Clinical trial NCT03579940
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2018-06-27; Completion date: 2018-08-09
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of this study is to evaluate the safety and tolerability of lasmiditan in healthy Japanese and Caucasian participants. The study will also investigate how much lasmiditan gets into the bloodstream and how long it takes the body to get rid of lasmiditan when given to Japanese and Caucasians. The study will last up to 47 days for each participant.

Detailed description:

Arms: arm 1: Single (50 milligram (mg), 100 mg, 200 mg, 400 mg) and repeated (2 × 200 mg) doses of Lasmiditan administered orally in up to three of three study periods. arm 2: Single and repeated (2 X placebo) doses of Placebo administered orally in up to one of three study periods. arm 3: Single (50 mg, 100 mg, 200 mg) dose of Lasmiditan administered orally in up to three of three study periods. arm 4: Single dose of Placebo administered orally in up to one of three study periods.
Interventions: intervention 1: Lasmiditan intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol H8H-JE-LAIE 
 
 
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Japanese and Caucasian 
Subjects 
 
NCT03579940 
 
Approval Date: 16-Apr-2018 
 
 
 


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Protocol H8H-JE-LAIE
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in 
Healthy Japanese and Caucasian Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
[lasmiditan (LY573144)], unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act Exemption 4 and 
may not be reproduced or otherwise disseminated without the written approval of Eli Lilly 
and Company or its subsidiaries.
Lasmiditan (LY573144)
Eli Lilly Japan K. K.
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 16-Apr-2018 GMT
PPD


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Table of Contents
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in 
Healthy Japanese and Caucasian Subjects
Section
Page
Protocol H8H-JE-LAIE Safety, Tolerability, and Pharmacokinetics of 
Lasmiditan in Healthy Japanese and Caucasian Subjects.....................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................13
3.1.
Study Rationale............................................................................................................13
3.2.
Background..................................................................................................................13
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................15
5.
Study Design.....................................................................................................................16
5.1.
Overall Design .............................................................................................................16
5.2.
Number of Participants.................................................................................................17
5.3.
End of Study Definition ...............................................................................................17
5.4.
Scientific Rationale for Study Design...........................................................................17
5.5.
Justification for Dose ...................................................................................................18
6.
Study Population...............................................................................................................19
6.1.
Inclusion Criteria..........................................................................................................19
6.2.
Exclusion Criteria ........................................................................................................20
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................22
6.3.
Lifestyle and/or Dietary Requirements .........................................................................23
6.3.1.
Meals and Dietary Restrictions.............................................................................23
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................23
6.3.3.
Activity................................................................................................................23
6.4.
Screen Failures.............................................................................................................23
7.
Treatment..........................................................................................................................24
7.1.
Treatment Administered...............................................................................................24
7.1.1.
Packaging and Labeling .......................................................................................25
7.2.
Method of Treatment Assignment ................................................................................25
7.2.1.
Selection and Timing of Doses.............................................................................25
7.3.
Blinding .......................................................................................................................25


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7.4.
Dose Modification........................................................................................................26
7.5.
Preparation/Handling/Storage/Accountability...............................................................26
7.6.
Treatment Compliance .................................................................................................26
7.7.
Concomitant Therapy...................................................................................................26
7.8.
Treatment After the End of the Study...........................................................................26
8.
Discontinuation Criteria ....................................................................................................27
8.1.
Discontinuation from Study Treatment.........................................................................27
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................27
8.2.
Discontinuation from the Study....................................................................................27
8.3.
Subjects Lost to Follow-up...........................................................................................28
9.
Study Assessments and Procedures ...................................................................................29
9.1.
Efficacy Assessments...................................................................................................29
9.2.
Adverse Events ............................................................................................................29
9.2.1.
Serious Adverse Events........................................................................................30
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................30
9.2.2.
Complaint Handling.............................................................................................31
9.3.
Treatment of Overdose.................................................................................................31
9.4.
Safety...........................................................................................................................31
9.4.1.
Laboratory Tests ..................................................................................................31
9.4.1.1.
Estimated Glomerular Filtration Rate..............................................................31
9.4.2.
Vital Signs ...........................................................................................................31
9.4.3.
Body Weight........................................................................................................32
9.4.4.
Electrocardiograms ..............................................................................................32
9.4.5.
Columbia-Suicide Severity Rating Scale ..............................................................33
9.4.6.
Safety Monitoring ................................................................................................33
9.4.6.1.
Hepatic Safety................................................................................................34
9.5.
Pharmacokinetics .........................................................................................................34
9.5.1.
Bioanalysis...........................................................................................................34
9.6.
Pharmacodynamics ......................................................................................................35
9.7.
Genetics .......................................................................................................................35
9.8.
Biomarkers...................................................................................................................35
9.9.
Health Economics ........................................................................................................35
10.
Statistical Considerations and Data Analysis.....................................................................36
10.1. Sample Size Determination ..........................................................................................36
10.2. Populations for Analyses..............................................................................................36
10.2.1.
Study Participant Disposition ...............................................................................36
10.2.2.
Study Participant Characteristics ..........................................................................36
10.3. Statistical Analyses ......................................................................................................36


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10.3.1.
Safety Analyses....................................................................................................36
10.3.1.1.
Clinical Evaluation of Safety..........................................................................36
10.3.1.2.
Statistical Evaluation of Safety.......................................................................37
10.3.2.
Pharmacokinetic Analyses....................................................................................37
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................37
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................37
10.3.3.
Data Review During the Study.............................................................................37
10.3.4.
Interim Analyses..................................................................................................38
11.
References ........................................................................................................................39


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List of Tables
Table
Page
Table LAIE.4.1.
Objectives and Endpoints .......................................................................15
Table LAIE.5.2.
Treatment Sequences for Cohort 1; Japanese Subjects ............................16
Table LAIE.5.3.
Treatment Sequences for Cohort 2; Japanese Subjects ............................16
Table LAIE.5.4.
Treatment Sequences for Cohort 3; Caucasian Subjects..........................17
Table LAIE.7.5.
Treatments Administered (All periods for Cohorts 1 and 3, 
Period 1 for Cohort 2).............................................................................24
Table LAIE.7.6.
Treatments Administered (Periods 2 and 3 for Cohort 2) ........................24


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................40
Appendix 2.
Clinical Laboratory Tests........................................................................44
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................45
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............48
Appendix 5.
Blood Sampling Summary......................................................................49


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1. Protocol Synopsis
Title of Study:
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Japanese and Caucasian Subjects
Rationale:
Lasmiditan is a highly selective and potent agonist of the 5-hydroxytryptamine 1F receptor that is being developed 
as a neurally acting treatment for migraine.
This study is the first clinical evaluation of lasmiditan in Japanese subjects, and will facilitate subsequent clinical 
trials in Japanese patients.  Characterization of the safety and pharmacokinetics (PK) of lasmiditan in Japanese 
subjects is essential for further clinical development in Japan.  Additionally, as the majority of migraine patients are 
female, and previous studies suggest a higher exposure in female subjects, the safety and PK in female Japanese 
subjects will also be explored.  Caucasian subjects are included to explore the relationship of safety, tolerability, and 
PK of lasmiditan between Japanese and Caucasian subjects.  
Objectives/Endpoints:
Objectives
Endpoints
Primary
To explore the safety and tolerability of single and 
repeated oral doses of lasmiditan in healthy Japanese 
subjects, and single oral doses of lasmiditan in healthy 
Caucasian subjects.
Incidence of treatment-emergent adverse events and 
serious adverse events.
Secondary
To evaluate the PK of lasmiditan in healthy Japanese 
and Caucasian subjects
Area under the concentration (AUC) versus time curve 
from time 0 extrapolated to infinity [AUC(0-∞)], 
maximum observed plasma concentration (Cmax), and
time of maximum observed plasma concentration 
(tmax).
Summary of Study Design:
This is a randomized, 3-period, subject- and investigator-blind crossover study in healthy Japanese and Caucasian 
subjects.
Subjects will be enrolled into 1 of 3 cohorts; Japanese subjects will be enrolled into Cohorts 1 and 2, and Caucasian 
subjects will be enrolled into Cohort 3.  Within each cohort, subjects will be randomized to a treatment sequence; 
there will be 3 treatment sequences in Cohort 1, and 4 treatment sequences in each of Cohorts 2 and 3.  
Randomization will be stratified by sex, such that there will be an approximately equal number of male and female 
subjects in each cohort.
Investigational product will be administered after a fast of at least 8 hours.  Blood samples for PK analysis will be 
collected predose and for up to 48 hours postdose in each period.  There will be a washout period of approximately 


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72-hours between dose administrations across periods.  Subjects will attend a follow-up visit 7 to 10 days following 
discharge from the clinical research unit.
Safety and tolerability will be assessed throughout the study by means of adverse event review, physical 
examinations, body weight, vital sign measurements, electrocardiograms, clinical laboratory tests, and
Columbia-Suicide Severity Rating Scale.
Treatment Arms and Planned Duration for an Individual Subject:  
Subjects will participate in: a screening period of up to 27 days; 3 treatment periods, each of either 4 days (Period 1) 
or 3 days (Periods 2 and 3) duration; and a follow-up period of up to 10 days.  The total study duration for each 
subject will be up to 47 days.
Cohorts 1 and 3:  Subjects will receive a single dose of 50 mg lasmiditan or placebo in Period 1, 100 mg lasmiditan 
or placebo in Period 2, and 200 mg lasmiditan or placebo in Period 3.
Cohort 2:  Subjects will receive single dose of 50, 100, or 200 mg lasmiditan or placebo in Period 1, 400 mg 
lasmiditan or placebo in Period 2, and 2 doses of 200 mg lasmiditan or 2 doses of placebo administered 2 hours 
apart in Period 3.
Number of Subjects:
Up to 16 Japanese and 11 Caucasian subjects may be enrolled and randomized so that approximately 14 Japanese 
and 8 Caucasian subjects (approximately 2 per treatment sequence) complete the study.
Statistical Analysis:
Safety parameters will be listed and summarized using standard descriptive statistics, where applicable.  The 
relationship between concentrations of lasmiditan and changes from baseline corrected QT interval based on 
Fridericia’s formula (ΔQTcF) will be explored to assess the effect of lasmiditan concentration on the ΔQTcF.
Pharmacokinetic parameters for lasmiditan will be evaluated to determine dose proportionality for Japanese and 
Caucasian subjects.  Log transformed Cmax and AUC(0-∞) will be evaluated using a power model (where the log 
of the dose will be an explanatory variable) to estimate ratios of dose-normalized geometric means and the 
corresponding 90% confidence intervals.  The estimated ratio between the highest and lowest doses for each race 
(Japanese, Caucasian) will be used to assess dose proportionality. 


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2. Schedule of Activities


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Study Schedule Protocol H8H-JE-LAIE
Screening
Period 1 
Period 2
Period 3
Follow-up/ED
Comments
Day
Procedure
-28 to -2 days 
prior to Day 1 
of Period 1
-1
1
2
3
1
2
3
1
2
3
7 to 10 days 
following Day 
3 of Period 3
Informed Consent
X
Subject Admission 
to CRU
X
Subject Discharge 
from CRU
X
Chest X-ray
X
Enrollment/
Randomization
X
Lasmiditan 
Administration
X
X
Xa
A washout of approximately 72 hours between 
doses across periods
Medical History
X
X
Interim medical history only on Day -1
Urine Drug Screen
X
X
Alcohol Test
X
Height
X
Body Weight
X
X
X
Triplicate Vital 
Signs (supine)
X
-1, -0.5, 
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 12
24, 
36
48
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 12
24, 
36
48
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 
3.5b, 4, 
4.5b, 5b, 
6, 8, 12
24, 
36
48
X
Time points relative to the time of investigational 
product administration in each period and shown 
in hours.  For repeated doses, timepoints relative 
to the first dose.  Single vital signs only at 
follow-up/ED.  Time points may be added, if 
warranted and agreed by Lilly and the 
investigator
Single Orthostatic 
Vital Signs
X
-1, P, 1, 
2, 3, 4, 6, 
8, 12
24, 
36
48
P, 1, 2, 3, 
4, 6, 8, 12
24, 
36
48
P, 1, 2, 3, 
4, 6, 8, 12
24, 
36
48
X
Time points relative to the time of investigational 
product administration in each period.  For 
repeated doses, time points relative to the first 
dose.  Time points may be added if warranted 
and agreed by Lilly and the investigator
Clinical 
Laboratory Tests
X
P
P
P
X
See Appendix 2, Clinical Laboratory Tests, for 
details


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Screening
Period 1 
Period 2
Period 3
Follow-up/ED
Comments
Day
Procedure
-28 to -2 days 
prior to Day 1 
of Period 1
-1
1
2
3
1
2
3
1
2
3
7 to 10 days 
following Day 
3 of Period 3
Adverse Event 
Review
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X
X
X
Serum pregnancy test for all females
Follicle-
stimulating 
hormone
X
Postmenopausal females only
Physical 
Examination
X
X
X
X
X
X
Full physical examination performed at 
screening.  At other time points, 
symptom-directed physical examination only
Triplicate 12-lead 
Electrocardiogram
X
-1, -0.5, 
P, 1, 1.5, 
2, 2.5, 3, 
4, 6, 8, 12
24, 
36
48
P, 1, 1.5, 
2, 2.5, 3, 
4, 6, 8, 12
24, 
36
48
P, 1, 1.5, 
2, 2.5, 3, 
4, 6, 8, 12
24, 
36
48
X
Time points relative to the time of investigational 
product administration in each period.  For 
repeated doses, time points relative to the first 
dose.  Refer to Section 9.4.4.  Performed after 
subject has rested in supine position for ~5 to 
10 minutes.  On days without dosing, should be 
performed close to the Day 1 dosing time, when 
possible.  Collected in triplicate except at 
screening and follow-up/ED
Columbia-Suicide 
Severity Rating 
Scale/Self-Harm
X
X
X
X
Genetic Sample
X
Period 1 only
Blood Sample for 
Lasmiditan and 
Metabolites 
Pharmacokinetics
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 12
24,
36
48
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 12
24,
36
48
P, 0.5, 1, 
1.5, 2c, 
2.5, 3, 
3.5b, 4, 
4.5b, 5b, 
6, 8, 12
24,
36
48
Time points relative to the time of investigational 
product administration in each period.  For 
repeated doses, time points relative to the first 
dose
Abbreviations:  CRU = clinical research unit; ED = early discontinuation; P = predose. 
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be use: electrocardiogram, vital signs, and venipuncture.


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a  Subjects in Period 3 of Cohort 2 will receive 2 doses separated by 2 hours.
b  Subjects in Period 3 of Cohort 2 only.
c  For subjects in Period 3 of Cohort 2, pharmacokinetic sample collected prior to second dose.


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3. Introduction
Lasmiditan (LY573144) is being developed by Eli Lilly and Company (Lilly) for the acute 
treatment of migraine attacks, with or without aura, in adults. This molecule has also been 
developed by CoLucid Pharmaceuticals, Inc. as COL-144.  Full details of the preclinical and 
clinical safety and tolerability data are contained in the Investigator’s Brochure (IB).
3.1.
Study Rationale
Lasmiditan is a highly selective and potent agonist of the 5-hydroxytryptamine (5-HT)1F
receptor that is being developed as a neurally acting treatment for migraine.
This study is the first clinical evaluation of lasmiditan in Japanese subjects, and will facilitate 
subsequent clinical trials in Japanese patients.  Characterization of the safety and 
pharmacokinetics (PK) of lasmiditan in Japanese subjects is essential for further clinical 
development in Japan.  Additionally, as the majority of migraine patients are female, and 
previous studies suggest a higher exposure in female subjects, the safety and PK in female 
Japanese subjects will also be explored. Caucasian subjects are included to explore the 
differences in safety, tolerability, and PK of lasmiditan between Japanese and Caucasian
subjects.  
3.2.
Background
Lasmiditan has a chemical structure and pharmacological profile that is distinct from triptans, 
which are the current standard of care for the treatment of acute migraine.  It does not contain the 
indole group found in all triptans, but instead has a pyridinoyl-piperidine scaffold that is unique 
to antimigraine medications. Lasmiditan is a low-molecular weight agonist of the 5-HT1F
receptor with a nonvascular and primarily neural mechanism of action.  It has a high affinity for 
the human 5-HT1F receptor and a >470-fold selectivity for the human 5-HT1F receptor relative to 
the 5-HT1B receptor. 
Lasmiditan doses of 0.1 to 400 mg have been evaluated in healthy subjects or patients with 
migraine across completed Phase 1, 2, and 3 clinical studies.  The most frequently reported 
lasmiditan treatment-emergent adverse events (TEAEs) in the two Phase 3, placebo-controlled 
studies in which patients treated 1 migraine attack with oral lasmiditan (50, 100, or 200 mg) or 
placebo were dizziness, paresthesia, somnolence, fatigue, lethargy, and nausea, and the majority 
were mild or moderate in severity.  Safety and tolerability in healthy subjects were similar up to 
400 mg, with tiredness, drowsiness, dizziness, and paresthesia being the most frequently reported 
adverse events (AEs).  The majority of these were mild in severity, and none were severe.  In 
healthy subjects, peak plasma concentrations of lasmiditan were observed approximately 1.5 to 
2.5 hours after a single oral dose ranging from 25 to 400 mg, and the geometric mean terminal 
half-life was approximately 4 hours. Lasmiditan PK was approximately dose linear.  There was 
an increase of approximately 20% to 30% in maximum observed plasma concentration (Cmax)
and a 30% increase in area under the concentration versus time curve (AUC) in female subjects
in a previous study.


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Following oral dosing with lasmiditan, up to 16 metabolites, including 3 major metabolites (M7, 
M8, and M18), were detected in human plasma and urine. These metabolites lacked significant 
pharmacological activity at the 5 HT1F receptor and were generally considered to be 
pharmacologically inactive. The relative proportions of metabolites to intact lasmiditan 
remained reasonably constant throughout the oral dose range studied and their PK was 
approximately linear. The half-life of the metabolites ranged from approximately 4.5 to 
21 hours.
3.3.
Benefit/Risk Assessment
Oral doses of lasmiditan up to the highest single oral dose given (400 mg) were well tolerated in 
healthy subjects, with no drug related serious adverse events (SAEs) or withdrawals due to AEs
as of 01 November 2017.  Lasmiditan caused no significant QT prolongation either at 100 or 
400 mg, and no clinically significant changes in clinical laboratory data. Although nervous 
system disorders were commonly reported as AEs, especially at higher dose levels, they were 
generally mild or moderate in intensity.  Dosing of subjects in this study will be conducted in an 
inpatient setting, and subjects will be monitored in-house for at least 48 hours after dosing.
There is no anticipated therapeutic benefit for the subjects.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of lasmiditan are to be found in the IB.  


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4. Objectives and Endpoints
Table LAIE.4.1 shows the objectives and endpoints of the study.
Table LAIE.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To explore the safety and tolerability of single and 
repeated oral doses of lasmiditan in healthy Japanese 
subjects, and single oral doses of lasmiditan in healthy 
Caucasian subjects.
Incidence of TEAEs and SAEs.
Secondary
To evaluate the PK of lasmiditan in healthy Japanese 
and Caucasian subjects.
AUC(0-∞), Cmax, and tmax.
Exploratory
To evaluate the PK of metabolites M7, M8, (S,R)-M18, 
and (S,S)-M18 in healthy Japanese and Caucasian
subjects.
To explore the safety, tolerability, and PK of lasmiditan 
in female subjects compared to male subjects.
AUC(0-∞), Cmax, and tmax.
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from time 0 extrapolated to infinity; 
Cmax = maximum observed plasma concentration; PK = pharmacokinetics; SAE = serious adverse event; TEAE=
treatment-emergent adverse event; tmax = time of maximum observed plasma concentration.


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5. Study Design
5.1.
Overall Design
This is a randomized, 3-period, subject- and investigator-blind, crossover study in healthy 
Japanese and Caucasian subjects.
Subjects will be evaluated for study eligibility ≤28 days prior to enrollment.  Subjects who fulfill 
the eligibility criteria will be admitted to the clinical research unit (CRU) on Day -1 in Period 1 
(the day before their first dose of lasmiditan or placebo; Section 2).
Subjects will be enrolled into 1 of 3 cohorts.  Within each cohort, subjects will be randomized to 
a treatment sequence, as indicated in Table LAIE.5.2, Table LAIE.5.3, and Table LAIE.5.4.
Randomization will be stratified by sex, such there will be an approximately equal number of 
male and female subjects in each cohort.
Table LAIE.5.2.
Treatment Sequences for Cohort 1; Japanese Subjects
Treatment Sequence
Period 1
Period 2
Period 3
1
Placebo
100 mg lasmiditan
200 mg lasmiditan
2
50 mg lasmiditan
Placebo 
200 mg lasmiditan
3
50 mg lasmiditan
100 mg lasmiditan
Placebo
Table LAIE.5.3.
Treatment Sequences for Cohort 2; Japanese Subjects
Treatment Sequence
Period 1
Period 2
Period 3a
1
Placebo
400 mg lasmiditan
2 × 200 mg lasmiditan
2
50 mg lasmiditan
Placebo
2 × 200 mg lasmiditan
3
100 mg lasmiditan
400 mg lasmiditan
2 × placebo
4
200 mg lasmiditan
400 mg lasmiditan
2 × 200 mg lasmiditan
a
Doses administered 2 hours apart.


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Table LAIE.5.4.
Treatment Sequences for Cohort 3; Caucasian Subjects
Treatment Sequence
Period 1
Period 2
Period 3
1
Placebo
100 mg lasmiditan
200 mg lasmiditan
2
50 mg lasmiditan
Placebo
200 mg lasmiditan
3
50 mg lasmiditan
100 mg lasmiditan
Placebo
4
50 mg lasmiditan
100 mg lasmiditan
200 mg lasmiditan
After randomization on Day 1, investigational medical product will be administered orally on the 
morning of Day 1 after an overnight fast of at least 8 hours.  Blood samples will be collected for 
PK analysis predose, and for up to 48 hours postdose in each period.  There will be a washout 
period of approximately 72 hours between dose administrations across periods.
Subjects will be discharged from the CRU following completion of all scheduled procedures on 
Day 3 of Period 3, as defined in the Schedule of Activities (Section 2), and will attend a 
follow-up visit 7 to 10 days following discharge from the CRU on Day 3 of Period 3.
Safety and tolerability will be assessed throughout the study by means of AE review, physical 
examinations, body weight, vital sign measurements, 12-lead electrocardiograms (ECGs), 
clinical laboratory tests, and Columbia-Suicide Severity Rating Scale (C-SSRS).
Details for the timing of dosing are presented in Section 10.3.3.
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Up to 16 Japanese and 11 Caucasian subjects may be enrolled and randomized so that 
approximately 14 Japanese and 8 Caucasian subjects (approximately 2 subjects per treatment 
sequence) complete the study.  For purposes of this study, a subject completes the study when all 
scheduled procedures shown in the Schedule of Activities (Section 2) have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
A subject- and investigator-blinded, randomized, and placebo-controlled design has been chosen
to minimize bias in the primary objective of this study, and a crossover design has been chosen 
to minimize the number of subjects required for the study.  The study design that has been 
chosen is considered to be the most feasible to execute operationally.  As this will be the first 
time that the commercial formulation of lasmiditan will be administered to humans, Caucasian 


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subjects have been included to allow comparisons between Japanese and Caucasian subjects to 
be made.
Single and repeated doses (2 single doses administered 2 hours apart) of 50, 100, and 200 mg
lasmiditan are considered the planned clinical doses.  Additionally, a supratherapeutic dose of 
400 mg lasmiditan has been included for the assessment of QT interval.  As patients currently 
receiving approved therapies for migraine may administer an additional dose 2 hours following 
their initial dose if symptoms do not alleviate, this study will also evaluate the safety, tolerability, 
and PK of 2 doses of 200 mg lasmiditan administered 2 hours apart.
Pharmacokinetic sampling time points have been selected to generate PK profiles sufficient to 
fulfill the study objectives.
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients.  Healthy subjects are frequently used in 
the assessment of bioavailability of both small and large molecules. Conducting this study in
Japanese subjects will support their inclusion in future studies with lasmiditan, and inclusion of 
Caucasian subjects enables the direct comparison between Japanese and Caucasian subjects.
5.5.
Justification for Dose
Oral doses of 50, 100, and 200 mg lasmiditan are envisaged to be clinically effective doses, 
based on data obtained from previous completed studies.  A supratherapeutic dose of 400 mg 
lasmiditan is being investigated to obtain additional PK data and to investigate any effects of 
lasmiditan on QT interval in Japanese subjects.  




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[1b]
women of non-childbearing potential may participate and include those who 
are:

infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as mullerian 
agenesis, or

postmenopausal, defined as:
o
a woman of at least 50 years of age with an intact uterus, not on 
hormone therapy, who has had either cessation of menses for at 
least 1 year or at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone level >40 mIU/mL, or
o
a woman 55 years of age or older, not on hormone therapy, who 
has had at least 6 months of spontaneous amenorrhea, or
o
a woman of at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy.
Note:  male subjects are not required to adhere to contraceptive requirements.
[2]
are aged between 20 and 64 years at screening
[3]
have a body mass index of 18.0 to 32.0 kg/m2, inclusive
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[5]
have venous access sufficient to allow for blood sampling as per the protocol
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[7]
are able and willing to give signed informed consent
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[9]
are Lilly or Covance employees
[10]
are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  
[11]
have known allergies to lasmiditan, related compounds or any components of 
the formulation of lasmiditan 


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[12]
have previously received the investigational product in this study, withdrawn 
from this study, or received lasmiditan in any other study investigating 
lasmiditan
[13]
have participated (dosed with investigational product), within the last 30 days, 
in a clinical study involving an investigational product.  If the previous 
investigational product has a long half-life, 5 half-lives or 30 days (whichever 
is longer) should have passed
[14]
have a history of, or ECG findings of, clinically significant bradycardia, heart 
block, tachycardia, sick sinus syndrome/sinoatrial block, or second or 
third-degree atrioventricular block, or have any other abnormality in the 
12-lead ECG that, in the opinion of the investigator, confounds assessment of 
QT interval
[15]
have an abnormal supine blood pressure (defined as systolic blood pressure 
<95 or >140 mmHg or diastolic blood pressure <65 or >90 mmHg) at 
screening. After screening, additional assessments may be performed to 
confirm eligibility
[16]
have a history of syncope, presyncope, uncontrolled vertigo, postural 
dizziness, or a risk of falls, as judged to be clinically significant by the 
investigator, or have orthostatic decreases in supine blood pressure of 
>20 mmHg, or have orthostatic decreases in diastolic blood pressure of 
>10 mmHg at screening. Measurements of orthostatic blood pressure may be 
repeated if asymptomatic
[17]
have an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2
as assessed using the Chronic Kidney Disease Epidemiology Collaboration 
formula (Section 9.4.1.1)
[18]
have a significant history of or current cardiovascular, respiratory (including 
bronchospasm or bronchial asthma, or chronic obstructive airways disease), 
hepatic, renal, gastrointestinal, endocrine, hematological, or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs; of constituting a risk when taking the study medication; 
or of interfering with the interpretation of data. Appendectomy, splenectomy, 
and cholecystectomy are considered acceptable
[19]
show evidence of significant active neuropsychiatric disease (for example, 
manic depressive illness, schizophrenia, depression)
[20]
have a history of central nervous system conditions such as strokes, transient 
ischemic attack significant head trauma, central nervous system infections, 
migraines, brain surgery or any other neurological conditions that, in the 
opinion of the investigator, increases the risk of participating in the study
[21]
currently use or have a history of recreational drug abuse within the past 
1 year, show evidence of substance dependence within the past 6 months, or 
show positive findings on drug screening


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[22]
show evidence of human immunodeficiency virus infection and/or positive 
human immunodeficiency virus antibodies
[23]
show evidence of hepatitis C and/or positive hepatitis C antibody
[24]
show evidence of hepatitis B and/or positive hepatitis B surface antigen
[25]
are women who are pregnant, lactating, or have a positive pregnancy test at 
screening or admission to the CRU
[26]
have used or intend to use over-the-counter or prescription medication 
including herbal medications within 14 days prior to admission to the CRU
and until discharge from the study (with the exception of hormone 
replacement therapy or occasional acetaminophen use).  If minor or 
inadvertent use of such a product occurs, enrollment of a subject may still be 
considered appropriate if approved by the investigator and Lilly clinical 
pharmacologist (CP)/ clinical research physician (CRP; or designee)
[27]
have a history of hypersensitivity to any foods or medications, which in the 
opinion of the investigator, is considered clinically significant
[28]
have donated blood of more than 500 mL within 1 month prior to screening
[29]
have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
for 48 hours prior to admission to and while resident at the CRU (1 unit = 
12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled 
spirits)
[30]
are smokers of more than 10 cigarettes or e-cigarettes, or 3 cigars or 3 pipes 
per day, and are unable to refrain from smoking for 48 hours prior to 
admission to and while resident at the CRU
[31]
are unwilling to abide by the dietary or activity restrictions (Section 6.3)
[32]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.2.1. Rationale for Exclusion of Certain Study Candidates
Criteria [1] to [7] define a healthy population that is suitable for evaluation in a Phase 1 study
and define the Japanese population for the purposes of this study. The use of lasmiditan in 
Japanese patients is anticipated, thus this study will specifically examine the PK, safety, and 
tolerability in Japanese subjects.
Criteria [8] and [9] prevent conflict of interest in study participants.  Criteria [10] to [32] 
predominantly exclude medical conditions, medical intolerances, and concomitant medications 
that may confound the assessment of study endpoints, or may affect subject or investigative site 
safety.


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6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Lasmiditan will be administered after an overnight fast of at least 8 hours. Following single 
doses of lasmiditan, subjects will be fasted for approximately 3 hours postdose. Following 
repeated doses of lasmiditan, subjects will be fasted for approximately 5 hours following the first 
dose.  With the exception of water given with the lasmiditan dose, subjects will abstain from 
fluid intake for 1 hour before and for 1 hour after dosing.
Standardized meals will be provided at all other times while resident at the CRU.  Japanese 
subjects may be provided with meals that are consistent with a typical Japanese diet.  When not 
resident at the CRU, subjects will be encouraged to maintain their normal dietary habit.
6.3.2. Caffeine, Alcohol, and Tobacco
Subjects will refrain from consuming xanthine- or caffeine-containing food and drinks from 
48 hours prior to admission to the CRU and while resident at the CRU.  At other times during the 
outpatient period, subjects will be allowed to maintain their regular caffeine consumption.
Subjects will refrain from consuming grapefruit and grapefruit-containing products from 7 days 
prior to admission to the CRU until discharge from the study.
Alcohol consumption is not permitted for 48 hours prior to admission to and while resident at the 
CRU.
Subjects will refrain from smoking for 48 hours prior to admission to and while resident at the 
CRU.
6.3.3. Activity
No strenuous exercise is permitted for 48 hours prior to admission to the CRU until discharge 
from the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of single doses of 50, 100, 200, and 400 mg lasmiditan and 
repeated doses of 200 mg lasmiditan administered orally, with placebo.  
Table LAIE.7.5 and Table LAIE.7.6 show the treatment regimens.
Table LAIE.7.5.
Treatments Administered (All periods for Cohorts 1 and 3, Period 1 
for Cohort 2) 
Treatment Name
LY50 
LY100
LY200 
PLA
Unit dose, dose level
1 LY50 + 3 × PLA 2 LY50 + 2 × PLA
4 LY50
4 × PLA
Dosing instructions
single oral dose
Number of tablets 
administered
4
4
4
4
Abbreviations:  LY50 =50 mg lasmiditan, LY100 =100 mg lasmiditan, LY200 =200 mg lasmiditan, PLA=placebo.
Table LAIE.7.6.
Treatments Administered (Periods 2 and 3 for Cohort 2)
Period 2
Period 3
Treatment Name
LY400
PLA
2 × LY200
PLA
Unit dose, dose level
8 LY50
8 PLA
2 doses of 
4 LY50
2 doses of
4 PLA
Dosing instructions
single oral dose
2 single oral doses separated by 
2 hours
Number of tablets administered
8
8
2 × 4
2 × 4
Abbreviations: LY50 =50 mg lasmiditan, LY200 =200 mg lasmiditan, LY400 =400 mg lasmiditan, PLA=placebo.
Tablets of lasmiditan or placebo will be administered orally with approximately 200 mL of room 
temperature water in the morning of each dosing day in a sitting position.  Subjects will not be 
allowed to lie supine for 2 hours after dosing, unless clinically indicated or for study procedures.
Lasmiditan tablets will be supplemented with the appropriate number of placebo tablets such that 
each subject receives a total of 4 or 8 tablets in each period (Table LAIE.7.5 and
Table LAIE.7.6).
The investigator or designee is responsible for:

explaining the correct use of the investigational product(s) to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study


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Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials. 
7.1.1. Packaging and Labeling
The 50 mg lasmiditan tablets will be provided in bulk bottles. Placebo-to-match tablets are of 
identical appearance to 50 mg lasmiditan tablets and will be provided in bulk bottles, but contain 
no active ingredient.
The investigational product will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Japanese subjects will be enrolled in Cohort 1 or 2, and Caucasian subjects will be enrolled into 
Cohort 3.
Within each cohort, subjects will be randomized to a treatment sequence using a 
computer-generated allocation schedule.  There will be no randomization between cohorts.  
Randomization will be stratified by sex, such that there will be an approximately equal number 
of male and female subjects in each cohort.
7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same times on each day.  
The actual time of all dose administrations will be recorded in the subject’s electronic case report 
form (eCRF).
7.3.
Blinding
The investigator and subjects will be blinded to the study treatment assignments.
Blinding will be maintained throughout the conduct of the study as described in the separate 
Blinding Plan.
Emergency codes will be available to the investigator.  A code, which reveals the treatment for a 
specific study subject, may be opened during the study only if the subject’s well-being requires 
knowledge of the subject’s treatment assignment.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly CP or CRP for the study 
participant to continue in the study.  During the study, emergency unblinding should occur only 
by accessing the study subject’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event. The 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.


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Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
Dose modification will not be allowed in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all investigational product
received and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational product should be stored in an environmentally controlled and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
Hormonal contraception and hormone replacement therapy are permitted.
In general, concomitant medication should be avoided; however, acetaminophen (maximum 
2 g/24 hours) may be administered at the discretion of the investigator for treatment of headaches 
etc.  If the need for concomitant medication (other than acetaminophen) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator after consultation with a 
Lilly CP/CRP (or designee).  Any medication used during the course of the study must be 
documented.
7.8.
Treatment After the End of the Study
Not applicable.


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8. Discontinuation Criteria
Subjects discontinuing from the treatment prematurely for any reason should complete AE and 
other early discontinuation procedures per Section 2 of this protocol.
Subjects discontinuing from the study prematurely for any reason must complete AE and early 
discontinuation procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of lasmiditan in subjects with abnormal liver tests should be considered by the 
investigator when a subject meets 1 of the following conditions after consultation with the Lilly-
designated medical monitor:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of 
normal (ULN)

ALT or AST >3 × ULN sustained for more than 2 weeks

ALT or AST >3 × ULN and total bilirubin level (TBL) >2 × ULN or international 
normalized ratio >1.5

ALT or AST >3 × ULN the appearance of fatigue, nausea, vomiting, right upper-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase (ALP) >3 × ULN

ALP >2.5 × ULN and TBL >2 × ULN

ALP >2.5 × ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
investigational product.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study.

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice.


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
The investigator decides that the subject should be discontinued from the study.

The subject requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the informed consent form is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product, study device and/or study procedure, and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CP/CRP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
investigational product, AND is considered reasonably possibly related to a study procedure,
then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements, any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  Lilly 


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has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances. 
9.2.2. Complaint Handling 
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements. 
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed. 
9.3. Treatment of Overdose 
For the purposes of this study, an overdose of lasmiditan is considered any dose higher than the 
dose assigned through randomization. 
There is no specific antidote for lasmiditan.  In the event of overdose, the subject should receive 
appropriate supportive care and AEs should be documented. 
Refer to the IB for further information. 
9.4. Safety 
9.4.1. Laboratory Tests 
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  
9.4.1.1. Estimated Glomerular Filtration Rate 
Estimated glomerular filtration rate will be assessed at screening based on estimated creatinine 
clearance, using the Chronic Kidney Disease Epidemiology Collaboration formula. 
eGFR ൌ141 ൈ݉݅݊൬ܵܥݎ
݇, 1൰
௔
ൈ݉ܽݔ ൬ܵܥݎ
݇, 1൰
ିଵ.ଶ଴ଽ
ൈ0.993௔௚௘ሺൈ1.018 if femaleሻ 
Where:  a = -0.329 for females and -0.411 for males; k = 0.7 for females and 0.9 for males; 
SCr = serum creatinine (mg/dL); max = maximum of SCr/k or 1; and min = minimum of SCr/k 
or 1. 
9.4.2. Vital Signs 
For each subject, vital signs (including orthostatic vital signs) measurements should be 
conducted according to the Schedule of Activities (Section 2).  Supine vital signs should be 
measured in triplicate; orthostatic vital signs should be measured singly. 
Blood pressure and pulse rate should be measured after at least 5 minutes supine.   
For orthostatic measurements, subjects should be supine for at least 5 minutes and stand for at 
least 2 minutes.  If the subject feels unable to stand, supine vital signs only will be recorded.  


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Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  
Additional vital signs may be measured during each study period if warranted.
9.4.3. Body Weight
For each subject, measurements of body weight will be conducted according to the Schedule of 
Activities (Section 2).  
9.4.4. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities.  
For each subject, a 12-lead digital ECG will be collected in triplicate (single at screening)
according to the Schedule of Activities (Section 2).  Electrocardiograms must be recorded before 
collecting any blood samples.  Subjects must be supine for approximately 5 to 10 minutes before 
ECG collection and remain supine but awake during ECG collection.  Consecutive replicate 
ECGs will be obtained at approximately one minute intervals.  Electrocardiograms may be 
obtained at additional times, when deemed clinically necessary.  
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  Any clinically significant findings from ECGs that result in a diagnosis and that occur 
after the subject receives the first dose of the investigational product, should be reported to Lilly, 
or its designee, as an AE via eCRF. 
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the subject can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in subject management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements.  
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report (in which case the overread data would be used).


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9.4.5. Columbia-Suicide Severity Rating Scale
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicidal ideation 
and/or behavior during the assessment period.  The scale includes suggested questions to solicit 
the type of information needed to determine if suicidal ideation and/or behavior occurred.  Any 
occurrence of suicide-related thoughts and behaviors will be assessed as indicated in the 
Schedule of Activities (Section 2) using the C-SSRS.  The C-SSRS is administered by an 
appropriately trained healthcare professional with at least 1 year of patient care/clinical 
experience.
Before administering the C-SSRS, study site personnel will question the subject about any 
change in the pre-existing condition(s) and the occurrence and nature of any AEs.  If a 
suicide-related event is discovered during the C-SSRS administration, but was not captured as an 
AE, the site should not change the AE form.  If an event is serious or leads to discontinuation, 
this is an exception where the SAE and/or AE leading to discontinuation should be included on 
the AE form and the process for reporting SAEs should be followed.  
The first time the scale is administered in this study, the C-SSRS ‘Baseline-Screening’ version 
will be used, and the findings will constitute the baseline assessment.  The C-SSRS ‘Since Last 
Visit’ scale will be used for all subsequent assessments.  If a clinically significant finding is 
identified, the investigator will determine if the subject can continue in the study.  The 
investigator, or qualified designee, is responsible for determining if any change in subject 
management is needed.
The Lilly Self-Harm Supplement should be completed every time the C-SSRS is administered.  
If there are positive findings on the Self-Harm Supplement, then the Lilly Self-Harm Follow-up 
Form will be used to collect additional information to allow for a more complete assessment of 
these behaviors.
9.4.6. Safety Monitoring
The Lilly CP or CRP/clinical research scientist will monitor safety data throughout the course of 
the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly 
CP/CRP will periodically review the following data:

trends in safety data

laboratory analytes

adverse events
When appropriate, the Lilly CP/CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.


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9.4.6.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3 × ULN, ALP ≥2 × ULN, or elevated total 
bilirubin ≥2 × ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to 
confirm the abnormality and to determine if it is increasing or decreasing.  If the abnormality 
persists or worsens, clinical and laboratory monitoring should be initiated by the investigator 
based on consultation with the Lilly CP/CRP.  Monitoring should continue until levels normalize 
and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2 × ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests 

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be a SAE.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of 
approximately 2 mL each will be collected to determine the plasma concentrations of lasmiditan
and metabolites M7, M8, (S,R)-M18, and (S,S)-M18.  A maximum of 3 samples may be 
collected at additional time points during the study if warranted and agreed upon between both 
the investigator and sponsor.  Instructions for the collection and handling of blood samples will 
be provided by the sponsor.  The actual date and time (24-hour clock time) of each sampling will 
be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of lasmiditan and metabolites M7, M8, (S,R)-M18, and (S,S)-M18 will be 
assayed using a validated liquid chromatography with tandem mass spectrometry method.  
Analyses of samples collected from placebo-treated subjects are not planned.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.


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9.6.
Pharmacodynamics
Not applicable.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
lasmiditan and to investigate genetic variants thought to play a role in migraine.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or institutional review board impose shorter time limits, for the 
study at a facility selected by Lilly or its designee.  This retention period enables use of new 
technologies, response to regulatory questions, and investigation of variable response that may 
not be observed until later in the development of lasmiditan or after lasmiditan is commercially 
available.  
Molecular technologies are expected to improve during the 15 year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The sample size is customary for Phase 1 studies evaluating safety and PK, and is not powered 
on the basis of statistical hypothesis testing.
Subjects who are randomized but not administered treatment may be replaced to ensure that 
approximately 14 Japanese and 8 Caucasian subjects (approximately 2 per treatment sequence) 
may complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The subjects’ age, sex, weight, height, body mass index, and other demographic characteristics 
will be recorded and summarized using descriptive statistics overall and by race.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least one 
dose of the investigational product and have evaluable PK.  Safety analyses will be conducted for 
all enrolled subjects, whether or not they completed all protocol requirements.  
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis.  
Where applicable, safety and PK data will be presented separately for Japanese and Caucasian 
subjects.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, along with the date and 
time of their occurrence (where available).
If the frequency of events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to enrollment (immediately prior to dose administration on Day 1 of Period 1) will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.


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The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include body weight, vital sign measurements, ECG 
parameters, clinical laboratory tests, and C-SSRS.  The parameters will be listed, and 
summarized using standard descriptive statistics.  Additional analysis will be performed if 
warranted upon review of the data.
Prior to any statistical analysis of QT interval, QT values will be corrected for heart rate 
(corrected QT interval based on Fridericia’s formula [QTcF]).  The relationship between 
concentrations of lasmiditan and changes from baseline QTcF (ΔQTcF) will be explored to 
assess the effect of lasmiditan concentration on the ΔQTcF.  A detailed analysis for QT interval 
will be provided in the statistical analysis plan.  Additional analysis will be performed if 
warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameters for lasmiditan and metabolites M7, M8, (S,R)-M18, and (S,S)-M18
will be calculated by standard noncompartmental methods of analysis.
The primary parameters for analysis will be time of maximum observed plasma concentration 
(tmax), Cmax, and AUC of lasmiditan and metabolites M7, M8, (S,R)-M18, and (S,S)-M18.  
Other noncompartmental parameters, such as half-life, apparent clearance, and apparent volume 
of distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters for lasmiditan will be evaluated to determine dose proportionality 
for Japanese (Cohorts 1 and 2 over the 50 to 400 mg dose range, excluding any data from
Period 3 in Cohort 2) and Caucasian subjects (Cohort 3, over the 50 to 200 mg dose range).  
Log-transformed Cmax and AUC from time 0 extrapolated to infinity [AUC(0-∞)] will be 
evaluated using a power model (where the log of the dose will be an explanatory variable) to 
estimate ratios of dose-normalized geometric means and the corresponding 90% confidence 
intervals.  The estimated ratio between the highest and lowest doses for each race (Japanese, 
Caucasian) will be used to assess dose proportionality.  The intersubject coefficient of variation 
will be derived, and the intrasubject coefficient of variation may also be derived.
Data for Japanese and Caucasian subjects may be pooled if required, and data for male and 
female subjects may be presented separately to explore the effect of sex.
Additional analysis will be performed if warranted upon review of the data.
10.3.3. Data Review During the Study
All available safety and tolerability data obtained up to Day 1 of Period 3 of Cohort 1 and 
Period 1 of Cohort 2 will be reviewed by the investigator prior to dosing in Period 2 of Cohort 2; 
i.e., dosing in Period 1 of Cohort 2 can commence prior to dosing in Period 3 of Cohort 1.  


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Dosing of subjects in Cohort 3 can commence irrespective of dosing of subjects in Cohorts 1 
and 2.
Safety and PK data may be reviewed throughout the study to support the next study of lasmiditan 
in Japanese subjects.
10.3.4. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP/CRP/investigator or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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11.
References
Not applicable.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
5-HT
5-hydroxytryptamine
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve from time 0 extrapolated to infinity
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received.
Cmax
maximum observed plasma concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice requirements, and 
the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
Clinical Pharmacologist
CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale


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ΔQTcF
changes from baseline corrected QT interval based on Fridericia’s formula
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
Ig
immunoglobulin
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IRB
institutional review board
randomize
the process of assigning subjects to an experimental group on a random basis
PK
pharmacokinetic
PLA
placebo
QTcF
corrected QT interval based on Fridericia’s formula


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SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions 
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
tmax
time of maximum observed plasma concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count
Chloride
Mean cell volume 
Calcium
Mean cell hemoglobin 
Phosphorus
Mean cell hemoglobin concentration 
Glucose (random)
Leukocytes (WBC)
Blood urea nitrogen
Platelets
Uric acid
Differential WBC (Absolute counts of):
Total cholesterol
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase 
Basophils
Aspartate aminotransferase
Alanine aminotransferase
Urinalysis
Creatinine
Specific gravity
Gamma-glutamyl transferase
pH
Estimated glomerular filtration ratea,b
Protein
Glucose
Ketones
Alcohol testingc
Bilirubin
Urine drug screend,e
Urobilinogen
Hepatitis B surface antigena
Blood
Hepatitis C antibodya
Nitrite
Human immunodeficiency virus antibodiesa
Leukocyte-esterase
Pregnancy testf
Color and appearance
Follicle-stimulating hormonea,f
Abbreviations:  WBC = white blood cells.
a
Performed at screening only.
b
Calculated using Chronic Kidney Disease Epidemiology Collaboration formula (Section 9.4.1.1).
c
Performed at check-in only.
d
Performed at screening and check-in.
e
Includes amphetamines/methamphetamines, barbiturates, benzodiazepines, cocaine (metabolite), methadone, 
phencyclidine, opiates, and tetrahydrocannabinol/cannabinoids.
f
Females only.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject.  This includes obtaining the 
appropriate signatures and dates on the informed consent form (ICF) prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant and retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment
material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the institutional
review board (IRB) was properly constituted and convened as required by International Council 
for Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of IRB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site.  All ICFs must be compliant with the ICH guideline on 
good clinical practice (GCP).
The study site’s IRB should be provided with the following:

the current Investigator’s Brochure and updates during the course of the study

ICF

relevant curricula vitae


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the electronic case report forms, and 
study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate electronic case report form data and/or use standard computer edits 
to detect errors in data collection

conduct a quality review of the database


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In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable IRBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the IRB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee clinical research 
physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
Red blood cells
Prothrombin Time
White blood cells
Prothrombin Time, International Normalized Ratio
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase
Anti-nuclear antibodya
Aspartate aminotransferase
Alkaline Phosphatase Isoenzymesa
Gamma-glutamyl transferase
Creatine kinase
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviation:  Ig = immunoglobulin.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  The 
table below is representative of the cohort for which the highest volume of blood will be drawn.
Protocol H8H-JE-LAIE Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
19.5
1
19.5
Clinical laboratory testsa
12.5
4
50
Pregnancy tests
3.5
2
7
Pharmacokineticsb
2
45
90
Pharmacogenetics
10
1
10
Total
176.5
Total for clinical purposes
180
a
Additional samples may be drawn if needed for safety purposes.
b
A maximum of 3 samples may be collected at additional time points during the study if warranted.


Leo Document ID = 4fc1c794-6709-49d9-92b2-6cedf961e9e6
Approver: 
Approval Date & Time: 16-Apr-2018 15:11:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 16-Apr-2018 15:11:01 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan H8H-JE-LAIE (Version 2) 
 
 
 
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Japanese and Caucasian 
Subjects 
 
NCT03579940  
 
Approval Date: 30-Aug-2018 
 
 
 


Final v2, 28 August 2018
             Page 1 of 17
STATISTICAL ANALYSIS PLAN
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Japanese and 
Caucasian Subjects
Statistical Analysis Plan Status:  Final v2
Statistical Analysis Plan Date:  28-August-2018
Study Drug: Lasmiditan (LY573144)
Sponsor Reference:  H8H-JE-LAIE
Covance CRU Study: 1000071-8381378
Clinical Phase I
Approval Date: 30-Aug-2018 GMT


Final v2, 28 August 2018
             Page 2 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8381378
Sponsor Reference H8H-JE-LAIE
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objective................................................................................................ 5
4.3
Exploratory Objectives ............................................................................................ 5
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS............................................................................................................. 7
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 8
9.1
General.................................................................................................................... 8
9.2
Demographics and Subject Disposition.................................................................... 8
9.3
Pharmacokinetic Assessment................................................................................... 8
9.3.1
Pharmacokinetic Analysis............................................................................... 8
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 12
9.4
Safety and Tolerability Assessments...................................................................... 12
9.4.1
Adverse events ............................................................................................. 12
9.4.2
Concomitant medication............................................................................... 13
9.4.3
Clinical laboratory parameters...................................................................... 14
9.4.4
Vital signs .................................................................................................... 14
9.4.5
Electrocardiogram (ECG)............................................................................. 14
9.4.6
Hepatic Monitoring ...................................................................................... 15
9.4.7
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................... 16
9.4.8
Other assessments......................................................................................... 16
9.4.9
Safety and Tolerability Statistical Methodology............................................ 16
10. INTERIM ANALYSES ............................................................................................... 16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 16
12. REFERENCES ............................................................................................................ 16
13. DATA PRESENTATION ............................................................................................ 17
13.1 Derived Parameters ............................................................................................... 17
13.2 Missing Data ......................................................................................................... 17
13.3 Insufficient Data for Presentation .......................................................................... 17
14. REVISION OF CHANGES FROM PREVIOUS SAP VERSIONS .............................. 17


Final v2, 28 August 2018
             Page 3 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8381378
Sponsor Reference H8H-JE-LAIE
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
BQL
Below the lower limit of quantitation
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MR
Metabolic ratio
MRE
Magnetic resonance elastography
PK
Pharmacokinetic
QTcF
QT interval corrected using Fridericia’s formula


Final v2, 28 August 2018
             Page 4 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8381378
Sponsor Reference H8H-JE-LAIE
SAP
Statistical Analysis Plan
SD
Standard deviation 
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization
ΔQTcF
changes from baseline in QTcF


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Statistical Analysis Plan 
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Covance Clinical Study No. 8381378
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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 16 
April 2018).
This SAP describes the planned analysis of the safety, tolerability, and pharmacokinetic (PK) 
data from this study. A detailed description of the planned TFLs to be presented in the clinical 
study report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as 
the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective

To explore the safety and tolerability of single and repeated oral doses of lasmiditan in 
healthy Japanese subjects, and single oral doses of lasmiditan in healthy Caucasian 
subjects.
4.2
Secondary Objective

To evaluate the PK of lasmiditan in healthy Japanese and Caucasian subjects.
4.3
Exploratory Objectives

To evaluate the PK of metabolites M7, M8, (S,R)-M18, and (S,S)-M18 in healthy 
Japanese and Caucasian subjects.

To explore the safety, tolerability, and PK of lasmiditan in female subjects compared to 
male subjects.


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5. STUDY DESIGN
This is a randomized, 3-period, subject- and investigator-blind, crossover study in healthy 
Japanese and Caucasian subjects.
Subjects will be evaluated for study eligibility ≤28 days prior to enrollment.  Subjects who fulfil 
the eligibility criteria will be admitted to the clinical research unit (CRU) on Day -1 in Period 1 
(the day before their first dose of lasmiditan or placebo.
Subjects will be enrolled into 1 of 3 cohorts.  Within each cohort, subjects will be randomized to 
a treatment sequence, as indicated in Table 1, Table 2, and Table 3.  Randomization will be 
stratified by sex, such there will be an approximately equal number of male and female subjects 
in each cohort.
Table 1. Treatment Sequences for Cohort 1; Japanese Subjects
Treatment Sequence
Period 1
Period 2
Period 3
1
Placebo
100 mg lasmiditan
200 mg lasmiditan
2
50 mg lasmiditan
Placebo
200 mg lasmiditan
3
50 mg lasmiditan
100 mg lasmiditan
Placebo
Table 2. Treatment Sequences for Cohort 2; Japanese Subjects
Treatment Sequence
Period 1
Period 2
Period 3a
1
Placebo
400 mg lasmiditan
2 x 200 mg lasmiditan
2
50 mg lasmiditan
Placebo
2 x 200 mg lasmiditan
3
100 mg lasmiditan
400 mg lasmiditan
2 x placebo
4
200 mg lasmiditan
400 mg lasmiditan
2 x 200 mg lasmiditan
a Doses administered 2 hours apart
Table 3. Treatment Sequences for Cohort 3; Caucasian Subjects
Treatment Sequence
Period 1
Period 2
Period 3
1
Placebo
100 mg lasmiditan
200 mg lasmiditan
2
50 mg lasmiditan
Placebo
200 mg lasmiditan
3
50 mg lasmiditan
100 mg lasmiditan
Placebo
4
50 mg lasmiditan
100 mg lasmiditan
200 mg lasmiditan
After randomization on Day 1, investigational medical product will be administered orally on the 
morning of Day 1 after an overnight fast of at least 8 hours.  Blood samples will be collected for 
PK analysis predose, and for up to 48 hours postdose in each period.  There will be a washout 
period of approximately 72 hours between dose administrations across periods.
Subjects will be discharged from the CRU following completion of all scheduled procedures on 
Day 3 of Period 3, as defined in the Schedule of Activities (Section 2 in the protocol), and will 
attend a follow-up visit 7 to 10 days following discharge from the CRU on Day 3 of Period 3.
Safety and tolerability will be assessed throughout the study by means of an adverse event (AE) 
review, physical examinations, body weight, vital sign measurements, 12-lead 


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electrocardiograms (ECGs), clinical laboratory tests, and Columbia-Suicide Severity Rating 
Scale (C-SSRS).
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order 
in TFL
Placebo
1
2 x Placebo
2
50 mg lasmiditan
3
100 mg lasmiditan
4
200 mg lasmiditan
5
400 mg lasmiditan
6
2 x 200 mg lasmiditan
7
7. SAMPLE SIZE JUSTIFICATION
The sample size is customary for Phase 1 studies evaluating safety and PK, and is not powered 
on the basis of statistical hypothesis testing.
Subjects who are randomized but not administered treatment may be replaced to ensure that 
approximately 14 Japanese and 8 Caucasian subjects (approximately 2 per treatment sequence) 
may complete the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data.  Subjects may be excluded from the PK summary 
statistics and statistical analysis if a subject has an adverse event of vomiting that occurs at or 
before 2 times median time of maximum observed drug concentration (tmax).
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.


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9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that are databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration 
versus time curve [AUCs] and maximum observed drug concentration [Cmax]) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
subjects included in the relevant analysis population. For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the time point. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, population 
(Japanese or Caucasian), ethnicity, country of enrolment, site ID, body weight, height and body 
mass index will be summarized overall and by population, and listed.
Associated person demographic data for individual subjects will be listed.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
Pharmacokinetic parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 6.4 or later).
Plasma concentrations of lasmiditan (LY573144) and its metabolites (M7, M8, (S,R)-M18 and 
(S,S)-M18) will be used to determine the following PK parameters, when possible:  


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Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration (LY573144 only)
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration (LY573144 only)
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration (LY573144 only)
MR
metabolic ratioa
a no molar correction will be applied since the metabolites are very similar in molecular weight  and within 5% of 
the molecular weight for lasmiditan.
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the clinical study report. Any exceptions or special 
handling of data will be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. 

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. 

AUC(0-) values where the percentage of the total area extrapolated is more than 20% 
will be flagged. Any AUC(0-) value excluded from summary statistics will be noted in 
the footnote of the summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 


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phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on last predicted quantifiable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.


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
A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all pharmacokinetic analyses is not a requirement. Rather, this 
procedure provides justification for exclusion of data when scientifically appropriate. This 
procedure describes the methodology for identifying an individual value as an outlier for 
potential exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For pharmacokinetic profiles during single dosing of non-endogenous compounds, the 
concentration in a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1. If n<6, then the dataset is too small to conduct a reliable range test.  Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e. If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.


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Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
All PK parameters will be summarised by population, as well as population and sex for each 
treatment, and listed.  Plots of mean (+/- SD) plasma concentrations by population, as well as 
population and sex for each treatment over time will be presented. 
Pharmacokinetic parameters for lasmiditan will be evaluated to determine dose proportionality 
for Japanese (Cohorts 1 and 2 over the 50 to 400 mg dose range, excluding any data from 
Period 3 in Cohort 2) and Caucasian subjects (Cohort 3, over the 50 to 200 mg dose range). 
Log-transformed Cmax and AUC from time 0 extrapolated to infinity [AUC(0-∞)] will be 
evaluated using a power model (where the log of the dose will be an explanatory variable and 
subject will be a random effect) to estimate ratios of dose-normalized geometric means and the 
corresponding 90% confidence intervals (CIs). The estimated ratio between the highest and 
lowest doses for each population (Japanese, Caucasian) will be used to assess dose 
proportionality. The intersubject coefficient of variation (CV) will be derived, and the 
intrasubject CV will also be derived, as appropriate.
Example SAS code:
proc mixed data=pk01;
by popul param;
title1 j=c "Estimate of slope";
class usubjid;
model log_pk = log_dose / solution residual cl alpha=0.1;
random usubjid;
ods output solutionf=doseprop;
run;
Additional analysis will be performed if warranted upon review of the data.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables.  A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent.  A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing.  A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose.  
The summary and frequency AE tables will be presented for all causalities and those considered 
related to the study drug.  All AEs will be listed.  


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Treatment-emergent AEs will be summarized by treatment (including overall lasmiditan 
treatment periods and overall placebo treatment period), severity and relationship to the study 
drug, in separate outputs, split by population, as well as sex within population.  Hence the 
following summary tables will be created:

Summary of Treatment-Emergent AE (All Causalities) by Population

Summary of Treatment-Emergent AE (Related to Study Treatment) by Population

Summary of Treatment-Emergent AE (All Causalities) by Sex Within Population

Summary of Treatment-Emergent AE (Related to Study Treatment) by Sex Within 
Population
The frequency (the number of AEs, the number of subjects experiencing an AE and the 
percentage of subjects experiencing an AE) of treatment-emergent AEs will be summarized by 
treatment (including overall lasmiditan treatment periods and overall placebo treatment periods),  
Medical Dictionary for Regulatory Activities (MedDRA) version 21.0 system organ class and 
preferred term, and split by population, as well as sex within population, in separate outputs. Any 
serious AEs will be tabulated. Hence the following frequency tables will be created:

Frequency of Subjects with Treatment-Emergent AE (All Causalities) by Population

Frequency of Subjects with Treatment-Emergent AE (Related to Study Treatment) by 
Population

Frequency of Subjects with Treatment-Emergent AE (All Causalities) by Sex Within 
Population

Frequency of Subjects with Treatment-Emergent AE (Related to Study Treatment) by 
Sex Within Population
Similar outputs but sorting by preferred term, instead of by system organ class and preferred 
term, will be created. Hence the following summary tables will be created:

Summary of Treatment-Emergent AE (All Causalities) by Population and Treatment in 
Order of Frequency

Summary of Treatment-Emergent AE (Related to Study Treatment) by Population and 
Treatment in Order of Frequency

Summary of Treatment-Emergent AE (All Causalities) by Treatment and Sex Within 
Population in Order of Frequency

Summary of Treatment-Emergent AE (Related to Study Treatment) by Treatment and 
Sex Within Population in Order of Frequency
Subject numbers for all TEAEs will be listed.  Pre-existing conditions for individual subjects will 
also be listed.
9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2018 
Enhanced B2).  Concomitant medication will be listed.


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9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by population, parameter, and 
treatment, and listed.  Urinalysis data will be listed.  Additionally clinical chemistry, hematology
and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.4.4
Vital signs
Where supine blood pressure and pulse rate are measured in triplicate, the mean value will be
calculated and used in all subsequent calculations. When triplicate blood pressure or pulse rate
measurements precede a standing measurement, the last supine blood pressure or pulse rate
measurement will be used for orthostatic calculations.
Vital signs data will be summarized by treatment in separate outputs for each population 
(Japanese, Caucasian), as well as for each sex within population, together with changes from 
baseline.
Baseline is defined as follows:
For supine parameters, baseline is the mean of the average values of the triplicate assessments 
collected at -1 hour, -0.5 hours, and predose on Period 1. All other time points are considered as 
post baseline, including predose on Periods 2 and 3.
For standing parameters, baseline is the mean of the assessments collected at -1 hour, -0.5 hours, 
and predose on Period 1.  All other time points are considered as post baseline, including predose 
on Periods 2 and 3.
For orthostatic parameters, baseline is the mean of -1 hour (standing - last supine), -0.5 hours 
(standing - last supine), and predose (standing - last supine) assessments on Period 1. The other 
time points are considered as post baseline, including predose on Periods 2 and 3. Here "last 
supine" means the last supine value taken prior to the standing value.
Figures of mean vital signs and mean changes from baseline profiles will be presented by 
treatment over time in separate outputs for each population (Japanese, Caucasian), as well as for 
each sex within population. Furthermore, values for individual subjects will be listed.
9.4.5
Electrocardiogram (ECG)
The ECG data will be obtained directly from the 12-lead ECG traces.  These data include the PR 
and QT intervals, QRS duration and heart rate. In addition, QTcF (the QT interval corrected 
using Fridericia’s formula) will be calculated as follows:


3 60 HR
QT
QTcF 


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The ECG data will be listed and summarized by population and treatment, together with changes 
from baseline, where baseline is defined as the mean of the average values of the triplicate 
assessments collected at -1 hour,  -0.5 hours, and predose on Period 1. All other time points are 
considered as post baseline, including predose on Periods 2 and 3.
Figures of mean ECG data and mean changes from baseline will be presented by population and 
treatment.  The frequency of subjects with a maximum increase from baseline in QTcF interval 
will be summarized by population and treatment according to the following categories: >30 ms 
and >60 ms.  In addition, the frequency of subjects with QTcF postdose values, according to the 
following categories: >450 ms, >480 ms and >500 ms, will be summarized by population and
treatment.
The relationship between concentrations of lasmiditan and changes from baseline QTcF 
(ΔQTcF) will be explored graphically, using different symbols and colours for each group. The 
comparisons to be explored are:

Japanese vs Caucasian

Japanese (Male vs Female)

Caucasian (Male vs Female)
A linear mixed-effects model will be fitted with the change from baseline in QTcF (ΔQTcF) as 
the response, the time-matched concentration as a covariate, population or sex and time-matched 
concentration-by-population (or sex) as fixed effects for the population or sex analysis 
respectively, and subject as a random effect.  Population and sex will be fitted as binary 
variables, as appropriate (0=Caucasian, 1=Japanese, 0=Male, 1=Female accordingly).  The 
intercept, slope, and random effect covariance from the model along with their 90% CI will be 
reported.  If the model fails to converge, alternative models will be tested.  A scatter plot of 
ΔQTcF versus the concentrations with the fitted lines will also be plotted.  Additional analysis 
may be performed, if deemed necessary.
Example SAS Code:
proc mixed data=ecg alpha=0.1;
class usubjid effect;
model chg_qtcf = conc + effect + conc*effect / alpha=0.1 cl solution 
residual ddfm=bw;
random intercept conc / subject=usubjid type=un s;
run;
where effect represents “population” for the comparison of Japanse versus Caucasian, and “sex” 
for the comparison of males versus females within each population.
9.4.6 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3 × upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2 × ULN, or elevated total bilirubin (TBL) ≥2 × ULN, liver 
tests will be performed to confirm the abnormality.


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Additional safety data should be collected if 1 or more of the following conditions occur:

elevation of ALT to ≥5 × ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2 × ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests
The subjects’ liver disease history and associated person liver disease history data will be listed.  
Any concomitant medication of acetaminophen/paracetamol will be listed.  Results from any 
hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan, and a 
biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed.  Liver related signs and symptoms data will be 
summarized by population and treatment, and listed.  Alcohol and recreational drug use data will 
also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed.  Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.7 Columbia-Suicide Severity Rating Scale (C-SSRS)
Data from the C-SSRS questionnaire (suicidal ideation and behavior data, self-harm follow-up 
questionnaire data) will be listed for individual subjects.
9.4.8 Other assessments
Dosing details and body weight for individual subjects will be listed.
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.4.9 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.


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2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received.  N and percentage 
values should be reported as whole numbers.  Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”
14.
REVISION OF CHANGES FROM PREVIOUS SAP VERSIONS
Version 2 of the SAP was created to include the following major changes/clarifications:

Overall:  The word “race” (Japanese, Caucasian) was replaced by “population”.

Section. 9.4.4 Vital Signs: The baseline definition was clarified.

Section. 9.4.5 Electrocardiogram (ECG): The baseline definition was clarified.  
Additionally, the example SAS code was updated so that the slope can be different for 
different effect group.


Leo Document ID = 51376821-27eb-4716-8423-df8b02d43af5
Approver: 
Approval Date & Time: 29-Aug-2018 12:28:56 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 29-Aug-2018 13:09:33 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Aug-2018 02:25:24 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Aug-2018 04:33:58 GMT
Signature meaning: Approved
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