Clinical trial NCT04081324
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2019-11-13; Completion date: 2020-06-15
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of lasmiditan in healthy Chinese participants. The purposes are:

* To evaluate the safety of lasmiditan
* To learn more about how the body processes lasmiditan

The study will last up to 50 days for each participant.

Detailed description:

Arms: arm 1: Participants received placebo administered orally on Day 1 and repeated doses on Days 4 to 10 (7 days of dosing). arm 2: Participants received 50 mg lasmiditan administered orally once on the morning of Day 1 after an overnight fast of at least 8 hours. Following a period of at least 72 hours without dosing, participants received multiple once-daily oral doses of 50 mg lasmiditan on Days 4 to 10 (7 days of dosing) after overnight fasts of at least 8 hours prior to each dose. arm 3: Participants received 100 mg lasmiditan administered orally once on the morning of Day 1 after an overnight fast of at least 8 hours. Following a period of at least 72 hours without dosing, participants received multiple once-daily oral doses of 100 mg lasmiditan on Days 4 to 10 (7 days of dosing) after overnight fasts of at least 8 hours prior to each dose. arm 4: Participants received 200 mg lasmiditan administered orally once on the morning of Day 1 after an overnight fast of at least 8 hours. Following a period of at least 72 hours without dosing, participants received multiple once-daily oral doses of 200 mg lasmiditan on Days 4 to 10 (7 days of dosing) after overnight fasts of at least 8 hours prior to each dose.
Interventions: intervention 1: Lasmiditan intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol H8H-MC-LAIC(a) 
 
 
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Chinese Subjects 
 
 
NCT04081324 
 
 
Approval Date: 1-Feb-2019 
 
 


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Protocol H8H-MC-LAIC(a)
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in 
Healthy Chinese 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 
LY573144, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Lasmiditan (LY573144)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Approved by Lilly:  09 Aug 2018
Amendment (a) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 01-Feb-2019 GMT


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Table of Contents
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in 
Healthy Chinese Subjects
Section
Page
Protocol H8H-MC-LAIC(a) Safety, Tolerability, and Pharmacokinetics of 
Lasmiditan in Healthy Chinese Subjects..............................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................11
3.1.
Study Rationale............................................................................................................11
3.2.
Background..................................................................................................................11
3.3.
Benefit/Risk Assessment..............................................................................................12
4.
Objectives and Endpoints..................................................................................................13
5.
Study Design.....................................................................................................................14
5.1.
Overall Design .............................................................................................................14
5.2.
Number of Participants.................................................................................................14
5.3.
End of Study Definition ...............................................................................................15
5.4.
Scientific Rationale for Study Design...........................................................................15
5.5.
Justification for Dose ...................................................................................................15
6.
Study Population...............................................................................................................16
6.1.
Inclusion Criteria..........................................................................................................16
6.2.
Exclusion Criteria ........................................................................................................17
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................19
6.3.
Lifestyle and/or Dietary Requirements .........................................................................19
6.3.1.
Meals and Dietary Restrictions.............................................................................19
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................20
6.3.3.
Activity................................................................................................................20
6.4.
Screen Failures.............................................................................................................20
7.
Treatment..........................................................................................................................21
7.1.
Treatment Administered...............................................................................................21
7.1.1.
Packaging and Labeling .......................................................................................21
7.2.
Method of Treatment Assignment ................................................................................21
7.2.1.
Selection and Timing of Doses.............................................................................22
7.3.
Blinding .......................................................................................................................22


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7.4.
Dose Modification........................................................................................................22
7.5.
Preparation/Handling/Storage/Accountability...............................................................22
7.6.
Treatment Compliance .................................................................................................23
7.7.
Concomitant Therapy...................................................................................................23
7.8.
Treatment after the End of the Study............................................................................23
8.
Discontinuation Criteria ....................................................................................................24
8.1.
Discontinuation from Study Treatment.........................................................................24
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................24
8.2.
Discontinuation from the Study....................................................................................24
8.3.
Subjects Lost to Follow-up...........................................................................................25
9.
Study Assessments and Procedures ...................................................................................26
9.1.
Adverse Events ............................................................................................................26
9.1.1.
Serious Adverse Events........................................................................................27
9.1.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................27
9.1.2.
Complaint Handling.............................................................................................28
9.2.
Treatment of Overdose.................................................................................................28
9.3.
Safety...........................................................................................................................28
9.3.1.
Laboratory Tests ..................................................................................................28
9.3.2.
Vital Signs ...........................................................................................................28
9.3.3.
Electrocardiograms ..............................................................................................28
9.3.4.
Colombia-Suicide Severity Rating Scale ..............................................................29
9.3.5.
Safety Monitoring ................................................................................................30
9.3.5.1.
Hepatic Safety................................................................................................30
9.4.
Pharmacokinetics .........................................................................................................30
9.4.1.
Bioanalysis...........................................................................................................31
9.5.
Pharmacodynamics ......................................................................................................31
9.6.
Genetics .......................................................................................................................31
9.7.
Biomarkers...................................................................................................................31
9.8.
Health Economics ........................................................................................................31
10.
Statistical Considerations and Data Analysis.....................................................................32
10.1. Sample Size Determination ..........................................................................................32
10.2. Populations for Analyses..............................................................................................32
10.2.1.
Study Participant Disposition ...............................................................................32
10.2.2.
Study Participant Characteristics ..........................................................................32
10.3. Statistical Analyses ......................................................................................................32
10.3.1.
Safety Analyses....................................................................................................32
10.3.1.1.
Clinical Evaluation of Safety..........................................................................32
10.3.1.2.
Statistical Evaluation of Safety.......................................................................33


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10.3.2.
Pharmacokinetic Analyses....................................................................................33
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................33
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................33
10.3.3.
Data Review During the Study.............................................................................33
10.3.4.
Interim Analyses..................................................................................................33
11.
References ........................................................................................................................34


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List of Tables
Table
Page
Table LAIC.1.
Objectives and Endpoints .......................................................................13
Table LAIC.2.
Treatments Administered........................................................................21
Table LAIC.3.
Amendment Summary for Protocol H8H-MC-LAIC 
Amendment(a)........................................................................................45


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................35
Appendix 2.
Clinical Laboratory Tests........................................................................39
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................40
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............43
Appendix 5.
Blood Sampling Summary......................................................................44
Appendix 6.
Protocol Amendment H8H-MC-LAIC(a) Summary Safety, 
Tolerability, and Pharmacokinetics of Lasmiditan in Healthy 
Chinese Subjects ....................................................................................45


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1. Protocol Synopsis
Title of Study:
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Chinese Subjects
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 single and multiple oral doses of lasmiditan in Chinese subjects, and will 
facilitate subsequent clinical trials in Chinese patients.  Characterization of the safety and pharmacokinetics (PK) of 
lasmiditan in Chinese subjects is essential for further clinical development in China.  
Objectives/Endpoints:  
Objectives
Endpoints
Primary
To evaluate the PK of single and multiple doses of 
lasmiditan in healthy Chinese subjects.
AUC(0-∞) [single-dose only], AUC(0-τ) Cmax, and 
tmax.
Secondary
To explore the safety and tolerability of single and 
multiple oral doses of lasmiditan in healthy Chinese 
subjects.
Incidence of SAEs and TEAEs.
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from time zero extrapolated to infinity;
AUC(0-τ) =  area under the concentration versus time curve over a dosing interval; Cmax = maximum observed 
plasma concentration; PK = pharmacokinetics; SAE = serious adverse event; TEAE = treatment-emergent 
adverse event; tmax = time of maximum observed plasma concentration.
Summary of Study Design:  
Study H8H-MC-LAIC is an investigator- and subject-blinded, randomized, placebo-controlled study in healthy 
Chinese subjects.  The study will evaluate the safety, tolerability, and PK of lasmiditan following single and 
multiple oral doses of 50, 100, and 200 mg.   
Treatment Arms and Planned Duration for an Individual Subject:  
All subjects will participate in a screening visit up to 28 days prior to study drug dosing.
Subjects will be enrolled into 1 of 3 cohorts. All subjects will be admitted to the clinical research unit (CRU) on 
Day -1.  Each subject will receive a single dose of lasmiditan or placebo on Day 1 and multiple once-daily doses of 
lasmiditan or placebo on Days 4 to 10 of the study.  Subjects will discharge from the CRU on Day 12 and attend a 
follow-up visit approximately 7 to 10 days following their final dose of investigational product (IP).
The planned study duration for each subject will be up to 50 days.


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Number of Subjects:
Up to 36 subjects (12 subjects per cohort) may be enrolled and randomized so that approximately 8 subjects per 
cohort, who receive lasmiditan, complete the study.  
Statistical Analysis:
Safety parameters that will be assessed include safety lab parameters and vital signs. The parameters will be listed 
and summarized using descriptive statistics as appropriate. 
Pharmacokinetic parameter estimates for lasmiditan and metabolites M7, M8, (S,R)-M18, and (S,S)-M18 will be 
calculated by standard noncompartmental methods of analysis. Trough concentrations of lasmiditan and its 
metabolites will be evaluated graphically and/or descriptively for achievement of steady-state.
Log-transformed Cmax and AUC parameters (AUC[0-∞] for Day 1 and AUC[0-τ] for Day 10) 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 (CIs).  The estimated ratio 
between the highest and lowest doses will be used to assess dose proportionality.  The intersubject coefficient of 
variation will be derived.


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2. Schedule of Activities
Study Schedule Protocol H8H-MC-LAIC
Screening
Day
FU/
ED
Comments
Procedure
D-28 to 
D-2
-1
1
2
3
4
5 to 9
10
11
12
FU approximately 7 to 10 days post 
final dose.
Informed Consent
X
Subject 
Admission to 
CRU
X
Subject Discharge 
from CRU
X
Lasmiditan or 
Placebo 
Administration
X
X
X
X
Approximately 72 hours between 
the first (D1) and second (D4) 
lasmiditan/placebo doses.
Medical History
X
Urine Drug 
Screen
X
X
Alcohol test
X
X
Height
X
Weight
X
X
X
Single Vital Signs 
(supine)
X
P, 0.5, 1, 
2, 2.5, 3, 
4, 6, 8, 
12 h
24 h
P, 0.5, 1, 
2, 2.5, 3, 
4, 6, 8, 
12 h
24 h 
(D5)
P, 0.5, 1, 
2, 2.5, 3, 
4, 6, 8, 
12 h
24 h
X
Time points relative to dosing on 
D1, D4, and D10.  Vital signs may 
be performed at other times as 
clinically indicated, determined by 
the investigator.
Single Orthostatic 
Vital Signs
X
P, 2 h
24 h
P, 2 h
24 h
(D5)
P, 2 h
24 h
Time points relative to dosing on 
D1, D4, and D10.  Vital signs may 
be performed at other times as 
clinically indicated, determined by 
the investigator.
Clinical 
Laboratory Tests
X
X
P
P
P
X
X
See Appendix 2, Clinical 
Laboratory Tests, for details.


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Screening
Day
FU/
ED
Comments
Procedure
D-28 to 
D-2
-1
1
2
3
4
5 to 9
10
11
12
FU approximately 7 to 10 days post 
final dose.
HIV/Hepatitis
Tests
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
Pregnancy Test 
X
X
X
Female subjects of childbearing 
potential only.  Serum pregnancy 
test will be performed at screening.  
Urine pregnancy test will be 
performed at admission and at FU.
FSH
X
Postmenopausal females only.
Physical 
Examination
X
X
X
X
X
After screening, medical 
assessment only performed to 
include medical review and 
targeted examination, as 
appropriate.
Single 12-Lead 
ECG
X
P, 2, 4 h
24 h
P, 2, 4 h
24 h 
(D5)
P, 2, 4 h
24 h
X
Time points relative to dosing on 
D1, D4, and D10.
C-SSRS and Lilly 
Self-Harm 
Supplement
X
X
X
X
C-SSRS “Baseline” questionnaire 
to be used at screening, all other 
time points use “Since Last Visit” 
questionnaire.
Adverse Event 
Review
X
X
X
X
X
X
X
X
X
X
Plasma Samples 
for Lasmiditan 
and Metabolite 
Pharmacokinetics
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 12 h
24, 
36 h
48 h
P
P
P, 0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 12 h
24, 
36 h
48 h
Time points relative to dosing on 
D1, D4, and D10.
Predose samples to be taken on D5 
to D9 for assessment of 
steady-state. 
Abbreviations:  CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; ED = early 
discontinuation; FSH = follicle-stimulating hormone; FU = follow-up; HIV = human immunodeficiency virus; P = predose. 
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be use: ECG, vital signs, and venipuncture.


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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 single and multiple doses of lasmiditan in Chinese 
subjects, and will facilitate subsequent clinical trials in Chinese patients.  Characterization of the 
safety and pharmacokinetics (PK) of lasmiditan in Chinese subjects is essential for further 
clinical development in China.  
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.  Cumulatively through 05 March 
2018, a total of 3948 subjects/patients have received lasmiditan. The most frequently reported 
lasmiditan treatment-emergent adverse events (TEAEs) in the 2 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
the highest dose of 400 mg administered as a single and multiple (once daily for 7 days) dose, 
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.  
Following dose administration of a single oral tablet to healthy subjects, lasmiditan was absorbed 
with a median tmax of 1.5 to 2.5 hours, and rapidly eliminated with a mean t1/2 of approximately 
4 hours.  Over the clinical dose range of 50 to 200 mg, the mean estimates of lasmiditan Cmax
and AUC(0-) increased in a dose-dependent manner that was approximately linear with dose.
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 


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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.
The characterization of lasmiditan PK in Asian subjects has been limited.  Therefore, it is not 
known whether there are PK differences between subjects of Asian descent, relative to the 
overall population.
3.3.
Benefit/Risk Assessment
Oral doses of lasmiditan up to the highest single and multiple 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 05 March 2018.  Lasmiditan caused no significant QT prolongation 
either at 100 or 400 mg, and no clinically significant changes in clinical laboratory data.  
Lasmiditan has been associated with transient lowering of heart rate (on average about 8 to 
12 bpm). Throughout this study, vital signs will be closely monitored for effects of lasmiditan on 
heart rate.  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 the last dose of investigational product (IP).
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 LAIC.1 shows the objectives and endpoints of the study.
Table LAIC.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the PK of single and multiple doses of 
lasmiditan in healthy Chinese subjects.
AUC(0-∞) [single-dose only], AUC(0-τ), Cmax, and 
tmax.
Secondary
To explore the safety and tolerability of single and 
multiple oral doses of lasmiditan in healthy Chinese 
subjects.
Incidence of SAEs and TEAEs.
Exploratory
To evaluate the PK of metabolites M7, M8, (S,R)-M18, 
and (S,S)-M18 in healthy Chinese subjects.
AUC(0-∞), Cmax, and tmax.
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from time zero extrapolated to infinity;
AUC(0-τ) = area under the concentration versus time curve over a dosing interval; 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 study is a Phase 1, investigator- and subject-blinded, randomized, placebo-controlled study 
in healthy Chinese subjects. 
Subjects will be enrolled into 1 of 3 cohorts and receive single and multiple doses of lasmiditan 
or placebo in a parallel design. Each cohort will comprise 12 subjects (10 lasmiditan:2 placebo) 
and will be assigned the following doses:

Cohort 1 = 50 mg lasmiditan (or placebo)

Cohort 2 = 100 mg lasmiditan (or placebo)

Cohort 3 = 200 mg lasmiditan (or placebo)
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 (the day 
before their first dose of lasmiditan or placebo; Section 2).
After randomization on Day 1, IP (lasmiditan or placebo) will be administered orally once on the 
morning of Day 1 after an overnight fast of at least 8 hours.  Following a period of at least 
72 hours without IP dosing, subjects will receive multiple once-daily oral doses of IP on Days 4 
to 10 (7 days of dosing), after overnight fasts of at least 8 hours prior to each dose.  The doses of 
lasmiditan administered on Days 4 to 10 will be the same dose as that administered on Day 1 for 
each subject.  
Subjects will be discharged from the CRU on Day 12 following completion of all scheduled 
procedures, as defined in the Schedule of Activities (Section 2), and will attend a follow-up visit 
approximately 7 to 10 days following final oral dose of IP.
The planned study duration for each subject will be up to 50 days.
Blood samples will be collected for PK analysis.  Safety and tolerability will be assessed 
throughout the study by means of AE review, physical examinations, vital sign measurements, 
12-lead electrocardiograms (ECGs), clinical laboratory tests, and Columbia-Suicide Severity 
Rating Scale (C-SSRS).
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Up to 36 subjects (12 subjects per cohort) may be enrolled and randomized so that approximately 
8 subjects per cohort, who receive lasmiditan, 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.


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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 safety and tolerability objective of this study.
Single and repeated doses of 50, 100, and 200 mg lasmiditan are considered the planned clinical 
doses.  
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, other medical conditions, and concomitant medications in patients.  Conducting 
this study in Chinese subjects will provide PK data for evaluation on ethnic sensitivity of 
lasmiditan.  In addition, it will support the inclusion of Chinese subjects in a future global Phase 
3 study with lasmiditan. 
It is not considered necessary to conduct safety data reviews of previous cohorts (lower dose 
levels) prior to dosing the next cohort.  The relative dosing of cohorts (parallel or sequential) will 
therefore be at the discretion of the investigator.
5.5.
Justification for Dose
Oral doses of 50, 100, and 200 mg lasmiditan are envisaged to be clinically effective doses for 
the target population, based on data obtained from previous completed studies.  


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy Chinese (all 4 biological grandparents and both biological 
parents to be of Chinese origin) males or females, as determined by medical 
history and physical examination  
[1a] male subjects will not be subject to any specific contraception 
requirements
[1b] women of childbearing potential must test negative for pregnancy at 
screening and on Day -1, and must agree to use 1 highly effective (<1% 
failure rate) method of contraception or 2 effective methods of contraception 
during the study and for 30 days following the last dose of IP.  
Highly effective methods of contraception include oral contraceptives, 
implanted contraceptives, or intrauterine devices.  Effective methods of 
contraception include male or female condoms with concomitant use of
spermicide, diaphragm with spermicide, or cervical sponges.  Barrier
methods without the concomitant use of spermicide or the use of male and 
female condoms as a double-barrier method are not acceptable. 
Women of childbearing potential who practice abstinence or are in same-sex 
relationships, as their preferred and usual lifestyle, must agree to either 
remain abstinent or stay in a same-sex relationship without sexual 
relationships with males.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, postovulation methods), declaration of abstinence for the 
purpose of the study, and withdrawal are not acceptable.


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[1c] 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
[2]
are aged between 18 and 65 years, inclusive, at screening
[3]
have a body mass index (BMI) 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 employees or are employees of third-party organizations involved 
with the study
[10]
are currently enrolled in a clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study  
[11]
have participated, within the last 30 days, in a clinical study involving an IP.  
If the previous IP has a long half-life, 5 half-lives or 30 days (whichever is 
longer) should have passed


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[12]
have previously completed or withdrawn from this study or any other study 
investigating lasmiditan, and have previously received the IP
[13]
have known allergies to lasmiditan, related compounds or any components of 
the formulation
[14]
have a history of, or ECG findings of, clinically significant bradycardia, heart 
block, tachyarrhythmia, bradyarrhythmia, or have any other abnormality that, 
in the opinion of the investigator, increases the risk of participating in the 
study 
[15]
have an abnormal blood pressure and/or pulse rate as determined clinically 
significant by the investigator
[16]
have a significant history of or current cardiovascular, respiratory, 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 IP; or of interfering with the 
interpretation of data.  Examples of excluded conditions include, but are not 
limited to; hypertension, angina, heart failure, asthma (childhood asthma is 
acceptable), chronic obstructive airways disease, hepatitis, cirrhosis, renal 
impairment, diabetes, anemia, migraine, fits, seizures (except febrile 
convulsions), significant head trauma, surgical resection of bowel 
(appendectomy is acceptable), or any other condition requiring chronic 
medication
[17]
have a history of, show evidence of, or are undergoing treatment for 
significant active neuropsychiatric disease (for example, manic depressive 
illness, schizophrenia, depression) 
[18]
have a recent history of a suicide attempt (30 days within screening visit and
any time between screening visit and baseline), evidence of suicide-related 
thought or behavior as identified by the C-SSRS, or are clinically judged by 
the investigator to be at risk for suicide
[19]
have a history of central nervous system (CNS) conditions such as strokes, 
transient ischemic attack, significant head trauma, CNS infections, migraines, 
brain surgery, or any other neurological conditions that, in the opinion of the 
investigator, increases the risk of participating in the study
[20]
regularly use known drugs of abuse and/or show positive findings on drug 
screening
[21]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[22]
show evidence of hepatitis C and/or positive hepatitis C antibody
[23]
show evidence of hepatitis B and/or positive hepatitis B surface antigen
[24]
are women with a positive pregnancy test or women who are lactating


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[25]
have used or intend to use over-the-counter or prescription medication 
including herbal medications and Chinese traditional medicine within 14 days 
prior to admission to the CRU and until discharge from the study (with the 
exception of hormone-replacement therapy, oral contraceptives, or occasional 
acetaminophen use)
[26]
have donated blood of more than 400 mL within 1 month prior to screening 
[27]
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 
48 hours prior to admission and throughout the duration of the study (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)
[28]
currently use or have a history of drug or alcohol abuse
[29]
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
[30]
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 Chinese population for the purposes of this study.  The use of lasmiditan in 
Chinese patients is anticipated, thus this study will specifically examine the PK, safety, and 
tolerability in Chinese subjects. 
Criteria [8] and [9] prevent conflict of interest in study participants.  Criteria [10] to [30] 
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.
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.  Subjects will remain 
fasting for 3 hours postdose on Days 1 and 10.  On Days 2 to 9, a light breakfast will be allowed 
1 hour postdose.  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.  


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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 until the end of the study period.
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 the CRU and for the 
duration of the study.
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 (Day 1) and repeated (Days 4 to 10) doses of 50, 100, 
and 200 mg lasmiditan administered orally, with placebo.
Table LAIC.2 shows the treatment regimens at for each cohort.
Table LAIC.2.
Treatments Administered
Cohort
Dose level
Number of tablets administered 
per dose
1
50 mg lasmiditan or placebo
1 x 50-mg tablet
2
100 mg lasmiditan or placebo
1 x 100-mg tablet
3
200 mg lasmiditan or placebo
2 x 100-mg tablet
Tablets of lasmiditan or placebo will be orally administered with approximately 240 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.
The investigator or designee is responsible for:

explaining the correct use of the IP(s) to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
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
Each tablet of lasmiditan contains 50 or 100 mg of active ingredient and is provided in a blister.  
Placebo tablets look identical but contain no active ingredient and will be provided in a similar 
blister.
The IP will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS). The IWRS will be used to assign a blister 
containing double-blind IP to each subject.  


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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 case report form (CRF).
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 unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the subject’s well-being requires knowledge of the subject’s treatment assignment.  All 
unblinding events are recorded and reported by the IWRS.
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 clinical pharmacologist (CP)
or clinical research physician (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.
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 sponsor, during transit for all IP received and any discrepancies 
are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply or administer IP. All IP 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).


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7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
In general, concomitant medication should be avoided; however, acetaminophen (1g, maximum 
3 g/24 hours) may be administered at the discretion of the investigator for treatment of minor 
AEs.  For female subjects, the use of hormone-replacement therapy will be permitted. 
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 adverse 
event and other follow-up procedures per Section 2 of this protocol.
Subjects discontinuing from the study prematurely for any reason must complete adverse event 
and follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the IP for 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 (INR) >1.5

ALT or AST >3 × ULN and 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 
IP.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

The investigator decides that the subject should be discontinued from the study


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
The subject, or legal representative, requests to be withdrawn from the study

If a suicide-related thought or behavior is identified at any time during the study, or if 
during the study a subject gives:
o
A “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the “Suicidal Ideation” portion of the C-SSRS; or
o
A “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the “Suicidal Ideation” portion of the C-SSRS; or
o
A “yes” answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act, or behavior) on the “Suicidal Behavior” 
portion of the C-SSRS.
In addition, a subject will also be evaluated for discontinuation if they have self-injurious 
behavior that would be classified as non-suicidal self-injurious behavior. It is recommended that 
a subject be assessed by a psychiatrist or appropriately trained professional to assist the 
investigator in deciding whether the subject should be discontinued 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.
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.
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 healthcare option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the subject to discontinue the IP 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 (ICF) is signed, study site personnel will record, via electronic 
CRF (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 IP, 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.
If a subject’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via eCRF.


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9.1.1. 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 CRP/CP, 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 IP.  However, if 
an SAE occurs after signing informed consent, but prior to receiving IP, 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 CRF 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 IP) does not meet the definition of an adverse event.  
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.
9.1.1.1.
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 IP or procedure.  Lilly 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.


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9.1.2. Complaint Handling
Lilly collects product complaints on IPs 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 IP so that the situation can be assessed.
9.2.
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.
9.3.
Safety
9.3.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
All safety laboratory tests during the study will be analyzed by a local laboratory.
9.3.2. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
When orthostatic measurements are required, 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. 
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.
9.3.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP, should be reported to Lilly, or its designee, as an AE via 
eCRF. 


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For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities.  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.  Electrocardiograms may be obtained at additional times, when 
deemed clinically necessary.  All ECGs recorded should be stored at the investigational site.
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.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, 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, and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE.
9.3.4. Colombia-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 preexisting 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 


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Form will be used to collect additional information to allow for a more complete assessment of 
these behaviors.
9.3.5. Safety Monitoring
The Lilly CP/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 or 
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.
9.3.5.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3 × ULN, ALP ≥2 × ULN, or elevated TBL ≥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 an SAE.
9.4.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), 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 plasma 
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 


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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.
9.4.1. 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 IP 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.
9.5.
Pharmacodynamics
Not applicable. 
9.6.
Genetics
Not applicable.
9.7.
Biomarkers
Not applicable. 
9.8.
Health Economics
Not applicable.


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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 8 subjects per cohort, who receive lasmiditan, 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, BMI, and other demographic characteristics will be 
recorded and summarized using descriptive statistics.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.  Further detail on required analyses will be presented in the statistical analysis plan. 
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least one 
dose of the IP 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 purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All safety analyses will be performed using the safety population which will consist of subjects 
who received at least 1 dose of IP.
All IP and protocol procedure AEs will be listed and, 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 IP as perceived by the investigator.  Symptoms reported to occur prior to enrollment 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.
The number of IP-related SAEs will be reported.


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10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety lab parameters and vital signs.  The 
parameters will be listed, and summarized using standard descriptive statistics, as appropriate.
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 parameter estimates 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 area under the concentration versus time curve 
(AUC) from zero to infinity (AUC[0-∞]) [single-dose only], AUC over a dosing interval 
(AUC[0-τ]), maximum observed drug concentration (Cmax), and  time of maximum observed 
drug concentration (tmax).  Other noncompartmental parameters, such as half-life, apparent 
clearance, apparent volume of distribution, and accumulation ratio may be reported.
Trough concentrations of lasmiditan and its metabolites will be evaluated graphically and/or 
descriptively for achievement of steady-state. No formal analysis will be performed for 
attainment of steady-state.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters for lasmiditan will be evaluated to estimate dose proportionality 
over the 50 to 200-mg dose range on Day 1 and Day 10.  Log-transformed Cmax and AUC 
parameters (AUC[0-∞] for Day 1 and AUC[0-τ] for Day 10) 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 (CIs).  The 
estimated ratio between the highest and lowest doses will be used to assess dose proportionality.  
The intersubject coefficient of variation will be derived.
10.3.3. Data Review During the Study
This section is not applicable for this study. 
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
None cited.


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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 zero to infinity
AUC(0-τ)
area under the concentration versus time curve over a dosing interval
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
BMI
body mass index
CI
confidence interval
Cmax
maximum observed drug 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 (GCP) 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
CRF/eCRF
case report form/electronic case report form


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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
ECG
electrocardiogram
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.
ERB
ethical review board
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
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.
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.
IP
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.
IWRS
interactive web-response system
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.
PK
pharmacokinetic
randomize
The process of assigning subjects/patients to an experimental group on a random basis.
SAE
serious adverse event


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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.  
SUSAR
suspected unexpected serious adverse reaction 
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 drug concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Testsa
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Chloride 
Mean cell volume 
Calcium
Mean cell hemoglobin 
Phosphorus
Mean cell hemoglobin concentration 
Magnesium 
Leukocytes (WBC) 
Glucose (random)
Platelets
Urea
Differential WBC (absolute counts and % of):
Uric acid 
Neutrophils
Total cholesterol 
Lymphocytes
Total protein
Monocytes
Albumin
Eosinophils
Total bilirubin
Direct bilirubinb
Basophils
Alkaline phosphatase
Aspartate aminotransferase
Urinalysis
Alanine aminotransferase 
Specific gravity
Creatinine
pH
Gamma-glutamyl transferase
Protein
Glucose
Ketones
Urine drug screenc
Bilirubin
Alcohol testingc
Urobilinogen
Hepatitis B surface antigend
Blood
Hepatitis C antibodyd
Nitrite
Human immunodeficiency virus antibodiesd
Microscopic examination (reflex if blood or nitrite is 
positive)
Pregnancy test 
FSH (postmenopausal females only)d
Abbreviations:  FSH = follicle-stimulating hormone; RBC = red blood cells; WBC = white blood cells.
a
All safety laboratory tests will be analyzed at a local laboratory  
b
Direct bilirubin will be analyzed if total bilirubin is elevated above upper limit of normal
c
Performed at screening and admission to Clinical Research Unit only
d
Performed at screening 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 or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of IP.

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 or the participant’s legal representative 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 ethical review 
board (ERB) was properly constituted and convened as required by International Council for 
Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF 

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:


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1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) 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 CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the 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, 


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applicable regulatory agencies, and applicable ERBs 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 ERB 
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 CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
Red blood cells
Prothrombin time
White blood cells
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologya,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
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase
Anti-nuclear antibodya
Aspartate aminotransferase
Alkaline phosphatase isoenzymesa
Gamma-glutamyl transferase
Creatine phosphokinase
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  Ig = immunoglobulin; INR = international normalized ratio.
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.  
Protocol H8H-MC-LAIC Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
21.5
1
21.5
Clinical laboratory testsa
7.5
6
45
Pharmacokineticsb
2
34
68
Total
134.5
Total for clinical purposes (rounded up to nearest 10 mL)
140
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.


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Appendix 6.
Protocol Amendment H8H-MC-LAIC(a) 
Summary Safety, Tolerability, and Pharmacokinetics of 
Lasmiditan in Healthy Chinese Subjects
Overview
Protocol H8H-MC-LAIC [Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy 
Chinese Subjects] has been amended.  The new protocol is indicated by Amendment (a) and will 
be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Table LAIC.3.
Amendment Summary for Protocol H8H-MC-LAIC Amendment(a)
Section # and Name
Description of Change
Brief Rationale
6.2. Exclusion Criteria
Exclusion criteria 16 has been 
expanded to include a list of 
excluded medical history/current 
medical conditions.  
The list has been added to provide 
clarity to the study site.  
7.1.1.  Packaging and Labelling
Provision of lasmiditan and placebo 
tablets has been changed from bulk 
supply in bottles to a blister.
Change reflects current format of 
tablet supply.
7.2.  Method of Treatment 
Assignment
The method of randomization has 
been changed from using a computer 
generated randomization schedule to 
a computer-generated random 
sequence using an interactive 
web-response system (IWRS)
Change reflects randomization 
method used by the study site.  
7.3 Blinding
The method of unblinding has been 
changed from emergency codes to
being performed through the IWRS.
Change reflects unblinding 
procedure when using an IWRS.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
6.2.
Exclusion Criteria
[16] have a significant history of or current cardiovascular, respiratory, 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 IP; or of interfering with the 
interpretation of data.  Examples of excluded conditions include, but are not 
limited to; hypertension, angina, heart failure, asthma (childhood asthma is 
acceptable), chronic obstructive airways disease, hepatitis, cirrhosis, renal 
impairment, diabetes, anemia, migraine, fits, seizures (except febrile 
convulsions), significant head trauma, surgical resection of bowel 
(appendectomy is acceptable), or any other condition requiring chronic 
medication
7.1.1.Packaging and Labelling
Each tablet of lasmiditan contains 50 or 100 mg of active ingredient and is provided as bulk 
supply in bottles in a blister.  Placebo tablets look identical but contain no active ingredient and 
will be provided in a similar bulk bottles blister.
The IP will be labeled according to the country’s regulatory requirements.
7.2
Method of Treatment Assignment
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS). The IWRS will be used to assign a blister 
containing double-blind IP to each subject.  Subjects will be randomized to lasmiditan or placebo 
treatment using a computer generated allocation schedule.
7.3
Blinding
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. Emergency unblinding for AEs may be 
performed through the IWRS.  This option may be used ONLY if the subject’s well-being 
requires knowledge of the subject’s treatment assignment.  All unblinding events are recorded 
and reported by the IWRS.


Leo Document ID = 0e586acf-57b6-42f4-b0f9-d7e8b27ce943
Approver: 
Approval Date & Time: 01-Feb-2019 03:35:52 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 01-Feb-2019 14:33:16 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan H8H-MC-LAIC 
 
 
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Chinese Subjects 
 
 
NCT04081324 
 
 
Approval Date: 25-Sep-2018 
 
 


Final, 24 September 2018
             Page 1 of 14
STATISTICAL ANALYSIS PLAN
Safety, Tolerability, and Pharmacokinetics of Lasmiditan in Healthy Chinese Subjects
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  24-September-2018
Study Drug:  Lasmiditan (LY573144)
Sponsor Reference:  H8H-MC-LAIC
Covance CRU Study: 1001215-8390215
Clinical Phase I
Approval Date: 25-Sep-2018 GMT


Final, 24 September 2018
             Page 2 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8390215
Sponsor Reference H8H-MC-LAIC
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 objective ....................................................................................................5
5.
STUDY DESIGN.................................................................................................................6
6.
TREATMENTS...................................................................................................................6
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................7
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................7
9.
STATISTICAL METHODOLOGY .....................................................................................7
9.1
General..........................................................................................................................7
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............................................................................13
9.4.4
Vital signs ..........................................................................................................13
9.4.5
Electrocardiogram ..............................................................................................13
9.4.6
Columbia Suicide Severity Rating Scale and Lilly Self-Harm Supplement .........13
9.4.7
Other assessments...............................................................................................14
9.4.8
Safety and Tolerability Statistical Methodology..................................................14
10. INTERIM ANALYSES .....................................................................................................14
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............14
12. REFERENCES ..................................................................................................................14
13. DATA PRESENTATION ..................................................................................................14
13.1 Derived Parameters .....................................................................................................14
13.2 Missing Data ...............................................................................................................14
13.3 Insufficient Data for Presentation ................................................................................14


Final, 24 September 2018
             Page 3 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8390215
Sponsor Reference H8H-MC-LAIC
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
 AUCτ
Area under the concentration versus time curve during one dosing interval 
(i.e. 24 h)
 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 quantifiable lower limit of the assay
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
IP
Investigational product
LLOQ
Lower limit of quantification 
MedDRA
Medical Dictionary for Regulatory Activities
MR
Metabolic ratio
NA
Not applicable
PK
Pharmacokinetic
RA
Accumulation ratio (based on Cmax and AUCτ)


Final, 24 September 2018
             Page 4 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8390215
Sponsor Reference H8H-MC-LAIC
RI
linearity ratio between AUCτ after multiple dosing day and AUC(0-∞) after 
single dosing day
SAP
Statistical Analysis Plan
SD
Standard deviation 
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
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Final, 24 September 2018
             Page 5 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8390215
Sponsor Reference H8H-MC-LAIC
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
09 August 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 evaluate the PK of single and multiple doses of lasmiditan in healthy Chinese subjects.
4.2
Secondary objective
To explore the safety and tolerability of single and multiple oral doses of lasmiditan in healthy 
Chinese subjects.
4.3
Exploratory objective
To evaluate the PK of metabolites M7, M8, (S,R)-M18, and (S,S)-M18 in healthy Chinese 
subjects


Final, 24 September 2018
             Page 6 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1001215-8390215
Sponsor Reference H8H-MC-LAIC
5. STUDY DESIGN
This study is a Phase 1, investigator- and subject-blinded, randomized, placebo-controlled study 
in healthy Chinese subjects.
Subjects will be enrolled into 1 of 3 cohorts and receive single and multiple doses of lasmiditan 
or placebo in a parallel design. Each cohort will comprise 12 subjects (10 lasmiditan:  2 placebo) 
and will be assigned the following doses:

Cohort 1 = 50 mg lasmiditan (or placebo)

Cohort 2 = 100 mg lasmiditan (or placebo)

Cohort 3 = 200 mg lasmiditan (or placebo)
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 (the day 
before their first dose of lasmiditan or placebo).
After randomization on Day 1, investigational product (IP: lasmiditan or placebo) will be 
administered orally once on the morning of Day 1 after an overnight fast of at least 8 hours.  
Following a period of at least 72 hours without IP dosing, subjects will receive multiple 
once-daily oral doses of IP on Days 4 to 10 (7 days of dosing), after overnight fasts of at least 
8 hours prior to each dose.  The doses of lasmiditan administered on Days 4 to 10 will be the 
same dose as that administered on Day 1 for each subject.
Subjects will be discharged from the CRU on Day 12 following completion of all scheduled 
procedures and will attend a follow-up visit approximately 7 to 10 days following final oral dose 
of IP.
The planned study duration for each subject will be up to 50 days.
Blood samples will be collected for PK analysis.  Safety and tolerability will be assessed 
throughout the study by means of adverse event (AE) review, physical examinations, vital sign 
measurements, 12-lead 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
50 mg lasmiditan
2
100 mg lasmiditan
3
200 mg lasmiditan
4


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8390215
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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 8 subjects per cohort, who receive lasmiditan, may complete the study. 
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects who received at least 1 dose of IP, 
whether or not they completed all protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who receive at least one dose of 
lasmiditan and have evaluable PK.
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.
Placebo subjects will be pooled across cohorts.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is 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 curves [AUCs] and the 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 timepoint. 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.


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Covance Clinical Study No. 1001215-8390215
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9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized and listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
Pharmacokinetic (PK) parameter estimates will be determined using non-compartmental 
procedures in a 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 for single and multiple dose 
(unless otherwise specified), when possible: 
Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUCτ
ng.h/mL
area under the concentration versus time curve during one dosing 
interval (i.e. 24 h)
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(0-∞)
ng.h/mL
area under the concentration versus time curve from time zero to infinity
(after single dose only)
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated (after single dose only)
t1/2
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)
RA
accumulation ratio (based on Cmax and AUCτ) (after multiple dose only -
LY573144 only)
RI
linearity ratio between AUCτ after multiple dosing day and AUC(0-∞) 
after single dosing day (LY573144 only)
MR
metabolic ratioa (after multiple dose only)
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.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8390215
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Trough concentrations of lasmiditan and its metabolites will be evaluated graphically and 
descriptively for achievement of steady-state. No formal analysis will be performed for 
attainment of steady-state.
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. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

Both Cmax and time of maximum observed drug concentration (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 
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.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8390215
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
The parameters based on predicted 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.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.
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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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8390215
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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 PK 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 PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK 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.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8390215
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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.
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 summarized by analyte and treatment, and listed.  Plots of 
mean (+/- SD) plasma concentrations by analyte and treatment over time will be presented. 
Pharmacokinetic parameters for lasmiditan will be evaluated to estimate dose proportionality 
over the 50 to 200-mg dose range on Day 1 and Day 10 separately and will be presented 
graphically, as well as in analysis tables. Log-transformed Cmax and AUC parameters 
(AUC[0-∞] for Day 1 and AUCτ for Day 10) 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 (CIs). The estimated ratio between the 
highest and lowest doses will be used to assess dose proportionality.  The intersubject coefficient 
of variation will be derived.
Example SAS code:
proc mixed data=pk01;
by param pkday;
title1 j=c "Estimate of slope";
model log_pk = log_dose / solution residual cl alpha=0.1;
estimate 'xx mg' intercept 1 log_dose yy / alpha=0.1 cl; /*Log value 
of xx*/
estimate 'zz mg - xx mg' log_dose pp / alpha=0.1 cl; /*Difference in 
log values of zz and xx*/
ods output estimates=estims;
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 


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8390215
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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. Adverse events by day of onset will be presented.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. 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, Medical Dictionary for Regulatory Activities (MedDRA)
version 21.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.4.2 Concomitant medication
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version March 2018 Enhanced B2). Concomitant medication will be listed.
9.4.3 Clinical laboratory parameters
All clinical chemistry and hematology data will be listed and summarized by parameter,
treatment, and timepoint together with changes from baseline, where baseline is defined as 
Day 1, predose. 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
Orthostatic vital signs will be calculated as the standing value, minus the last supine value taken 
prior to the standing value.
Vital signs data will be summarized by treatment and timepoint together with changes from 
baseline, where baseline is defined as Day 1, predose. Figures of mean vital signs and mean 
changes from baseline profiles by treatment will be presented. 
Furthermore, values for individual subjects will be listed.
9.4.5 Electrocardiogram
For each subject, ECGs will be performed for safety purposes only, and will not be reported.
9.4.6 Columbia Suicide Severity Rating Scale and Lilly Self-Harm Supplement
Data from the C-SSRS questionnaire will be listed for individual subjects.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1001215-8390215
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9.4.7 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.8 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.
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.”


Leo Document ID = e249a52e-e5ab-449a-998f-5800f065f1c0
Approver: 
Approval Date & Time: 25-Sep-2018 10:35:52 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 25-Sep-2018 13:44:58 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 25-Sep-2018 14:19:40 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 25-Sep-2018 20:18:21 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD