: arm 1: single oral tablet arm 2: single oral tablet arm 3: single oral tablet of each
Interventions: intervention 1: lasmiditan 200 mg intervention 2: Sumatriptan intervention 3: matching placebo
Intervention descriptions: intervention 1: drug including single placebo tablet intervention 2: drug including single placebo tablet intervention 3: single oral tablet -given with single lasmiditan tablet and with single sumatriptan tablet.

Protocol documents:
Prot_000.pdf: 
Protocol H8H-CD-LAHI  
 
 
A Randomized, Double-Blind, Three Period, Cross-Over Study to Evaluate the Effect of Single 
Oral Doses of Lasmiditan when Coadministered with Single Oral Doses of Sumatriptan (lmitrex) 
in Healthy Male and Female Subjects  
 
NCT03076970 
 
Approval Date: 17-Feb-2017 
 
 
 


Colucid 
phormoceutlcol1, Inc. 
Clinical Protocol 
A Randomized, Double-Blind, Three Period, Cross-Over 
Study to Evaluate the Effect of Single Oral Doses of 
Lasmiditan when Coadministered with Single Oral Doses of 
Sumatriptan (lmitrex) in Healthy Male and Female Subjects 
Protocol No. COL MIG-118 
February 17, 2017 
Version 1.0 
Colucid Pharmaceuticals, Inc. 
222 Third Street 
Suite 1320 
Cambridge, MA 02142 
Confidentiality Statement: 
This document contains confidential information of Colucid Pharmaceuticals, Inc. Do not copy 
or distribute without written permission from the Sponsor. 


Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
SPONSOR SIGNATORY 
CoLucid Pharmaceuticals, Inc. 
222 Third Street 
Suite 1320 
Cambridge, MA 02142 
IND 103,420 
February 17, 2017 
Protocol: COL MIG-118 "A Randomized, Double-Blind, Three Period, Cross-Over Study to 
Evaluate the Effect of Single Oral Doses of Lasmiditan when Coadministered with Single Oral 
Doses of Sumatriptan (Imitrex) in Healthy Male and Female Subjects" 
Version 1.0 date 17 Feb 2017 
This protocol has been approved by CoLucid Pharmaceuticals, Inc. The following signatures 
document this approval. 
 
Head Clinical/Regulatory Operations 
CoLucid Pharmaceuticals, Inc. 
 MD 
Medical Monitor 
Date (dd/month/year) 
17/02/2017 
-Date (dd/month/year) 
Proprietary and confidentia
l 
Page 
PPD
11 
PPD
PPD


SPONSOR SIGNATORY 
CoLucid Pharmaceuticals, Inc. 
222 Third Street 
Suite 1320 
Cambridge, MA 02142 
Protocol: COL MIG-118 " A Randomized, Double-Blind, Three Period, Cross-Over Study to Evaluate 
the Effect of Single Oral Doses ofLasmiditan when Coadministered with Single Oral Doses of 
Sumatriptan (lmitrex) in Healthy Male and Female Subjects" 
Version 1.0 date 17 Feb 2017 
This protocol has been approved by CoLucid Pharmaceuticals, Inc. The following signatures 
document this approval. 
Digitally ilgned by Bernie~ Kuca 
ON: cn:zfk>rnke Kuc:._ o.Coluc:ld 
enarmaceutlcals,lnc. ou, 
 
Date: 2o17.02.17 14:17;48 -os'OO' 
 
Head Clinical/Regulatory Operations 
CoLucid Pharmaceuticals, lnc. 
 MD 
Medical Monitor 
Date ( 
dd/month/year) 
PPD
Date (dd/month/year) 
PPD PPD
PPD


Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
INVESTIGATOR STATEMENT 
Protocol Number: COL MIG-118 
IND 103,420 
February 17, 2017 
Protocol Title: A Randomized, Double-Blind, Three Period, Cross-Over Study to 
Evaluate the Effect of Single Oral Doses of Lasmiditan when Co-administered with 
Single Oral Doses of Sumatriptan (lmitrex) in Healthy Male and Female Subjects 
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 a
l
l 
the conditions, instructions, and restrictions contained in Protocol Number COL 
MIG-118, and will conduct the trial in accordance with Good Clinical Practice (GCP) and 
applicable regulatory requirements. 
Investigator's Printed Name " 
Investigator's Signature 
Date 
Propr
ietary and confidentia
l 
Page 
PPD
12 
PPD


CoLucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
SYNOPSIS 
Name of Sponsor Company: 
CoLucid Pharmaceuticals, Inc. 
Drug Under Study: 
Lasmiditan (COL-144) 
IND 103,420 
February 17, 2017 
Title of Protocol: A Randomized, Double-Blind, Three Period, Cross-Over Study to Evaluate the Effect 
of Single Oral Doses of Lasmiditan when Co-administered with Single Oral Doses of Sumatriptan 
(lmitrex) in Healthy Male and Female Subjects 
Protocol Number: COL MIG-118 
Phase: 1 
Study Objectives 
Primary Objective: To compare and contrast the pharmacodynamics of lasmiditan 200 mg and 
sumatriptan (lmitrex) 100 mg administered together to the pharmacodynamics of single doses of either 
drug administered alone. 
Secondary Objectives: 
• 
To compare and contrast the pharmacokinetics of lasmiditan 200 mg and sumatriptan (lmitrex) 
100 mg administered together to the pharmacokinetics of single doses of either drug 
administered alone. 
• 
To evaluate the safety and tolerability of lasmiditan 200 mg and sumatriptan (lmitrex) 100 mg 
administered together to the safety and tolerability of single doses of either drug administered 
alone. 
• 
To compare and contrast the subjective drug effects of lasmiditan 200 mg and sumatriptan 
(lmitrex) 100 mg administered together to the subjective drug effects of single doses of either 
drug administered alone. 
Study Endpoints 
Primary Endpoint: The pharmacodynamics of lasmiditan as measured by serial vital signs, ECGs, and 
AEs. 
Secondary Endpoints: 
-
The pharmacokinetic (PK) parameters of lasmiditan 200 mg when given with sumatriptan 
(lmitrex) 100 mg. 
-
The safety and tolerability of lasmiditan 200 mg as defined by adverse events, laboratory 
parameters, vital signs and electrocardiograms (ECGs) when given with sumatriptan (lmitrex) 
100 mg. 
Exploratory Endpoint: The subjective drug effects of lasmiditan 200 mg when given with sumatriptan 
(lmitrex) 100 mg as compared with either drug alone and as measured by results of the VAS scales and 
the DEQ-5. 
Study Design: 
This is a randomized, double-blind, three-period, cross-over study to investigate the effect of 
sumatriptan (lmitrex) 100 mg on the pharmacodynamics and pharmacokinetics of lasmiditan 200 mg. 
Proprietary and confidential 
Page 13 


Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
Study Day 
-1 
1 2 3 4 5 6 
7 
8 9 10 11 12 
13 14 
15 16 17 
18 
19 20 
21 
Period 1 
-1 
1 2 
Wash-out 1 
Period 2 
1-· 
-1 
1 2 
-- -- 1---
Wash-out2 
1-
,....___ 
Period 3 
-1 
1 
2 
EoS 
1-
-.-· 
The dosing periods are: 
• 
A: Lasmiditan 200 mg + lasmiditan 200 mg placebo 
• 
B: Sumatriptan (lmitrex) 100 mg + lasmiditan 200 mg placebo 
• 
C: Lasmiditan 200 mg co-administered with sumatriptan (lmitrex) 100 mg 
There will be a six day wash-out period between each dose. 
Each subject will be randomly allocated to one of six treatment sequences: ABC, ACB, BAC, BCA, CAB 
or CBA. 
Subject Population: Healthy male and female subjects aged 18-60 years, inclusive. 
Number of Subjects: At least 42 subjects, 
Number of Centers: One Phase 1 unit 
(approximately 60% female subjects are planned) 
to ensure that approximately 36 subjects 
complete the study. 
Test Products and Doses 
Route of Administration: Oral 
Lasmiditan 200 mg tablet 
Sumatriptan (I mitrex) 1 00 mg tablet 
Lasmiditan 200 mg placebo tablet 
Duration: The duration of the study is approximately 6 weeks, including up to 3 weeks for screening 
and 22 days on study. 
Criteria for Inclusion/Exclusion: 
Inclusion: Subjects may be included in the study only if all the following criteria are met: 
1. 
2. 
3. 
4. 
5. 
6. 
Male or female aged 18-60 years, inclusive. 
Able and willing to give written informed consent. 
BMI between 18 and 32 kg/m2, inclusive. 
Subjects must be able to refrain from consuming xanthine, quinine and caffeine containing 
beverages, and must refrain from prolonged intensive physical exercise during the study (from 
72 hours prior to dosing until the last study visit). 
Women must be: 
- not pregnant 
- not breast-feeding 
- not planning to become pregnant during the study 
All females must have a negative serum pregnancy test at screening and a negative urine 
pregnancy test at check-in on Day -1 of each period. All women must agree to use an 
adequate method of contraception during the study and for 30 days following the end-of-study 
visit. Accepted methods of contraception include: mechanical products (e.g., intrauterine 
device) or double-barrier methods (e.Q., diaphraQm, condoms, cervical cap) with spermicide, 
Proprietary and confidential 
Page 14 


Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
IND 103,420 
February 17, 201 7 
hormonal contraceptives (i.e., oral, implanted or injectable contraceptive hormones) or be 
surgically sterile (i.e hysterectomy, bilateral tubal ligation, bilateral oophorectomy). The 
subject's understanding of this requirement must be documented by the Investigator or 
designee. 
7. 
Male subjects must agree to utilize a highly effective method of contraception (condom plus 
spermicide) during heterosexual intercourse from clinic admission until 30 days following the 
end of study visit. 
8. 
Male subjects must agree to refrain from sperm donation from clinic admission until at least 
30 days following the end of study visit. 
9. 
Subjects must be able to swallow multiple pills simultaneously. 
10. Subjects must be able to understand the requirements of the study and must be willing to 
comply with the requirements of the study. 
Exclusion: Subjects are excluded from the study if any of the following criteria are met: 
1. Any medical condition, clinical laboratory test or other reason which in the judgment of the 
Investigator or designee makes the subject unsuitable for the study. 
2. 
Any clinically significant abnormalities (as determined by the Principal Investigator or designee) 
in hematology, blood chemistry and/or urinalysis lab tests at screening or at Period 1 D-1. 
3. 
Known hypersensitivity to lasmiditan, sumatriptan (lmitrex), or to any excipient of lasmiditan or 
sumatriptan (lmitrex) oral tablets. 
4. 
Use of any prescription medication, including MAO-A inhibitors and other drugs associated with 
serotonin syndrome, within 14 days prior to dosing (except hormonal contraceptives) except for 
5-HT1 (serotonin) agonists and selective serotonin reuptake inhibitors which are restricted as 
noted in the table below. Any exceptions must be approved by the Investigator and Medical 
Monitor. Use of over-the-counter medications, including vitamins and herbal or dietary 
supplements within 7 days prior to dosing unless approved by the Investigator and Medical 
Monitor. Acetaminophen for symptomatic relief of pain is allowed until 24 hours prior to dosing 
in each period. 
Drug Class 
Brands (examples provided) 
Restricted prior to Day -
1 in all periods for: 
5-HT1 (serotonin) agonists 
Frova 
6 weeks 
Selective serotonin reuptake 
Prozac 
2.5 months 
inhibitors (SSRI)/Serotonin 
norepinephrine reuptake 
Vivactil 
3 weeks 
inhibitors (SNRI)/tricyclic 
antidepressants (TCA) 
Any other prescription 
14 days 
medication(s) 
Over-the-counter medications, 
including vitamins and herbal 
--
7 days 
or dietary supplements 
5. 
History, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral vascular 
syndromes including but not limited to angina pectoris, myocardial infarction, silent myocardial 
ischemia (Ischemic cardiac syndromes}, stroke, transient ischemic attacks (cerebrovascular 
syndromes}, and ischemic bowel disease (peripheral vascular disease). 
6. History, symptoms, or signs of vasospastic coronary artery disease. 
7. 
Proprietary and confidential 
Page 15 


CoLucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
could affect the subject's safety in the opinion of the Investigator or designee. 
8. 
History, symptoms, or signs of severe hepatic impairment. 
9. 
History, symptoms, or signs of diabetes. 
10. History within the previous 3 years or current evidence of abuse (according to DSM-IV criteria) 
of any drug, prescription or illicit, or alcohol; a positive urine screen for drugs of abuse or 
breathalyzer alcohol test. 
11. Positive urinary test for drugs of abuse and/or alcohol breath test at Screening and/or at check-
in on Day -1 of each Period. Cotinine will be included at screening only. 
12. History of orthostatic hypotension with or without syncope. 
13. Supine systolic blood pressure (BP) > 135 mm Hg, diastolic BP > 85 mm Hg, respiratory 
rate >20 breaths per minute, pulse >90 beats per minute, or temperature >37.5° at Screening. 
Low values on any vital sign measurement will be assessed at the discretion of the Investigator 
or designee. For orthostatic vital signs, any decrease in systolic and/or diastolic blood pressure 
great than 20 mmHg. Any other changes will be assessed at the discretion of the Investigator 
or designee. 
14. ECG changes including QT interval prolongation and congenital long QT syndrome. 
15. Electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, or 
other medicinal products that lead to QT prolongation. 
16. Any clinically significant alanine aminotransferase (AL T), alkaline phosphatase (AP), aspartate 
aminotransferase (AST), or bilirubin abnormalities judged by the Investigator or designee at 
Screening. 
17. Treatment with centrally active drugs or those affecting peripheral cholinergic transmission 
within 3 months of study entry. 
18. Consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange juice, or 
beverages containing any of these juices or consumption of members of the mustard green 
family (including kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, and 
mustard (i.e. seeds, greens, spice or the condiment)) within 72 hours of dosing. 
19. Tobacco or nicotine users except subjects who stopped using tobacco or nicotine 1 year or 
more before signing the informed consent. 
20. Subject is at imminent risk of suicide or had a suicide attempt within 6 months prior to the 
screening visit. 
21. Participation in any clinical trial of an experimental drug or device in the previous 30 days. 
22. Positive Hepatitis C antibody, Hepatitis B surface antigen, or positive human immunodeficiency 
virus (HIV) antibody. 
23. Subjects who donated plasma in the 7 days or blood in the 3 months preceding study drug 
administration. 
24. Subjects with an inability to communicate well with the Investigator or designee and study staff 
(i.e., language problem, poor mental development or impaired cerebral function). 
25. Inability to fast or consume the food provided in the study. 
26. Relatives of or staff directly reporting to the Investigator. 
Subjects must give written informed consent for participation in the study before any study-specific 
screening tests or evaluations. 
Proprietary and confidential 
Page 16 


CoLucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
IND 103,420 
February 17, 2017 
Subjects with test results which do not meet the above inclusion/exclusion criteria may have the 
relevant 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 be considered a screen 
failure and should not be enrolled in the study. Subjects may be rescreened once. 
Criteria for Evaluation: 
Pharmacodynamics: AEs, serial vital signs, ECGs, and physical examination results will be used to 
assess pharmacodynamics. 
Pharmacokinetics: Standard PK parameters (including Cmax. tmax. ty., and AUC [AUC<o-last> and 
AUC<o-co)D will be determined using noncompartmental (model independent) methods for lasmiditan 
from blood samples collected pre-dose and serially following oral administration of study drug during 
each of the dosing periods (at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 and 30 hours following the 
dose at time 0 in each dosing period). 
Safety: The incidence of adverse events, physical examination findings, measurement of vital signs 
(BP, HR, respiration rate, and temperature), 12-lead ECG results, and routine clinical laboratory 
findings (hematology, serum chemistry, and urinalysis) will be used to assess safety. The Drug Effects 
Questionnaire (DEQ) and Visual Analogue Scales (VAS) will be used as an exploratory assessment of 
safety. 
Statistical Methods: 
PD parameters: 
The number and percentage of subjects who experience adverse events and/or vital signs that are 
outside the normal range and clinically significant will be presented by treatment at the time of finding. 
AEs will be presented by severity, relationship to study drug, System Organ Class, preferred term, and 
treatment at the time of event. Clinically significant ECG findings will be tabulated and summarized 
along with the treatment. For continuous variables, data will be summarized using descriptive statistics 
(sample size, mean, median, and standard deviation, minimum, maximum). For discrete variables, 
data will be summarized using frequencies and percentages or median and range, as applicable. Data 
listings will be tabulated by subject. 
PK parameters: 
All evaluable subjects will be included in the PK analysis. The evaluable PK population will include 
all subjects who completed at least one treatment period without any protocol violations that would 
likely affect the PK results, who have evaluable plasma concentration data for lasmiditan and/or 
sumatriptan (lmitrex), and for whom at least a subset of the designated PK parameters can be 
determined. 
Data will be summarized using descriptive statistics (sample size, mean, median, standard deviation, 
minimum, and maximum) for continuous variables and using frequency and percentage for discrete 
variables for each treatment unless additional analysis is deemed appropriate based upon a review of 
the PK results. 
Standard PK parameters (Cmax. tmax. ty. and AUC [AUC<o-last) and AUC(o-oo)] of lasmiditan 200 mg will be 
used to describe the characteristics of the drug when co-administered with sumatriptan (lmitrex) or 
when taken alone. 
The primary statistical analysis will use the paired t-test applied to log-transformed PK parameter 
(lasmiditan Cmax or AUC30 separately) in the lasmiditan/sumatriptan (lmitrex) treatment period paired 
with the same subject's parameter value in the lasmiditan treatment period. From this model the 
means for each treatment and mean differences to the reference lasmiditan treatment will be 
estimated with the corresponding 90% confidence intervals. These estimates will then be 
exponentiated to produce the estimates of geometric mean ratios with their 90% confidence intervals. 
Proprietary and confidential 
Page 17 


Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
It will be concluded that sumatriptan (lmitrex) has no effect on lasmiditan PK, if 90% confidence 
intervals for ratios of PK parameters derived in lasmiditan/sumatriptan (lmitrex) treatment period to 
those derived in lasmiditan treatment period are within the 80-125% interval. 
The sample size of 36 subjects will provide at least 80% power to show equivalence of the PK of 
lasmiditan in the absence and presence of sumatriptan (lmitrex), assuming a 25% within subject 
coefficient of variation. 
Safety: 
All randomized subjects who receive at least one dose of study drug will be included in the safety and 
baseline analyses. 
The safety analysis will evaluate adverse events and additional safety parameters. The number and 
percentage of subjects experiencing at least one adverse event will be summarized by body system, 
preferred term, and treatment. If appropriate, adverse events will also be summarized by intensity 
and relationship to study drug. Serious adverse events, if any, will be tabulated. 
Additional safety parameters will be assessed from summaries of physical examinations, 12-lead 
ECGs and vital signs. The 12-lead ECG results will be categorized as normal, clinically significant 
abnormal, and not clinically significant abnormal. Hematology, chemistry and urinalysis laboratory 
test results will be categorized as low, normal, or high relative to the normal ranges and values 
outside the normal range will be assessed for clinical significance. The changes from baseline for 
each of these parameters at post-dose time points will be presented. 
Proprietary and confidential 
Page 18 


Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
Table 1. Schedule of Events (Overview) 
Screening 
Dosing Period 1 
Visit 1 
Visit2 
Day 
- 21 to -1 
-1 
1 
In-house 
X 
X 
Outpatient 
X 
Informed consent 
X 
Eligibility/Confirm continued 
X 
X 
eligibility 
Demographics, Body Weight, 
X 
Height, Calculate BMI 
Medical history review/update 
X 
X 
Complete physical examination1 
X 
Targeted physical exam 
X 
X 
(symptom related, if applicable) 
Urine screen for drugs of abuse2 
X 
X 
and Breathalyzer test 
Hepatitis B/C and HIV-Screen 
X 
Serum pregnancy tese 
X 
Urine pregnancy tese 
X 
12-lead ECG4 
X 
X 
Vital signs (BP, HR, RR and oral 
temperature)5 
X 
X 
X 
Orthostatic Vital signs (BP and 
HR)6 
X 
X 
Clinical Laboratory Tests (CBC, 
X 
X 
Chemistry, Urinalysis) 
Training on VAS instruments7 
X 
Bipolar Drug liking VAS 
X 
Bipolar High VAS 
X 
Unipolar Sedation VAS 
X 
DEQ-5 
X 
Unipolar ()verall drug liking VAS 
X 
2 
X 
X 
X 
X 
X 
X 
Dosing Period 2 
Visit3 
-1 
1 
2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X . 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IND 103,420 
February 17, 2017 
Dosing Period 3 
EoS 
-1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-
------
Visit4 
VisitS 
--- ·-
1 
2 
21 (+/- 2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- --··· -
-
Proprietary and confidential 
Page 19 
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I 
I 
! 
i 
I 
I 


Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
Day 
Unipolar Take drug again VAS 
C-SSRS8 
Randomization 
Study drug administration9 
Adverse events 10 
Prior I Concomitant medication 11 
PK blood sampling 12 
Screening 
Dosing Period 1 
Visit 1 
Visit2 
- 21 to - 1 
-1 
1 
X 
X 
X 
X 
X 
X J. 
Dosing Period 2 
Visit3 
2 
-1 
1 
X 
X 
X 
X 
X 
X 
X 1 
l 
X 
l 
2 
-1 
X 
X 
X 
X 
X 
l 
IND 103,420 
February 17, 2017 
Dosing Period 3 
EoS 
1 
Visit4 
VisitS 
1 
2 
21 (+/- 2) 
X 
X 
X 
X 
X 
X 
l 
X 
l 
Proprietary and confidential 
Page 110 


Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
1. Physical examination will include general appearance, skin, HEENT, heart, lymph nodes, lungs, abdomen, extremities/joints, neurological systems, and mental 
status. 
2. Urine drug screen at screening will include amphetamine, opiate, cocaine, barbiturates, benzodiazepines, cotinine and marijuana (tetrahydrocannabinol [THC]). 
Urine drug screen at D-1 for all periods will include amphetamine, opiate, cocaine, barbiturates, benzodiazepines, and marijuana (tetrahydrocannabinol [THC]). 
3. Serum and urine pregnancy tests will be done on all females. 
4. 12-lead EGGs will be taken after the subject has been supine for at least 5 minutes. EGGs are recorded +/- 15 minutes of the nominal times and at all times 
after the subject has been supine for at least 5 minutes according to the schedule in the Detailed Schedule of Events, Table 2. 
5. Vital signs will be taken after the subject has been supine for at least 5 minutes. Vitals signs are recorded +/- 15 minutes of the nominal times and at all times, 
after the subject has been supine for at least 5 minutes according to the schedule in the Detailed Schedule of Events, Table 2. 
6. Orthostatic vital signs are recorded after the subject has been at least 5 minutes supine then at least 2 minutes standing and will include systolic blood pressure 
(SBP), diastolic blood pressure (DBP), and heart rate (HR) according to the schedule in the Detailed Schedule of Events, Table 2. 
7. Training on VAS scoring will be comprised of three bipolar VAS scales unrelated to drug use that will be administered to each subject at the beginning of each 
period. The same three scales will be used in all periods. 
8. C-SSRS Screening version will be used at Screening. On Day -1 and Day 2 of each period and at EoS, C-SSRS Since the last visit version will be used. 
9. Study drug administration on Day 1 at approximately the same time in each period at time 0. Subjects will fast 10 hours before and 4 hours after study drug 
administration. 
10. Adverse event collection will start at the time of signing the ICF and continue throughout the study. Adverse events that occur prior to dosing in period 1 will be 
recorded as medical history. 
11 . Prior medications are medications that were being taken within 30 days of signing the informed consent and finished prior to administration of the study drug. 
Concomitant medications are medications started prior to the start of the study and continued after administration of study drug or started during the study after 
administration of study drug 
12. Blood samples for PK will be taken serially for 30 hours relative to time 0 (dosing) following the schedule in the Detailed Schedule of events, Table 2. In cases 
where blood sampling for PK analysis and other assessments (vital signs or EGGs) are scheduled to occur at the same time, the order of procedures will be: 
5 minutes supine rest, ECG, supine vitals followed by standing vitals, and PK blood draw. Every effort should be made to collect the PK samples at the exact 
times as specified (Table 2). Samples taken pre-dose and up to and including 8 hours post-dose will be taken +/-5 minutes of the nominal time. Samples 
taken after 8 hours post-dose will be taken +/-10 minutes of the nominal time. 
Proprietary and confidential 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
Table 2. Detailed Schedule of Events 
Day of each 
Dosing Period 
Hour 
Pre-
0 
0.25 
dose 
Targeted physical exam 
(symptom-related, if 
X 
applicable} 1 
12-lead ECG 
x2 
Vital signs (BP, HR, RR 
x3 
and Temperature) 
Orthostatic vital signs (BP, 
x3 
HR) 
Bipolar Drug liking VAS 
x3 
Bipolar High VAS 
x3 
Unipolar Sedation VAS 
x3 
DEQ-5 
x3 
Unipolar Overall drug liking 
x3 
VAS 
Unipolar Take drug again 
x3 
VAS 
C-SSRS4 
Randomization:> 
X 
Study Drug Administration6 
X 
Adverse Events' 
Concomitant Medications8 
PK blood sampling\! 
X 
X 
0.5 
1 
1.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
2 
2.5 
3 
4 
6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8 
12 
16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IND 103,420 
February 17, 2017 
2 
24 
30 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Targeted physical exam to be performed in each period on Day 1 pre-dose, as needed during Days 1 and 2 depending upon emergent symptoms, and on 
Day 2 at 30 hours +/- 1 0 hours. 
2. 
Pre-dose 12-lead ECG to be collected within 75 minutes of dosing. 
3. 
Pre-dose vital signs, orthostatic vital signs, VAS scales, and DEQ-5 to be collected within 60 minutes of dosing. 
4. 
C-SSRS Since the last visit version to be used on Day 2 at 30 hours +/-10 hours. 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
5. 
Randomization to take place in period 1 only 
IND 103,420 
February 17, 2017 
6. 
Study drug administration on Day 1 at time 0, approximately the same time in each period. Subjects will fast 10 hours before and 4 hours after study drug 
administration. 
7. 
Adverse event collection will start at the time of signing the ICF and continue throughout the study. Adverse events that occur prior to dosing in period 1 will 
be recorded as medical history. 
8. 
Documentation of concomitant medication use will be made throughout Days 1 and 2 of each period. 
9. 
The pre-dose PK sample will be collected within 60 minutes of dosing. Blood samples for PK will be taken serially for 30 hours, at pre-dose and 0.25, 0.5, 1, 
1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 and 30 h following the dose at time 0 in each dosing period. In cases where blood sampling for PK analysis and other 
assessments (vital signs or ECGs) are scheduled to occur at the same time, the order of procedures will be: 5 minutes supine rest, ECG, supine vitals 
followed by standing vitals, and PK blood draw. Every effort should be made to collect the PK samples at the exact times as specified (Table 2). Samples 
taken pre-dose and up to and including 8 hours post-dose will be taken +/- 5 minutes of the nominal time. Samples taken after 8 hours post-dose will be taken 
+I- 1 0 minutes of the nominal time. 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
TABLE OF CONTENTS 
IND 103,420 
February 17, 2017 
INVESTIGATOR STATEMENT .................................................................................................. 2 
SYNOPSIS ..................... ...................................................................................................... ...... 3 
TABLE OF CONTENTS ............................................................................................................ 14 
LIST OF ABBREVIATIONS ...................................................................................................... 18 
1. 
INTRODUCTION ......................................................................................................... 21 
1.1 
Background ...... ........................................................ ....................................... 21 
1.2 
Clinical Studies to Date ................................................................................... 22 
1.3 
Rationale for the Clinical Study ....................................................................... 24 
1.4 
Risk-Benefit Assessment ................................................................................ 24 
1.5 
Dose Rationale ................................................................................................ 25 
1.6 
Conduct of the Study ....................................................................................... 25 
2. 
TRIAL OBJECTIVES ................................................................................................... 26 
2.1 
Primary Objective ............................................................................................ 26 
2.2 
Secondary Objective ....................................................................................... 26 
3. 
OVERALL DESIGN AND PLAN OF THE STUDY ........................................................ 27 
3.1 
Overview ......................................................................................................... 27 
3.2 
Schedule of Events ......................................................................................... 27 
3.3 
Assessments by Study Visit .......................................................................... .. 27 
3.3. 1 
Screening (Day -21 to -1) .................................................................. 27 
3.3.2 
Clinical Pharmacology Center (CPC) Admission (Day -1 of each 
dosing period) .................................................................................... 28 
3.3.3 
Day 1 of each dosing period .............................................................. 28 
3.3.4 
Day 2 of each dosing period .............................................................. 30 
3.3.5 
End-of-Study/Early Termination ......................................................... 30 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................... ....... 32 
4. 1 
Inclusion Criteria ............................................................................................. 32 
4.2 
Exclusion ......................................................................................................... 32 
4.3 
Protocol Exceptions and Deviations ................................................................ 35 
4.4 
Subject Withdrawal Criteria ............................................................................. 35 
5. 
TREATMENT OF SUBJECTS ...................................................................................... 37 
5.1 
Subject Identification and Randomization ........................................................ 37 
5.2 
Description of Study Drug ............................................................................... 37 
5.3 
Concomitant Medications ................................................................................ 37 
5.4 
Restrictions ........................................................................... .......................... 38 
5.4.1 
Dietary and Fluid Restrictions ............................................................ 38 
5.4.2 
Other Restrictions .............................................................................. 38 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
IND 103,420 
February 17, 2017 
5.5 
Treatment Compliance .................................................................................... 39 
5.6 
Randomization and Blinding ............................................................................ 39 
6. 
STUDY DRUG MATERIAL AND MANAGMENT ......................................................... .40 
6.1 
Lasmiditan ....................................................................................................... 40 
6.2 
Lasmiditan Placebo ......................................................................................... 40 
6.3 
Lasmiditan and Lasmiditan Placebo Packaging and Labelling ... ................. ..... 40 
6.4 
Storage of Lasmiditan and Lasmiditan Placebo ............................................... 40 
6.5 
Lasmiditan and Lasmiditan Placebo Administration ......................................... 41 
6.6 
Sumatriptan (lmitrex) ....................................................................................... 41 
6. 7 
Sumatriptan (lmitrex) Administration ............................................................... 41 
6.8 
Sumatriptan Storage ....................................................................................... 41 
6.9 
Drug Accountability, Dispensing and Destruction ............................................ 41 
7. 
METHODS OF ASSESSMENT .................................................................................... 43 
7.1 
Informed Consent. ........................................................................................... 43 
7.2 
Inclusion/Exclusion Criteria ............................................................................. 43 
7.3 
Demographics ................................................................................................. 43 
7.4 
Medical History ................................................................................................ 43 
7.5 
Physical Examination ...................................................................................... 44 
7.6 
Vita1Signs ....................................................................................................... 44 
7. 7 
Orthostatic Vital Signs ..................................................................................... 45 
7.8 
ECG ................................................................................................................ 45 
7.9 
VAS scales ...................................................................................................... 46 
7.9.1 
Bipolar Drug liking ............................................................................. 46 
7.9.2 
Bipolar High VAS ............................................................................... 46 
7.9.3 
Unipolar Sedation .............................................................................. 46 
7.9.4 
Unipolar Overall drug liking VAS ........................................................ 46 
7.9.5 
Unipolar Take drug again VAS .......................................................... 47 
7.9.6 
Training on VAS scales ..................................................................... 47 
7.9.7 
Drug Effects Questionnaire (DEQ-5) .................................................. 47 
7.10 
C-SSRS .......................................................................................................... 47 
7.11 
Clinical Laboratory .......................................................................................... 48 
7 .11 .1 Laboratory Parameters ...................................................................... 48 
7.11.2 
Clinical Laboratory Sample Collection, Storage, and Shipping ........... 50 
7.11.3 Abnormal and Clinically Significant Results ........................ ............... 50 
7.12 
Breathalyzer Test ............................................................................................ 50 
7.13 
Pharmacokinetics Samples ............................................................................. 50 
7.14 
Adverse Events and Serious Adverse Events ................................................. 52 
7.14.1 
Adverse Events ............ ..................................................................... 52 
7.14.2 Treatment Emergent Adverse Events (TEAE) ................................... 53 
7. 14.3 
Serious Adverse Events .................................................................... 54 
7.14.4 
Unexpected Adverse Event ........ ....................................................... 54 
7.15 
Reporting Serious Adverse Events ................................................ .................. 54 
7.16 
Follow-up of Adverse Events ........................................................................... 55 
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7.17 
Procedures for unblinding Investigational Product.. ......................................... 55 
7.18 
Reporting Safety Information to the I RB .......................................................... 56 
7.19 
Pregnancies ..................................... ............................................................... 56 
8. 
STATISTICAL METHODS ........................................................................................... 57 
8.1 
Sample Size .................................................................................................... 57 
8.2 
Study Population .......................................................................................... ... 57 
8.2.1 
Disposition of Subjects ...................................................................... 57 
8.2.2 
Protocol Deviations ............................................................................ 57 
8.2.3 
Analysis Populations ......................................................................... 57 
8.3 
General Considerations ................................................................................... 58 
8.4 
Pharmacodynamic Analyses ........................................................................... 58 
8.4.1 
Adverse Events .............................................................................. ... 58 
8.4.2 
Vital Signs ......................................................................................... 58 
8.4.3 
ECG Results ...................................................................................... 59 
8.4.4 
Physical Examination Results ............................................................ 59 
8.5 
Pharmacokinetic Analyses .............................................................................. 59 
8.6 
Safety Analyses ..................... ......................................................................... 60 
8.6.1 
Adverse Events ................................................................................. 60 
8.6.2 
Clinical Laboratory ............. .. .............................................................. 60 
8.7 
Interim Analyses ............................................................................................ .. 60 
9. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................ 61 
9.1 
Study Monitoring ............................................................................................. 61 
9.2 
Data collection ................................................................................................. 61 
9.3 
Audits and Inspections .................................................................................... 61 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 63 
11 . 
ETHICS ....................................................................................................................... 65 
11.1 
Ethics Review ................................................................................................. 65 
11.1.1 
IRB opinion ........................................................................................ 65 
11.2 
Written Informed Consent ............................................................................... 65 
11.3 
Amendments to the protocol ............................................................................ 66 
11.4 
Discontinuation of the study ............................................................................ 66 
11 .5 
Study drug supply, storage and tracking ......................................................... 66 
11.6 
Confidentiality ................................................................................................. 67 
11.7 
Publication policy ............................................................................................ 67 
12. 
ADMINISTRATIVE CONSIDERATIONS ...................................................................... 68 
12.1 
Investigator and Study Administrative Structure .............................................. 68 
12.2 
Records Retention .......................................................................................... 69 
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COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
13. 
REFERENCES ............................................................................................................ 70 
14. 
APPENDIX 1. DRUG EFFECTS QUESTIONNAIRE (DEQ-5) ...................................... 72 
15. 
APPENDIX 2. VISUAL ANALOGUE SCALES (VAS) ................................................... 73 
16. 
APPENDIX 3. COLUMBIA SUICIDE SEVERITY RATING SCALE-SCREENING 
VISIT ............................................................................................................................ 77 
17. 
APPENDIX 4. COLUMBIA SUICIDE SEVERITY RATING SCALE- SINCE LAST 
VISIT ............................................................................................................................ 81 
Table 1. Schedule of Events (Overview) ..................................................................................... 9 
Table 2. Detailed Schedule of Events ....................................................................................... 12 
Table 3: List of Laboratory Tests .............................................................................................. 49 
Table 4: Study Administrative Structure ................................................................................... 68 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
LIST OF ABBREVIATIONS 
IND 103,420 
February 17, 2017 
The following abbreviations and specialist terms are used in this study protocol. 
Approximately 
> 
Greater than 
2: 
Greater than or equal to 
5-HT 
AE 
ALT 
AMPP 
AP 
API 
AST 
AU Co-t 
AU Co-.. 
~
 
BMI 
BP 
bpm 
BUN 
CBC 
Cl 
Cmax 
CNS 
CPC 
CRF 
cs 
C-SSRS 
CTCAE 
DBP 
DCF 
DEQ-5 
DMP 
DSM 
ECG 
5-Hydroxytryptamine 
Adverse event 
Alanine aminotransferase 
American Migraine Prevalence and Prevention 
Alkaline phosphatase 
Active pharmaceutical ingredient 
Aspartate aminotransferase 
Area under the plasma concentration-time curve from time zero to last 
measurable concentration 
Area under the plasma concentration-time curve from time zero to infinity 
Beta human chorionic gonadotropin 
Body Mass Index 
Blood Pressure 
Beats per minute 
Blood urea nitrogen 
Complete blood count 
Confidence interval 
Maximum observed concentration 
Central nervous system 
Clinical Pharmacology Center 
Case report form 
Clinically significant 
Columbia-suicide severity rating scale 
Common Terminology Criteria for Adverse Events 
Diastolic blood pressure 
Data Correction Forms 
Drug Effects Questionnaire 
Data Management Plan 
Diagnostic and statistical manual 
Electrocardiogram 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
EDTA 
EoS 
FDA 
GABA 
GCP 
GMP 
GPCR 
h 
HDL 
HOPE 
HEENT 
HIV 
HR 
18 
ICF 
ICH 
IND 
IRS 
IUD 
IV 
LC/MS/MS 
LDL 
LOC 
MAO-A 
MCH 
MCHC 
MCV 
MedORA 
mg 
Min 
ml 
mmHg 
MOS 
nM 
NCS 
PCAS 
PO 
Ethylenediaminetetraacetic acid 
End of Study 
Food and Drug Administration 
Gamma-aminobutyric acid 
Good Clinical Practice 
Good Manufacturing Practice 
G-Protein coupled receptor 
Hour(s) 
High density lipoprotein 
High-density polyethylene 
Head, eyes, ears, nose, and throat 
Human Immunodeficiency Virus 
Heart rate 
Investigator Brochure 
Informed consent form 
International Conference on Harmonization 
Investigational New Drug 
Institutional Review Board 
Intrauterine device 
Intravenous 
Liquid chromatography-tandem mass spectrometry 
Low density lipoprotein 
Limit of quantitation 
Monoamine oxidase A 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Medical Dictionary for Regulatory Activities 
Milligrams 
Minutes 
Milliliters 
Millimeters of mercury 
Margins of safety 
Nanomolar 
Not clinically significant 
Produits Chimiques Auxillaires et de Synthese 
Pharmacodynamic(s) 
IND 103,420 
February 17, 2017 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
Principal investigator 
Pharmacokinetic( s) 
PQ interval 
PR interval 
QRS complex 
IND 103,420 
February 17, 2017 
PI 
PK 
PQ 
PR 
QRS 
QT 
QTc 
QTcB 
QTcF 
RBC 
RN 
RR 
SAE 
SAP 
SSP 
SNRI 
SSRI 
Interval measured from the start of the Q wave to the end of the T wave 
Corrected QT interval 
t1/2 
tmax 
TCA 
THC 
TEAE 
us 
VAS 
WBC 
WHO 
WPW 
QTc obtained using Bazett's formula 
QTc obtained using Fridericia's formula 
Red blood cells 
Registered nurse 
Respiratory rate 
Serious adverse event 
Statistical Analysis Plan 
Systolic blood pressure 
Serotonin norepinephrine reuptake inhibitor 
Selective Serotonin Reuptake Inhibitor 
Terminal half-life 
Time of occurrence of Cmax 
Tricyclic antidepressant 
Tetrahydrocannabinol 
Treatment emergent adverse event 
United States of America 
Visual Analogue Scale 
White blood cells 
World Health Organization 
Wolff Parkinson White syndrome 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
1. INTRODUCTION 
IND 103,420 
February 17, 2017 
Migraine is a common neurological disorder and was ranked by the World Health 
Organization (WHO) in its 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.W 
Although the introduction of triptans greatly improved the acute treatment of migraine, a 
large percentage of patients still lack adequate treatment. A recent American Migraine 
Prevalence and Prevention (AMPP) study 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 
. ~ 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 acute treatment for 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. 
1.1 
Background 
Lasmiditan is a highly selective and potent 5-HT1F receptor agonist it
~ 
470-fold 
higher affinity (Ki 2.21 nM) for the 5-HT1F receptor than for 5-HT1st10 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 f.JM) 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 f.JM). 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.14·5·61 Unlike triptans, 
lasmiditan did not constrict rabbit saphenous vein, 141 an assay predictive of human 
coronary artery constriction.171 Lasmiditan is under development as a neurally acting 
treatment for migraine without the vasoconstrictor liability of triptans. 
The in vivo systemic response to lasmiditan has been defined in oral toxicology studies 
with durations ranging from one day (single dose) to 39 weeks (repeat dose) in rats, 
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Colucid Pharmaceuticals, Inc. 
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February 17, 2017 
dogs, mice and rabbits. Toxicokinetic data from pivotal toxicology studies provided 
robust margins of safety (MOS) for lasmiditan across species (mouse, rat, dog, rabbit), 
and demonstrated comprehensive toxicological characterization of the 4 major human 
metabolites in genotoxicity, general toxicity and reproductive toxicity studies. Common 
adverse effects across species were Cmax-driven CNS-related clinical signs (tremors, 
ataxia, and convulsions). Aside from the CNS-related clinical signs, there was no 
evidence of test article-related target organ toxicity. 
1.2 Clinical Studies to Date 
Five Phase 1 studies have been completed in Europe using intravenous (IV), 
sublingual, and oral formulations of lasmiditan. These trials enrolled 213 healthy 
subjects. Two European Phase 2 studies have been completed with lasmiditan in the 
acute treatment of migraine. One Phase 3, randomized, double-blind, placebo-
controlled trial in migraine patients has been completed in the United States. A second 
Phase 3, randomized, double-blind, placebo-controlled trial and an open-label, 
year-long safety study in migraine patients are ongoing in the United States. The 
open-label safety study is open to subjects who have completed one of the two Phase 3 
trials. 
Two trials, one in healthy volunteers and one in migraine patients, evaluated IV 
formulations of lasmiditan. 
Lasmiditan was studied in healthy volunteers at IV dose levels ranging from 0.1 to 180 
mg. Few AEs were reported following 20 minute IV infusions at dose levels of 0.1 to 
20 mg (clinical study H8H-BD-LACA). The number of reported AEs increased after 
20 minute IV infusions of higher doses (30 and 60 mg). Most of these were rated as 
mild. When the infusion time for the 60 mg dose was increased to 60 minutes, the 
number of subjects reporting AEs was similar to that following the shorter infusion time 
but the total number of AEs dropped. Similar numbers of AEs were reported after 60 
minute infusions of 120 and 180 mg. 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 
Lasmiditan IV 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 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
IND 103,420 
February 17, 2017 
paresthesia; however, most of these events were reported as 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. 
Oral formulations of lasmiditan have been studied in four Phase 1 and one Phase 2 
trials as well as the one completed (clinical study COL MIG-301) and two ongoing 
(clinical studies COL MIG-302 and COL MIG-305) Phase 3 trials. 
A Phase 1 placebo-controlled study assessed the safety and tolerability and 
pharmacokinetic (PK) profile of sublingual and orallasmiditan (clinical study COL 
MIG-1 02). 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. AU CO-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 lasmiditan 400 mg. 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). This study also assessed safety and tolerability of lasmiditan. 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 International Conference on Harmonization (ICH) 
E14 guidance,ffil the primary objective was to assess the effect of lasmiditan 100 mg 
and 400 mg on cardiac de- and re-polarization. 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. llil 
A food effect study (clinical study COL MIG-104) investigated the bioavailability, 
pharmacokinetics, safety, and tolerability of oral lasmiditan (200 mg) in 30 healthy 
subjects in the fed and fasted states. All subjects who enrolled completed the study 
which found that food had a small effect on the pharmacokinetics of lasmiditan. 
Somnolence and dizziness were the most commonly reported AEs. 
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 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
IND 103,420 
February 17, 2017 
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, 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. 
The first Phase 3 double-blind, placebo-controlled, parallel-group study of lasmiditan 
evaluated the proportion of subjects who were headache pain-free at 2 hours post-dose, 
safety, and other measures of migraine pain relief (clinical study COL MIG-301, 
SAMURAI). The study compared 100 mg and 200 mg doses of lasmiditan with placebo 
in 2232 adult subjects who treated one acute migraine attack. In this study both doses 
of lasmiditan were statistically significant over placebo (p<.001) on the primary endpoint 
of headache pain free at 2 hours post dose and on the key secondary endpoint of most 
bothersome symptom free at 2 hours post dose. 191 
During the clinical development of lasmiditan, there have been no deaths and no 
subjects have been 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 lasmiditan 200 mg, 
and resolved without sequelae. Across the clinical trials in the lasmiditan development 
program, somnolence, dizziness, and fatigue have been the mostly frequently reported 
adverse events. The sponsor has thus advised subjects in ongoing trials to not drive or 
operate machinery for 12 hours after dosing and plans to complete a skilled 
performance study. 
More information on the preclinical and clinical experience with lasmiditan are given in 
the Clinical Investigators' Brochure (IB). 1101 
1.3 
Rationale for the Clinical Study 
This study will assess the effect of single doses of sumatriptan (lmitrex) 1 00 mg on the 
pharmacodynamics of single doses of lasmiditan 200 mg as measured by serial vital 
signs, ECGs, and adverse events. Safety and tolerability will also be reported. 
1.4 Risk-Benefit Assessment 
In previous Phase 1 studies including healthy male and female subjects, oral doses of 
lasmiditan up to 400 mg were well tolerated with no drug related SAEs or withdrawals 
due to adverse events (AEs). The AE profile was qualitatively similar to that observed in 
previous clinical studies with dizziness, somnolence and paresthesia being the mostly 
frequently reported AEs. 
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February 17, 2017 
The healthy subjects will not derive any medical benefits from study participation. 
1.5 
Dose Rationale 
Lasmiditan 200 mg has been tested and shown to be safe and well tolerated in both 
healthy subjects and in patients with acute migraine. In preclinical toxicology studies, 
adequate margins of safety have been established for lasmiditan 200 mg. This study will 
further evaluate the pharmacokinetics and safety of lasmiditan 200 mg both ~l ne and 
when co-administered with sumatriptan (lmitrex) 100 mg. 
1.6 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 ICH. Further information on the ethical 
conduct of the study is provided in Section 11 . 
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Colucid Pharmaceuticals, Inc. 
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2. TRIAL OBJECTIVES 
2.1 
Primary Objective 
IND 103,420 
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The primary objective is to compare and contrast the pharmacodynamics of 
lasmiditan 200 nig and sumatriptan (lmitrex) 1 00 mg administered together to the 
pharmacodynamics of single doses of either drug administered alone. 
2.2 
Secondary Objective 
Secondary objectives are to: 
• 
Compare and contrast the pharmacokinetics of lasmiditan 200 mg and 
sumatriptan (lmitrex) 100 mg administered together to the pharmacokinetics of 
single doses of either drug administered alone. 
• 
Evaluate the safety and tolerability of lasmiditan 200 mg and sumatriptan 
(lmitrex) 100 mg administered together to the safety and tolerability of single 
doses of either drug administered alone. 
• 
Compare and contrast the subjective drug effects of lasmiditan 200 mg and 
sumatriptan (lmitrex) 100 mg administered together to the subjective drug effects 
of single doses of either drug administered alone. 
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IND 103,420 
February 17, 2017 
3. OVERALL DESIGN AND PLAN OF THE STUDY 
3.1 
Overview 
This is a randomized, double-blind, three-period, cross-over study to investigate the 
effect of single doses of sumatriptan (lmitrex) 100 mg on the pharmacodynamics of 
single doses of lasmiditan 200 mg. The study will last approximately 6 weeks including 
up to 3 weeks for screening and 22 days on study. Screening will be conducted within 
approximately 21 days of the first dose of study medication. Each dosing period will last 
3 days (Day -1, Day 1, and Day 2). A wash-out period of 6 days will take place between 
each dose. The End of Study Visit (EoS) will take place 5 (+/- 2) days after the third 
dosing period is completed. 
Study Day 
-1 
1 2 3 4 5 6 
7 
8 9 10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Period 1 
-1 
1 2 
Wash-out 1 
Period 2 
-1 
1 2 
Wash-out 2 
Period 3 
-1 
1 
2 
EoS 
3.2 
Schedule of Events 
The overall Schedule of Events for the study is provided in Table 1. The detailed 
schedule for Days 1 and 2 in each period is provided in Table 2. 
3.3 
Assessments by Study Visit 
3.3.1 
Screening (Day -21 to -1) 
The following procedures and assessments will be performed up to 21 days prior to 
study drug administration during the screening period. The results will be documented 
in the CRF and source documents 
• 
Informed consent 
• 
Eligibility criteria 
• 
Demographics 
• 
Height/weight/calculate BMI 
• 
Medical history 
• 
Complete physical examination 
• 
Urine drug screen 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
• 
Breathalyzer test 
• 
Serology (HIV 1 and 2, HBsAg and hepatitis C) 
• 
Serum pregnancy test (for all women) 
• 
Safety 12-lead ECG 
• 
Vital signs (BP, HR, oral temperature, and RR) 
• 
Orthostatic vital signs (BP and HR) 
IND 103,420 
February 17, 2017 
• 
Safety clinical laboratory evaluations (hematology, chemistry and urinalysis) 
• 
C-SSRS: Screening 
• 
Prior medications 
3.3.2 Clinical Pharmacology Center (CPC) Admission (Day -1 of each dosing 
period) 
• 
CPC admission on Day -1 
• 
Confirm eligibility criteria 
• 
Review medical history and update if necessary 
• 
Targeted physical exam, if applicable 
• 
Urine drug screening 
• 
Breathalyzer test 
• 
Urine pregnancy test 
• 
Vital signs (BP, HR, oral temperature, and RR) 
• 
Safety clinical laboratory evaluations (hematology, chemistry and urinalysis) 
• 
Training on VAS scales 
• 
C-SSRS: Since the last visit 
• 
Adverse events 
• 
Prior I concomitant medications 
3.3.3 
Day 1 of each dosing period 
3.3.3.1 
Pre-Dose 
Prior to the start of the dosing on Day 1 of each period, the following procedures and 
assessments will be performed: 
• 
Targeted physical exam, if applicable 
• 
Safety 12-lead ECG within 75 minutes of dosing 
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• 
Vital signs within 60 minutes prior to dosing 
• 
Orthostatic vital signs within 60 minutes prior to dosing 
• 
DEQ-5 within 60 minutes prior to dosing 
IND 103,420 
February 17, 2017 
• 
Bipolar Drug liking, Bipolar High, and Unipolar Sedation, Unipolar Overall drug 
liking and Unipolar Take drug again VAS scales within 60 minutes prior to dosing 
• 
Collection of Adverse Events throughout the study 
• 
Documentation of concomitant medication begins and will continue throughout 
the day 
• 
PK sample collection within 60 minutes prior to the start of dosing 
Additionally, in Period 1 only, subjects will be randomized to one of six treatment 
sequences. 
Upon completion of the pre-dose procedures and assessments, each dosing period will 
be initiated according to the subjects' randomly assigned dosing sequence. 
• 
Dosing at approximately the same time in each dosing period. Subjects will fast 
for 10 hours before and 4 hours after dosing. 
3.3.3.2 
Post-Dose 
After initiating dosing in each period at 0 minutes, the following procedures and 
assessments will be performed during the remainder of Day 1: 
• 
Targeted physical exam as needed 
• 
Safety 12-lead ECG at 1, 1.5, 2, 2.5, 4 and 8 hours after dosing 
• 
Vital signs at 1, 2, 4, and 8 hours after dosing 
• 
Orthostatic vital signs at 1 and 2 hours after dosing 
• 
DEQ-5 at 1, 2, 4, and 8 hours after dosing 
• 
Bipolar Drug liking, Bipolar High, and Unipolar Sedation VAS scales at 1, 2, 4, 
and 8 hours after dosing 
• 
Adverse event assessment will continue throughout study participation (i.e., 
through EoS or early termination) 
• 
Documentation of concomitant medication use will continue throughout study 
participation (i.e., through EoS or early termination).\ 
• 
Post dose PK sampling at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 16 hours 
after dosing. 
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COL MIG-118 V1 .0 
3.3.4 
Day 2 of each dosing period 
IND 103,420 
February 17, 2017 
The following procedures and assessments will be performed during the remainder of 
Day 2: 
• 
Targeted physical exam as needed and at 30 hours after dosing 
• 
Safety 12-lead ECG at 24 hours after dosing 
• 
Vital signs at 24 hours after dosing 
• 
Unipolar Overall drug liking and Unipolar Take drug again VAS scales at 
24 hours after dosing 
• 
DEQ-5 at 24 hours after dosing 
• 
C-SSRS: Since the last visit at 30 hours after dosing 
• 
Adverse event assessment will continue throughout study participation (i.e., 
through EoS or early termination). 
• 
Documentation of concomitant medication use will continue throughout study 
participation (i.e., through EoS or early termination). 
• 
Post dose PK sampling at 24 and 30 hours after dosing. 
• 
For Periods 1 and 2, upon completion of all protocol-specified procedures and 
assessments, exit from the Phase 1 unit on Day 2 and continuation of the 
wash-out period until the return to the Phase 1 unit on Day -1 of the next period. 
The wash-out period will be 6 days between each dose. For Day 2 of Period 3, 
upon completion of all protocol-specified procedures and assessments, exit from 
the Phase 1 unit on Day 2. The subjects will return for the EoS on Day 21 (+/- 2 
days). 
3.3.5 
End-of-Study/Early Termination 
The subjects are asked to return to the Phase 1 unit for the EoS assessments on Day 
21 (+/- 2 days). The following procedures and assessments will be performed: 
• 
Complete physical exam 
• 
Serum pregnancy test (for all women) 
• 
Safety 12-lead ECG 
• 
Vital signs 
• 
Safety clinical laboratory evaluations (hematology, chemistry and urinalysis) 
• 
C-SSRS: Since the last visit. 
• 
Adverse events 
• 
Concomitant medications 
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COL MIG-11 8 V1 .0 
• 
The subject's participation in the study is complete. 
IND 103,420 
February 17, 2017 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
4. SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects may be included in the study only if all the following criteria are met: 
1. Male or female aged 18-60 years, inclusive. 
2. Able and willing to give written informed consent. 
3. BMI between 18 and 32 kg/m2, inclusive. 
4. Subjects must be able to refrain from consuming xanthine, quinine and caffeine 
containing beverages, and must refrain from prolonged intensive physical 
exercise during the study (from 72 hours prior to dosing until the last study visit). 
5. Women must be: 
- not pregnant 
- not breast-feeding 
- not planning to become pregnant during the study 
6. All females must have a negative serum pregnancy test at screening and a 
negative urine pregnancy test at check-in on Day -1 of each period. All women 
must agree to use an adequate method of contraception during the study and 
for 30 days following the end-of-study visit. Accepted methods of contraception 
include: mechanical products (e.g., intrauterine device) or double-barrier 
methods (e.g., diaphragm, condoms, cervical cap) with spermicide, hormonal 
contraceptives (i.e., oral, implanted or injectable contraceptive hormones) or be 
surgically sterile (i.e hysterectomy, bilateral tubal ligation, bilateral 
oophorectomy). The subject's understanding of this requirement must be 
documented by the Investigator or designee. 
7. Male subjects must agree to utilize a highly effective method of contraception 
(condom plus spermicide) during heterosexual intercourse from clinic 
admission until 30 days following the end of study visit. 
8. Male subjects must agree to refrain from sperm donation from clinic admission 
until at least 30 days following the end of study visit. 
9. Subjects must be able to swallow multiple pills simultaneously. 
10. Subjects must be able to understand the requirements of the study and must be 
willing to comply with the requirements of the study 
4.2 
Exclusion 
Subjects are excluded from the study if any of the following criteria are met: 
1. Any medical condition, clinical laboratory test or other reason which in the 
judgment of the Investigator or designee makes the subject unsuitable for the 
study. 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
2. Any clinically significant abnormalities (as determined by the Principal 
Investigator or designee) in hematology, blood chemistry and/or urinalysis lab 
tests at screening or at Period 1 D-1 . 
3. Known hypersensitivity to lasmiditan, sumatriptan (lmitrex), or to any excipient of 
lasmiditan or sumatriptan (lmitrex) oral tablets. 
4. Use of any prescription medication, including MAO-A inhibitors and other drugs 
associated with serotonin syndrome, within 14 days prior to dosing (except 
hormonal contraceptives) except for 5-HT1 (serotonin) agonists and selective 
serotonin reuptake inhibitors which are restricted as noted in the table below. 
Any exceptions must be approved by the Investigator and Medical Monitor. Use 
of over-the-counter medications, including vitamins and herbal or dietary 
supplements within 7 days prior to dosing unless approved by the Investigator 
and Medical Monitor. Acetaminophen for symptomatic relief of pain is allowed 
until 24 hours prior to dosing in each period. 
Drug Class 
Brands (examples provided) 
Restricted prior to Day -
1 in all periods for: 
5-HT1 (serotonin) agonists 
Frova 
6 weeks 
Selective serotonin reuptake 
Prozac 
2.5 months 
inhibitors (SSRI)/Serotonin 
norepinephrine reuptake 
Vivactil 
3 weeks 
inhibitors (SNRI)/tricyclic 
antidepressants (TCA) 
Any other prescription 
14 days 
medication(s) 
Over-the-counter medications, 
including vitamins and herbal 
--
7 days 
or dietary supplements 
5. History, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral 
vascular syndromes including but not limited to angina pectoris, myocardial 
infarction, silent myocardial ischemia (Ischemic cardiac syndromes), stroke, 
transient ischemic attacks (cerebrovascular syndromes), and ischemic bowel 
disease (peripheral vascular disease). 
6. History, symptoms, or signs of vasospastic coronary artery disease. 
7. History, symptoms, or signs of arrhythmia or Wolff Parkinson White (WPW) 
syndrome that could affect the subject's safety in the opinion of the Investigator 
or designee. 
8. History, symptoms, or signs of severe hepatic impairment. 
9. History, symptoms, or signs of diabetes. 
10. History within the previous 3 years or current evidence of abuse (according to 
DSM-IV criteria) of any drug, prescription or illicit, or alcohol; a positive urine 
screen for drugs of abuse or breathalyzer alcohol test. 
11. Positive urinary test for drugs of abuse and/or alcohol breath test at Screening 
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COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
and/or at check-in on Day -1 of each Period. Cotinine will be included at 
screening only. 
12. History of orthostatic hypotension with or without syncope. 
13. Supine systolic blood pressure (BP) > 135 mm Hg, diastolic BP > 85 mm Hg, 
respiratory rate >20 breaths per minute, pulse >90 beats per minute, or 
temperature >37.5° at Screening. Low values on any vital sign measurement will 
be assessed at the discretion of the Investigator or designee. For orthostatic vital 
signs, any decrease in systolic and/or diastolic blood pressure great than 20 
mmHg. Any other changes will be assessed at the discretion of the Investigator 
or designee. 
14. ECG changes including QT interval prolongation and congenital long QT 
syndrome. 
15. Electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive 
heart failure, or other medicinal products that lead to QT prolongation. 
16.Any clinically significant alanine aminotransferase (AL T), alkaline phosphatase 
(AP), aspartate aminotransferase (AST), or bilirubin abnormalities judged by the 
Investigator or designee at Screening. 
17. Treatment with centrally active drugs or those affecting peripheral cholinergic 
transmission within 3 months of study entry. 
18. Consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange 
juice, or beverages containing any of these juices or consumption of members 
of the mustard green family (including kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts, and mustard (i.e. seeds, greens, spice or 
the condiment)) within 72 hours of dosing. 
19. Tobacco or nicotine users except subjects who stopped using tobacco or nicotine 
1 year or more before signing the informed consent. 
20. Subject is at imminent risk of suicide or had a suicide attempt within 6 months 
prior to the screening visit. 
21. Participation in any clinical trial of an experimental drug or device in the previous 
30 days. 
22. Positive Hepatitis C antibody, Hepatitis 8 surface antigen, or positive human 
immunodeficiency virus (HIV) antibody. 
23. Subjects who donated plasma in the 7 days or blood in the 3 months preceding 
study drug administration. 
24. Subjects with an inability to communicate well with the Investigator or designee 
and study staff (i.e., language problem, poor mental development or impaired 
cerebral function). 
25. 1nability to fast or consume the food provided in the study. 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
26. Relatives of or staff directly reporting to the Investigator. 
IND 103,420 
February 17, 201 7 
Subjects must give written informed consent for participation in the study before any 
study-specific screening tests or evaluations. 
Subjects with test results which do not meet the above inclusion/exclusion criteria may 
have the relevant 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 be considered a screen failure and should not be enrolled in the 
study. Subjects may be rescreened once. 
4.3 
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 (IRS) in accordance with the site's 
IRS requirements. 
4.4 
Subject Withdrawal Criteria 
Subjects may voluntarily withdraw from the study or be removed from the study at the 
discretion of the Investigator or designee, or Sponsor at any time. The Investigator or 
designee 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, the Investigator or 
designee 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 
• 
AE 
• 
Subject request 
• 
Investigator or designee request 
• 
Sponsor request 
If a subject withdraws or is withdrawn after randomization and administration of study 
drug under the above criteria or for any other reason, study staff should make every 
effort to complete the full panel of assessments scheduled until 4 hours after study drug 
administration. The reason for subject withdrawal must be documented. 
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COL MIG-11 8 V1 .0 
IND 103,420 
February 17, 2017 
If a subject withdraws or is withdrawn from the study due to an adverse event (clinical or 
laboratory), the subject will be instructed to return to the clinic for, at a minimum, the 
evaluations scheduled for EoS. If the adverse event has still not resolved, additional 
follow-up will be performed as appropriate and documented. As a minimum 
requirement, AEs should be followed for at least 1 week after the subject's dose of 
study medication. 
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 or designee 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. 
Any subject who discontinues from the study between Screening and dosing in Dosing 
Period 1 may be replaced. 
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Colucid Pharmaceuticals, Inc. 
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5. TREATMENT OF SUBJECTS 
5.1 
Subject Identification and Randomization 
IND 103,420 
February 17, 2017 
At screening, each subject will be assigned a unique three-digit subject number starting 
with 001. Numbers will be assigned by the study site personnel in ascending sequential 
order to each unique subject screened. If a subject is rescreened, the reason for 
rescreening will be noted and the subject will be assigned a new screening number. If a 
subject fails to be enrolled, the reason should be documented on the enrollment log. 
The subject will be considered a screen failure. 
On Dosing Period 1 /Day 1 subjects will be assigned a treatment sequence by a three 
digit randomization number starting with 101. The number is only for identifying a 
subject with their assigned treatment and not for subject identification. 
5.2 Description of Study Drug 
There are three study drugs: lasmiditan 200 mg oral tablet, lasmiditan 200 mg placebo 
oral tablet, and sumatriptan (lmitrex) 100 mg oral tablet. For purposes of the study all 
are referred to as study drug. 
5.3 
Concomitant Medications 
Use of any prescription medication, including MAO-A inhibitors and other drugs 
associated with serotonin syndrome, within 14 days prior to dosing (except hormonal 
contraceptives) except for 5-HT1 (serotonin) agonists and selective serotonin reuptake 
inhibitors which are restricted as noted in the table below. Any exceptions must be 
approved by the Investigator and Medical Monitor. Use of over-the-counter 
medications, including vitamins and herbal or dietary supplements within 7 days prior to 
dosing unless approved by the Investigator or designee and Medical Monitor. 
Acetaminophen for symptomatic relief of pain is allowed until 24 hours prior to dosing in 
each period. 
Drug Class 
Brands (examples provided) 
Restricted prior to Day -
1 in all periods for: 
5-HT1 (serotonin) agonists 
Frova 
6 weeks 
Selective serotonin reuptake 
Prozac 
2.5 months 
inhibitors (SSRI)/Serotonin 
norepinephrine reuptake 
Vivactil 
3 weeks 
inhibitors (SNRI)/tricyclic 
antidepressants (TCA) 
Any other prescription 
14 days 
medication(s) 
Over-the-counter medications, 
including vitamins and herbal 
--
7 days 
or dietary supplements 
Prior medications are medications that were being taken within 30 days of signing the 
informed consent and finished prior to administration of the study drug. Concomitant 
medications are medications started prior to the start of the study and continued after 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1.0 
IND 103,420 
February 17, 2017 
administration of study drug or started during the study after administration of study 
drug. Prior and concomitant medication use will be collected from Screening to EoS. 
It is not anticipated that the healthy volunteers participating in this study will be taking 
any prescription medications for any disorder. 
If intake of a drug should become necessary for any reason during the course of ttie 
study, the subject is required to inform the Investigator or designee immediately. The 
Investigator or designee will record the drug, the dose, and the time of intake in the 
subject's CRF. 
5.4 
Restrictions 
5.4.1 Dietary and Fluid Restrictions 
Subjects will fast for at least 10 hours prior to dosing and will continue to fast until at 
least 4 hours after dosing in each period. Meals during each dosing period will be 
standardized. All subjects will consume the same food during each meal. The 
composition of each meal may vary from day to day and between dosing periods. 
Subjects will fast at least 8 hours prior to any blood draw for clinical laboratory 
assessments. 
The study drugs will be taken with 240 ml of water. Subjects will be allowed to drink 
non-sparkling water ad libitum, except for the time from 1 hour prior to dosing until 
1 hour post-dose. 
The consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange juice, 
or beverages containing any of these juices or consumption of members of the 
mustard green family (including kale, broccoli, watercress, collard greens, kohlrabi, 
Brussels sprouts, and mustard (i.e. seeds, greens, spice or the condiment)) is 
prohibited within 72 hours of dosing. 
The consumption of alcohol is prohibited beginning 72 hours prior to dosing (Day 1) in 
each dosing period until discharge from the unit. During all other times, the maximum 
intake of alcohol is limited to 1 unit per day (or 7 units per week; 1 unit of alcohol 
corresponds to 250 ml beer, 125 ml of wine, or 25 ml of spirits). 
The consumption of tobacco is not allowed during the study. 
Subjects are to refrain from consumption of caffeine-containing food or beverages (e.g. 
coffee, tea, cola, cocoa, chocolate) and of energy drinks for 72 hours before Screening 
and in each dosing period from 72 hours before each administration of the study drug 
until discharge (Days -1 to 2). 
5.4.2 
Other Restrictions 
Subjects will be confined to the Phase 1 unit for each dosing period from Day -1 to 
Day 2. Subjects will be discharged after the last assessment has been performed within 
that period (at least 30 hours post-dose for PK sample). In case of persisting adverse 
events, the subject may remain in the unit at the discretion of the Investigator or 
designee. 
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COL MIG-118 V1.0 
5.5 
Treatment Compliance 
IND 103,420 
February 17, 2017 
Study medication will be administered in the Phase 1 unit under supervision. A mouth 
and hand check will be conducted for each subject after each dose to ensure 
compliance and proper ingestion. 
5.6 
Randomization and Blinding 
This is a randomized, double-blind, three-period, cross-over, study to investigate the 
effect of single doses of sumatriptan (lmitrex) 100 mg on the pharmacodynamics of a 
single dose of lasmiditan 200 mg. The dosing periods are: 
• 
A: Lasmiditan 200 mg co-administered with lasmiditan 200 mg placebo 
• 
B: Sumatriptan (lmitrex) 100 mg co-administered with lasmiditan 200 mg 
placebo 
• 
C: Lasmiditan 200 mg co-administered with sumatriptan (lmitrex) 1 00 mg 
The study will be conducted at a single center. Subjects will be randomized using a 
Williams square design to one of six treatment sequences, as follows: 
ABC 
ACB 
BAC 
BCA 
CAB 
CBA 
Seven of the planned 42 subjects will be included in each treatment sequence. The 
design is balanced for period and first order carryover effects. 
Double-blinding will be accomplished as follows: 
• 
Dosing staff, comprised of an unblinded pharmacist or designee (who prepared 
the medication), an unblinded dosing assistant, and an unblinded registered 
nurse (RN) will administer all study medications. They will have no other role in 
the trial and will not communicate their activities in the trial to other staff 
involved in the trial in any way. 
• 
Investigational product, prepared in the Pharmacy by an unblinded Pharmacist 
or designee, will be dispensed from the Pharmacy in an amber medication vial 
(with a subject specific label blinded to the identity of the investigational 
product) to the unblinded dosing staff and dosed to the subject directly from the 
amber vial to the subject's mouth. 
• 
Prior to dosing, each subject will be blind-folded and will remain blind-folded 
until the hand and mouth check has been completed. Curtains will be drawn 
around the bed prior to dosing and will remain in place until the hand and mouth 
check has.been completed. No one will enter the curtained space other than 
the subject, the unblinded RN, and the unblinded dosing assistant. 
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Colucid Pharmaceuticals, Inc. 
COL MIG-118 V1 .0 
IND 103,420 
February 17, 2017 
6. STUDY DRUG MATERIAL AND MANAGMENT 
6.1 
Lasmiditan 
Lasmiditan drug product is a tablet containing 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 Synthese (PCAS), 19 route de Meulan, F-78520 
Limay (France). The drug product was manufactured by Patheon 111 Consumers 
Drive, Whitby, Ontario L 1 N 5Z5 Canada, or by Patheon 2100 Syntex Court, 
Mississauga, Ontario L5N 7K9, Canada and contains the following inactive excipients: 
purified water, microcrystalline cellulose PH1 02, Starch 1500, sodium croscarmellose, 
sodium lauryl sulphate, magnesium stearate (non-bovine) and Opadry II White (film 
coating). 
6.2 
Lasmiditan Placebo 
Lasmiditan matching placebo contains purified water, microcrystalline cellulose PH102, 
Starch 1500, sodium croscarmellose, sodium lauryl sulphate, magnesium stearate (non-
bovine) and Opadry II White (film coating). The placebo tablets match the active tablets 
in size, shape, and appearance. 
Placebo was manufactured by Patheon 111 Consumers Drive, Whitby, Ontario L 1 N 5Z5 
Canada, or by Patheon 2100 Syntex Court, Mississauga, Ontario L5N 7K9, Canada. 
6.3 
Lasmiditan and Lasmiditan Placebo Packaging and Labelling 
Lasmiditan 200 mg matching placebo oral tablets will be delivered as bulk supplies in 
high-density polyethylene (HOPE) bottles from Catalent Pharma Solutions, Kansas City, 
Missouri, US. 
All packaging and labeling will be performed according to Good Manufacturing Practice 
(GMP) and GCP rules. The lot number and date of manufacture for the clinical lot used 
in the study will be provided to the clinical site and will be reported in the Clinical Study 
Report. All study drug will be labeled with: 
• 
Protocol number 
• 
Sponsor's name and address 
• 
Investigational New Drug statement 
• 
Instructions for use and storage 
6.4 
Storage of Lasmiditan and Lasmiditan Placebo 
All lasmiditan and its matching placebo should be stored by the study site at controlled 
room temperature of 25°C (?rF); excursions are permitted to+/- 15°C (59°F-1 04°F). 
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Colucid Pharmaceuticals, Inc. 
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6.5 
Lasmiditan and Lasmiditan Placebo Administration 
Double blinding will be accomplished as described in Section 5.6. 
IND 103,420 
February 17, 2017 
Investigational site staff will dispense lasmiditan 200 mg or its placebo according to the 
dosing plan. Lasmiditan will be co-administered with either sumatriptan (lmitrex) or 
lasmiditan placebo. The two study drugs will be swallowed simultaneously with 240 ml 
of water. 
After dosing and rinsing with water, a hand and mouth check will be performed. 
Subjects will receive study drug in a sitting position on the bed. For the first 4 hours after 
each dose, the subjects will continue to fast and must remain seated on their bed at an 
angle of approximately 45° except to use the bathroom. They may then move freely 
within the Phase 1 unit per Institution policy, but should refrain from engaging in any 
strenuous activity throughout the study period. 
6.6 
Sumatriptan (lmitrex) 
Sumatriptan (lmitrex) 100 mg will be supplied by the Investigator (or designee) as 
tablets for oral administration. Branded lmitrex is planned to be used in this study. In 
the event that it becomes unavailable, a generic substitute may be used. 
6.7 
Sumatriptan (lmitrex) Administration 
Investigational site staff will dispense sumatriptan (lmitrex) 1 00 mg according to the 
dosing plan. Sumatriptan (lmitrex) will be co-administered with either lasmiditan or 
lasmiditan placebo. The two study drugs will be swallowed simultaneously with 240 ml 
of water. 
After dosing and rinsing with water, a hand and mouth check will be performed. 
Subjects will receive study drug in a sitting position on the bed. For the first 4 hours after 
each dose, the subjects will continue to fast and must remain seated on their bed at an 
angle of approximately 45° except to use the bathroom. They may then move freely 
within the Phase 1 unit per Institution policy but should refrain from engaging in any 
strenuous activity throughout the study period. 
6.8 
Sumatriptan Storage 
Sumatriptan (lmitrex) tablets should be stored according to manufacturer's instructions. 
6.9 
Drug Accountability, Dispensing and Destruction 
Under supervision of the Investigator or designee, the study pharmacist or designee will 
be responsible for drug accountability. The pharmacist or designee will keep an 
accurate inventory of both study drugs 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. 
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IND 103,420 
February 17,2017 
The Investigator or designee will administer the study drugs only to the identified 
subjects of this study, following the procedures described in this study protocol. 
If any unused study drug remains 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. 
The study drugs supplied for this study are only intended for use by subjects in this 
study. They must not be diverted for use by other subjects or personnel. 
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7. 
METHODS OF ASSESSMENT 
IND 103,420 
February 17, 2017 
So that data capture can be standardized, all assessments should be performed as 
indicated. In cases where blood sampling for PK analysis and other assessments (vital 
signs or EGGs) are scheduled to occur at the same time, the order of procedures will 
be: 5 minutes supine rest, ECG, supine vitals followed by standing vitals, and PK blood 
draw. This does not apply to screening procedures. 
Every effort should be made to collect the PK samples at the exact times as specified 
(Table 2). Samples taken pre-dose and up to and including 8 hours post-dose will be 
taken ±5 minutes of the nominal time. Samples taken after 8 hours post-dose will be 
taken ±1 0 minutes of the nominal time. 
7.1 
Informed Consent 
The ICF must be executed prior to performing any study-related activities associated 
with the study. The ICF must be approved by the reviewing IRB prior to being given to 
any subject. Informed consent will be obtained for all subjects participating in the study. 
Subjects may withdraw consent at any time. Participation in the study may be 
terminated at any time without the subject's consent as determined by the Investigator 
or designee. 
7.2 
Inclusion/Exclusion Criteria 
Eligibility screening of healthy subjects will be completed within 21 days prior to 
administration of the study drug in the first period and will be documented on the CRF. 
Confirmation of eligibility will be performed after check-in of each dosing period. 
Screen failures and the reason for failure to meet the study eligibility requirements will 
be documented in the study site source documents but not entered into the study 
database. 
7.3 
Demographics 
During Screening, subject initials, date of birth, age, gender, race and ethnicity will be 
recorded on source documents and on the CRF. Name, address, phone number, and 
emergency contact information will be documented in the source documents only. 
7.4 
Medical History 
General and relevant medical history will be recorded during Screening on the source 
document and CRF and will include information relating to any prior or existing medical 
conditions involving the following disease types or systems: allergic, endocrine, 
musculoskeletal, dermatologic, eyes, ears/hearing, nose/throat, reproductive, 
respiratory, cardiovascular, gastrointestinal, genitourinary, neurological, immune 
system, blood disorders, cancer and psychiatric. History of hospitalization, history of 
surgery, pre-planned future surgeries (e.g., elective procedures for preexisting 
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conditions that did not worsen) will be recorded. History of 
tobacco/nicotine/alcohol/caffeine/drug use will also be recorded. 
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February 17, 2017 
Prior medication used in the last 30 days to treat any medical conditions will be 
recorded on the CRF. 
7.5 
Physical Examination 
A complete physical examination will be completed and recorded at Screening and EoS. 
The examination will be done at the nominal time +/- 10 hours. 
A complete physical examination will include the following: general appearance, skin, 
HEENT, heart, lymph nodes, lungs, abdomen, extremities/joints, neurological systems, 
and mental status. 
A brief, targeted (symptom-related) physical examination will be performed if indicated 
by an AE during each dosing period. 
Height, Weight (without shoes) and BMI calculation will be performed at Screening only. 
7.6 
Vital Signs 
Vital signs, measured after at least 5 minutes supine, will include supine systolic blood 
pressure (SBP), supine diastolic blood pressure (DBP), heart rate (HR), respiration rate 
(RR), and oral body temperature. All vital sign measurements will be performed by 
appropriately qualified and authorized study personnel, using appropriate equipment. 
BP and HR will be measured if possible in the same arm at each visit by using 
automated devices. BP results will be recorded in millimeters of mercury (mmHg). HR 
will be measured in the humeral artery in the dominant arm for approximately 30 
seconds and will be recorded as beats per minute (bpm). RR will be measured and 
recorded in breaths per minute. Oral body temperature will be measured in degrees 
Celsius. 
At Screening and for interim and study exit vital signs, subjects who have a supine 
systolic BP > 135 mm Hg or < 90 mm Hg or who have a supine diastolic BP > 85 
mm Hg or < 50 mm Hg will undergo at least one BP reassessment within 15 minutes of 
the original. Subjects who have a heart rate > 90 bpm or < 50 bpm will undergo at least 
one heart rate reassessment within 15 minutes of the original. All out of range results 
will be assessed by the PI, Sub-Investigator, or designee. 
If interim BP or heart rate values are deemed clinically significant, subjects should be 
monitored by study staff and if deemed necessary from a safety standpoint, the patient 
will be discontinued. 
Vital signs will be taken at Screening and at EoS. During each dosing period, they will 
be taken at check-in on Day -1, on Day 1 within 60 minutes of dosing and 1, 2, 4, and 
8 hours after dosing, and on Day 2, 24 hours after dosing. Assessments will be 
performed at the nominal times +/- 15 minutes. 
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7.7 
Orthostatic Vital Signs 
IND 103,420 
February 17, 2017 
Orthostatic vital signs will be measured after at least 5 minutes supine then at least 2 
minutes standing and will include systolic blood pressure (SBP), diastolic blood 
pressure (DBP), and heart rate (HR). Any subjects experiencing a decrease in systolic 
and/or diastolic blood pressure great than 20 mmHg will undergo at least one 
reassessment within 15 minutes of the original. All out of range results will be assessed 
at the discretion of the PI, Sub-Investigator, or designee. If interim results are deemed 
clinically significant, subjects should be monitored by study staff and if deemed 
necessary from a safety standpoint, the patient will be discontinued. 
Orthostatic vital signs will be taken at Screening. During each dosing period they will be 
taken at Day 1 within 60 minutes of dosing and 1 and 2 hours after dosing. 
Assessments will be performed at the nominal times +/- 15 minutes. 
7.8 ECG 
A standard, digital 12-lead ECG with a 1 0-second rhythm strip will be used to assess 
cardiac function after subjects have been at least 5 minutes supine. 
ECGs will be taken at Screening and at EoS. During each dosing period they will be 
taken on Day 1 within 75 minutes prior to dosing and 1, 1.5, 2, 2.5, 4, and 8 hours after 
dosing, and on Day 2 at 24 hours after dosing. Assessments will be performed at the 
nominal times +/- 15 minutes. 
Trained study staff 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. ECG values of HR, RR, PQ/PR, QRS, QT QTcF and QTcB, calculated by the 
Fridericia formula (QTc = QT/(RR)0·33 and Bazett formula (QTc = QT/(RR)0·5, 
respectively will be presented. The Investigator or a designee will evaluate whether the 
ECG is normal or abnormal. Abnormal findings will be identified as either clinically 
significant (CS), or not clinically significant (NCS). CS findings that emerge after dosing 
in all periods are to be reported as AEs by the Investigator or designee. 
The clinical significance of ECG changes will be determined by the Investigator or 
designee after review of the ECG report with relation to the subject's medical history, 
physical examination, and concomitant medications. 
ECGs may be repeated for quality reasons and the repeat used for analysis. Additional 
ECGs may be collected by the Investigator or designee for safety reasons. The 
electronic version of the ECG is regarded as source data. The conduct and evaluation 
of ECG recordings will be carried out according to the Institution's procedures. 
If treatment-related abnormal ECG changes occur, subjects may be treated with 
medications such as nitroglycerin, aspirin, or may be given supplemental oxygen. 
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7.9 
VAS scales 
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VAS scales will be administered following dosing according to the schedules in Table 1 
and Table 2. These scales are 100 mm scales. The subject chooses the point along 
the scale that is consistent with their current state. They will be administered by paper. 
Subjects will be trained on Day -1 of each dosing period as described in Section 7.9.6. 
Scoring of the scales will be done by trained staff. 
7 .9.1 
Bipolar Drug liking 
Subjects will rate "At this moment, my liking for the drug is" on the bipolar drug liking 
scale. Anchors will be 
• 
0: Strong disliking 
• 
50: Neither liking nor disliking 
• 
1 00: Strong liking 
The bipolar drug liking VAS will be completed during each dosing period on Day 1 within 
60 minutes prior to dosing and at 1, 2, 4, and 8 hours+/- 20 minutes after dosing. 
7 .9.2 
Bipolar High VAS 
Subjects will rate "I am feeling high" on the bipolar drug high scale using the anchors: 
• 
0: Definitely not 
• 
50: Neutral 
• 
100: Definitely so 
The bipolar high VAS will be completed during each dosing period on Day 1 within 60 
minutes prior to dosing and at 1, 2, 4, and 8 hours+/- 20 minutes after dosing. 
7.9.3 
Unipolar Sedation 
Subjects will rate "At this moment, I am feeling ... " with the anchors: 
• 
0: Alert 
• 
1 00: Drowsy 
The unipolar sedation VAS will be completed during each dosing period on Day 1 within 
60 minutes prior to dosing and at 1, 2, 4, and 8 hours+/- 20 minutes after dosing. 
7.9.4 
Unipolar Overall drug liking VAS 
Subjects will rate "Overall, my liking for the drug is ... " on the unipolar overall drug liking 
scale using the anchors: 
• 
0: Strong disliking 
• 
100: Strong liking 
The unipolar overall drug liking VAS will be completed on Day 1 within 60 minutes prior 
to dosing and on Day 2 at 24 hours+/- 20 minutes after dosing. 
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7.9.5 
Unipolar Take drug again VAS 
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Subjects will rate "I would take this drug again' on the unipolar scale using the anchors: 
• 
0: Definitely not 
• 
1 00: Definitely so 
The unipolar take drug again VAS will be completed on Day 1 within 60 minutes prior to 
dosing and on Day 2 at 24 hours +/- 20 minutes after dosing. 
7.9.6 
Training on VAS scales 
Subjects will be trained on the VAS scales on Day -1 of each period. Training will 
include a brief review of how the scales are completed and the completion of three 
training scales. The same three scales will be used for every period. 
The training scales will be: 
• 
Bipolar: "Last night, I slept. .. " using the anchors 0: Very badly, 50: Neither well 
nor badly, and 1 00: Very well. 
• 
Bipolar: "My dinner last night was ... " using the anchors 0: the worst I have ever 
had, 50: neither good nor bad, and 100: the best I have ever had. 
• 
Unipolar: "The weather yesterday was great" using the anchors 0: Definitely not 
and 100: Definitely so. 
7.9.7 
Drug Effects Questionnaire (DEQ-5) 
The standardized Drug Effects Questionnaire (DEQ-5) [Il l is composed of five DEQ 
constructs: Feel, High, Dislike, Like, and More. Studies have demonstrated that it 
reliably shows differences in subjects' subjective experience of substances and placebo 
and that it has convergent, concurrent, and predictive validity. 
The DEQ-5 will be completed during each dosing period on Day 1 within 60 minutes 
prior to dosing and at 1, 2, 4, and 8 hours after dosing and on Day 2 at 24 hours +/- 20 
minutes after dosing. 
7.10 C-SSRS 
C-SSRS 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. 
At Screening, the Screening version of the C-SSRS will be used. The 'Since the last 
visit' version will be used in each dosing period at check-in on Day -1 and on Day 2 at 
30 hours +/- 10 hours after dosing and at EoS. 
If present, suicidal 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 
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6 classes (actual attempt, interrupted attempt, aborted attempt, preparatory acts 
towards and attempt, suicidal behavior, suicide). 
7.11 Clinical Laboratory 
7 .11.1 Laboratory Parameters 
Laboratory testing (hematology with differential, serum chemistry and urinalysis) will be 
performed using standard methods. 
All subjects must fast at least 8 hours prior to any clinical laboratory assessment blood 
draw. 
The urine screen for drugs of abuse will be performed at Screening and on Day -1 of 
each dosing period at check-in. Hepatitis B/C and HIV serology will be performed at 
Screening. Serum pregnancy testing will be done on all female subjects at Screening 
and EoS. Urine pregnancy testing will be completed on all female subjects on Day -1 of 
each dosing period at check-in. Clinical laboratory testing (CBC, chemistry, and 
urinalysis) will be performed at Screening, Day -1 of each dosing period, and EoS. 
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Table 3: List of Laboratory Tests 
Hematology 
RBC 
Hematocrit 
Hemoglobin 
Mean corpuscular 
hemoglobin 
(MCH) 
Mean corpuscular 
volume 
(MCV) 
Mean corpuscular 
hemoglobin 
concentration (MCHC) 
Platelet count 
WBC count (with 
differential) 
Neutrophils 
(granulocytes) 
Lymphocytes 
Monocytes 
Basophils 
Eosinophils 
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Serum Chemistry 
Creatinine 
Potassium (K+) 
Sodium (Na+) 
Chloride (CI-) 
Magnesium (Mg++) 
Glucose 
Urea 
Bilirubin (Total) 
Bilirubin (direct) 
eGFR 
AST 
ALT 
AP 
Total Protein 
Albumin 
C02 
Urinalysis: Macroscopic examination routinely including specific gravity, pH, 
protein, glucose, ketones, blood and urobilinogen. A microscopic examination will 
be performed if warranted based on macroscopic results. 
Urine drug screen: A urine sample will be collected and analyzed (positive or 
negative) for drugs of abuse including amphetamine, opiate, cocaine, barbiturates 
benzodiazepines, and marijuana (tetrahydrocannabinol [THC]). 
For the Screening visit only, cotinine will be included in the urine drug screen 
panel. 
Serology: Testing for HbsAg, Hepatitis C antibody and HIV 1 and 2 will be 
performed at the screening visit only. Results of each serology test will be 
reported as either positive or negative. 
For females: A serum_hCG test at the screening visit and EoS, urine_hCG test 
on the day of Phase 1 unit admission for each of the three treatment periods (Day 
-1 of each dosing period). 
AST: aspartate aminotransferase; AL T: alanine aminotransferase; AP: alkaline 
phosphatase; HbsAg: hepatitis B surface antigen; hCG: human chorionic 
gonadotropin; HIV: human immunodeficiency virus; RBC: red blood cell; WBC: 
white blood cell 
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7.11.2 Clinical Laboratory Sample Collection, Storage, and Shipping 
Detailed instructions for laboratory sample collection, processing, and shipping 
instructions will be provided in the Laboratory Manual. 
Biological material will be stored and secured, in a way that assures that unauthorized 
access is prohibited and the samples are not lost, deteriorated or accidentally or illegally 
destroyed. Details for storage and shipping will be provided in the Laboratory Manual. 
7 .11.3 Abnormal and Clinically Significant Results 
The Investigator or designee 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 or designee will use the 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 as a guide when 
evaluating the clinical significance of all abnormal clinical laboratory results. In case of 
CS laboratory results, the Investigator or designee 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 or designee has judged that the abnormal 
values are not related to the administration of study drug or other protocol specific 
procedures. 
7.12 Breathalyzer Test 
A breathalyzer assessment of breath alcohol concentration will be performed. Subjects 
with a positive test result at Screening or Day -1 of Period 1 will be excluded from the 
study; subjects with a positive result at Day -1 of Period 2 or 3 will be terminated from 
the study. 
The breathalyzer assessment will be performed will be performed at Screening and on Day 
-1 of each dosing period at check-in 
7.13 Pharmacokinetics Samples 
Blood samples will be collected within 60 minutes prior to the start of dosing and then 
0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 and 30 hours following the dose at time 0 
in each dosing period. Samples collected during the first 8 hours post-dosing (including 
the 8 hour time-point) will be collected at the nominal times +/- 5 minutes. Samples 
collected after the first 8 hours post-dosing will be collected at the nominal times +/- 10 
minutes 
Samples taken pre-dose and up to and including 8 hours post-dose will be taken 
±5 minutes of the nominal time. Samples taken after 8 hours post-dose will be taken 
±1 0 minutes of the nominal time. In cases where blood sampling for PK analysis and 
other assessments (vital signs or ECGs) are scheduled to occur at the same time, the 
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order of procedures will be: 5 minutes supine rest, ECG, supine vitals followed by 
standing vitals, and PK blood draw. 
7.13.1.1 Sample Collection, Preparation, and Handling 
Blood samples will be collected into lithium heparinized polypropylene tubes (6.0 mL). 
The tubes should be mixed immediately after filling by gently inverting the tubes at least 
8 to 10 times and should be placed on ice after the sample is collected. Thereafter, the 
tubes will be centrifuged as soon as possible (within 30 minutes of collection) at a 
minimum of 1500 g for 15 minutes at 2°C until cells and plasma are well separated. 
The resulting plasma samples will be transferred into two (duplicate) 1.8 ml cryovial 
tubes and labeled appropriately. The samples will be frozen as soon as possible (within 
24 hours) of collection and stored frozen at - 60 to -80°C until time of shipment to 
Covance Laboratories, Inc., 3301 Kinsman Blvd. Madison, WI 53704, US for analysis. 
The times of blood sample collection, pipetting and freezing will be recorded in the 
source documents. 
7. 13. 1.2 Assay Methodology 
Plasma samples will be analyzed for lasmiditan at Covance Laboratories, Inc., Madison, 
US, using a validated liquid chromatography with tandem mass spectrometric detection 
(LC/MS/MS) method (limit of quantification (LOQ): 1 ng/mL). 
A detailed method description, including validation, calibration and quality assurance 
procedures will be included in the bioanalytical report which will be part of the Final 
Study Report. 
7.13.1.3 Pharmacokinetic Parameters 
The following compartmental pharmacokinetic parameters will be derived from plasma 
concentrations of lasmiditan: 
Cmax 
Maximum plasma concentration as observed 
AUC0.<1) 
Area under the plasma concentration vs. time curve from time 0 to infinity, 
calculated as AUC = AUCo-t + AUCextra· AUCextra represents an extrapolated 
value obtained by C /'Az, where C is the observed concentration at time t at 
or above LOQ, and 'Az is the estimated apparent terminal rate constant 
AUC0.1 
Area under the plasma concentration vs. time curve from time 0 to the time t 
of the last quantifiable concentration, calculated by means of the mixed log-
linear trapezoidal rule 
tmax 
Time to maximum plasma concentration 
'Az 
Apparent terminal rate constant determined from the slope of the 
log-transformed plasma concentration curve 
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t1,2 
Apparent terminal elimination half-life, calculated as ln(2)/Az 
7.14 Adverse Events and Serious Adverse Events 
7.14.1 Adverse Events 
An AE is defined as any unfavorable and unintended sign (including abnormal 
laboratory findings), symptom, or disease temporally associated with the use of a study 
treatment or procedure that may or may not be considered related to the study 
treatment or procedure. AEs are collected from the time the subject signs the informed 
consent form until the completion of EoS. AEs that occur prior to dosing in period 1 will 
be recorded as medical history. Those occurring during and/or after dosing in period 1 
will be recorded as adverse events. 
Adverse events will be classified according to the Common Terminology Criteria for 
Adverse Events (CTCAE), v4.03 published June 14, 2010, the most recent version 
available.r121 
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, designee, or medical staff, and 
• 
Changes in laboratory values that are clinically relevant as assessed by the 
Investigator or designee and for which a medical intervention was initiated. 
All AEs must be recorded in the site's study records and the AE CRF with the following 
information: 
1. Relationship to Study Drug: The Investigator or designee must assess whether they 
consider an AE drug-related. In assessing this relationship, the Investigator or 
designee must use information about the drug as outlined in the Investigators' 
Brochure, 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 designee) 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 of evaluation, are considered by the 
Investigator (or designee) to have no relationship, or no reasonable possibility 
of a relationship, to study drug. 
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2. Event Severity: The Investigator or designee will be asked to assess the severity of 
the AE using the CTCAE V4.031121• These criteria assign a grade of 1 through 5 to 
indicate the severity of AEs. For AEs that are not listed in these criteria, the 
Investigator or designee will use medical judgment to assess the severity of the AE. 
A general guideline to these grades of severity, taken from CTCAE V4.03, is: 
- Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
- Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (see CTCAE for more details). 
- Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization of prolongation of hospitalization indicated; disabling; limiting self care 
Activities of Daily Living. 
- Grade 4: Life-threatening consequences; urgent intervention indicated. 
- Grade 5: Death related to AE. 
The following are guidelines to be used by the Investigator or designee to judge the 
event severity of an AE that is not in CTCAE: 
• 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 
• Death related to AE 
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 signs, symptoms and/or other clinical information. In such cases, the diagnosis, and 
not the individual signs/symptoms or laboratory abnormalities, should be documented 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. 
7 .14.2 Treatment Emergent Adverse Events (TEAE) 
A TEAE will be an AE that occurred during the study after a subject ingested the dose of 
study drug until 48 hours post-dose or that was present prior to dosing and exacerbated 
after the dose of study drug. This pertains to all dosing periods. 
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7 .14.3 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. 
7 .14.4 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 or in the 
lmitrex (sumatriptan) labeling. 
7.15 Reporting Serious Adverse Events 
The Investigator or designee is responsible for reporting all SAEs, regardless of 
causality, to the Sponsor or their designated representative by phone, fax or email 
within 24 hours of learning of the occurrence. The reporting timeframe starts when the 
subject signs the informed consent form and ends at EoS. At a minimum, a description 
of the event and the Investigator's (or designee) 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 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 or designee. A follow-up SAE Report must be submitted within 24 
hours of the Investigator or designee 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. 
The procedures for reporting SAEs are as follows: 
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• 
Complete the "Serious Adverse Event Report Form". The Investigator or 
designee may contact the Medical Monitor, Lisa Beth Ferstenberg, MD at 
240-688-8572 or lbferstenberg@gmail.com. 
• 
Email the SAE Form to the attention of the Medical Monitor within 24 hours of 
the Investigator's (or designee's) knowledge of the event. The Sponsor will 
also be notified of the SAE by phone or email. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept 
with the source documentation at the study site. 
Follow-up information should be communicated in the same way using a new SAE 
Report Form stating that it is a follow-up to the previously reported SAE and giving the 
date of the original report. 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 or his designee for reporting to the relevant regulatory 
authority. 
The Investigator and study personnel should institute any supplemental investigations of 
SAEs based on their clinical judgment of likely causative factors. This may include 
clinical laboratory tests not specified in the protocol, histopathologic examinations, or 
consultations with specialists. The Sponsor or their designee may also request the 
Investigator or designee to conduct supplemental assessments. 
The Investigator or designee should notify the Medical Monitor 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. 
7.16 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 or designee. Other non-
serious adverse events should be followed through the EoS. 
7.17 Procedures for unblinding Investigational Product 
When it is required to ensure the safety and appropriate care of the subject, the 
Investigator can break the blinded treatment assignment to determine which treatment a 
subject has received and to initiate appropriate medical care. When possible, the 
Medical Monitor should be notified prior to breaking the blind. If not possible in 
advance, the Investigator or designee will inform the Medical Monitor as soon as 
possible after the event. The reason for breaking the blind will be recorded in the 
source documents. 
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7.18 Reporting Safety Information to the IRB 
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February 17, 2017 
The Investigator or designee is responsible for following all local regulations for the 
reporting of safety information, including the reporting of SAEs to the IRB. 
The Investigator or designee must promptly report to his or her IRB 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 in accordance with the IRB's requirements. 
Lasmiditan has been filed under an Investigational New Drug (IN D) application with the 
US FDA AnSAE 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 or designee is 
responsible for submitting the safety report (initial and follow-up) or other safety 
information (e.g., revised Investigator's Brochure) to the IRB in accordance with the 
IRB's requirements and to keep a copy in their files. 
7.19 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 or designee to the 
Medical Monitor. 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. 
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8. STATISTICAL METHODS 
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February 17, 2017 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate 
document, providing detailed methods for the analyses outlined below. 
Any deviations from the planned analyses will be described and justified in the final 
integrated clinical study report. 
8.1 
Sample Size 
To ensure that at least 36 subjects complete, at least 42 subjects (approximately 60% 
female) will be enrolled. 
8.2 
Study Population 
8.2.1 
Disposition of Subjects 
The number and percentage of subjects entering and completing each period of the 
clinical study will be presented, by dosing sequence. 
8.2.2 
Protocol Deviations 
Deviations from the protocol, including deviations of inclusion/exclusion criteria will be 
assessed as "minor" or "major" in agreement with the Sponsor. Major deviations from 
the protocol will lead to the exclusion of a subject from the PK analysis set. Deviations 
will be defined before the database lock report planning meeting. 
8.2.3 
Analysis Populations 
Pharmacodynamic population:AII randomized subjects who received at least one dose 
of any study drug. 
Safety population: 
All randomized subjects who received at least one dose 
of any study drug. 
Pharmacokinetic population: All subjects with evaluable PK data will be included in the 
pharmacokinetic population. Subjects with incomplete 
PK data, e.g. data missing from one entire study period, 
will be listed and the derived PK parameters will not be 
considered for summary statistics and analytical 
evaluations. 
The primary results will be based on the pharmacodynamic population. All safety 
analyses will be based on the safety population. 
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8.3 
General Considerations 
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February 17, 2017 
Continuous measurements will be summarized by means of descriptive statistics (i.e., 
number of observations, mean, standard deviation, minimum, median, maximum), 
90% confidence intervals may be given additionally. Categorical data will be 
summarized using frequencies or percentages. 
8.4 
Pharmacodynamic Analyses 
8.4.1 
Adverse Events 
The discrete outcome variables are the treatment emergent adverse events. A general 
linear random model will be used to compare and contrast the frequency difference of 
TEAEs in the different treatment groups, lasmiditan 200 mg co-administered with 
sumatriptan (lmitrex) 100 mg, lasmiditan 200 mg co-administered with lasmiditan 
placebo 200 mg, or sumatriptan (lmitrex) 100 mg co-administered with lasmiditan 
placebo 200 mg. 
Adverse events will be summarized by treatment group (Medical dictionary for medical 
activities (MedORA) terminology (latest version), severity and relation to study drug. 
The descriptive statistics presented for each system-organ class and preferred term will 
be the number of subjects with event (N), the percent of subjects exposed with 
event(%), and the number of events (E). All AEs will be listed by subject, including 
demographic information, dose sequence, MedORA latest version, system organ class, 
and preferred term. 
8.4.2 
Vital Signs 
The continuous outcome variables, vital signs (BP, HR, RR and oral body temperature), 
will be summarized by treatment (lasmiditan 200 mg co-administered with sumatriptan 
(lmitrex) 100 mg, lasmiditan 200 mg co-administered with lasmiditan placebo 200 mg, 
or sumatriptan (lmitrex) 1 00 mg co-administered with lasmiditan placebo 200 mg) using 
descriptive statistics. Changes from baseline in vital signs will be summarized by 
descriptive statistics for each dosing sequence. 
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8.4.3 
ECG Results 
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February 17, 2017 
All ECG endpoints will be listed by treatment (lasmiditan 200 mg co-administered with 
sumatriptan (lmitrex) 100 mg, lasmiditan 200 mg co-administered with lasmiditan 
placebo 200 mg, or sumatriptan (lmitrex) 100 mg co-administered with lasmiditan 
placebo 200 mg), subject and time of assessment and summarized by descriptive 
statistics. Changes from baseline in ECG parameters will be summarized by descriptive 
statistics by dosing sequence. 
8.4.4 
Physical Examination Results 
Subjects with any changes in the physical examination evaluation from Screening to 
EoS will be listed and the temporal occurrence of the change relative to the treatment 
(lasmiditan 200 mg co-administered with sumatriptan (lmitrex) 100 mg, lasmiditan 200 
mg co-administered with lasmiditan placebo 200 mg, or sumatriptan (lmitrex) 100 mg 
co-administered with lasmiditan placebo 200 mg) identified. A description of the study 
population in terms of baseline measures and demographics will be presented. 
8.5 Pharmacokinetic Analyses 
All evaluable subjects will be included in the PK analysis. The evaluable PK 
population will include all subjects who completed at least one treatment period 
without any protocol violations that would likely affect the PK results, who have 
evaluable plasma concentration data for lasmiditan and/or sumatriptan (lmitrex), and 
for whom at least a subset of the designated PK parameters can be determined. 
Data will be summarized using descriptive statistics (sample size, mean, median, 
standard deviation, minimum, and maximum) for continuous variables and using 
frequency and percentage for discrete variables for each treatment unless additional 
analysis is deemed appropriate based upon a review of the PK results. 
Standard PK parameters (Cmax. tmax. tv. and AUC [AUC(o-last) and AUC(o-co)] of lasmiditan 
200 mg will be used to describe the characteristics of the drug when co-administered 
with sumatriptan (lmitrex) or when taken alone. 
The primary statistical analysis will use the paired t-test applied to log-transformed PK 
parameter (lasmiditan Cmax or AUC30 separately) in the lasmiditan/sumatriptan (lmitrex) 
treatment period paired with the same subject's parameter value in the lasmiditan 
treatment period. From this model the means for each treatment and mean differences 
to the reference lasmiditan treatment will be estimated with the corresponding 90% 
confidence intervals. These estimates will then be exponentiated to produce the 
estimates of geometric mean ratios with their 90% confidence intervals. It will be 
concluded that sumatriptan (lmitrex) has no effect on lasmiditan PK, if 90% confidence 
intervals for ratios of PK parameters derived in lasmiditan/sumatriptan (lmitrex) 
treatment period to those derived in lasmiditan treatment period are within the 80-125% 
interval. 
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IND 103,420 
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The sample size of 36 subjects will provide at least 80% power to show equivalence of 
the PK of lasmiditan in the absence and presence of sumatriptan (lmitrex), assuming a 
25% within subject coefficient of variation. 
8.6 
Safety Analyses 
Complete listings and summary tables for all safety information including AEs, 
laboratory safety data, ECG, vital signs and physical examination will be included in the 
study report. 
8.6.1 
Adverse Events 
Discussion of Adverse Event Analysis is in Section 8.4.1. 
8.6.2 
Clinical Laboratory 
Clinical laboratory values will be summarized by descriptive statistics by treatment 
(lasmiditan 200 mg co-administered with sumatriptan (lmitrex) 100 mg, lasmiditan 200 
mg co-administered with lasmiditan placebo 200 mg, or sumatriptan (lmitrex) 100 mg 
co-administered with lasmiditan placebo 200 mg). Changes from baseline in clinical 
laboratory values will be summarized by descriptive statistics. All clinical laboratory 
values outside normal range (including Screening and EoS examination) will be listed 
by treatment (lasmiditan 200 mg co-administered with sumatriptan (lmitrex) 100 mg, 
lasmiditan 200 mg co-administered with lasmiditan placebo 200 mg, or sumatriptan 
(lmitrex) 100 mg co-administered with lasmiditan placebo 200 mg) and subject number, 
including demographic information and flagging of values. 
8.7 Interim Analyses 
No formal interim analysis is planned for this study. 
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February 17, 2017 
9. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
9.1 
Study Monitoring 
The investigator will allow the Sponsor or a designee to: 
• 
inspect the site, the facilities, and the material used for the study; 
• 
meet all members of the team involved in the study; 
• 
consult all the documents relevant to the study; 
• 
check that the CRFs have been correctly completed; 
• 
have direct access to source documents for comparison of data therein with the data 
in the CRFs; 
• 
check that AEs have been documented; and 
• 
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 or designee will provide the sponsor with the following: 
• 
Progress reports at regular intervals 
• 
Adequately completed CRFs 
9.2 
Data collection 
The Investigational site will be supplied with instructions on completing the CRFs. 
Designated site staff will enter the data with respect to protocol procedures, drug 
administration, laboratory data, and safety data on the CRFs. 
Completed and reviewed CRFs must be available for monitoring and collection by the 
monitor at the end of the study. 
All corrections on a CRF and on source data/documents must be made in a way which 
does not obscure the original entry. The correct data must be inserted, dated and 
initialed by relevant, authorized study site personnel. If the reason for the correction is 
not obvious, an explanation should be provided. 
The Principal Investigator must, as a minimum, sign the final CRF page to attest to the 
accuracy and completeness of all the data. 
9.3 
Audits and Inspections 
If the Sponsor chooses to conduct an audit before, during, or after the study, the 
Investigator or designee will be informed that an audit will take place. 
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The Investigator will be informed that the Regulatory Agencies may also carry out an 
inspection. In this case, the Investigator or designee 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; 
• 
consult all the documents relevant to the study. 
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10. QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator or the appointed persons agree to complete the subject's CRF at each 
investigation. Only the Investigator or appointed persons in his/her team may fill out or 
correct the CRFs. The CRFs will display the subject number corresponding to the order 
of inclusion in the study (3 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 CRFs 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. 
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 CRFs must be made by the Investigator or 
by the appointed persons as instructed in the CRF 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 designee. 
It is the responsibility of the monitor to make certain that all data are completed on the 
CRFs. 
At the end of each study period, the Investigator and the monitor must sign and date the 
CRF per the CRF procedure in order to attest respectively to the: 
• 
authenticity of the data collected in the CRF, and 
• 
coherence between the data in the CRF 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 MedORA 
terminology. 
ECGs will be processed at the Phase 1 unit. Clinical laboratory samples will be 
processed through the laboratory at the Phase 1 unit. 
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. 
The Investigator or designee 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 Sponsor or their designee as 
defined in the study manual. The Investigator or designee must submit to the Sponsor 
or its representatives a completed CRF for each subject who receives any study drug. 
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If computerized medical files are used and if the computer system allows, no change 
made in the medical files by the Investigator or designee 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 or designee 
will save data at regular intervals. 
The Investigator or designee 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. 
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11. ETHICS 
The study will be carried out in accordance with: 
IND 103,420 
February 17, 2017 
• 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. 
11.1 Ethics Review 
11.1.1 IRB opinion 
Before initiation of the study, the Investigator or designee 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 (IRB) before study start. A signed and dated statement that the protocol, 
informed consent, and advertisement (as applicable) have been approved by the IRB 
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 or designee is responsible for obtaining continued review of the study 
at intervals not exceeding one year or otherwise specified by the IRB. The Investigator 
or designee must supply Colucid Pharmaceuticals, Inc. with written documentation of 
continued review of the clinical study. 
The Investigator or designee must promptly inform their IRB of all SAEs or other safety 
information reported from Sponsor. 
11.2 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 
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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 or designee 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. 
A copy of the approved version must be provided to the Colucid monitor or designated 
representative(s) after IRB approval. 
11.3 Amendments to the protocol 
To alter the protocol, amendment approvals must be received from all parties that 
approved the original protocol (IRB 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 approval. Notwithstanding the 
need for approval of formal protocol amendments, the investigator or designee 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 Pharmaceuticals 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. 
11.4 Discontinuation of the study 
Colucid Pharmaceuticals reserves the right to discontinue this study under the 
conditions specified in the clinical trial agreement. 
11.5 Study drug supply, storage and tracking 
Study drug 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, study drug should be stored 
according to the instructions specified on the drug labels. Drug labels will be in the local 
language and will comply with the legal requirements of the country. Clinical supplies 
are to be dispensed only in accordance with the protocol. 
All empty packaging, partially used containers, and unused supplies may be destroyed 
at the site, retrieved by the study monitor, or shipped to a designated facility approved 
by Colucid Pharmaceuticals 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. 
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The Investigator or designee 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. 
11.6 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 Pharmaceuticals. 
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 Pharmaceuticals, or its designated representative, by 
their initials and/or assigned subject number. Documents that identify the subject (e.g., 
the signed informed consent form) will not be submitted to Colucid Pharmaceuticals or 
its designated representative and must be maintained in confidence by the Investigator 
and designee. 
11.7 Publication policy 
Publication by the study site 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 Investigator, in accordance with 
current guidelines and requirements of medical journals. 
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12. ADMINISTRATIVE CONSIDERATIONS 
12.1 Investigator and Study Administrative Structure 
The study admini
stration structure is provi
ded in Table 4. 
Table 4: Study Administrative Structure 
CPC Principal Investigator: 
Sponsor Contact: 
Medical Monitor: 
Study Monitoring (CRA): 
PK Sample Analyses and Bioanalytical Report 
Data Managem ent, & Statistical Analyses: 
Safety Clinical Laboratory Testing: 
Clinical Trial Drug Supply: 
, MD 
SNBL CPC 
800 W . Baltimore St., 61h Floor 
Baltimore, Maryland 21201, USA 
 
 
Head Clinical and Regulatory Operations 
Co Lucid Pharmaceuticals, Inc 
. 
222 Third Street, suite 1320 
Cambridge, MA 02142 
 
, MD 
 
 
 
 
 
 
Senior Principal Investigator 
Bioanalytical Chemistry 
Covance Laboratories, Inc. 
3301 Kinsman Boulevard 
Madison, WI 53704-2523 
E-Mail: 
 
Phone: 
 
Fax: 
 
 
3 Independence Way Suite 106 
Princeton, NJ 08540 
SNBL CPC 
800 W 
. Baltimore St., 51h Floor 
Baltimore 
, Maryland 21201, USA 
 
Cata 
lent Pharma Solut
ions 
10245 Hickman Mills Drive 
Kansas City, MO 64137 
USA 
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12.2 Records Retention 
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After the study, the Investigator or designee will keep all information relevant to the 
study for 15 years. 
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13. REFERENCES 
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1. 
SteinerT J, Stovner LJ, Birbeck GL, Migraine: The seventh disabler. J Headache 
and Pain 2013;14:1-2. 
2. 
Buse DC, Serrano D, Pearlman SH, Ng-Mak OS, 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 OW, 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. 
Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, et 
ai.,Preclinical pharmacological profile of the selective 5-HT1 F receptor agonist 
lasmiditan. Cephalalgia 2010;30(10):1159-1169. 
5. 
Shepheard S, Edvinsson L, Cumberbatch M, Williamson D, Mason G, Webb J, et 
ai.,Possible antimigraine mechanisms of action of the 5HT1 F receptor agonist 
LY334370. Cephalalgia 1999;19(10):851-858. 
6. 
Goadsby PJ, Glassey JD, Evidence for serotonin (5-HT)1 B, 5-HT1 D and 5-HT1 F 
receptor inhibitory effects on trigeminal neurons with craniovascular input. 
Neuroscience 2003; 122(2):491-498. 
7. 
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. 
8. 
E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-antiarrhythmic Drugs: Guidance to Industry, 2005. 
9. 
Co lucid Pharmaceuticals, Inc. Clinical Study Report: A Study of Two Doses of 
Lasmiditan (1 00 mg and 200 mg) compared to Placebo in Acute Treatment of 
Migraine: A randomized, double-blind, placebo-controlled parallel group study 
(SAMURAI). 
10. Colucid Pharmaceuticals, Inc. COL-144 Investigator Brochure, Version 8.0, 23 
February 2016. 
11. Marean ME, de WitH, King AC, et al., The Drug Effects Questionnaire: 
Psychometric Support across Three Drug Types. Psychopharmacology (Berl) 
2013; 227:177-192. 
12. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
published June 14, 2010. US Department of Health and Human Services, NIH, 
National Cancer Institute. 
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15. 
Appendix 2. Visual Analogue Scales (VAS) 
Bipolar Drug liking 
At this moment, my liking for the drug is: 
0 
Strong disliking 
Bipolar High 
I am feeling high 
0 
Definitely not 
50 
Neither liking nor 
disliking 
50 
Neutral 
100 
Strong liking 
100 
Definitely so 
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Unipolar Sedation 
At this moment, I am feeling ... 
0 
Alert 
Unipolar Overall Drug Liking 
Overall, my liking for the drug is ... 
0 
Strong disliking 
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100 
Drowsy 
100 
Strong liking 
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Unipolar Take drug again 
I would take this drug again 
0 
Definitely not 
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100 
Definitely so 
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VAS Training Scales 
Bipolar: Last night, I slept ... 
0 
50 
Very badly 
Neither well nor badly 
Bipolar: My dinner last night was ... 
0 
The worse I have ever 
had 
50 
Neither good nor bad 
Unipolar: The weather yesterday was great 
0 
Definitely not 
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100 
Very well 
100 
The best I have ever 
had 
100 
Definitely so 
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SAP_001.pdf: 
Statistical Analysis Plan H8H-CD-LAHI 
 
 
 
A Randomized, Double-Blind, Three Period, Cross-Over Study to Evaluate the Effect of Single 
Oral Doses of Lasmiditan when Coadministered with Single Oral Doses of Sumatriptan (lmitrex) 
in Healthy Male and Female Subjects 
 
NCT03076970  
 
Approval Date: 24-May-2017 
 
 
 


COLUCID PHARMACEUTICALS INC 
Statistical Analysis Plan 
PROTOCOL: 
COL-MIG-I 18 
Version: 
Final 1.0 
Date: 
24/May/20 17 
A Randomized, Double-Blind, Three Period, Cross-Over 
Study to Evaluate the Effect of Single Oral Doses of 
Lasmiditan when Coadministered with Single Oral Doses of 
Sumatriptan (lmitrex) in Healthy Male and Female Subjects 
 
 
I 
PPD
Date 
(dd-mmm-yyyy) 
Date 
( 
dd-mmm-yyyy) 
Date 
( 
dd-mmm-yyyy) 
Date 
(dd-mmm-yyyy) 
PPD


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Statistical Analysis Plan  
Study Code COL-MIG-118 
Version Final 1.0 
Date 24/May/2017 
2   
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ....................................................................................................... 1 
TABLE OF CONTENTS ..................................................................................... 2 
LIST OF ABBREVIATIONS .............................................................................. 4 
1. 
INTRODUCTION ............................................................................................... 6 
2. 
STUDY DETAILS ............................................................................................... 6 
2.1 
Study Objectives .................................................................................................. 6 
2.2 
Study Design........................................................................................................ 6 
3. 
DATA ANALYSIS CONSIDERATIONS ........................................................... 7 
3.1 
Determination of Sample Size .............................................................................. 7 
4. 
STUDY ENDPOINTS ......................................................................................... 7 
4.1 
Pharmacodynamic (PD) Endpoint ........................................................................ 7 
4.2 
Pharmacokinetic (PK)Endpoints........................................................................... 7 
4.3 
Safety Endpoints .................................................................................................. 8 
5. 
DEFINITIONS .................................................................................................... 8 
6. 
STATISTICAL METHODOLOGY ................................................................... 10 
6.1 
General Considerations ...................................................................................... 10 
6.2 
Analysis Populations .......................................................................................... 10 
6.2.1 
Safety Population ............................................................................................... 10 
6.2.2 
PD Population .................................................................................................... 11 
6.2.3 
PK Population .................................................................................................... 11 
6.3 
Coding Dictionaries Used .................................................................................. 11 
6.4 
Analysis Methods............................................................................................... 11 
6.4.1 
Study Subjects Disposition ................................................................................. 11 
6.4.2 
Demographic and Baseline Characteristics ......................................................... 11 
6.4.3 
Medical History/ Surgical History/Hospitalization ............................................. 12 
6.4.4 
Prior and Concomitant Medications ................................................................... 12 
6.4.5 
Protocol Deviations ............................................................................................ 12 
6.4.6 
Study Drug Administration ................................................................................ 12 
6.4.7 
Pharmacodynamic Analysis ............................................................................... 12 
6.4.8 
Pharmacokinetic Analysis .................................................................................. 14 
6.4.9 
Plasma PK Concentrations ................................................................................. 14 
6.4.9.1 
PK Parameter Estimation ................................................................................... 14 


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6.4.9.2 
Pharmacokinetic Statistical Inference ................................................................. 15 
6.4.10 
Safety Analysis .................................................................................................. 15 
6.4.10.1 Clinical Laboratory Parameters .......................................................................... 15 
6.4.10.2 Electrocardiogram (ECG)................................................................................... 17 
6.4.10.3 Physical Examination ......................................................................................... 17 
6.4.10.4 Columbia Suicide Severity Rating Scale (C-SSRS) ............................................ 17 
6.4.10.5 Visual Analogue Scale (VAS) ............................................................................ 18 
6.4.10.6 Drug Effects Questionnaire (DEQ-5) ................................................................. 18 
7. 
REFERENCES .................................................................................................. 18 
8. 
APPENDICES ................................................................................................... 19 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
ALT 
Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
ATC 
Anatomic-Therapeutic-Chemical 
AUC 
Area Under the Plasma Concentration Versus Time Curve 
AUC(0-last) 
Area under the plasma concentration versus time curve 
from time 0 to last post-dose 
AUC(0-) 
Area under the plasma concentration versus time curve 
from time 0 to infinity 
BMI 
Body Mass Index 
BQL 
Below Quantification Limit 
CBC 
Complete Blood Count 
Cmax 
Maximum Measured Plasma Concentration 
CPK 
Creatine Phosphokinase 
CRU 
Clinical Research Unit 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
CYP3A4 
Cytochrome P450 3A4, an enzyme 
DDI 
Drug-Drug Interaction 
DEQ-5 
Drug Effects Questionnaire 
ECG 
Electrocardiogram 
eGFR 
Glomerular Filtration Rate 
EOS 
End of Study 
eCRF 
Electronic Case Report Form 


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Abbreviation 
Definition 
EW 
Early Withdrawal 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HDL 
High-Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
IMP 
Investigational Medicinal Product 
LDL 
Low-Density Lipoprotein 
LOQ 
Limit of Quantification 
LS 
Least-Squares 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PKE 
Pharmacokinetic Evaluation 
RBC 
Red Blood Cell 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment Emergent Adverse Event 
t1/2 
Apparent terminal elimination half-life 
THC 
Tetrahydrocannabinol 
Tmax 
Time to Reach Maximum Measured Plasma Concentration 
VAS 
Visual Analog Scale 
Vd/F 
Apparent Volume of Distribution 
WBC 
White Blood Cell 
WHO 
World Health Organization 
λz 
Apparent First-Order Terminal Elimination Rate Constant 
 


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1. 
INTRODUCTION 
Lasmiditan is being developed as a novel acute therapy for migraine. Migraine is a common 
neurological disorder and was ranked by the World Health Organization (WHO) in its 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. Five Phase 1 studies have 
been completed in Europe using intravenous (IV), sublingual, and oral formulations of 
Lasmiditan. This study is designed to assess the effect of single doses of Sumatriptan (Imitrex) 
100 mg on the pharmacodynamics of single doses of Lasmiditan 200 mg as measured by serial 
vital signs, ECGs, and adverse events.  Safety and tolerability will also be reported. 
The purpose of this statistical analysis plan (SAP) is to provide all details and specifications 
for the analysis of the study COL MIG-118, "A Randomized, Double-Blind, Three Period, 
Cross-Over Study to Evaluate the Effect of Single Oral Doses of Lasmiditan when Co-
administered with Single Oral Doses of Sumatriptan (Imitrex) in Healthy Male and Female 
Subjects’ " as set forth in the clinical study protocol version 1.0 dated 17 February 2017.  
2. 
STUDY DETAILS 
2.1 
Study Objectives 
The study objectives are: 
 
Primary Objective- To compare and contrast the pharmacodynamics of Lasmiditan 
200 mg and Sumatriptan (Imitrex) 100 mg administered together to the pharmacodynamics of 
single doses of either drug administered alone. 
Secondary Objective- 
 To compare and contrast the pharmacokinetics of Lasmiditan 200 mg and Sumatriptan 
(Imitrex) 100 mg administered together to the pharmacokinetics of single doses of 
either drug administered alone. 
 To evaluate the safety and tolerability of Lasmiditan 200 mg and Sumatriptan 
(Imitrex) 100 mg administered together to the safety and tolerability of single doses of 
either drug administered alone. 
 To compare and contrast the subjective drug effects of Lasmiditan 200 mg and 
Sumatriptan (Imitrex) 100 mg administered together to the subjective drug effects of 
single doses of either drug administered alone. 
 
2.2 
Study Design 
This is a Phase 1, single-center, randomized, double-blind, three-period, cross-over study to 
investigate the effect of single doses of Sumatriptan (Imitrex) 100 mg on the 


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pharmacodynamics of single doses of Lasmiditan 200 mg.  A total of 42 subjects will be 
enrolled to ensure at least 36 subjects complete the study with approximately 60% females.  
The three dosing periods are as follows- 
 A:  Lasmiditan 200 mg co-administered with Lasmiditan 200 mg placebo 
 B:  Sumatriptan (Imitrex) 100 mg co-administered with Lasmiditan 200 mg placebo 
 C:  Lasmiditan 200 mg co-administered with Sumatriptan (Imitrex) 100 mg 
Subjects are randomized using the William square design into one of the six treatment 
sequences ABC, ACB, BAC, BCA, CAB, CBA. 
The study will last approximately 6 weeks including up to 3 weeks for screening and 22 days 
on study.  Screening will be conducted within approximately 21 days of the first dose of study 
medication.  Each dosing period will last 3 days (Day -1, Day 1, and Day 2).  A wash-out 
period of 6 days will take place between each dose.  The End of Study Visit (EoS) will take 
place 5 (+/- 2) days after the third dosing period is completed. 
3. 
DATA ANALYSIS CONSIDERATIONS 
3.1 
Determination of Sample Size 
The sample size calculation for this study is based on the proportion of adverse events in the 
two treatment groups namely the combination therapy (Lasmiditan + Sumatriptan) vs a single 
drug (Lasmiditan). The calculation is performed using a test for two proportions in a repeated 
measures design. To ensure that at least 36 subjects complete, 42 subjects (approximately 60% 
female) will be enrolled.  
The sample size of 36 subjects will provide at least 80% power to show equivalence of the PK 
of Lasmiditan in the absence and presence of Sumatriptan (Imitrex), assuming a 25% within 
subject coefficient of variance.  
4. 
STUDY ENDPOINTS 
4.1 
Pharmacodynamic (PD) Endpoint 
Adverse Event and Vital Signs are considered as the pharmacodynamic endpoints in this 
study. All other PD endpoints will be considered under safety. 
4.2 
Pharmacokinetic (PK)Endpoints 
Pharmacokinetic endpoints will include: 
 Cmax - maximum measured plasma concentration 
 Tmax - time to reach maximum measured plasma concentration 
 AUC(0-tlast) - area under the plasma concentration versus time curve from time 0 to 
last measurable concentration. 


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 AUC(0-)- area under the plasma concentration versus time curve from time 0 to 
infinity 
 t1/2 - terminal phase half-life. 
 CL/F- Apparent total clearance of the drug from plasma. 
 Vz/F- Apparent volume of distribution during terminal phase. 
 λz - terminal rate constant. 
 
These PK parameters will be derived from Lasmiditan plasma concentration, Sumatriptan 
plasma concentration as well as the combination of Lasmiditan and Sumatriptan versus 
time curves following dosing on Day 1 (pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 
16, 24 and 30 h following the dose at time 0 in each dosing period). 
4.3 
Safety Endpoints 
Safety will be assessed by physical examinations, standard 12-lead ECGs, clinical 
laboratory tests (clinical chemistry panel, CBC, and urinalysis), Columbia Suicide severity 
rating scale (C-SSRS), DEQ-5, Visual Analogue scales (VAS) and collection of adverse 
events.  
 
5. 
DEFINITIONS 
AUC(0-tlast) 
Area under the concentration-time curve from time zero (pre-dose) to time t of the last 
quantifiable concentration of each dose of Lasmiditan, Sumatriptan or 
(Lasmiditan+Sumatriptan) calculated by means of the mixed log-linear trapezoidal rule. 
 
AUC(0-) 
Area under the plasma concentration vs. time curve from time 0 to infinity, calculated as 
AUC = AUC0–t + AUCextra. AUCextra represents an extrapolated value obtained by C 
/λz, where C is the predicted concentration at time t at or above LOQ, and λz is the 
estimated apparent terminal rate constant. 
 
%AUCextrap 
Area under the plasma concentration-time curve extrapolated from time t to infinity as a 
percentage of total AUC. 


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Cmax 
Maximum concentration in plasma following each dose of Lasmiditan, Sumatriptan or 
(Lasmiditan+Sumatriptan), obtained directly from the observed concentration versus time 
data. 
 
λz  
Apparent terminal elimination rate constant, determined from the slope of the log-transformed 
plasma concentration curve. 
 
CL/F 
Apparent total clearance of the drug from plasma. 
Vz/F 
Apparent volume of distribution during terminal phase. 
 
t1/2 
Apparent terminal elimination half-life , is determined as ln(2)/λz. 
 
Tmax 
Time to maximum plasma concentration. 
 
Study Day  
This is the number of days from the date of the first study drug administration: 
Study Day = (Target Date - Date of the first study drug administration) + 1 if target date is 
greater than or equal to the date of the first study drug administration or 
Study Day = (Target Date - Date of the first study drug administration) if target date is less 
than date of the first study drug administration. 
 
Baseline 
Baseline is defined as the latest assessment prior to the first study drug administration within 
each period unless otherwise specified. If the assessment occurs on the same date as the dose 
administration, then the time of assessment should be compared to the time of dose 
administration. If time is not available, protocol schedule of events should be considered.  


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6. 
STATISTICAL METHODOLOGY 
6.1 
General Considerations 
All pharmacokinetic evaluations will be performed using non-compartmental methods in 
Phoenix® WinNonlin® version 6.4 or higher (Pharsight Corporation, Mountain View, 
California, USA). All statistical evaluations will be conducted using SAS® version 9.3 or 
higher (SAS® Institute, Cary, North Carolina). All tables, figures and listings will be 
produced in landscape format.  
The term “study drug” may refer to either Lasmiditan or Sumatriptan (or both Lasmiditan and 
Sumatriptan together). 
In general, all data will be listed by subject, period, treatment and visit/time point where 
appropriate. The total number of subjects in the study group (N) under the stated population 
will be displayed in the header of summary tables. 
Data will be summarized using descriptive statistics for continuous variables. Unless 
otherwise specified, descriptive statistics will include number of subjects, mean, standard 
deviation, minimum, median and maximum. In case of n<2, where n indicates the number of 
evaluable subjects at the particular time point, the standard deviation will be empty. The 
minimum and maximum statistics will be presented to the same number of decimal places as 
the original data. The mean and median will be presented to one more decimal place than the 
original data, whereas the standard deviation will be presented to two more decimal places 
than the original data.  
In summary tables of categorical variables, counts and percentages will be used. The count [n] 
indicates the actual number of subjects with a particular value of a variable or event, which 
should always be less than or equal to the total number of subjects with non-missing value of 
the variable or event in the respective study group [M]. 
Percentage will be obtained by: % = (n/M)*100. Unless otherwise stated, all percentages will 
be expressed to one decimal place. 
The closest non-missing measurement (whether from scheduled or unscheduled visit) taken 
prior to the first study drug administration within each period will be considered as the 
baseline value. The change from baseline values will be derived for each subject as the post-
baseline evaluation minus the baseline evaluation within each period. 
All dates will be displayed in DD/MMM/YYYY format. 
6.2 
Analysis Populations 
The analysis populations defined in this study are as follows: 
6.2.1 
Safety Population 
Safety population will consist of all subjects who received any amount of study medication 
(Lasmiditan or Sumatriptan). The safety population will be used for all safety analyses. 


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6.2.2 
PD Population 
Pharmacodynamic (PD) population will consist of all subjects who received a single dose of 
study medication (Lasmiditan or Sumatriptan) and have completed at least one treatment 
period.  
6.2.3 
PK Population 
Pharmacokinetic (PK) population will consist of all subjects who completed at least one 
treatment period without any protocol violations, who have evaluable plasma concentration 
data for Lasmiditan and/or Sumatriptan (Imitrex), and for whom at least a subset of the 
designated PK parameters can be determined.  
The reason for excluding a subject from the PK population will be documented. 
The PK population will be used for all PK analyses. 
6.3 
Coding Dictionaries Used  
Adverse event and medical history verbatim terms provided by the investigator will be coded 
using the Medical Dictionary for Drug Regulatory Affairs (MedDRA, version 20.0). The 
resultant primary system organ class and preferred term will be used for AE summaries and 
medical history listing.   
Prior and concomitant medication generic terms provided by the investigator will be coded per 
WHO Drug Insight and classified by preferred terms and ATC classes. The resultant ATC 
class and preferred term will be used for prior and concomitant medication listings. 
6.4 
Analysis Methods 
6.4.1 
Study Subjects Disposition  
Subject disposition will be tabulated by an overall summary of the number of subjects who 
were randomized into the study, completed all treatment periods, were included into the 
safety, PK population and PD population, completed the study and prematurely discontinued 
(with breakdown by reason for early discontinuation). The summary will be based on all 
enrolled subjects.  
A listing will be presented to describe whether the subject completed the study, date of 
completion or early withdrawal, and the reason for early discontinuation, if applicable. A 
listing will also be provided to describe when informed consent was obtained and if the 
subject meets all inclusion/exclusion criteria. The date of consent and reason for entry criteria 
violation, if any, will be presented. 
6.4.2 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics such as age, sex, race, ethnicity, height (cm), weight 
(kg) and BMI (kg/m2) will be summarized overall and by sequence. The summary will be 
based on the safety populations. 


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Descriptive statistics will be presented for age, height, weight and BMI. Frequency counts and 
percentage will be presented for sex, race and ethnicity. 
The demographic and baseline characteristic data will also be presented as a data listing.  
6.4.3 
Medical History/ Surgical History/Hospitalization 
Medical history details as collected on the eCRF such as category, description, the date of 
onset and stop date will be presented in a by-subject data listing. History of 
surgery/hospitalization might be included in the medical history or presented as a separate 
listing. 
6.4.4 
Prior and Concomitant Medications 
All information on concomitant therapy (including all prescription/non-prescription 
medications, herbal medications and vitamin supplements) taken within 30 days prior to the 
informed consent and during the study must be recorded on the subject’s eCRF and should 
include the name of the procedure or drug and duration of the treatment (start and stop dates). 
Concomitant treatments (non-pharmacological treatments) include any surgical or diagnostic 
procedures. Non-pharmacological treatments would not be listed. 
Prior medications are defined as those taken only before the date of the first dose of the study 
medication i.e. stopped before the start of the study medication. Concomitant medications are 
defined as any non-study medication taken during the course of the study i.e. on or after the 
date of the first dose of the study medication. Additionally, the medications will be 
considered concomitant if the start and stop date of the medication are missing (not 
available). 
Prior and concomitant medication information will be presented in a by-subject listing with 
anatomical-therapeutic-chemical (ATC) classification and WHO Drug Dictionary preferred 
term, start and stop date, dosage, route, frequency and indication. 
6.4.5 
Protocol Deviations  
The study site will record all deviations occurred through the study and all protocol deviations 
will be listed by subject.  
6.4.6 
Study Drug Administration 
The study medication administration details including the dosing date and time, dose, fasting 
status will be presented in a by-subject listing.  
The number and percentage of subjects receiving each of the 3 scheduled treatments will be 
presented by treatment group.  
6.4.7 
Pharmacodynamic Analysis 
Pharmacodynamic analysis will involve the analysis of all adverse events (AE) and the 
analysis of vital signs. All AEs and vital signs data will be listed and summarized. 


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Adverse Events 
Adverse Events will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA version 20.0) AE coding system for purpose of summarization.  
An AE will be defined as treatment-emergent (TEAE) if its time of onset or worsening is on 
or after the time of the study drug administration. 
An AE will be defined as treatment related if its relationship to the study drug is recorded as 
Possibly Related or Related on the eCRF. 
An overall summary of number of events and number and percentage of subjects with at least 
one AE, TEAE, serious TEAE, treatment-related TEAE, serious treatment-related TEAE and 
TEAE leading to discontinuation will be presented. 
A summary of the frequency (number and percentage of subjects with events) of TEAEs will 
be presented by system organ class, preferred term, and treatment group. Adverse events will 
also be analyzed by their severity (mild, moderate, severe, life threatening or fatal) and 
relationship to study drug (related or not related).  
A subject experiencing the same AE multiple times will be counted only once for that 
preferred term. Similarly, if a subject experiences multiple AEs (preferred terms) within the 
same system organ class then that subject will be counted only once for that system organ 
class. When summarizing by severity and relationship, only event with highest severity or 
relationship will be counted. All AEs will be presented in alphabetical order of system organ 
classes and preferred terms. 
All information pertaining to adverse events noted during the study will be listed by subject, 
detailing verbatim term given by the investigator, preferred term, system organ class, start 
date, stop date, severity, outcome, action taken and drug relatedness. Separate listings will be 
created for Serious TEAEs and TEAEs leading to study drug discontinuation if deemed 
necessary. 
Vital Signs/Orthostatic Vital Signs 
Vital signs will be obtained at Screening, Day -1, Day1 (predose, 1hr, 2hr, 4hr, 8hr, 24hr post 
dose) and Day 2 of each period.  
Vital signs will include body temperature, respiratory rate, heart rate and systolic and diastolic 
blood pressure.  
Orthostatic vital signs will be obtained at Screening and Day 1 (predose, 1hr, 2hr) of each 
period and may or may not include all the vital parameters. 
Height, weight and BMI will be measured only at the Screening Visit only. 
Actual values of vital signs and changes from baseline will be summarized using descriptive 
statistics by treatment and time point. Only subjects with both non-missing baseline and time 
point values will be summarized at each time point. 
 
 


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6.4.8 
Pharmacokinetic Analysis 
Calculation of PK parameters will be performed using Phoenix® WinNonlin® version 6.4 (or 
later). Statistical analysis and generation of summary tables and listings will be performed in 
SAS. 
All PK analyses will be performed on the PK population. 
6.4.9 
 Plasma PK Concentrations 
Blood samples for determination of plasma concentrations will be collected on Day1 and Day 
2 for each treatment period and at the time points indicated in the following table: 
Day(s)  
PK Collection Time Points  
Day 1  
Pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5,3, 
4, 6, 8, 12, and 16, hours post-dose  
Day 2  
24 and 30 hours following the Day 1 
dose of IMP  
Plasma concentrations that are below quantification limits (BQL) will be treated as follows in 
the pharmacokinetic analyses and clearly identified in listings. 
1.       If it is a leading BQL - treat as 0 (zero) 
2.       If it a middle BQL - treat missing value (depending on the situation)  
3.       If it is a tailing BQL, treat as missing valve.   
Descriptive statistics of Lasmiditan, and Sumatriptan plasma concentrations will be presented 
for each treatment period and timepoint. The statistics will additionally include geometric 
mean and CV (%). All plasma concentrations will be listed. 
Figures (linear and semi-logarithmic) illustrating the relationship between time after study 
drug administration and plasma drug concentrations will be created for each subject and for 
the mean results. 
6.4.9.1 
PK Parameter Estimation 
Pharmacokinetic parameters Cmax, Tmax, AUC0-tlast, AUC0-inf, t1/2, λz, CL/F, Vz/F will be 
estimated.  The exact time of sample collection, relative to time of dose, will be used in the 
analyses. No imputation of missing samples will occur. If a scheduled sample’s concentration 
is missing, the pharmacokinetic analyses will be conducted as if that sample had not been 
scheduled for collection. The time of dosing will be considered as time 0 and the pre-dose 
assessment will be treated as if it occurred at time 0. Any subject with sufficient data to 
adequately characterize their concentration-time profile will be included in the 
pharmacokinetic analyses. If the terminal half-life for any case is physiologically implausible, 
and a suitable set of terminal concentrations cannot be selected from the semi logarithmic 
concentration-time plot, then no elimination parameter estimates will be reported.  t1/2 can 
only be estimated for those cases where the apparent elimination rate constant has been 
estimated. 
Descriptive statistics will be presented for each PK parameter for each study medication by 
treatment period (Lasmiditan and, Sumatriptan). All PK parameters will be listed. 


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6.4.9.2 
Pharmacokinetic Statistical Inference 
The PK parameters, Cmax and AUC0-tlast and AUC0-∞ will be the primary PK analysis 
variables. An ANCOVA model will be fit for log-transformed PK parameter (Cmax or 
AUC0-tlast AUC0-∞ separately) as the outcome, with the fixed effect of treatment group. From 
this model, least square (LS) Means for each treatment and LS Mean differences to the 
reference drug Lasmiditan will be estimated with the corresponding 90% confidence intervals. 
These estimates will then be exponentiated to produce the estimates of geometric mean ratios 
(Combination vs standalone PK for lasmiditan and sumatriptan) with their 90% confidence 
intervals. It will be concluded that the IMP has no effect on PK, if 90% confidence intervals 
for combination/standalone is within the 80-125% interval.  
6.4.10 
Safety Analysis 
All safety data will be listed and tabulated. The analysis will be performed on the Safety 
population. 
Safety parameters include adverse events, laboratory parameters, vital signs, ECG, physical 
examination findings, C-SSRS and DEQ-5 and VAS. 
 
6.4.10.1 Clinical Laboratory Parameters 
The clinical laboratory tests will be obtained at Screening, Day -1 of each treatment period, 
and end of study. The following laboratory evaluations will be performed. 
 


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Hematology 
Serum Chemistry 
RBC 
Hematocrit 
Hemoglobin 
Mean corpuscular 
hemoglobin 
(MCH) 
Mean corpuscular volume 
(MCV) 
Mean corpuscular 
hemoglobin concentration 
(MCHC) 
Platelet count 
WBC count (with 
differential) 
      Neutrophils 
(granulocytes) 
      Lymphocytes  
      Monocytes 
      Basophils  
      Eosinophils  
Creatinine 
Potassium (K+) 
Sodium (Na+) 
Chloride (Cl-) 
Magnesium (Mg++) 
Glucose 
Urea 
Bilirubin (Total) 
Bilirubin (direct) 
eGFR 
AST 
ALT 
AP 
Total Protein 
Albumin 
CO2 
Urinalysis:  Macroscopic examination routinely including specific gravity, pH, protein, 
glucose, ketones, blood and urobilinogen.  A microscopic examination will be performed 
if warranted based on macroscopic results. 
Urine drug screen:  A urine sample will be collected and analyzed (positive or negative) 
for drugs of abuse including amphetamine, opiate, cocaine, barbiturates benzodiazepines, 
and marijuana (tetrahydrocannabinol [THC]).   
For the Screening visit only, cotinine will be included in the urine drug screen panel. 
Serology:  Testing for HbsAg, Hepatitis C antibody and HIV 1 and 2 will be performed at 
the screening visit only.  Results of each serology test will be reported as either positive or 
negative. 
For females:  A serum hCG test at the screening visit and EoS, urine hCG test on the day 
of Phase 1 unit admission for each of the three treatment periods (Day -1 of each dosing 
period). 
AST: aspartate aminotransferase; ALT: alanine aminotransferase; AP: alkaline 
phosphatase; HbsAg: hepatitis B surface antigen; hCG: human chorionic gonadotropin; 
HIV: human immunodeficiency virus; RBC: red blood cell; WBC: white blood cell 
 
Laboratory test results for Clinical Chemistry, Hematology and Urinalysis, will be listed and 
summarized descriptively by treatment and visit. There will be no change from baseline 
calculations performed for Laboratory data. 


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Breathalyzer Test- The breathalyzer assessment for breadth alcohol concentration will be 
performed at Screening and Day-1 of each dosing period. A by subject listing of the data will 
be generated. 
All individual subject clinical laboratory test results will be presented in listings by period, 
subject and visit. 
6.4.10.2 Electrocardiogram (ECG) 
ECG will be obtained at Screening, Day 1 (predose, 1hr, 1.5hr, 2hr, 2.5hr, 4hr, 8hr) Day 2 
(24hr) of each treatment period and end of study. 
Standard 12-lead ECGs evaluations will include heart rate and interval information such as 
RR, PQ/PR, QRS, QT, QTcF and QTcB. Overall interpretation (normal, abnormal not 
clinically significant or abnormal clinically significant) will also be recorded. 
For continuous ECG parameters, actual values and changes from baseline will be summarized 
using descriptive statistics by treatment and time point.  For ECG interpretation, the number 
and percentage of subjects will be summarized by treatment and time point.  Additionally, a 
shift table from baseline to Day 2 will be presented for each treatment. 
All ECG data will be provided as a by-subject listing. 
6.4.10.3 Physical Examination 
Complete physical examination will be performed at Screening and end of study. A brief 
targeted physical examination will be performed if indicated by an AE during each dosing 
period.  
Physical examination will include the assessment of general appearance, head, eyes, ears, 
nose, throat (HEENT), thyroid (endocrine), heart, chest, lungs, abdomen, skin, neurological, 
extremities, and back. Each body system will be assessed as normal, abnormal not clinically 
significant or abnormal clinically significant. 
Physical examination findings will be summarized by visit and body system. The number and 
percentage of subjects with normal, abnormal not clinically significant and abnormal 
clinically significant findings will be presented for each body system. 
All physical examination data will be provided in a listing. 
6.4.10.4 Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS will be performed at screening with the screening/baseline version of the form. The 
‘Since last visit’ version would be used in each dosing period at Day-1, Day 2 and end of 
study. A by subject listing and summary table for C-SSRS will be generated only for positive 
responses to any questions in the C-SSRS. If there are no positive responses, there will be a 
line indicating ‘None of the study subjects responded with a positive response’ for the listing 
and summary table.  


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6.4.10.5 Visual Analogue Scale (VAS) 
VAS scales will be administered on 100mm scales as per the protocol. The following VAS 
scales will be performed and subjects will be trained on Day-1 of each period.  
1. Bipolar drug liking 
2. Bipolar High VAS 
3. Unipolar sedation 
4. Unipolar overall drug liking VAS 
5. Unipolar take drug again VAS 
All VAS data will be provided as a by-subject listing and summarized by period, treatment 
and visit. 
6.4.10.6 Drug Effects Questionnaire (DEQ-5) 
The DEQ-5 will be completed as per the protocol. All DEQ-5 data will be provided as a by-
subject listing and summarized by period, treatment and visit. 
 
7. 
REFERENCES 
1. Steiner TJ, Stovner LJ, Birbeck GL, Migraine: The seventh disabler. J Headache and 
Pain 2013;14:1-2. 
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. CoLucid Pharmaceuticals, Inc. Clinical Study Report:  A Study of Two Doses of 
Lasmiditan (100 mg and 200 mg) compared to Placebo in Acute Treatment of 
Migraine:  A randomized, double-blind, placebo-controlled parallel group study 
(SAMURAI). 
4. CoLucid Pharmaceuticals, Inc. COL-144 Investigator Brochure, Version 8.0, 23  
February 2016.  
5. Morean ME, de Wit H, King AC, et al., The Drug Effects Questionnaire:  
Psychometric Support across Three Drug Types.  Psychopharmacology (Berl) 2013; 
227:177-192. 
6. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, published 
June 14, 2010.  US Department of Health and Human Services, NIH, National Cancer 
Institute. 
 
 


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8. 
APPENDICES 
Schedule of Assessments and Procedures  
 
Screening 
Visit 1 
Dosing Period 1 
Visit 2 
Dosing Period 2 
Visit 3 
Dosing Period 3 
Visit 4 
EoS 
Visit 5 
Day 
–21 to –1 
-1 
1 
2 
-1 
1 
2 
-1 
1 
2 
21 (+/- 2) 
In-house 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Outpatient 
X 
 
 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility/Confirm continued 
eligibility 
X 
X 
 
 
X 
 
 
X 
 
 
 
Demographics, Body Weight, 
Height, Calculate BMI 
X 
 
 
 
 
 
 
 
 
 
 
Medical history review/update 
X 
X 
 
 
X 
 
 
X 
 
 
 
Complete physical examination1 
X 
 
 
 
 
 
 
 
 
 
X 
Targeted  physical exam (symptom 
related, if applicable) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine screen for drugs of abuse2 and 
Breathalyzer test  
X 
X 
 
 
X 
 
 
X 
 
 
 
Hepatitis B/C and HIV-Screen 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test3 
X 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test3 
 
X 
 
 
X 
 
 
X 
 
 
 
12-lead ECG4 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
Vital signs (BP, HR, RR and oral 
temperature)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Orthostatic Vital signs (BP and HR)6 
X 
 
X 
 
 
X 
 
 
X 
 
 
Clinical Laboratory Tests (CBC, 
Chemistry, Urinalysis) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Training on VAS instruments7 
 
X 
 
 
X 
 
 
X 
 
 
 
Bipolar Drug liking VAS 
 
 
X 
 
 
X 
 
 
X 
 
 
Bipolar High VAS 
 
 
X 
 
 
X 
 
 
X 
 
 
Unipolar Sedation VAS 
 
 
X 
 
 
X 
 
 
X 
 
 
DEQ-5 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
Unipolar Overall drug liking VAS 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
Unipolar Take drug again VAS 
 
 
X 
X 
 
X 
X 
 
X 
X 
 


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Screening 
Visit 1 
Dosing Period 1 
Visit 2 
Dosing Period 2 
Visit 3 
Dosing Period 3 
Visit 4 
EoS 
Visit 5 
Day 
–21 to –1 
-1 
1 
2 
-1 
1 
2 
-1 
1 
2 
21 (+/- 2) 
C-SSRS8 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Study drug administration9 
 
 
X 
 
 
X 
 
 
X 
 
 
Adverse events10 
 
X 
Prior / Concomitant medication11 
X 
PK blood sampling12 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
1. Physical examination will include general appearance, skin, HEENT, heart, lymph nodes, lungs, abdomen, extremities/joints, neurological systems, and mental status. 
2. Urine drug screen at screening will include amphetamine, opiate, cocaine, barbiturates, benzodiazepines, cotinine and marijuana (tetrahydrocannabinol [THC]). Urine drug 
screen at D-1 for all periods will include amphetamine, opiate, cocaine, barbiturates, benzodiazepines, and marijuana (tetrahydrocannabinol [THC]). 
3. Serum and urine pregnancy tests will be done on all females. 
4. 12-lead ECGs will be taken after the subject has been supine for at least 5 minutes. ECGs are recorded +/- 15 minutes of the nominal times and at all times after the subject has 
been supine for at least 5 minutes according to the schedule in the Detailed Schedule of Events, Table 2. 
5. Vital signs will be taken after the subject has been supine for at least 5 minutes.  Vitals signs are recorded +/- 15 minutes of the nominal times and at all times, after the subject 
has been supine for at least 5 minutes according to the schedule in the Detailed Schedule of Events, Table 2.   
6. Orthostatic vital signs are recorded after the subject has been at least 5 minutes supine then at least 2 minutes standing and will include systolic blood pressure (SBP), diastolic 
blood pressure (DBP), and heart rate (HR) according to the schedule in the Detailed Schedule of Events, Table 2. 
7. 
Training on VAS scoring will be comprised of three bipolar VAS scales unrelated to drug use that will be administered to each subject at the beginning of each 
period.  The same three scales will be used in all periods. 
8. C-SSRS Screening version will be used at Screening.  On Day -1 and Day 2 of each period and at EoS, C-SSRS Since the last visit version will be used. 
9. Study drug administration on Day 1 at approximately the same time in each period at time 0.  Subjects will fast 10 hours before and 4 hours after study drug administration. 
10. Adverse event collection will start at the time of signing the ICF and continue throughout the study.  Adverse events that occur prior to dosing in period 1 will be recorded as 
medical history. 
11. Prior medications are medications that were being taken within 30 days of signing the informed consent and finished prior to administration of the study drug.  Concomitant 
medications are medications started prior to the start of the study and continued after administration of study drug or started during the study after administration of study 
drug. Blood samples for PK will be taken serially for 30 hours relative to time 0 (dosing) following the schedule in the Detailed Schedule of events, Table 2.  In cases where 
blood sampling for PK analysis and other assessments (vital signs or ECGs) are scheduled to occur at the same time, the order of procedures will be:  5 minutes supine rest, 
ECG, supine vitals followed by standing vitals, and PK blood draw.  Every effort should be made to collect the PK samples at the exact times as specified (Table 2).  Samples 
taken pre-dose and up to and including 8 hours post-dose will be taken +/-5 minutes of the nominal time.  Samples taken after 8 hours post-dose will be taken +/-10 minutes of 
the nominal time. 


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Table 1. 
Detailed Schedule of Events  
Day of each 
Dosing Period 
1 
2 
Hour 
Pre-dose 
0 
0.25 
0.5 
1 
1.5 
2 
2.5 
3 
4 
6 
8 
12 
16 
24 
30 
Targeted physical exam 
(symptom-related, if 
applicable)1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
X2 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
Vital signs (BP, HR, RR and 
Temperature) 
X3 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
Orthostatic vital signs (BP, 
HR) 
X3 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Bipolar Drug liking VAS 
X3 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
Bipolar High VAS 
X3 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
Unipolar Sedation VAS 
X3 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
DEQ-5 
X3 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
Unipolar Overall drug liking 
VAS 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Unipolar Take drug again 
VAS 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
C-SSRS4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events7 
X 
Concomitant Medications8 
X 
PK blood sampling9 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Targeted physical exam to be performed in each period on Day 1 pre-dose, as needed during Days 1 and 2 depending upon emergent symptoms, and on Day 2 at 30 hours +/- 
10 hours. 
2. 
Pre-dose 12-lead ECG to be collected within 75 minutes of dosing. 
3. 
Pre-dose vital signs, orthostatic vital signs, VAS scales, and DEQ-5 to be collected within 60 minutes of dosing.   
4. 
C-SSRS Since the last visit version to be used on Day 2 at 30 hours +/- 10 hours. 
5. 
Randomization to take place in period 1 only 
6. 
Study drug administration on Day 1 at time 0, approximately the same time in each period.  Subjects will fast 10 hours before and 4 hours after study drug administration. 


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7. 
Adverse event collection will start at the time of signing the ICF and continue throughout the study.  Adverse events that occur prior to dosing in period 1 will be recorded as 
medical history. 
8. 
Documentation of concomitant medication use will be made throughout Days 1 and 2 of each period. 
9. 
The pre-dose PK sample will be collected within 60 minutes of dosing.  Blood samples for PK will be taken serially for 30 hours, at pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 
6, 8, 12, 16, 24 and 30 h following the dose at time 0 in each dosing period.  In cases where blood sampling for PK analysis and other assessments (vital signs or ECGs) are 
scheduled to occur at the same time, the order of procedures will be:  5 minutes supine rest, ECG, supine vitals followed by standing vitals, and PK blood draw.  Every effort 
should be made to collect the PK samples at the exact times as specified (Table 2).  Samples taken pre-dose and up to and including 8 hours post-dose will be taken +/- 
5 minutes of the nominal time.  Samples taken after 8 hours post-dose will be taken +/- 10 minutes of the nominal time.