Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 68
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the effect of lasmiditan on simulated driving performance in healthy participants. Participants are expected to complete each of four study periods, which will last a total of about 10 days. During this time, participants will remain in the clinical research unit. Screening must be completed within 28 days before the start of the study. Follow-up will be completed about one week after discharge.

Detailed description:

Arms:
arm 1: Placebo administered orally in one of four study periods. arm 2: 100 mg lasmiditan administered orally in one of four study periods. arm 3: 200 mg lasmiditan administered orally in one of four study periods. arm 4: 50 mg diphenhydramine administered orally in one of four study periods.

Interventions: intervention 1: Lasmiditan intervention 2: Placebo intervention 3: Diphenhydramine
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally

Protocol document:
Prot_000.pdf: 
Protocol  H8H-MC-LAIF(a) A Phase 1, Randomized, Subject- and Investigator-Blink,Placebo-Controlled, 4-
Period Cross-Over Study Assessing the Duration of Effect of Lasmiditan on Stimulated Driving 
Performance in Healthy Volunteers 
 
NCT03459612 
Approval date: 21 Feb 2018 


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Protocol H8H-MC-LAIF(a)
A Phase I, Randomized, Subject- and Investigator-Blind, 
Placebo-Controlled, 4-Period Cross-Over Study Assessing 
the Duration of Effect of Lasmiditan on Simulated Driving 
Performance in Healthy Volunteers
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
lasmiditan (LY573144), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (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 Electronically Signed and Approved by Lilly:
15 February 2018
Amendment (a) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 21-Feb-2018 GMT


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Table of Contents
A Phase I, Randomized, Subject- and Investigator-Blind, 
Placebo-Controlled, 4-Period Cross-Over Study Assessing 
the Duration of Effect of Lasmiditan on Simulated Driving 
Performance in Healthy Volunteers
Section
Page
Protocol H8H-MC-LAIF(a) A Phase I, Randomized, Subject- and 
Investigator-Blind, Placebo-Controlled, 4-Period Cross-Over Study 
Assessing the Duration of Effect of Lasmiditan on Simulated Driving 
Performance in Healthy Volunteers.....................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.2.
Number of Participants.................................................................................................20
5.3.
End of Study Definition ...............................................................................................20
5.4.
Scientific Rationale for Study Design...........................................................................20
5.5.
Justification for Dose ...................................................................................................21
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................26
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................26
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................26
6.3.3.
Activity................................................................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28
7.1.
Treatment Administered...............................................................................................28
7.1.1.
Packaging and Labeling .......................................................................................29


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7.2.
Method of Treatment Assignment ................................................................................29
7.2.1.
Selection and Timing of Doses.............................................................................29
7.3.
Blinding .......................................................................................................................30
7.4.
Dose Modification........................................................................................................30
7.5.
Preparation/Handling/Storage/Accountability...............................................................30
7.6.
Treatment Compliance .................................................................................................31
7.7.
Concomitant Therapy...................................................................................................31
7.8.
Treatment after the End of the Study............................................................................31
8.
Discontinuation Criteria ....................................................................................................32
8.1.
Discontinuation from Study Treatment.........................................................................32
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................32
8.2.
Discontinuation from the Study....................................................................................32
8.3.
Patients/Subjects Lost to Follow-up..............................................................................33
9.
Study Assessments and Procedures ...................................................................................34
9.1.
Efficacy Assessments...................................................................................................34
9.2.
Adverse Events ............................................................................................................34
9.2.1.
Serious Adverse Events........................................................................................35
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................35
9.2.2.
Complaint Handling.............................................................................................36
9.3.
Treatment of Overdose.................................................................................................36
9.3.1.
Overdose of Lasmiditan .......................................................................................36
9.3.2.
Overdose of Diphenhydramine.............................................................................36
9.4.
Safety...........................................................................................................................36
9.4.1.
Laboratory Tests ..................................................................................................36
9.4.2.
Vital Signs ...........................................................................................................36
9.4.3.
Electrocardiograms ..............................................................................................37
9.4.4.
Safety Monitoring ................................................................................................37
9.4.4.1.
Hepatic Safety................................................................................................38
9.5.
Pharmacokinetics .........................................................................................................38
9.5.1.
Bioanalysis...........................................................................................................38
9.6.
Pharmacodynamics ......................................................................................................39
9.6.1.
Country Vigilance-Divided Attention Driving Scenario on 
the CRCDS-MiniSim ...........................................................................................39
9.6.2.
Karolinska Sleepiness Scale .................................................................................39
9.6.3.
Self-Perceived Safety to Drive Question...............................................................39
9.6.4.
CogScreen Symbol Digit Coding..........................................................................39
9.6.5.
Visual Analog Scale to Assess Subject’s Motivation and 
Self-Appraisal......................................................................................................40


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9.7.
Genetics .......................................................................................................................40
9.8.
Health Economics ........................................................................................................40
10.
Statistical Considerations and Data Analysis.....................................................................41
10.1. Sample Size Determination ..........................................................................................41
10.2. Populations for Analyses..............................................................................................41
10.2.1.
Study Participant Disposition ...............................................................................41
10.2.2.
Study Participant Characteristics ..........................................................................41
10.3. Statistical Analyses ......................................................................................................41
10.3.1.
Safety Analyses....................................................................................................42
10.3.1.1.
Clinical Evaluation of Safety..........................................................................42
10.3.1.2.
Statistical Evaluation of Safety.......................................................................42
10.3.2.
Pharmacokinetic Analyses....................................................................................42
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................42
10.3.3.
Pharmacodynamic Analyses.................................................................................42
10.3.3.1.
Pharmacodynamic Statistical Inference...........................................................43
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................44
11.
References ........................................................................................................................45


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List of Tables
Table
Page
Table LAIF.1.
Objectives and Endpoints .......................................................................18
Table LAIF.2.
Treatments Administered........................................................................28
Table LAIF.3.
Treatment Schedule................................................................................28


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List of Figures
Figure
Page
Figure LAIF.1.
Study schematic......................................................................................20
Figure LAIF.2
Timing of doses......................................................................................29
Figure LAIF.3.
Pharmacodynamic statistical inference – graphical multiple 
comparisons procedure...........................................................................43


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................46
Appendix 2.
Clinical Laboratory Tests........................................................................50
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................51
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............54
Appendix 5.
Blood Sampling Summary......................................................................55
Appendix 6.
Protocol Amendment H8H-MC-LAIF(a) Summary: A Phase I, 
Randomized, Subject- and Investigator-Blind, Placebo-Controlled, 
4-Period Cross-Over Study Assessing the Duration of Effect of 
Lasmiditan on Simulated Driving Performance in Healthy 
Volunteers..............................................................................................56


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1. Protocol Synopsis
Title of Study:
Protocol H8H-MC-LAIF: A Phase I, Randomized, Subject- and Investigator-Blind, Placebo-Controlled, 4-Period 
Cross-Over Study Assessing the Duration of Effect of Lasmiditan on Simulated Driving Performance in Healthy 
Volunteers
Rationale:
Lasmiditan is a highly selective and potent agonist at the 5-hydroxytryptamine1F receptor and is under development 
as a neurally acting acute treatment for migraine.  The most frequently reported adverse events (AEs) identified in 
the lasmiditan clinical development program are central nervous system in nature based on the mechanism of action 
of the drug.  Due to treatment-related adverse effects of dizziness and fatigue observed in the Phase 2 clinical 
program, Study COL-MIG-106/H8H-MC-LAHG evaluated the impact of lasmiditan on driving performance at 90 
minutes postdose.  The results of this study showed impaired driving performance, but the duration of the 
impairment could not be estimated.  The primary objective of the current study is to determine the duration of effect 
of lasmiditan compared to placebo on simulated driving performance in healthy subjects as measured by standard 
deviation of lateral position (SDLP) using the Cognitive Research Corporation Driving Simulator-MiniSim 
(CRCDS-MiniSim) at 8, 12, and 24 hours after dosing.
Objectives
Endpoints
Primary
To determine the duration of effect of acute doses of 
lasmiditan 100 mg and 200 mg compared to placebo 
on simulated driving performance in healthy subjects
Standard deviation of lateral position (SDLP) using the 
Cognitive Research Corporation Driving Simulator-
MiniSim (CRCDS-MiniSim) at 8, 12, and 24 hours 
postdose
Secondary
To determine the effects of lasmiditan 100 mg, and 
200 mg compared to placebo on

self-reported endpoints

Sleepiness endpoint - KSS

Self-reported readiness to drive (“Right now do 
you feel safe to drive?)

VAS to assess subject’s motivation and 
self-appraisal of their driving performance

performance endpoints, and
CogScreen SDC test

Number of correct responses

Response accuracy

Standard deviation of reaction time

driving performance endpoints.

Lane exceedance; including number, maximum, 
duration, and area of exceedance

Average speed, speed deviation, speed count

Excessive Ay (cornering speed threshold 
exceeded)

Total collisions

Divided attention (DA): correct responses, 
omission errors, commission errors, reaction time, 
standard deviation of reaction times
To evaluate the PK of lasmiditan in healthy subjects 

PK parameters:  


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following a single 100- or 200-mg oral dose of 
lasmiditan
o
Cmax, 
o
tmax, and 
o
AUC(0-∞)
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from zero to infinity; Cmax = maximum 
observed drug concentration; DA = divided attention; KSS = Karolinska Sleepiness Scale; PK = 
pharmacokinetics; SDC = Symbol Digit Coding; tmax = time of maximum observed drug concentration; VAS = 
Visual Analog Scale.
Summary of Study Design:
Study H8H-MC-LAIF is a multicenter, randomized, subject- and investigator-blind, active- and placebo-controlled 
Williams square design with 4-period (full) crossover using lasmiditan 200 mg, lasmiditan 100 mg, and 
diphenhydramine 50 mg. Subjects will be randomized to treatment sequences and will complete all 4 periods within 
that treatment sequence.
Each period will be of 3 days duration.  It is anticipated that Study Periods 1, 2, 3, and 4 will commence on Study 
Days 1, 4, 7, and 10, respectively. For logistical reasons, the interval between periods may be extended by up to 2
days to accommodate site schedules.  The minimum washout between periods is 3 days.  
Screening (Visit 1) will include procedures to access subject eligibility including clinical laboratory tests, physical 
examination, and driving simulation training/screening. Prior to randomization, subjects will be screened for 
simulator sickness and will receive standardized training on the driving simulator and cognitive test battery. 
Screening procedures and screening assessments may be performed on different days but must be completed within 
28 days before Period 1 (Visit 2). The training drives on the driving simulator must be completed no more than 21 
days prior to the first dose of study drug. 
Study drug or placebo will be administered by site staff during each period at 0 (Dose 1), 6 (Dose 2), and 10 
(Dose 3) hours on Day 1 and at 22 hours (Dose 4) on Day 2 according to the treatment sequence assigned. Subjects 
will wear a blindfold when taking each dose to maintain the blind. The tablet size and shape are deemed similar 
enough to maintain the blind provided the subject is blindfolded.  Driving assessments commence at 8, 12, and 
24 hours after Dose 1.
The positive control (diphenhydramine 50 mg) is included to establish the sensitivity of the study endpoints.
Treatment Arms:  


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Treatment Sequences:
Subjects will be assigned and dosed with study medication (lasmiditan, diphenhydramine, or placebo) according to 
the treatment sequence they are randomized to.  Subjects will be randomized equally into 1 of 4 treatment 
sequences: 
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
1
Placebo
Lasmiditan 100 mg
Diphenhydramine 50 mg
Lasmiditan 200 
mg
2
Lasmiditan 100 mg
Lasmiditan 200 mg
Placebo
Diphenhydramine 
50 mg
3
Lasmiditan 200 mg
Diphenhydramine 50 mg
Lasmiditan 100 mg
Placebo
4
Diphenhydramine 50 mg
Placebo
Lasmiditan 200 mg
Lasmiditan 100 
mg
Duration of Study: 
On Day -1, prior to the first dose administration (the evening of clinical research unit [CRU] admission) subjects 
will complete a 20-minute practice drive on the CRCDS-MiniSim and a practice trial on the CogScreen SDC test.
Period 1, Day 1 subjects will be administered Dose 1 between approximately 0700 hours (7:00 AM) and 1000 hours
(10:00 AM).  On subsequent dosing days of Periods 2 to 4, doses will be administered at approximately the same 
time of day as doses in Period 1.
Approximately 8 hours following Dose 1, subjects will perform the CogScreen SDC test, KSS, and indicate their 
self-perceived safety to drive. Subjects will then perform the Country Vigilance-Divided Attention driving scenario 
on the CRCDS-MiniSim. Upon completion of the driving scenario, subjects will be administered a VAS to assess 
subjects’ motivation and self-appraisal of their driving performance. Subjects repeat this testing procedure at 
approximately 12 hours and 24 hours after Dose 1 in all dosing periods.
While resident at the CRU, lights out will occur at approximately 2300 hours (11:00 PM) every night.  
Subjects will remain a resident of the CRU from admission until discharge following the completion of study 
assessments. Blood draws for PK will be taken at pre- and post-dose according to the schedule of activities in all 
periods. 


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The total duration of subject participation will be approximately 5 weeks (range 3 to 7 weeks).
Number of Subjects:
Approximately 72 subjects will be enrolled so that 60 healthy volunteers complete the study. This will lead to 90% 
or more power for testing each of the hypotheses of primary interest regarding the driving assessment endpoints.
Statistical Analysis:
Safety:
Safety analysis will be based on all subjects enrolled who receive at least 1 dose of study medication. The safety 
analysis will evaluate AEs and additional safety parameters. The number and percentage of subjects experiencing at 
least 1 AE will be summarized by body system, preferred term, and treatment. If appropriate, AEs will also be 
summarized by intensity and relationship to study drug. Serious adverse events, if any, will be tabulated. 
Additional safety parameters will be assessed from summaries of physical examinations, 12-lead electrocardiograms 
and vital signs. Hematology, chemistry, and urinalysis laboratory test results will be categorized relative to the 
normal ranges. The changes from baseline for each of these parameters at postdose time points will be presented. 
Complete listings and summary tables for all safety information including AEs, laboratory safety data, vital signs,
and physical examination will be included in the study report. 
Pharmacokinetics:
Pharmacokinetic parameter estimates for lasmiditan and its metabolites will be calculated using standard 
noncompartmental methods of analysis and summarized using descriptive statistics.  Plasma concentrations of 
diphenhydramine will be listed and summarized using descriptive statistics.
Pharmacodynamics: 
The primary endpoint, SDLP, will be analyzed using a mixed model with fixed effects for sequence, period, and 
treatment, and a random effect for subject within sequence for each of the driving time points. Secondary endpoints 
will be evaluated similarly; however, Lane Exceedance will be log transformed (more specifically ln[x+1]) prior to 
analyses. Pairwise comparisons for readiness to drive will be analyzed using McNemar test. 
Graphical analyses will be performed to explore the relationship between PK concentrations with SDLP and/or other 
pharmacodynamic (PD) measures.  Additional analyses may be performed to further characterize the PK/PD 
relationship(s), if warranted.


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2. Schedule of Activities
Screening
Study Informed Consent
Medical History 
Subject Eligibility
Weight/Height (BMI)
Drug and Alcohol Screen (repeat alcohol screen prior to Driving 
Sim Training/Practice if performed at a separate visit)
Vital Signs
Physical Examination (may be performed through Day -1)
Epworth Sleepiness Scale
Clinical Laboratory Tests
Twelve-Lead ECG
Temperature
Serum Pregnancy Test (females only)
CogScreen SDC Training/Screening
Driving Sim Training/Screening
Simulator Sickness Questionnaire
Concomitant Medication assessment
Day -1 (Period 1)
Admission to Clinic
Confirm Subject Eligibility
Drug and Alcohol Screen
Serum Pregnancy Test (females only)
Vital Signs
Directed Physical Examination (symptom driven)
CogScreen SDC Practice
Driving Sim Practice
Adverse Event Assessment
Concomitant Medication Assessment (monitor throughout study)
Day 1 (Periods 1-4)
Predose
Vital Signs
Directed Physical Examination (symptom driven)
Lasmiditan and Metabolites PK Sampling (predose)
Diphenhydramine PK Sampling(predose)
+0.0 h
Study Drug Administration (Dose 1)
+0.5 h
Lasmiditan and Metabolites PK Samplea
+1.0 h
Lasmiditan and Metabolites PK Samplea
Breakfast
+1.5 h
Lasmiditan and Metabolites PK Samplea
+2.0 h
Vital Signs/Lasmiditan and Metabolites PK Samplea
+3.0 h
Lasmiditan and Metabolites PK Samplea
+4.0 h
Vital Signs/Lasmiditan and Metabolites PK Samplea
Lunch
+6.0 h


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Lasmiditan and Metabolites PK Samplea
Study Drug Administration (Dose 2)
+8.0 h
KSSb
Adverse Event Assessmentb
CogScreen SDC Testb
Self-Perceived Questionnaire (safe to drive)
Lasmiditan and Metabolites PK Samplea
Diphenhydramine PK Samplea
CVDA Drive
VAS (immediately after drive)
+10.0 h
Lasmiditan and Metabolites PK Samplea
Study Drug Administration (Dose 3)
+11.0 h
Dinner
+12.0 h
KSSb
Adverse Event Assessmentb
CogScreen SDC Testb
Self-Perceived Questionnaire (safe to drive)
Lasmiditan and Metabolites PK Samplea
Diphenhydramine PK Samplea
CVDA Drive
VAS (immediately after drive)
Day 2 (Periods 1-4)
+22 h
Study Drug Administration (Dose 4)
+23 h
Breakfast
+24 h
KSSb
Adverse Event Assessmentb
CogScreen SDC Testb
Self-Perceived Questionnaire (safe to drive)
Lasmiditan and Metabolites PK Samplea
Diphenhydramine PK Samplea`
CVDA Drive
VAS (immediately after drive)
+36 h
Lasmiditan and Metabolites PK Samplea
Day 3 (Periods 1-4)
+48 h
Lasmiditan and Metabolites PK Samplea
Discharge (Day 3, 
Period 4)
Discharge from 
Clinical Unit
Vital Signs
Physical Examination
Clinical Laboratory Tests
Adverse Event Assessment
Concomitant Medication Assessment
Early Discontinuation
Vital Signs


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Physical Examination
Clinical Laboratory Tests
Twelve-Lead ECG
Urinalysis Samples 
Serum Pregnancy Test (females only)
Adverse Event Assessment
Concomitant Medication assessment
Within 5 to 9 days 
after Discharge
Follow-up
Vital Signs
Physical Examination
Clinical Laboratory Tests
Twelve-Lead ECG
Urinalysis Samples
Serum Pregnancy Test (females only)
Adverse Event Assessment
Concomitant Medication Assessment
Abbreviations:  BMI = body mass index; CVDA = Country Vigilance-Divided Attention; ECG = electrocardiogram; 
h = hours, KSS = Karolinska Sleepiness Scale; PK = pharmacokinetic; SDC = Symbol Digit Coding; VAS = 
Visual Analog Scale.
a
Pharmacokinetic and pharmacodynamic sampling times are given as targets to be achieved within reasonable 
limits.  For PK sampling scheduled prior to driving assessments, the sampling window should be within -5 min to 
avoid conflict with driving assessment.  Otherwise, the standard PK sampling windows: predose: -15 minutes; 
>0 to 2 hours postdose: ±5 minutes; 2.5 to 6 hours postdose: ±10 minutes; 7 to 12 hours postdose: ±20 minutes; 
>12 hours postdose: ±30 minutes.  The samples will be taken as per schedule to maintain the blind but samples 
will be analyzed according to the randomization table.
b
This accompanying driving assessment procedure should occur within -30 minutes before the scheduled CVDA 
drive targeted for this sampling time


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3. Introduction
Lasmiditan 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 been developed by Lilly as 
LY573144 and by CoLucid Pharmaceuticals, Inc. as COL-144 under the Investigational New 
Drug application 103420.  Full details of lasmiditan’s preclinical and clinical safety and 
tolerability information are contained in the Investigator’s Brochure (IB).
3.1.
Study Rationale
Lasmiditan is a highly selective and potent agonist at the 5-hydroxytryptamine (5-HT)1F receptor 
and is under development as a neurally acting treatment for migraine.  The most frequently 
reported adverse events (AEs) identified in the lasmiditan clinical development program are 
central nervous system (CNS) in nature based on the mechanism of action of the drug.  Due to 
treatment-related adverse effects of dizziness and fatigue observed in the Phase 2 clinical 
program, Study COL-MIG-106/H8H-MC-LAHG (106/LAHG) evaluating the impact of 
lasmiditan on driving performance was conducted in accordance with the United States Food and 
Drug Administration (FDA)’s Evaluating Drug Effects on the Ability to Operate a Motor 
Vehicle: Guidance for Industry (2017)
Study 106/LAHG was a randomized, subject-and investigator-blind, placebo-controlled,
five-period, crossover study with the following treatments:

Lasmiditan 50 mg

Lasmiditan 100 mg

Lasmiditan 200 mg

Alprazolam 1 mg (positive control)

Placebo
Subjects were randomized equally into 1 of 10 Latin square treatment sequences. The five 
periods were approximately 7 days in duration. 
The simulated driving test was commenced 90 minutes after dosing (on Days 1, 7, 14, 21, and 
28).
The effect of lasmiditan on simulated driving performance was primarily measured by the
standard deviation of lateral position (SDLP) using the Cognitive Research Corporation Driving 
Simulator (CRCDS)-MiniSim.  During testing, subjects were instructed to drive a 100-km 
highway segment with steady lane position and constant speed with a primary outcome measure 
of vehicle control, the SDLP (i.e. amount of “weaving” of the car in the lane). 
Driving performance as assessed by SDLP was inferior for lasmiditan 50 mg, 100 mg, and 
200 mg relative to placebo. This was further confirmed by symmetry analysis. A majority of 


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subjects exceeded the impairment threshold (4.4 cm, comparable to 0.05% blood alcohol count 
[BAC]) at even the lowest dose of lasmiditan.  Sensitivity of the simulator and the model used in 
the research design were supported by significant findings on primary and secondary driving 
endpoints for alprazolam 1.0 mg. 
Secondary driving endpoints provide further support to the conclusion that lasmiditan 50 mg, 
100 mg, and 200 mg at 1.5 hours postdose had an adverse impact on simulated driving 
performance.
The time interval in 106/LAHG was chosen to capture the effect at the time of the peak 
concentration of lasmiditan and major metabolites M7 and M8, in accordance with the FDA 
guidance.  However, the point at which patients should resume operation of a motor vehicle after 
taking lasmiditan is still unclear.  The primary objective in the current study is to determine the 
duration of effect of lasmiditan compared to placebo on simulated driving performance in 
healthy subjects as measured by SDLP using the CRCDS-MiniSim at 8, 12, and 24 hours after 
dosing with lasmiditan.  The 90-minute postdose simulated driving assessment used in 
106/LAHG will not be repeated in the current study.  For the positive control, diphenhydramine 
treatment doses will be administered 2 hours prior to driving assessments to ensure the maximum 
cognitive and sedative effect of the positive control (Ramaekers and O’Hanlon 1994). 
3.2.
Background
Lasmiditan is being investigated for the acute treatment of migraine in adults with and without
aura.  Lasmiditan is a high-affinity, highly selective 5-HT (serotonin)1F receptor agonist that is 
being developed as a novel therapy for the acute treatment of migraine.  It has a chemical 
structure and pharmacologic profile that is distinct from the triptans, the current standard of care 
for the treatment of acute migraine.  Lasmiditan does not contain the indole group observed in all 
triptans; instead it has a pyridinoyl-piperidine scaffold, which is unique to antimigraine 
medications.  Lasmiditan is a low-molecular weight 5-HT1F receptor agonist with a nonvascular, 
primarily neural mechanism of action.  It has high affinity for the human 5-HT1F receptor and 
>470-fold selectivity for the human 5-HT1F receptor relative to the 5-HT1B receptor.  Across the 
completed Phase 1, 2, and 3 clinical studies, lasmiditan doses of 0.1 mg to 400 mg were 
evaluated in healthy subjects or patients with migraine. In two Phase 3, placebo-controlled 
studies in which patients treated 1 migraine attack with oral lasmiditan (50, 100, or 200 mg) or 
placebo, the most frequently reported lasmiditan treatment-emergent adverse events (TEAEs) 
were dizziness, paresthesia, somnolence, fatigue, lethargy, and nausea. A majority of these 
TEAEs were mild or moderate in severity.  In healthy subjects, peak plasma concentrations of 
lasmiditan were observed approximately 1.5 hours to 2.5 hours after a single oral dose ranging 
from 25 mg to 400 mg, and the geometric mean terminal half-life was approximately 4 hours.  
Lasmiditan pharmacokinetics (PK) was approximately dose linear.
Following oral dosing with lasmiditan, up to 11 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 ~4.5 hours to 21 hours.
3.3.
Benefit/Risk Assessment
The primary objective of this study is to determine the duration of effect of lasmiditan on 
simulated driving performance in healthy subjects.  There is no anticipated therapeutic benefit 
for the healthy subjects.
Lasmiditan has been generally well tolerated by healthy subjects as single oral doses up to 
400 mg with no drug-related serious adverse events (SAEs) or withdrawals due to AEs in 
completed Phase 1 trials (as of 01 Nov 2017).  Dosing of lasmiditan and diphenhydramine will 
be conducted in an inpatient setting, and subjects will be monitored in the clinical research unit 
(CRU) for the length of the study until discharge on Day 3, Period 4.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of lasmiditan is to be found in the IB.  
More detailed information about the known and expected benefits and risks of diphenhydramine 
may be found on the package information.


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4. Objectives and Endpoints
Table LAIF.1 shows the objectives and endpoints of the study.
Table LAIF.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine the duration of effect of acute doses of 
lasmiditan 100 mg and 200 mg compared to placebo 
on simulated driving performance in healthy subjects
Standard deviation of lateral position (SDLP) using the 
Cognitive Research Corporation Driving Simulator-
MiniSim (CRCDS-MiniSim) at 8, 12, and 24 hours 
postdose
Secondary
To determine the effects of lasmiditan 100 mg and 
200 mg compared to placebo on

self-reported endpoints

Sleepiness endpoint - KSS

Self-reported readiness to drive (“Right now do 
you feel safe to drive?)

VAS to assess subject’s motivation and 
self-appraisal of their driving performance

performance endpoints, and
CogScreen SDC test

Number of correct responses

Response accuracy

Standard deviation of reaction time

driving performance endpoints

Lane exceedance, including number, maximum, 
duration, and area of exceedance

Average speed, speed deviation, speed count

Excessive Ay (cornering speed threshold 
exceeded)

Total collisions

DA: correct responses, omission errors, 
commission errors, reaction time, standard 
deviation of reaction times
To evaluate the PK of lasmiditan in healthy subjects 
following a single 100- or 200-mg oral dose of 
lasmiditan

PK parameters:
o
Cmax, 
o
tmax, and 
o
AUC(0-∞)
Exploratory
To determine the effect of acute doses of lasmiditan 
100 mg and 200 mg at 8, 12, and 24 hours compared 
with positive control (diphenhydramine 50 mg) at tmax
SDLP using the CRCDS-MiniSim at 8, 12, and 24 hours 
To determine the effects of lasmiditan 100 mg and 
200 mg compared with positive control 
(diphenhydramine 50 mg) on:

self-reported endpoints,

Sleepiness endpoint - KSS

Self-reported readiness to drive (“Right now do 
you feel safe to drive?)

VAS to assess subject’s motivation and self-
appraisal of their driving performance


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
performance endpoints, and 
CogScreen SDC test

Number of correct responses

Response accuracy

Standard deviation of reaction time

driving performance endpoints

Lane exceedance, including number, maximum, 
duration, and area of exceedance

Average speed, speed deviation, speed count

Excessive Ay (cornering speed threshold 
exceeded)

Total collisions

Divided attention (DA): correct responses, 
omission errors, commission errors, reaction time, 
standard deviation of reaction times
To evaluate the PK of diphenhydramine
Diphenhydramine concentrations
To evaluate the PK of lasmiditan metabolites M8, 
M7, and M18

PK parameters:
o
Cmax, 
o
tmax, and 
o
AUC(0-∞)
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from zero to infinity; Cmax = maximum 
observed drug concentration; CRCDS = Cognitive Research Corporation Driving Simulator; DA = divided 
attention; KSS = Karolinska Sleepiness Scale; PK = pharmacokinetics; SDC = Symbol Digit Coding; SDLP = 
standard deviation of lateral position; tmax = time of maximum observed drug concentration; VAS = Visual 
Analog Scale.


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5. Study Design
5.1.
Overall Design
This study is a multicenter, randomized, subject- and investigator-blind, active- and placebo-
controlled Williams square design with 4-period (full) crossover using a single dose of 
lasmiditan (Figure LAIF.1).  Subjects will be randomized to treatment sequences and should
complete all 4 periods within that treatment sequence.
Figure LAIF.1.
Study schematic.
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Approximately 72 healthy subjects may be enrolled so that at least 60 healthy volunteers 
complete the study.  For the purposes of this study, a subject completes the study when all 
scheduled procedures shown in the Schedule of Activities (Section 2) have been completed.
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
Subjects will enter the CRU on Day -1.  For the duration of the 4-period study, subjects will 
remain in the CRU.  Each period will be of 3 days duration.  It is anticipated that Study Periods 
1, 2, 3, and 4 will commence on Study Days 1, 4, 7, and 10, respectively. For logistical reasons, 
the interval between periods may be extended by up to 2 days to accommodate site schedules.  
The minimum washout between periods is 3 days.  Cognitive testing and driving simulation will 
be conducted approximately 8, 12, and 24 hours after Dose 1 on Day 1 of each study period.  
These driving assessment time points are expected to provide a wide range of responses 
including reversal of impairment.
The study design incorporates a positive control (diphenhydramine 50 mg) to confirm assay 
sensitivity.  Per the FDA’s Evaluating Drug Effects on the Ability to Operate a Motor Vehicle: 
Guidance for Industry (2017), sedating antihistamines are commonly used to understand the 
magnitude and duration of impairment.  Diphenhydramine is a well-known sedating 
antihistamine available over the counter in the US and has been shown to have a significant 
Screening
• Subject 
Eligibility
Admission to 
Clinic (Day -1)
• Confirm 
Eligibility
• Driving 
Assessment 
Practice
Period 1
• 3 Days
• Driving 
Assessments 
(8, 12, and 24 
hours)
Period 2
• 3 Days
• Driving 
Assessments 
(8, 12, and 24 
hours)
Period 3
• 3 Days
• Driving 
Assessments 
(8, 12, and 24 
hours)
Period 4
• 3 Days
• Driving 
Assessments 
(8, 12, and 24 
hours)
Discharge
• After all 
assessments 
on Day 3, 
Period 4


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effect on driving performance (Kay et al. 1997, 2016).  Diphenhydramine will be administered 
no more frequently than every 4 hours per package directions, coinciding with time points 2 
hours prior to each driving assessment so that the maximum cognitive and sedative effect of the 
positive control coincide with the initiation of the driving simulation task.
5.5.
Justification for Dose
The upper lasmiditan dose level of 200 mg has been generally well tolerated in previous studies 
on healthy subjects and patients enrolled in the completed Phase 3 program and is anticipated as 
the highest recommended dose for lasmiditan.  The therapeutic dose range also includes 100 mg 
lasmiditan, which will be evaluated in the current study to explore any differences in the duration 
of driving impairment effect.
Diphenhydramine is an over-the-counter antihistamine medication for the treatment, as a
temporary relief, of runny nose, itchy and watery eyes, sneezing and itching of the nose or throat 
due to hay fever or other upper respiratory allergies, or runny nose and/or sneezing due to 
common cold.  The recommended dosage of diphenhydramine includes 50 mg taken every 4 to 
6 hours.  Urine drug screen and alcohol screen tests will be conducted on all potential subjects. 
Serum pregnancy tests will be conducted on all female subjects. 


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6. Study Population
Only medically healthy subjects with clinically acceptable laboratory profiles and 
electrocardiograms (ECGs) will be enrolled into the study. The informed consent documents 
will be discussed with each potential participant, and each individual will sign an informed 
consent document for the study prior to any study-specific procedures being performed.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening procedures and screening assessments may be performed on different days but must 
be completed within 28 days prior to enrollment.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is 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. Continued eligibility will be assessed through serum pregnancy (females only) and 
screening for alcohol and drugs of abuse on the day of admission.
[1]
are overtly healthy males or females, as determined through medical history 
and physical examination.
[1a] male subjects:
are not required to adhere to contraceptive requirements.
[1b] female subjects: 
of childbearing potential, must test negative for pregnancy at screening, and agree to 
use a reliable method of birth control during the study from admission and for 
30 days following the last dose of study drug. Reliable methods of contraception for 
female subjects of childbearing potential include the use of stable hormonal 
contraception (including hormonal intrauterine devices) for at least 28 days prior to 
admission.
of childbearing potential who are abstinent (if this is complete abstinence, as their
preferred and usual lifestyle) or in a same sex relationship (as part of 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, post-ovulation methods), declaration of 
abstinence just for the duration of a trial, and withdrawal are not acceptable methods 
of contraception. 
of non-childbearing potential, i.e., postmenopausal or permanently sterile following 
hysterectomy, bilateral salpingectomy, or tubal ligation, as determined through
medical history. Surgical tubal occlusion (i.e., Essure®) is also an acceptable form 
of surgical sterilization, provided the procedure was completed at least 3 months


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prior to enrollment. Postmenopausal is defined as spontaneous amenorrhea for at 
least 12 months, and a follicle-stimulating hormone level greater than 40 mIU/mL, 
unless the subject is taking hormone replacement therapy (HRT). 
[2]
are between the ages of 21 and 50 years (inclusive).  Attempts will be made to 
enroll no more than 60% of 1 gender in the study.
[3]
are able to reliably perform study assessments (SDLP no higher than 1 
standard deviation [SD] greater than the mean for normal healthy adults 
completing the practice scenario; Symbol Digit Coding [SDC] Correct no less 
than 1 SD below the mean for healthy adults in their age range); demonstrate 
the ability to understand task instructions; and are physically capable (e.g.,
adequate manual dexterity, vision, and hearing) and cognitively capable of 
performing study tasks.
[4]
possess a valid driver’s license and is an active drivers at screening. Driven a 
minimum of 8,000 miles (about 13,000 km) per year for the preceding 3 years.
[5]
must also demonstrate sufficient simulator sickness questionnaire scores,
which are not indicative of simulator sickness as defined in the driving 
simulation operations manual.
[6]
have a regular sleep pattern, and in general, have at least 7 hours of sleep each
night (bedtime occurs between 2100 hours and 2400 hours).
[7]
have a score of <10 on the Epworth Sleepiness Scale.
[8]
have a body mass index (BMI) of 18 kg/m2 to 35 kg/m2, inclusive 
[9]
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.
[10] have venous access sufficient to allow for blood sampling as per the protocol.
[11] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[12] 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:
[13] 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.
[14] are Lilly employees or are employees of any third party involved in the study 
who require exclusion of their employees.


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[15] are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[16]
have participated, within the past 30 days of admission, in a clinical study 
involving an investigational product.  If the previous investigational product 
has a long half-life, 5 half-lives or 30 days from last dose (whichever is 
longer) should have passed.
[17]
have previously completed or withdrawn from this study or any other study 
investigating lasmiditan, and have previously received the investigational 
product. 
[18]
have known allergies to lasmiditan, related compounds, or any components of 
the formulation, diphenhydramine, or a history of significant atopy.
[19]
have an abnormal blood pressure (BP) and/or pulse rate as determined by the 
investigator.
[20]
have a history or presence of or significant history of 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 
investigational product; or of interfering with the interpretation of data. 
Appendectomy, splenectomy, and cholecystectomy are considered as 
acceptable.
[21]
have a history within 3 months of admission, or current treatment for, a 
sleeping disorder (including excessive snoring, obstructive sleep apnea), or a 
chronic painful condition that interferes with the subject’s sleep.
[22]
have a history of difficulty either falling asleep or staying asleep in the 
previous 3 months of admission that is considered clinically significant by the 
investigator.
[23]
have a history or diagnosis of any of the following conditions:
i.
primary or secondary insomnia
ii.
narcolepsy
iii.
cataplexy (familial or idiopathic)
iv.
circadian rhythm sleep disorder
v.
parasomnia including nightmare disorder, sleep terror disorder, sleepwalking 
disorder, and rapid eye movement behavior disorder
vi.
sleep-related breathing disorder (obstructive or central sleep apnea syndrome, 
central alveolar hypoventilation syndrome)
vii.
periodic limb movement disorder
viii.
restless legs syndrome
ix.
primary hypersomnia
x.
excessive daytime sleepiness


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xi.
visual or auditory impairment which in the opinion of the investigator would 
interfere with study-related procedures or study conduct.
[24]
are expected to use any other medication or dietary supplement to promote 
sleep including over the-counter sleep medications, during their participation 
in the study.
[25]
consume excessive amounts of coffee, tea, cola, or other caffeinated 
beverages per day. Excessive amount is defined as greater than 6 servings (1 
serving is approximately equivalent to 120 mg of caffeine).
[26]
have traveled across 2 or more time zones (transmeridian travel) in the past 
2 weeks prior to randomization.
[27]
have worked in a night shift in the past 2 weeks prior to randomization.
[28]
show a history of CNS conditions such as strokes, transient ischemic attacks, 
significant head trauma, seizures, CNS infections, migraine, brain surgery, or 
any other neurological conditions that, in the opinion of the investigator, 
increase the risk of participating in the study.
[29]
have a known contraindication to diphenhydramine such as myasthenia gravis, 
epilepsy or seizure disorders, narrow-angle glaucoma, prostatic hypertrophy, 
urinary retention, asthma, bronchitis or chronic obstructive pulmonary 
disease.
[30]
have a history of orthostatic hypotension, fainting spells, or blackouts that are 
considered clinically significant by the investigator.
[31]
are intending to use over-the-counter or prescription medication, including 
dietary supplements, within 14 days prior to dosing and until study discharge 
(apart from occasional acetaminophen, hormonal contraception, or HRT).
[32]
show evidence of significant active neuropsychiatric disease (e.g., manic 
depressive illness, schizophrenia, depression) considered as clinically 
significant by the investigator.
[33]
currently use or show evidence of substance abuse (including alcohol abuse) 
or dependence within the past 6 months based on history at screening visit.
[34]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[35]
show evidence of hepatitis C and/or positive hepatitis C antibody. 
[36]
show evidence of hepatitis B and/or positive hepatitis B surface antigen. 
[37]
are women who are lactating.
[38]
have donated blood of more than 500 mL within the previous 2 months of 
study screening. 
[39]
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 while resident at the CRU.


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[40]
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 in Period 1, and while resident at the CRU. At all 
other times, subjects must agree to consume no more than 2 units per day 
(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).
[41]
consume alcohol on a regular basis (i.e., ≥5 times/week) within 2 hours of 
bedtime.
[42]
inability to comply with the dietary regimen of the clinical research center.
[43]
have a positive pregnancy test at screening or Day -1.
[44]
are planning to become pregnant during the study or within 1 month of study 
completion.
[45]
inability to use adequate contraception (as defined in [1] of the Inclusion 
Criteria) during the study.  Female subjects must agree to use adequate 
contraception for 30 days following the last dose of study drug.
[46]
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] through [12] define a healthy population suitable for evaluation in this Phase 1 study.  
Criteria [13] and [14] prevent conflict of interest in study participants.  Criteria [15] through [46] 
predominantly exclude medical conditions, medication intolerance, and concomitant medication 
use that may confound the assessment of study endpoints. 
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
During each confinement period, subjects will consume only food and beverages that are 
provided to them by the CRU staff.  Standard meals (e.g., breakfast, lunch, dinner, and snack) 
will be provided to the subjects while resident at the CRU.  Breakfast, lunch, and dinner will be 
provided according to the Schedule of Activities (Section 2). 
6.3.2. Caffeine, Alcohol, and Tobacco
From 48 hours prior to admission in Period 1, and while resident at the CRU, subjects are not 
allowed to

consume xanthine- or caffeine-containing food and drinks

consume alcoholic beverages


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o
At all other times, subjects must agree to consume no more than 2 units 
per day (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).

use tobacco products
6.3.3. Activity
From 48 hours prior to admission in Period 1, and while resident at the CRU, subjects are not 
allowed to engage in strenuous activity.
While resident at the CRU, lights out will occur at approximately 2300 hours (11:00 PM) every 
night.  
6.4.
Screen Failures
Individuals who do not meet the driving simulation criteria (Inclusion Criteria [2] and [4] to [7]) 
for participation in this study (screen failure) may not be re-screened.  Individuals who do not 
meet other criteria or driving simulation Inclusion Criterion [3] for participation in this study 
(screen failure) may be re-screened at the discretion of the investigator.  Individuals may be 
re-screened 1 time.  The interval between screenings should be at least 1 week.  When the 
re-screening is performed, the individual must sign a new informed consent form (ICF) and will 
be assigned a new identification number.


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7. Treatment
7.1.
Treatment Administered
This study involves orally administered lasmiditan with placebo. Diphenhydramine will be 
administered as a positive control.  Table LAIF.2 shows the treatment regimens.
Lasmiditan, diphenhydramine, or placebo will be administered orally with approximately 
240 mL of room temperature water according to the subject’s assigned treatment sequence 
(Table LAIF.3) and at the time points specified in the Schedule of Activities (Section 2).  
Subjects will not be allowed to lie supine for 2 hours after dosing, unless clinically indicated or 
for study procedures.
Table LAIF.2.
Treatments Administered
Treatment Name
Placebo
Lasmiditan (100 mg)
Lasmiditan (200 mg)
Diphenhydramine
Dosage Formulation
Tablet
Tablet
Tablet
Tablet
Unit Dose 
Strength(s)/Dosage 
Level(s)
2 tablets
(1 100-mg) tablets/
100 mg LY + 1 placebo 
tablet
(2 100-mg) tablets/
200 mg LY
(2 25-mg) tablets/
50 mg 
Table LAIF.3.
Treatment Schedule
Treatment 
Sequence
Period 1
Period 2
Period 3
Period 4
1
Placebo
Lasmiditan 100 mg
Diphenhydramine 50 
mg
Lasmiditan 200 mg
2
Lasmiditan 100 mg
Lasmiditan 200 mg
Placebo
Diphenhydramine 
50 mg
3
Lasmiditan 200 mg
Diphenhydramine 50 mg
Lasmiditan 100 mg
Placebo
4
Diphenhydramine 50 mg
Placebo
Lasmiditan 200 mg
Lasmiditan 100 mg
The investigator or designee is responsible for

explaining the correct use of the investigational product(s) to the subject

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection, and

returning all unused medications 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. 


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7.1.1. Packaging and Labeling
Each tablet of lasmiditan contains 100 mg of active ingredient and is provided as bulk supplies in 
bottles.  Diphenhydramine will be sourced by the investigative site.
Both lasmiditan and diphenhydramine tablets are small and round.  Placebo tablets are similar in 
size and shape to both lasmiditan and diphenhydramine tablets, but contain no active ingredient.  
Placebo tablets will be provided in similar bulk bottles as lasmiditan.
The investigational products will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
The sponsor (or designee) will be responsible for generating each of the randomization schedules 
and distributing them directly to the CRU pharmacist.
7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same time on each day (Figure LAIF.1).  
Period 1, Day 1 subjects will be administered Dose 1 between approximately 0700 hours (7:00 
AM) and 1000 hours (10:00 AM).  For each subject, the same time of Dose 1 in Period 1 should 
be targeted for Dose 1 in Periods 2 to 4 within reasonable limits.  Subjects are permitted, and 
encouraged, to engage in their normal sleep pattern between Doses 3 and 4. 
Figure LAIF.2
Timing of doses.
The actual time of all dose administrations will be recorded in the subject’s case report form 
(CRF).
Treatment sequences will be determined using a repeated 4×4 Williams square design (Table 
LAIF.3).  The randomization schedule will be securely maintained by the study center 
pharmacist who is responsible for dispensing the blinded study medication in accordance with 
the schedule.  The sponsor (or designee) will be responsible for generating the randomization 
schedule and distributing them directly to the study center pharmacists.


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7.3.
Blinding
Study drugs (lasmiditan, diphenhydramine, and/or placebo) will be prepared into individual 
dispensing containers by an unblinded pharmacist or designee and administered by an unblinded 
staff member who will not be involved in any study assessment procedures.  Each subject will be 
blindfolded prior to each dosing occasion to maintain the study blind.  The unblinded staff 
member will hand the dispensing container to each subject, who will then self-administer all 
tablets in the dispensing container without touching any of the tablets by hand.  Neither the 
investigator nor any study staff involved in the subject assessment will be allowed to witness the 
study drug administration.  The blindfold will be removed before any assessments commence.
Blinding will be maintained throughout the conduct of the study as described in the separate 
Blinding Plan.
Emergency codes will be available to the investigator.  A code, which reveals the treatment 
sequence for a specific study subject, may be opened during the study only if the subject’s 
well-being requires knowledge of the subject’s treatment assignment.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist 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 during the study
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all investigational products
received and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational products or study materials, 
and only authorized site staff may supply or administer investigational products.  All 
investigational products 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.


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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as 
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The investigational products will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
In general, concomitant medications should be avoided; however, acetaminophen (maximum 
3 g/24 hours) may be administered at the discretion of the investigator for the treatment of 
headache, etc.  Contraceptive medication is permitted as per the inclusion criteria.  Hormone 
replacement therapy is also allowed.
If the need for concomitant medication (other than acetaminophen, hormonal contraception, or 
HRT) arises, inclusion or continuation of the subject may be at the discretion of the investigator 
after consultation with a Lilly clinical pharmacologist, CRP, or designee.  Any medication used 
during the course of the study must be documented.
7.8.
Treatment after the End of the Study
Not applicable.


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8. Discontinuation Criteria
Subjects discontinuing from the treatment prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 of this protocol.
Subjects discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver test results 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), aspartate aminotransferase (AST) >5X upper limit of 
normal (ULN) for healthy subjects, or

ALT or AST >3X ULN for healthy subjects sustained for more than 2 weeks, or

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or international 
normalized ratio >1.5, or

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%), or

alkaline phosphatase (ALP) >3X ULN, or

ALP >2.5X ULN and TBL >2X ULN, or

ALP >2.5X 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 clinical pharmacologist 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 clinical 
pharmacologist to allow the inadvertently enrolled subject to continue in the study with or 
without continued treatment with investigational product.
8.2.
Discontinuation from the Study
Subjects will be discontinued under the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study


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


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


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If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e., 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 1
of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/clinical pharmacologist, or its designee, of any 
SAE as soon as practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
investigational product, AND is considered Reasonably Possibly Related to a study procedure 
then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary 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 investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  Lilly 


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has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
9.3.1. Overdose of Lasmiditan
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 case of an overdose, it is recommended that the subject be monitored for signs and symptoms 
of adverse reactions. Subjects who develop adverse reactions should receive appropriate 
supportive therapy and AEs should be documented.
9.3.2. Overdose of Diphenhydramine
For the purposes of this study, an overdose of diphenhydramine is considered any dose higher 
than the dose assigned through randomization.  Antihistamine overdosage reactions may vary 
from CNS depression to stimulation.  Atropine-like signs and symptoms; dry mouth; fixed, 
dilated pupils; flushing; and gastrointestinal symptoms may also occur.  In the event of a 
diphenhydramine overdose, the subject should receive appropriate medical care.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
9.4.2. Vital Signs
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Blood pressure and pulse rate should be measured singly after at least 5 minutes supine.  For 
each individual subject, the same cuff size should be used throughout the study for the 
measurements of BP.  The cuff should be attached to the subject’s dominant arm.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Where orthostatic measurements are required, subjects should be 
supine for at least 5 minutes and then subjects will stand, and standing BP will be measured after 


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2 minutes; no longer than 3 minutes. If the subject feels unable to stand, supine vital signs only
will be collected. 
Additional vital signs may be measured during each study period if warranted.
9.4.3. 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 investigational product should be reported to Lilly, or its 
designee, as an AE via eCRF. 
For each subject, a single12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 
samples.  Subjects must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection.  Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary.  All ECGs recorded should be stored at the 
investigative 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/corrected QT 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.
9.4.4. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes 

adverse events 
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.


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9.4.4.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatinine 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 clinical pharmacologist or 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 ≥5X ULN on 2 or more consecutive blood tests

elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

subject discontinued from the treatment due to a hepatic event or abnormality of
liver tests

hepatic event considered to be an SAE.
9.5. 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.  Time of blood collection will 
be based on Dose 1. Similarly, at times specified in the Schedule of Activities (Section 2), 2 
mL of venous blood samples will be collected to determine the plasma concentrations of 
diphenhydramine per Appendix 5 to confirm adequate washout and enable exploratory 
PK/pharmacodynamic (PD) analysis.  A maximum of 3 samples may be collected at additional 
time points during the study if warranted and agreed upon between both the investigator and 
sponsor.  Instructions for the collection and handling of blood samples will be provided by the 
sponsor.  The actual date and time (24-hour clock time) of each sampling will be recorded.
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of lasmiditan and its metabolites M8, M7, and M18 will be assayed using a 
validated liquid chromatography tandem-mass spectrometry (LC-MS/MS) method.  Analyses of 
lasmiditan samples collected from periods corresponding to placebo and positive control 
(diphenhydramine) are not planned with the exception of predose samples on Day 1 of each 
period.


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Concentrations of diphenhydramine will be assayed using a validated LC-MS/MS method.  
Analyses of diphenhydramine samples collected from periods corresponding to placebo and 
lasmiditan are not planned with the exception of predose samples on Day 1 of each period.  
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.
9.6.
Pharmacodynamics
9.6.1. Country Vigilance-Divided Attention Driving Scenario on the 
CRCDS-MiniSim
The present study employs the Country Vigilance-Divided Attention (CVDA) driving scenario, a 
100-km two-lane highway driving task that includes a secondary visual vigilance task (DA). The 
monotonous Country Vigilance scenario has been demonstrated to be sensitive to detect the 
effects of fatigue or sleepiness on driving performance. This scenario has been useful in 
measuring the effects of sleep deprivation, obstructive sleep apnea, chronic primary insomnia, 
and is sensitive to CNS depressants (e.g., alcohol and sedating antihistamines). Results obtained 
using this methodology are comparable to those obtained using over-the-road driving tests 
(Siemen et al. 2015). 
Subjects will perform the driving simulator test at the times specified in the Schedule of 
Activities (Section 2).  Data will be captured in electronic format. Details are provided in the 
Cognitive Research Corporation CRCDS Testing Operations Manual.
9.6.2. Karolinska Sleepiness Scale
The Karolinska Sleepiness Scale (KSS) (Akerstedt and Gillberg 1990) will be used to assess 
subjective level of sleepiness.  This is a subject self-reported measure of situational sleepiness 
and provides an assessment of alertness/sleepiness at a particular point in time.  The KSS has 
been found to correlate with electroencephalogram and behavioral variables (Kaida et al. 2006).
Subjects will self-report their KSS assessments at the times specified in the Schedule of 
Activities (Section 2). The subject’s self-reported scores will be recorded in the eCRF.
9.6.3. Self-Perceived Safety to Drive Question
Prior to driving, the subject will be asked a simple question as to whether they feel safe to drive 
(“Right now do you feel safe to drive?”). Subject will answer “yes” or “no”. The answer will be 
recorded in the eCRF.
9.6.4. CogScreen Symbol Digit Coding
Symbol Digit Coding will be used in this study to measure attention, visual scanning, working 
memory, and speed of information processing. Symbol Digit Coding is a computer analog of the 
conventional symbol-substitution task found in the WAIS-R Digit Symbol subtest and the 


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Symbol Digit Modalities Test (Wechsler 1981).  The SDC test will be administered by trained 
study site personnel. Subjects will perform the test prior to the driving simulation test at the 
times specified in Section 2. The subject will perform the test by interacting with an electronic 
monitor screen. Data will be captured in electronic format.  Details are provided in the 
CogScreen® Examiner Manual, CogScreen LLC, 2016.
9.6.5. Visual Analog Scale to Assess Subject’s Motivation and Self-
Appraisal
After completing the driving simulation, subjects will assess their own performance and their 
level of motivation to perform at their best during the driving simulation.
Subjects will respond to 2 questions:
1. How well you think you drove for the last 60 minutes?
2. How motivated did you feel to drive at your best during the last 60 minutes of driving?
Subjects will record their response to each question by writing a vertical line on a 100-mm 
horizontal, linear visual analog scale, indicating their level of performance (Not Satisfactory to 
Satisfactory) and motivation (Not Motivated to Motivated). Scores on the 100-mm linear scale 
will be measured to the nearest millimeter from the left. The subject’s scores will be recorded in 
the eCRF.
9.7.
Genetics
This section is not applicable for this study.
9.8.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 72 subjects will be enrolled so that approximately 60 healthy volunteers complete 
this study. This study is designed to test noninferiority (NI) of lasmiditan relative to placebo, 
with a diphenhydramine test versus placebo to confirm the sensitivity of the simulator to detect 
treatment effects. The following assumptions were made in the sample size computation: (a) SD
of differences between lasmiditan and placebo within subject for SDLP is approximately 9.5 cm; 
(b) the true difference between lasmiditan doses and placebo is 0; and (c) the NI margin is 
proposed to be 4.4 cm, which is the effect seen with 0.05% of BAC. Under these assumptions, a 
sample of 60 subjects would provide >90% power to establish NI of either dose of lasmiditan 
compared to placebo in terms of the primary end point, SDLP. This sample size is more than 
adequate to detect diphenhydramine differences, which are anticipated to exceed the NI margin, 
from placebo.
Subjects who are randomized but who do not complete all 4 periods during the Treatment Phase 
may be replaced. Replacement subjects will enter the same treatment sequence as the original 
subjects to complete all 4 periods. 
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’ year of birth, sex, weight, height, race, and other demographic characteristics will 
be recorded. Age and BMI will be calculated. Demographic and baseline characteristics will be 
summarized.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee. Complete 
details of the planned analyses will be contained in the statistical analysis plan.
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least 1 dose 
of the investigational products and have evaluable PK.
Pharmacodynamic analyses will be conducted on data from all subjects who receive at least 1 
dose of the investigational products and have evaluable PD.
Pharmacokinetic/pharmacodynamic analyses will be conducted on data from all subjects who 
receive at least 1 dose of the investigational products and have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.


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Additional exploratory analyses of the data will be conducted as deemed appropriate. In general, 
categorical variables will be summarized by the count (N) and percentage of subjects (%). 
Continuous variables will be summarized by the number of non-missing observations (N), mean, 
SD, median, minimum, and maximum values. 
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product 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 investigational product 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 Dictionary 
for Regulatory Activities.
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters and vital signs.  The 
parameters will be listed, and summarized using standard descriptive statistics.  Additional 
analysis will be performed if warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Plasma concentrations of lasmiditan, its metabolites, and diphenhydramine will be listed and 
summarized using descriptive statistics.
Pharmacokinetic parameter estimates for lasmiditan and its metabolites will be calculated using
standard noncompartmental methods of analysis and summarized using descriptive statistics by 
dose level.
The primary parameters for analysis will be maximum observed drug concentration (Cmax) and 
area under the concentration versus time curve (AUC).  Other noncompartmental parameters, 
such as half-life, apparent clearance, and apparent volume of distribution may be reported.
10.3.3. Pharmacodynamic Analyses 
The primary endpoint, SDLP, will be analyzed using a mixed model with fixed effects for 
sequence, period, and treatment, and a random effect for subject within sequence for each of the 
driving time points. Separate models will be used for each of the driving time points.
Secondary endpoints will be evaluated similarly; however, Lane Exceedance will be log 
transformed (more specifically, ln[x+1]) prior to analyses. Pairwise comparisons for readiness to 
drive will be analyzed using McNemar test.


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For the primary and secondary endpoints, pairwise comparisons (hypothesis tests) of differences 
in means, and 95% confidence intervals on differences will be provided at each time point for
1. Lasmiditan 100 mg versus placebo
2. Lasmiditan 200 mg versus placebo
3. Diphenhydramine 50 mg versus placebo
In addition, pairwise within-subject differences in SDLP greater than 4.4 cm in absolute value 
(equal to the previously found difference between placebo and 0.05% BAC for the CRCDS) will 
be compared using McNemar test. Furthermore, these pairwise, within-subject differences in 
SDLP will be tested for symmetry about zero using the maximally selected McNemar test.
10.3.3.1. Pharmacodynamic Statistical Inference
To address multiplicity of testing, 2 doses of lasmiditan versus placebo at 3 time points for the 
primary endpoint of SDLP, ascending doses of lasmiditan at descending time points will be 
interpreted in a sequential manner, starting with the 100-mg dose at 24 hours and proceeding to 
the 200-mg dose and earlier time points via a graphical multiple comparisons procedure (Figure 
LAIF.3). The value of w, the split of alpha after testing 100 mg at 24 hours, will be specified in 
the statistical analysis plan.
Figure LAIF.3.
Pharmacodynamic statistical inference – graphical multiple 
comparisons procedure.
Doses of lasmiditan will be considered noninferior to placebo at a time point if the upper 95% 
confidence limit on the difference in SDLP between that dose and placebo is less than 4.4 cm. 
No adjustment to alpha levels will be made for the comparison of diphenhydramine either to 
placebo or to lasmiditan, or for secondary endpoints or analyses. Formal statistical tests (where 
performed) will be 2-sided with testing at the alpha=0.05 level of significance.


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10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
Graphical analyses may be performed to explore the relationship between PK concentrations 
with driving performance (i.e., SDLP) and/or other PD measures.  Additional analyses may be 
performed to further characterize the PK/PD relationship(s), if warranted.


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11.
References
Akerstedt T, Gillberg M. Subjective and objective sleepiness in the active individual. Int J
Neurosci. 1990;52(1-2):29-37.
CRCDS Testing Operations Manual. Cognitive Research Corporation. Data on file.
[FDA] Food and Drug Administration. Evaluating Drug Effects on the Ability to Operate a 
Motor Vehicle Guidance for Industry (November 2017). Available 
at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida 
nces/UCM430374.pdf. Accessed January 16, 2018.
Kaida M, Takahashi T, Åkerstedt A, Nakata Y, Otsuka T, Haratani K, Fukasawa K. Validation 
of the Karolinska sleepiness scale against performance and EEG variables. Clin Neurophysiol.
2006;117(7):1574-1581.
Kay GG, Berman B, Mockoviak SH, Morris CE, Reeves D, Starbuck V, Sukenik E, Harris AG. 
Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, 
mood, and psychomotor performance. Arch Intern Med. 1997;157(20):2350-2356. 
Kay GG, Schwartz HI, Wingertzahn MA, Jayawardena S, Rosenberg RP. Next-day residual 
effects of gabapentin, diphenhydramine, and triazolam on simulated driving performance in 
healthy volunteers: a phase 3, randomized, double-blind, placebo-controlled, crossover trial. 
Hum Psychopharmacol. 2016;31(3):217-226.
Ramaekers JG, O’Hanlon, JF. Acrivastine, terfenadine and diphenhydramine effects on driving 
performance as a function of dose and time after dosing. Eur J Clin Pharmacol.
1994;47(3):261-266.
Siemen A, Gargano C, Cha J, Drexel M, Bautmans A, Heirman I, Laethem T, Hochadel T, 
Gheyle L, Bleys K, Beals C, Stoch A, Kay G, Struyk A. A randomized, crossover, placebo-
controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day 
residual effects of zopiclone. Ther Adv Drug Saf. 2015;6(3):86-97. 
Steiner TJ, Stovner LJ, Birbeck GL. Migraine: the seventh disabler. Cephalalgia.
2013;33(5):289-290.
Wechsler D. Wechsler Adult Intelligence Scale-Revised. San Antonio: Psychological
Corporation;1981.


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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
BAC
blood alcohol count
blinding
A procedure in which 1 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
BP
blood pressure
CNS
central nervous system
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 re-tested at some defined time point, depending on the steps required to obtain 
confirmed results.
CRCDS-MiniSim
Cognitive Research Corporation Driving Simulator-MiniSim
CRF
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
CVDA
Country Vigilance-Divided Attention
DA
Divided attention
ECG
electrocardiogram
eCRF
electronic case report form
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
FDA
Food and Drug Administration
GCP
good clinical practice
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
Investigational 
New Drug
An application to the FDA to allow testing of a new drug in humans.
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.  
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.


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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.
KSS
Karolinska Sleepiness Scale
LC-MS/MS
liquid chromatography tandem-mass spectrometry
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.
NI
noninferiority
PK/PD
pharmacokinetic/pharmacodynamic
randomize
The process of assigning subjects to an experimental group on a random basis.
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SD
standard deviation
SDC
Symbol Digit Coding
SDLP
standard deviation of lateral position
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin level
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 
ULN
upper limit of normal
VAS
Visual Analog Scale


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate (total CO2)
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Phosphorus 
Leukocytes (WBC) 
Platelets
Glucose (random)
Differential WBC (absolute counts) of
Blood urea nitrogen (BUN)
Neutrophils
Uric acid 
Lymphocytes
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Alkaline phosphatase (ALP)
Urinalysisa
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Creatinine
Protein
Glucose
Ketones
Ethanol testingb
Bilirubin
Urine drug screenb
Urobilinogen
Hepatitis B surface antigen c
Blood
Hepatitis C antibody c
Nitrite
HIV c
Pregnancy test (females only)
FSH (if applicable) c
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Performed at follow-up and early discontinuation only. 
b
Urine drug screen and ethanol (urine or breath) level may be repeated prior to admission to the clinical research 
unit and at other times indicated in the Schedule of Activities (Section 2).
c
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 investigational 
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant 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 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.
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
If the coordinating investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
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.


H8H-MC-LAIF(a) Clinical Pharmacology Protocol
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The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable 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
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


H8H-MC-LAIF(a) Clinical Pharmacology Protocol
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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-LAIF Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
19.5
1
19.5
Clinical laboratory testsa
12.5
2
25
Lasmiditan and metabolite 
pharmacokinetics 
2
52
104
Diphenhydramine 
pharmacokinetics
2
16
32
Total
180.5
Total for clinical purposes (rounded up to the nearest 10 mL)
190


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Appendix 6.
Protocol Amendment H8H-MC-LAIF(a)
Summary: A Phase I, Randomized, Subject- and 
Investigator-Blind, Placebo-Controlled, 4-Period Cross-
Over Study Assessing the Duration of Effect of 
Lasmiditan on Simulated Driving Performance in 
Healthy Volunteers
Overview
Protocol H8H-MC-LAIF A Phase I, Randomized, Subject- and Investigator-Blind, Placebo-
Controlled, 4-Period Cross-Over Study Assessing the Duration of Effect of Lasmiditan on 
Simulated Driving Performance in Healthy Volunteers 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 change and rationale for the change made to this protocol are as follows:

Pharmacogenetic blood sampling was removed from study in agreement with the 
Sponsor’s Tailored Therapeutics group.  The number of healthy volunteers is relatively 
small (<100) and a pharmacogenetic sample collection is unlikely to enable investigation 
of pharmacogenetic characteristics in migraine response to lasmiditan.


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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.


H8H-MC-LAIF(a) Clinical Pharmacology Protocol
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2. Schedule of Activities
Screening
Study Informed Consent
Medical History 
Subject Eligibility
Weight/Height (BMI)
Drug and Alcohol Screen (repeat alcohol screen prior to Driving 
Sim Training/Practice if performed at a separate visit)
Vital Signs
Physical Examination (may be performed through Day -1)
Epworth Sleepiness Scale
Clinical Laboratory Tests
Twelve-Lead ECG
Temperature
Serum Pregnancy Test (females only)
CogScreen SDC Training/Screening
Driving Sim Training/Screening
Simulator Sickness Questionnaire
Concomitant Medication assessment
Day -1 (Period 1)
Admission to Clinic
Sample for Pharmacogenetic Analysis (prior to or on Day 1, 
Period 1)
Confirm Subject Eligibility
Drug and Alcohol Screen
Serum Pregnancy Test (females only)
Vital Signs
Directed Physical Examination (symptom driven)
CogScreen SDC Practice
Driving Sim Practice
Adverse Event Assessment
Concomitant Medication Assessment (monitor throughout study)
Day 1 (Periods 1-4)
Predose
Vital Signs
Directed Physical Examination (symptom driven)
Lasmiditan and Metabolites PK Sampling (predose)
Diphenhydramine PK Sampling(predose)
+0.0 h
Study Drug Administration (Dose 1)
+0.5 h
Lasmiditan and Metabolites PK Samplea
+1.0 h
Lasmiditan and Metabolites PK Samplea
Breakfast
+1.5 h
Lasmiditan and Metabolites PK Samplea
+2.0 h
Vital Signs/Lasmiditan and Metabolites PK Samplea
+3.0 h
Lasmiditan and Metabolites PK Samplea
+4.0 h
Vital Signs/Lasmiditan and Metabolites PK Samplea
Lunch


H8H-MC-LAIF(a) Clinical Pharmacology Protocol
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+6.0 h
Lasmiditan and Metabolites PK Samplea
Study Drug Administration (Dose 2)
+8.0 h
KSSb
Adverse Event Assessmentb
CogScreen SDC Testb
Self-Perceived Questionnaire (safe to drive)
Lasmiditan and Metabolites PK Samplea
Diphenhydramine PK Samplea
CVDA Drive
VAS (immediately after drive)
+10.0 h
Lasmiditan and Metabolites PK Samplea
Study Drug Administration (Dose 3)
+11.0 h
Dinner
+12.0 h
KSSb
Adverse Event Assessmentb
CogScreen SDC Testb
Self-Perceived Questionnaire (safe to drive)
Lasmiditan and Metabolites PK Samplea
Diphenhydramine PK Samplea
CVDA Drive
VAS (immediately after drive)
Day 2 (Periods 1-4)
+22 h
Study Drug Administration (Dose 4)
+23 h
Breakfast
+24 h
KSSb
Adverse Event Assessmentb
CogScreen SDC Testb
Self-Perceived Questionnaire (safe to drive)
Lasmiditan and Metabolites PK Samplea
Diphenhydramine PK Samplea`
CVDA Drive
VAS (immediately after drive)
+36 h
Lasmiditan and Metabolites PK Samplea
Day 3 (Periods 1-4)
+48 h
Lasmiditan and Metabolites PK Samplea
Discharge (Day 3, 
Period 4)
Discharge from 
Clinical Unit
Vital Signs
Physical Examination
Clinical Laboratory Tests
Adverse Event Assessment
Concomitant Medication Assessment
Early Discontinuation


H8H-MC-LAIF(a) Clinical Pharmacology Protocol
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Vital Signs
Physical Examination
Clinical Laboratory Tests
Twelve-Lead ECG
Urinalysis Samples 
Serum Pregnancy Test (females only)
Adverse Event Assessment
Concomitant Medication assessment
Within 5 to 9 days 
after Discharge
Follow-up
Vital Signs
Physical Examination
Clinical Laboratory Tests
Twelve-Lead ECG
Urinalysis Samples
Serum Pregnancy Test (females only)
Adverse Event Assessment
Concomitant Medication Assessment
Abbreviations:  BMI = body mass index; CVDA = Country Vigilance-Divided Attention; ECG = electrocardiogram; 
h = hours, KSS = Karolinska Sleepiness Scale; PK = pharmacokinetic; SDC = Symbol Digit Coding; VAS = 
Visual Analog Scale.
a
Pharmacokinetic and pharmacodynamic sampling times are given as targets to be achieved within reasonable 
limits.  For PK sampling scheduled prior to driving assessments, the sampling window should be within -5 min to 
avoid conflict with driving assessment.  Otherwise, the standard PK sampling windows: predose: -15 minutes; 
>0 to 2 hours postdose: ±5 minutes; 2.5 to 6 hours postdose: ±10 minutes; 7 to 12 hours postdose: ±20 minutes; 
>12 hours postdose: ±30 minutes.  The samples will be taken as per schedule to maintain the blind but samples 
will be analyzed according to the randomization table.
b
This accompanying driving assessment procedure should occur within -30 minutes before the scheduled CVDA 
drive targeted for this sampling time
9.7. Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
lasmiditan and to investigate genetic variants thought to play a role in migraine.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 


H8H-MC-LAIF(a) Clinical Pharmacology Protocol
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to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of lasmiditan or after lasmiditan is commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
This section is not applicable for this study.
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-LAIF Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
19.5
1
19.5
Clinical laboratory testsa
12.5
2
25
Lasmiditan and metabolite 
pharmacokinetics 
2
52
104
Diphenhydramine 
pharmacokinetics
2
16
32
Pharmacogenetics
10
1
10
Total
190.5180.5
Total for clinical purposes (rounded up to the nearest 10 mL)
200190

SAP_001.pdf: 
Statistical Analysis Plan  H8H-MC-LAIF(a) A Phase 1, Randomized, Subject- and Investigator-
Blink,Placebo-Controlled, 4-Period Cross-Over Study Assessing the Duration of Effect of Lasmiditan on 
Stimulated Driving Performance in Healthy Volunteers 
 
NCT03459612 
Approval date: 22 May 2018 


Final, 14 May 2018
             Page 1 of 22
STATISTICAL ANALYSIS PLAN
A Phase I, Randomized, Subject- and Investigator-Blind, Placebo-Controlled, 4-Period 
Cross-Over Study Assessing the Duration of Effect of Lasmiditan on Simulated Driving
Performance in Healthy Volunteers
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  14-May-2018
Study Drug:  LY573144 (Lasmiditan)
Sponsor Reference:  H8H-MC-LAIF
Covance CRU Study: 1000071-8381131
Clinical Phase I
Approval Date: 22-May-2018 GMT


Final, 14 May 2018
             Page 2 of 22
Statistical Analysis Plan 
  CONFIDENTIAL
Covance Clinical Study No. 1000071-8381131
Sponsor Reference H8H-MC-LAIF
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
Primary Objective ..................................................................................................................6
Secondary Objectives.............................................................................................................6
Exploratory Objectives...........................................................................................................7
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENTS...................................................................................................................8
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................9
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................9
9.
STATISTICAL METHODOLOGY .....................................................................................9
9.1
General..........................................................................................................................9
9.2
Demographics and Subject Disposition........................................................................10
9.3
Pharmacokinetic Assessment.......................................................................................10
9.3.1
Pharmacokinetic Analysis...................................................................................10
9.3.2
General Pharmacokinetic Parameter Rules..........................................................11
9.3.3
Individual PK Parameter Rules...........................................................................12
9.3.4
Individual Concentration vs. Time Profiles.........................................................12
9.3.5
Average Concentration vs. Time Profiles............................................................12
9.3.6
Treatment of Outliers during Pharmacokinetic Analysis .....................................13
9.3.7
Pharmacokinetic Statistical Methodology ...........................................................14
9.4
Pharmacodynamic Assessment ....................................................................................14
9.4.1
Pharmacodynamic Analysis................................................................................14
9.4.2
Pharmacodynamic Statistical Methodology ........................................................16
9.4.3
Adjustments for Multiplicity...............................................................................18
9.5
Pharmacokinetic/Pharmacodynamic Assessment .........................................................18
9.6
Safety and Tolerability Assessments............................................................................19
9.6.1
Adverse Events...................................................................................................19
9.6.2
Concomitant Medication.....................................................................................19
9.6.3
Clinical Laboratory Parameters...........................................................................19
9.6.4
Vital Signs..........................................................................................................19
9.6.5
Electrocardiogram (ECG)...................................................................................20
9.6.6
Hepatic Monitoring ............................................................................................20
9.6.7
Meals .................................................................................................................20
9.6.8
Other assessments...............................................................................................20
9.6.9
Safety and Tolerability Statistical Methodology..................................................20


Final, 14 May 2018
             Page 3 of 22
Statistical Analysis Plan 
  CONFIDENTIAL
Covance Clinical Study No. 1000071-8381131
Sponsor Reference H8H-MC-LAIF
10. INTERIM ANALYSES .....................................................................................................20
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............20
12. REFERENCES ..................................................................................................................21
13. DATA PRESENTATION ..................................................................................................21
13.1 Derived Parameters .....................................................................................................21
13.2 Missing Data ...............................................................................................................21
13.3 Insufficient Data for Presentation ................................................................................21
14. STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES.....................................22


Final, 14 May 2018
             Page 4 of 22
Statistical Analysis Plan 
  CONFIDENTIAL
Covance Clinical Study No. 1000071-8381131
Sponsor Reference H8H-MC-LAIF
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-)
Area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-)
Percentage of AUC(0-∞) extrapolated
BMI
Body mass index
BQL
Below the lower limit of quantitation
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular 
administration
CRC
Cognitive Research Corporation
CRCDS
Cognitive Research Corporation Driving Simulator
CRF
Case Report Form
C-SSRS
Columbia Suicide Severity Rating Scale
CSR
Clinical Study Report
CV
Coefficient of variation
EC
Early Clinical
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation
KSS
Karolinska Sleepiness Scale
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MR
Metabolic ratio


Final, 14 May 2018
             Page 5 of 22
Statistical Analysis Plan 
  CONFIDENTIAL
Covance Clinical Study No. 1000071-8381131
Sponsor Reference H8H-MC-LAIF
MRE
Magnetic resonance elastography
NA
Not applicable
NI
Noninferiority
PD
Pharmacodynamic
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SD
Standard deviation 
SDC
Symbol Digit Coding
SDLP
Standard deviation of lateral position
TBL
Total bilirubin level
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual Analog Scale
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Final, 14 May 2018
             Page 6 of 22
Statistical Analysis Plan 
  CONFIDENTIAL
Covance Clinical Study No. 1000071-8381131
Sponsor Reference H8H-MC-LAIF
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 15 
February 2018) and Protocol Amendment (a) (final version dated 21 February 2018).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) and 
pharmacodynamic (PD) 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, Cognitive Research Corporation (CRC), 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
Primary Objective
To determine the duration of effect of acute doses of lasmiditan 100 mg and 200 mg compared to 
placebo on simulated driving performance in healthy subjects.
Secondary Objectives

To determine the effects of lasmiditan 100 mg and 200 mg compared to placebo on:
o
self-reported endpoints
o
performance endpoints, and
o
driving performance endpoints

To evaluate the PK of lasmiditan in healthy subjects following a single 100 mg or 200 mg 
oral dose of lasmiditan.


Final, 14 May 2018
             Page 7 of 22
Statistical Analysis Plan 
  CONFIDENTIAL
Covance Clinical Study No. 1000071-8381131
Sponsor Reference H8H-MC-LAIF
Exploratory Objectives

To determine the effect of acute doses of lasmiditan 100 mg and 200 mg at 8, 12, and 
24 hours compared with positive control (diphenhydramine 50 mg) at time of maximum 
observed drug concentration (tmax)

To determine the effects of lasmiditan 100 mg and 200 mg compared with positive control
(diphenhydramine 50 mg) on:
o
self-reported endpoints,
o
performance endpoints, and
o
driving performance endpoints

To evaluate the PK of diphenhydramine

To evaluate the PK of lasmiditan metabolites M8, M7, M18(S,R), and M18(S,S)
5. STUDY DESIGN
This study is a multicenter, randomized, subject- and investigator-blind, active- and 
placebo-controlled Williams square design with 4-period (full) crossover using single 100 mg 
and 200 mg doses of lasmiditan (Figure LAIF.1). Subjects will be randomized to treatment 
sequences and should complete all 4 periods within that treatment sequence.
Figure LAIF.1. Study schematic.
Each period will be of 3 days duration, and the minimum washout between periods is 3 days. 
Screening (Visit 1) will include procedures to access subject eligibility including clinical 
laboratory tests, physical examination, and driving simulation training/screening.  Prior to 
randomization, subjects will be screened for simulator sickness and will receive standardized 
training on the driving simulator and cognitive test battery.  Screening procedures and screening 
assessments may be performed on different days but must be completed within 28 days before 
Period 1 (Visit 2).  The training drives on the driving simulator must be completed no more than 
21 days prior to the first dose of study drug.  Study drug or placebo will be administered by site 
staff during each period at 0 (Dose 1), 6 (Dose 2), and 10 (Dose 3) hours on Day 1 and at 
22 hours (Dose 4) on Day 2 according to the treatment sequence assigned (Figure LAIF.2).  
Subjects will wear a blindfold when taking each dose to maintain the blind.  The tablet size and 
shape are deemed similar enough to maintain the blind provided the subject is blindfolded.  
Driving assessments commence at 8, 12, and 24 hours after Dose 1.  The positive control 
(diphenhydramine 50 mg) is included to establish the sensitivity of the study endpoints.


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Figure LAIF.2. Timing of doses.
Subjects will be assigned and dosed with study medication (lasmiditan, diphenhydramine, or 
placebo) according to the treatment sequence they are randomized to. Subjects will be 
randomized equally into 1 of 4 treatment sequences:
Treatment 
sequence
Period 1
Period 2
Period 3
Period 4
1
Placebo
Lasmiditan 
100 mg
Diphenhydramine 
50 mg
Lasmiditan 
200 mg
2
Lasmiditan 
100 mg
Lasmiditan 
200 mg
Placebo
Diphenhydramine 
50 mg
3
Lasmiditan 
200 mg
Diphenhydramine 
50 mg
Lasmiditan 
100 mg
Placebo
4
Diphenhydramine 
50 mg
Placebo
Lasmiditan 
200 mg
Lasmiditan 
100 mg
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
100 mg Lasmiditan 
2
200 mg Lasmiditan 
3
50 mg Diphenhydramine
4


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7. SAMPLE SIZE JUSTIFICATION
Approximately 72 subjects will be enrolled so that approximately 60 healthy volunteers complete
this study. This study is designed to test noninferiority (NI) of lasmiditan relative to placebo,
with a diphenhydramine test versus placebo to confirm the sensitivity of the simulator to detect
treatment effects. The following assumptions were made in the sample size computation: (a) 
standard deviation (SD) of differences between lasmiditan and placebo within subject for 
standard deviation of lateral position (SDLP) is approximately 9.5 cm; (b) the true difference 
between lasmiditan doses and placebo is 0; and (c) the NI margin is proposed to be 4.4 cm, 
which is the effect seen with 0.05% of blood alcohol count. Under these assumptions, a sample 
of 60 subjects would provide >90% power to establish NI of either dose of lasmiditan compared 
to placebo in terms of the primary end point, SDLP. This sample size is more than adequate to 
detect diphenhydramine differences, which are anticipated to exceed the NI margin, from 
placebo.
Subjects who are randomized but who do not complete all 4 periods during the Treatment Phase
may be replaced. Replacement subjects will enter the same treatment sequence as the original
subjects to complete all 4 periods. 
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
the investigational products and have evaluable PK data.  Subjects may be excluded from the PK 
summary statistics and statistical analysis if a subject has an adverse event (AE) of vomiting that 
occurs at or before 2 times median tmax. 
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
the investigational products and have evaluable PD data.  Subjects may be excluded from the PD 
summary statistics and statistical analysis if a subject has an AE of vomiting that occurs at or 
before 2 times median tmax.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that are databased. For continuous data, summary 
statistics will include the arithmetic mean, arithmetic SD, median, min, max and N; for log-
normal data (e.g. the PK parameters: area under the concentration versus time curve [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 


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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.
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 (BMI) will be summarized and 
listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
Pharmacokinetic parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 6.4 or later).
Concentrations for lasmiditan and metabolites based on predose samples evaluated for periods 2, 
3, 4 may be used for characterizing PK for the preceding period as an additional timepoint (ie 
72 hours)
Plasma concentrations of lasmiditan (LY573144) and its metabolites (M7, M8, (S,R)-M18, and 
(S,S)-M18) will be used to determine the following PK parameters, when possible:  


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Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time 
zero to infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time 
zero to time t, where t is the last time point with a 
measurable concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration (LY573144 only)
Vz/F
L
apparent volume of distribution during the terminal phase 
after extra-vascular administration (LY573144 only)
Vss/F
L
apparent volume of distribution at steady state after extra-
vascular administration (LY573144 only)
MR
metabolic ratioa
a: no molar correction will be applied since the metabolites are very similar in molecular weight  and within 5% of
the molecular weight for lasmiditan.
Plasma concentrations of diphenhydramine will be listed and summarized.
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.
9.3.2 General Pharmacokinetic Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax.  The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax.


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
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.

The parameters based on last predicted quantifiable drug concentration (Clast) will be 
reported.
9.3.3 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.
9.3.4 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.
9.3.5 Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.


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
The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

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.
9.3.6 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 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.


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d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not an 
outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an 
outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
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.
9.3.7 Pharmacokinetic Statistical Methodology
The PK parameters of lasmiditan and its metabolites will be listed and summarized using 
standard descriptive statistics, including estimates of intra-subject variability as appropriate. 
Arithmetic mean (+/- 1 SD) plasma concentration profiles, as well as individual subject profiles, 
will be presented graphically by treatment over time.
9.4
Pharmacodynamic Assessment
9.4.1 Pharmacodynamic Analysis
The primary endpoint (SDLP) and some of the secondary endpoints (Performance [CogScreen 
Symbol Digit Coding [SDC] test] and Driving performance endpoints) will be analyzed by CRC, 
whereas the self-reported secondary endpoints (Karolinska Sleepiness Scale [KSS], 
Self-Perceived Safety to Drive Question and Visual Analog Scale [VAS] to assess subject’s 
motivation and self-appraisal), will be analyzed by Covance EC Biometrics.


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SDLP using the Cognitive Research Corporation Driving Simulator- MiniSim 
(CRCDS-MiniSim) (reported and analyzed by CRC)
SDLP will be used to assess objective level of driving impairment.
The data will be listed, summarized, and analyzed by treatment as outlined in Section 9.4.2 
below.
Self-reported secondary endpoints (reported and analyzed by Covance EC Biometrics)
Karolinska Sleepiness Scale (KSS) 
The KSS will be used to assess subjective level of sleepiness.  This is a subject self-reported 
measure of situational sleepiness and provides an assessment of alertness/sleepiness at a 
particular point in time. 
The data will be listed, summarized by treatment in frequency tables, and analyzed as outlined in 
Section 9.4.2 below.
Self-Perceived Safety to Drive Question
Prior to driving, the subject will be asked a simple question as to whether they feel safe to drive 
(“Right now do you feel safe to drive?”).  Subject will answer “yes” or “no”. 
The data will be listed, summarized by treatment in frequency tables, and analyzed as outlined in 
Section 9.4.2 below.
VAS to Assess Subject’s Motivation and Self-Appraisal
After completing the driving simulation, subjects will assess their own performance and their 
level of motivation to perform at their best during the driving simulation.  Subjects will respond 
to 2 questions:
1. How well you think you drove for the last 60 minutes?
2. How motivated did you feel to drive at your best during the last 60 minutes of driving?
Subjects will record their response to each question by writing a vertical line on a 100-mm 
horizontal, linear visual analog scale, indicating their level of performance (0 = Not Satisfactory 
to 100 = Satisfactory) and motivation (0 = Not Motivated to 100 = Motivated). Scores on the 
100-mm linear scale will be measured to the nearest millimeter from the left. 
These data will be listed, summarized by treatment, and analyzed as outlined in Section 9.4.2 
below.


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Performance secondary endpoints (reported and analyzed by CRC)
CogScreen SDC Test
Number of correct responses, accuracy, and standard deviation of reaction time from the 
CogScreen SDC test will be used to assess treatment-related changes in cognitive functioning.
The data will be listed, summarized, and analyzed by treatment as outlined in Section 9.4.2 
below.
Driving performance secondary endpoints (reported and analyzed by CRC)
Lane Exceedance (including number, maximum and duration), Average Speed, Speed Deviation, 
Speed Count, Excessive Ay (cornering speed threshold exceeded), Total Collisions, and Divided 
Attention measures (correct responses, omission errors, commission errors, reaction time, 
standard deviation of reaction time) will be used to assess objective level of driving impairment.
The data will be listed, summarized, and analyzed by treatment as outlined in Section 9.4.2 
below.
9.4.2 Pharmacodynamic Statistical Methodology
The primary endpoint, SDLP, will be analyzed using a mixed repeated measures model with 
fixed effects for sequence, period, and treatment, with repeated observations for subjects for each 
of the driving time points.  An unstructured covariance structure and Kenward-Roger degrees of 
freedom will be used.  In the event an unstructured covariance structure fails to converge, a 
variance components covariance structure will be assumed. Separate models will be used for 
each of the driving time points.  In addition to assessments of treatment effect, p-values for 
significance testing of period and sequence effects will be provided.
All secondary endpoints (excluding total collisions and self-reported readiness) will be analyzed 
for each of the time points using a mixed repeated measures model similar to the one used for the 
primary analysis, with sequence, period, and treatment as fixed effects, with repeated 
observations for subject.  Separate models will be used for each of the driving and cognition time 
points. Lane Exceedance will be log transformed as ln[x+1] prior to analyses. 
For the primary and secondary endpoints (excluding total collisions and self-reported readiness), 
pairwise comparisons of differences in means and the corresponding 95% confidence intervals
(CIs) of the differences will be provided at each time point for:

Lasmiditan 100 mg versus placebo

Lasmiditan 200 mg versus placebo

Diphenhydramine 50 mg versus placebo 


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Example SAS code (mixed model for primary and secondary endpoints, including with data 
sorted for each endpoint as follows):
proc sort data=adxx; by atptn usubjid aperiod; run;
proc mixed data=adxx alpha=0.05;
by atptn;
class trtpn aperiod trtseqp usubjid ;
model aval = aperiod trtpn trtseqp / ddfm=kr;
repeated / sub=usubjid type=un;
lsmeans trtpn / cl pdiff alpha=0.05;
estimate '100 vs. Pbo' trtpn -1 1 0 0 / cl alpha=0.05;
estimate '200 vs. Pbo' trtpn -1 0 1 0 / cl alpha=0.05;
estimate 'Dip vs. Pbo' trtpn -1 0 0 1 / cl alpha=0.05;
run;
In addition, pair-wise within-subject differences in SDLP greater than 4.4 cm in absolute value 
(equal to the previously found difference between placebo and 0.05% BAC for the CRCDS) will 
be compared using McNemar’s test. Pair-wise, within subject differences in SDLP will also be 
tested for symmetry about zero (Laska 2012) using the maximally selected McNemar test).
Summary statistics for raw and change from baseline values will be provided (mean, SD, 
median, minimum, maximum) for primary and secondary endpoints (excluding total collisions 
and self-reported readiness) for each time point and treatment group.
Figures will be provided for the within subject difference scores by treatment and time point as 
both a histogram and scatter plot for SDLP.  
Self-reported Readiness to Drive
Pairwise comparisons for readiness to drive will be analyzed using McNemar test.
Example SAS code (Pairwise comparisons for readiness to drive using McNemar test):
proc freq data=xxx;
title "McNemar's test for Paired Samples";
tables treat1*treat2 /agree expected norow nocol nopercent; 
run;
Total Collisions
Summary statistics will be provided (mean, SD, median, minimum, maximum) for total number 
of collisions for each time point and treatment group.  Additionally, differences in number of 
collisions for each pair-wise comparison will be provided with their corresponding Wilcoxon 
Signed Rank p-value.  A bar chart will be provided pooling total number of collisions by 0, 1, 2, 
or >=3 for all 4 treatment groups. 
Additional analysis may be conducted if deemed appropriate.


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9.4.3 Adjustments for Multiplicity
To address multiplicity of testing associated with 2 doses of lasmiditan versus placebo at 3 time 
points for the primary endpoint of SDLP, ascending doses of lasmiditan at descending time 
points will be interpreted in a sequential manner, starting with the 100-mg dose at 24 hours and 
proceeding to the 200-mg dose and earlier time points via a graphical multiple comparisons 
procedure, as given in the following figure (Figure LAIF 3). The value of w, the split of alpha 
after testing 100 mg at 24 hours, will be set to 0.95 (i.e., propagating 95% of alpha to the 100 mg 
12 h end point and 5% of the alpha to the 200 mg 24 h end point, assuming the 100 mg 24 h end 
point is successful).
Figure LAIF.3 Pharmacodynamic statistical inference – graphical multiple comparisons 
procedure.
Doses of lasmiditan will be considered non-inferior to placebo at a time point if the upper 95%
CI on the difference in SDLP between that dose and placebo is less than 4.4 cm.
No adjustment to alpha levels will be made for the comparison of diphenhydramine either to
placebo or to lasmiditan, or for secondary endpoints or analyses. Strong control of Type I error 
for non-inferiority, for the primary endpoint will be at the 0.05 alpha-level (two-sided).
9.5
Pharmacokinetic/Pharmacodynamic Assessment
The relationship between the lasmiditan concentrations at 8, 12 and 24 hours (Lasmiditan 100 
and 200 mg) and the 8, 12 and 24 hour assessments for SDLP, Lane Exceedance, Speed 
Deviation, CogScreen SDC number correct, and KSS will be assessed by correlation at each 


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timepoint separately.  Both the Spearman and Pearson correlations will be reported.  Tables will 
provide the correlation coefficient and p-value, which will be provided separately for each 
treatment group.
For each endpoint of interest, scatterplots including data for both 100 mg and 200 mg will be 
provided with separate symbols for each dose level. 
9.6
Safety and Tolerability Assessments
9.6.1 Adverse Events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose. 
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 20.1 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.
9.6.2 Concomitant Medication
Concomitant medication will be coded using the WHO drug dictionary (Version September
2017).  Concomitant medication will be listed.
9.6.3 Clinical Laboratory Parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed.  Urinalysis data will be listed.  Additionally clinical chemistry, hematology and urinalysis 
data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.6.4 Vital Signs
Where two or more repeat measurements are performed for vital signs, the median of the original 
and the repeat values will be used in all subsequent calculations. Where only one repeat 
measurement is performed for vital signs, the repeat value will be used in all subsequent 
calculations.  


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Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as predose of each period. 
Furthermore, values for individual subjects will be listed.
9.6.5 Electrocardiogram (ECG)
For each subject, ECGs will be performed for safety purposes only, and will not be reported.
9.6.6 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality.
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medication of acetaminophen/paracetamol will be listed. Results from any 
hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan, and a 
biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.6.7 Meals
Meal data will be listed for individual subjects.
9.6.8 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.6.9 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
The mixed model specification was updated to use a REPEATED statement rather than a 
RANDOM statement in the SAS® MIXED procedure, to more readily allow for the estimation of 
an unstructured covariance matrix.  Additional details regarding model specification and outputs 
are also provided in Section 9.4.2.  


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Covance Clinical Study No. 1000071-8381131
Sponsor Reference H8H-MC-LAIF
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.
3. Laska E, Meisner M, Wanderling J. A maximally selected test of symmetry about zero.  Stat 
Med 2012;31:3178-91.
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.”