Clinical trial NCT03406260
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2018-01-25; Completion date: 2018-04-13
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purposes of this study are to evaluate the effect of lasmiditan on blood pressure, as well as to look at the amount of study drug that gets into the blood stream and how long it takes the body to get rid of it in healthy elderly participants. The tolerability of the study drug will also be evaluated. Information about any side effects that may occur will also be collected. This study will take about 11 days, not including screening. Screening is required within 28 days prior to the start of the study.

Detailed description:

Arms: arm 1: Participants received 200 mg of Lasmiditan tablet orally in the fasted state with approximately 240 (milliliter) mL of room temperature water in the morning of Days 1, 3, and 5, while participants were in a sitting position. arm 2: Participants received 100 mg of Lasmiditan tablet orally in the fasted state with approximately 240 mL of room temperature water in the morning of Days 1, 3, and 5, while participants were in a sitting position. arm 3: Participants received placebo tablet orally in the fasted state with approximately 240 mL of room temperature water in the morning of Days 1, 3, and 5, while participants were in a sitting position.
Interventions: intervention 1: Lasmiditan intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol H8H-MC-LAIG
A Study to Investigate the Cardiovascular Effects of Lasmiditan in Healthy Elderly Subjects
NCT03406260   
Approval Date:19-Dec-2017 


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Protocol H8H-MC-LAIG
A Study to Investigate the Cardiovascular Effects of 
Lasmiditan in Healthy Elderly Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of
lasmiditan (LY573144), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (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 on date 
provided below.
Approval Date: 19-Dec-2017 GMT


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Table of Contents
A Study to Investigate the Cardiovascular Effects of 
Lasmiditan in Healthy Elderly Subjects
Section
Page
Protocol H8H-MC-LAIG ............................................................................................................1
A Study to Investigate the Cardiovascular Effects of Lasmiditan in 
Healthy Elderly Subjects.....................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................15
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................18
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................19
6.
Study Population...............................................................................................................20
6.1.
Inclusion Criteria..........................................................................................................20
6.2.
Exclusion Criteria ........................................................................................................21
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................22
6.3.
Lifestyle and/or Dietary Requirements .........................................................................22
6.3.1.
Meals and Dietary Restrictions.............................................................................23
6.3.2.
Caffeine, Alcohol, Tobacco, and Grapefruit .........................................................23
6.3.3.
Activity................................................................................................................23
6.4.
Screen Failures.............................................................................................................23
7.
Treatment..........................................................................................................................24
7.1.
Treatment Administered...............................................................................................24
7.1.1.
Packaging and Labeling .......................................................................................24
7.2.
Method of Treatment Assignment ................................................................................25
7.2.1.
Selection and Timing of Doses.............................................................................25


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7.3.
Blinding .......................................................................................................................25
7.4.
Dose Modification........................................................................................................25
7.5.
Preparation/Handling/Storage/Accountability...............................................................25
7.6.
Treatment Compliance .................................................................................................26
7.7.
Concomitant Therapy...................................................................................................26
7.8.
Treatment after the End of the Study............................................................................26
8.
Discontinuation Criteria ....................................................................................................27
8.1.
Discontinuation from Study Treatment.........................................................................27
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................27
8.2.
Discontinuation from the Study....................................................................................27
8.3.
Subjects Lost to Follow-up...........................................................................................28
9.
Study Assessments and Procedures ...................................................................................29
9.1.
Efficacy Assessments...................................................................................................29
9.2.
Adverse Events ............................................................................................................29
9.2.1.
Serious Adverse Events........................................................................................30
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................30
9.2.2.
Complaint Handling.............................................................................................31
9.3.
Treatment of Overdose.................................................................................................31
9.4.
Safety...........................................................................................................................31
9.4.1.
Laboratory Tests ..................................................................................................31
9.4.2.
Vital Signs ...........................................................................................................31
9.4.2.1.
Ambulatory Blood Pressure Monitoring..........................................................31
9.4.3.
Electrocardiograms ..............................................................................................32
9.4.4.
Safety Monitoring ................................................................................................32
9.4.4.1.
Hepatic Safety................................................................................................33
9.5.
Pharmacokinetics .........................................................................................................33
9.5.1.
Bioanalysis...........................................................................................................33
9.6.
Pharmacodynamics ......................................................................................................34
9.7.
Genetics .......................................................................................................................34
9.8.
Biomarkers...................................................................................................................34
9.9.
Health Economics ........................................................................................................34
10.
Statistical Considerations and Data Analysis.....................................................................35
10.1. Sample Size Determination ..........................................................................................35
10.2. Populations for Analyses..............................................................................................35
10.2.1.
Study Participant Disposition ...............................................................................35
10.2.2.
Study Participant Characteristics ..........................................................................35
10.3. Statistical Analyses ......................................................................................................35
10.3.1.
Safety Analyses....................................................................................................35


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10.3.1.1.
Clinical Evaluation of Safety..........................................................................35
10.3.1.2.
Statistical Evaluation of Safety.......................................................................36
10.3.2.
Pharmacokinetic Analyses....................................................................................36
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................36
10.3.2.2.
Pharmacokinetic Statistical Analysis...............................................................36
10.3.3.
Cardiovascular Analyses ......................................................................................36
10.3.3.1.
Cardiovascular Parameter Estimation .............................................................36
10.3.3.2.
Statistical Inference of Cardiovascular Parameters..........................................36
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................37
10.3.5.
Interim Analyses..................................................................................................37
11.
References ........................................................................................................................38


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List of Tables
Table
Page
Table 4.1.
Objectives and Endpoints .......................................................................17
Table 5.1.
Sequences in Study LAIG.......................................................................18
Table 7.1.
Treatments Administered........................................................................24


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................39
Appendix 2.
Clinical Laboratory Tests........................................................................43
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................44
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............47
Appendix 5.
Blood Sampling Summary......................................................................48


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1. Protocol Synopsis
Title of Study:
A Study to Investigate the Cardiovascular Effects of Lasmiditan in Healthy Elderly Subjects
Rationale: 
Study H8H-MC-LAHA (LAHA) was recently conducted to determine the pharmacokinetics (PK) and safety of 
lasmiditan in elderly and young healthy subjects following a single oral administration of lasmiditan 200 mg. The 
study database has been locked but the clinical study report has not been finalized. A review of preliminary data 
from the elderly cohort showed that following administration of lasmiditan 200 mg, there was a transient elevation 
in mean supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) between 60 and 90 minutes 
postdose, with a mean maximum SBP increase of 14.5 mmHg and DBP increase of 3.8 mmHg compared with 
baseline. Because the number of subjects enrolled in LAHA was based on statistical power to detect differences in 
PK, it was not possible to determine if the observed effects on blood pressure (BP) were statistically significant.
Elderly patients with migraine are among those in the target population for lasmiditan.  Therefore, it is important to 
assess further safety due to the BP response observed in Study LAHA.  The current study will test whether each 
dose level of lasmiditan (100 and 200 mg) is noninferior to placebo with regard to increasing SBP.  The intended 
sample size will have at least 90% power to detect a true mean increase of 5 mmHg in SBP change from baseline
between lasmiditan and placebo, assuming a 1-sided significance level of 0.05 and a noninferiority margin of 
10 mmHg.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To test whether each oral dose of lasmiditan (100 and 
200 mg) is noninferior to placebo with regard to 
increasing blood pressure in healthy elderly subjects 
(≥65 years of age).

Systolic blood pressure  obtained via 
ambulatory blood pressure monitoring (ABPM)
Secondary
To determine the PK of lasmiditan in healthy elderly 
subjects (≥65 years of age) following single 100- and 
200-mg oral doses of lasmiditan.
To assess the safety and tolerability of 100- and 200-
mg oral doses of lasmiditan in healthy elderly subjects.

PK parameters:  maximum observed drug 
concentration (Cmax), time of Cmax (tmax), 
and the area under the concentration versus time 
curve from zero to infinity (AUC[0 ∞])

A summary of the number of treatment-
emergent adverse events (TEAEs) and serious 
adverse events (SAEs)
Summary of Study Design:
This is a randomized, subject- and investigator-blind, placebo-controlled crossover study with 3 treatment periods to 
assess BP, PK, and safety and tolerability of 100- and 200-mg oral doses of lasmiditan in healthy elderly subjects.  
All subjects will participate in 3 treatment periods.  The treatments are as follows:


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
Treatment A: Lasmiditan 200 mg

Treatment B: Lasmiditan 100 mg

Treatment C:  Placebo
Each subject will be randomized to 1 of 6 treatment sequences in a Williams design (i.e. ABC, BCA, CAB, CBA, 
ACB, BAC). 
Treatment Arms and Planned Duration for an Individual Subject:  
Screening Period:
All subjects will participate in a screening visit up to 28 days prior to study drug dosing.  
Dosing Period:
All subjects will participate in 3 treatment periods.  Subjects will be randomized to 1 of 6 treatment sequences.  
They will be admitted to the clinical research unit (CRU) the day prior to dosing (Day -1), and receive study drug on 
Days 1, 3, and 5.  Subjects will be discharged from the CRU on Day 7.  There will be a washout period of
approximately 48 hours between each dosing day.  Subjects will remain confined during the entire inpatient period. 
Number of Subjects:
Up to 36 subjects may be enrolled to ensure 30 subjects complete the study.  Subjects will be aged ≥65 years.  
Attempts will be made to enroll at least 6 subjects who are aged ≥75 years.
Statistical Analysis:
Cardiovascular parameters that will be assessed using ABPM include peak hourly mean values of SBP. The 
parameters will be listed, and summarized using descriptive statistics, as appropriate.  Changes from baseline in 
peak hourly mean values of SBP will be analyzed to test whether each dose of lasmiditan (100 and 200 mg) is 
noninferior to placebo, assuming a noninferiority margin of 10 mmHg.  A linear mixed-effects model with baseline 
as a covariate, fixed effects for treatment, period (1, 2, or 3), and treatment sequence, and a random effect for subject 
will be used to test the hypotheses at a 1-sided significance level of 0.05. A gatekeeping procedure will be used to 
adjust for multiplicity when conducting the hypothesis tests comparing lasmiditan 100 mg with placebo and 
lasmiditan 200 mg with placebo.
Safety parameters that will be assessed include safety laboratory parameters, vital signs, DBP, and pulse rate 
obtained via ABPM, and adverse events.  The parameters will be listed, and summarized using standard descriptive 
statistics, as appropriate.  
Pharmacokinetic parameter estimates for lasmiditan will be calculated using standard noncompartmental methods of 
analysis.  The parameters will be listed, and summarized using standard descriptive statistics, including estimates of 
intra-subject variability as appropriate.  


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2. Schedule of Activities


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Study Schedule Protocol H8H-MC-LAIG
Screening
Inpatient Period
Discharge 
from 
Clinic or 
Early 
Term 
Procedures
Follow up
Comments
Procedure
-28 to -2 
days prior 
to Day 1
Day -1
Day 1
Day 
2
Day 3
Day 
4
Day 5
Day 
6
Day 7
Day 10 ± 2 
days
Informed Consent
X
C-SSRS and Self 
Harm Supplement
Form
X
X
X
X
For the C-SSRS, use Baseline 
Version at screening and Since 
Last Visit Version at all other 
visits.
Subject Admission 
to CRU
X
Subject Discharge 
from CRU
X
Randomization
X
Randomization to occur prior to 
dosing.
Investigational 
Product 
Administration
X
X
X
Medical History
X
X
After screening, medical history 
should include interim medical 
history.
AEs and 
Medication review
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
Temperature
X
Vital Signs
(supine)
X
X
Pre-
dose
and 4 h
24 h
Pre-
dose 
and 4 h
24 
h
Pre-
dose
and 4 h
24 h
Xa
X
Vital signs will be single
measures.
The pre-dose measure is taken 


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before the ABPM recordings 
are started.
Time points may be added if 
warranted and agreed upon 
between Lilly and the 
investigator.


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Screening
Dosing Period
Discharge 
from Clinic 
or Early 
Term 
Procedures
Follow up
Comments
Procedure
-28 to -2 
days prior 
to Day 1
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 10 ± 2 
days
Orthostatic Vital 
Signs 
X
Ambulatory Blood 
Pressure 
Monitoring
X
X
X
The ABPM device 
will be worn for 
approximately 
2 hours before dosing 
and will continue to 
be worn until the 24-
hour postdose 
assessment is 
complete.  See 
Section 9.4.2.1 for 
details.
ABPM Training
X
Subjects should be
trained on the ABPM 
device on the evening 
of Day -1.  Data from 
this acclimation 
period will not be 
stored or analyzed.
Clinical Laboratory
Tests
X
X
X
See Appendix 2, 
Clinical Laboratory 
Tests, for details.
Ethanol Test
X
See Appendix 2, 
Clinical Laboratory 
Tests, for details.


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Urine Drug Screen 
X
X
See Appendix 2, 
Clinical Laboratory 
Tests, for details.
Physical 
Examination
X
X
X
X
X
X
X
Full physical 
examination at
screening.  Symptom-
driven physical 
examination for all 
other time points.
12-lead ECG
X
Pre-
dose
and 4 h
24 h
Pre-
dose
and 4 h
24 h
Pre-
dose
and 4 h
24 h
Single ECG readings 
will be taken. The 
pre-dose measure is 
taken before the 
ABPM recordings are 
started.
PK Samples
Pre-
dose, 
0.5, 1, 
1.5, 2, 
2.5, 3, 
4, 6, 8, 
12
24, 36
Pre-
doseb, 
0.5, 1, 
1.5, 2, 
2.5, 3, 
4, 6, 8, 
12
24, 36
Pre-
doseb, 
0.5, 1, 
1.5, 2, 
2.5, 3, 
4, 6, 8, 
12
24, 36
48c
Genetic Sample
X
Single sample for 
pharmacogenetic 
analysis taken prior 
to/on Day 1.
Abbreviations:  ABPM = ambulatory blood pressure monitoring; AE = adverse event; CRU = clinical research unit; C-SSRS = columbia-suicide severity rating 
scale; ECG = electrocardiogram; min = minutes; PK = pharmacokinetics. 
a
The Day 7 vital sign measurement should be taken approximately 48 hours after the previously administered dose
b
Pre-dose should be collected approximately 48 hours after the previously administered dose.
c
Unscheduled PK samples should be drawn for subjects following early termination procedures.
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used:  ECG, supine vital signs, and orthostatic vital 
signs, venipuncture.  Where venipuncture and other procedures take place at the same time point, the following time windows for obtaining blood samples 
should be maintained:  >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.  Where repeats of vital signs measurements are required, repeats should be performed after venipuncture.


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3. Introduction
3.1.
Study Rationale
Lasmiditan is a small molecule 5-hydroxytryptamine (5-HT1F) receptor agonist being developed 
for the acute treatment of migraine.  Triptans, which are 5-HT1B/1D receptor agonists, are well 
established as an acute therapy for migraine, though they are not effective in all patients or 
attacks. Triptans were developed as cerebral vasoconstrictors, mediated via their affinity for 
5-HT1B receptors located on vascular smooth muscle. Inherent in this mechanism of action is a 
liability for coronary vasoconstriction, and therefore, triptans are contraindicated in patients with 
cardiovascular disease. Unlike triptans, lasmiditan is a highly selective and potent agonist at the 
5-HT1F receptor with >470-fold higher affinity for the 5-HT1F receptor than for 5-HT1B/1D
receptors. Lasmiditan is under development as a neurally acting treatment for migraine without 
the vasoconstrictor liability of triptans.
The prevalence of migraine declines in the population older than 50 years of age; however, 5%
to 10% of the population older than 65 years of age still report suffering from migraine (Victor 
et al. 2010).  Thus, elderly patients are anticipated to receive lasmiditan.
Study H8H-MC-LAHA (LAHA) was recently conducted to determine the pharmacokinetics 
(PK) and safety of lasmiditan in elderly and young healthy subjects following a single oral 
administration of lasmiditan 200 mg. The study database has been locked but the clinical study 
report has not been finalized. A review of preliminary data from the elderly cohort showed that 
following administration of lasmiditan 200 mg, there was a transient elevation in mean supine 
systolic blood pressure (SBP) and diastolic blood pressure (DBP) between 60 and 90 minutes 
postdose, with a mean maximum increase in SBP of 14.5 mmHg and in DBP of 3.8 mmHg 
compared to baseline.  Since the number of subjects enrolled in LAHA was based on statistical 
power to detect differences in PK, it was not possible to determine if the observed effects on 
blood pressure (BP) were statistically significant. Therefore, it is important to assess further 
safety due to the response of BP observed in Study LAHA.  The current study will test whether 
each dose level of lasmiditan (100 and 200 mg) is noninferior to placebo with regard to 
increasing SBP.  The intended sample size will have at least 90% power to detect a true mean 
increase of 5 mmHg in change in SBP from baseline between lasmiditan and placebo, assuming 
a 1-sided significance level of 0.05 and a noninferiority margin of 10 mmHg.
3.2.
Background
Across the completed Phase 1, 2, and 3 clinical studies, doses of 0.1 to 400 mg of lasmiditan 
were evaluated in healthy subjects or patients with migraine. Compared with placebo, the most 
frequently reported lasmiditan treatment-emergent adverse events (TEAEs) included dizziness, 
paresthesia, somnolence, fatigue, lethargy, and nausea. A majority of these TEAEs were mild or 
moderate in severity and none led to subject withdrawal. One patient experienced a serious 
adverse event (SAE) of dizziness that was moderate in severity (lasmiditan 200 mg) (Färkkilä 
et al. 2012).


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In the thorough QT study in healthy subjects, no clinically significant changes in BP, heart rate, 
or 12-lead electrocardiogram (ECG) were observed at the 100- or 400-mg single-dose levels.
In healthy subjects, peak plasma concentrations of lasmiditan were observed approximately 
1.5 to 2.5 hours after a single oral dose ranging from 25 to 400 mg, and the geometric mean 
terminal half-life was approximately 4 hours. Lasmiditan exhibited dose-linear PK. 
Co-administration of lasmiditan with a high-fat diet led to a delay in median time of maximum 
observed drug concentration (tmax) value by approximately 1 hour and a modest (~20%) 
increase in lasmiditan maximum observed drug concentration (Cmax), and area under the 
concentration versus time curve (AUC) values, relative to that under fasted conditions.
Following oral dosing with lasmiditan, up to 11 metabolites were detected in human plasma and 
urine, including 3 major metabolites (M7, M8, and M18).  These metabolites lacked significant 
pharmacological activity at the 5 HT1F receptor and were generally considered to be 
pharmacologically inactive.  The relative proportions of metabolites to intact lasmiditan 
remained reasonably constant throughout the oral dose range studied and their PK was
approximately linear.  The half-life of the metabolites ranged from ~4.5 to 21 hours.
Preliminary PK results from Study LAHA demonstrated that in elderly subjects, exposure to 
lasmiditan as measured by AUC from zero to infinity was 26% (90% confidence intervals (CIs)
1.03, 1.55) higher than in young subjects following dosing with 200 mg lasmiditan.  There was 
no statistically significant difference in exposure to lasmiditan based on Cmax.  The tmax of 
lasmiditan was similar between age groups.  The geometric mean t1/2 was 5.46 and 4.10 hours in 
elderly and young subjects, respectively.
Preliminary safety data from Study LAHA show that single doses of 200 mg lasmiditan were 
well tolerated by 18 healthy elderly and 17 healthy young subjects in this study, with no reported
deaths, other SAEs, or discontinuations due to adverse events (AEs).  The types of TEAEs 
reported were consistent with previous studies of lasmiditan in healthy subjects.  In elderly 
subjects, postdose there was a transient elevation in mean supine systolic blood pressure (SBP) 
and diastolic blood pressure (DBP) between 60 and 90 minutes postdose, with a mean maximum 
SBP increase of 14.5 mmHg and DBP increase of 3.8 mmHg compared with baseline  . The 
changes in supine vital signs were maximal at approximately 1.5 hours postdose and had 
returned toward baseline values by the time of the assessment at 3 hours postdose.  No such 
changes were noted in elderly subjects receiving placebo or in young subjects receiving 
lasmiditan.  There were no apparent postdose trends in orthostatic vital signs for any age group.
3.3.
Benefit/Risk Assessment
The primary objective of this study is to evaluate the cardiovascular effects after single oral 100-
and 200-mg doses of lasmiditan in healthy elderly subjects.  There is no anticipated therapeutic 
benefit for the subjects.
Lasmiditan has been generally well tolerated by healthy subjects as single oral doses up to 
400 mg.  Elderly patients were enrolled in the completed Phase 3 program, for acute treatment of 
migraine, that tested single oral doses up to 200 mg, where a second dose was permitted within 


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the same day if migraine relief had not been achieved.  In addition, Study LAHA tested 200 mg 
lasmiditan in 18 elderly subjects.
In completed clinical studies with single lasmiditan oral doses up to 400 mg, the most frequently 
reported lasmiditan TEAEs included tiredness, drowsiness, dizziness, and paresthesia. A
majority of these TEAEs were mild in severity and none led to subject withdrawal. One patient 
experienced an SAE of dizziness that was moderate in severity (lasmiditan 200 mg).  Dosing of 
lasmiditan in this study will be conducted in an inpatient setting, and subjects will be monitored 
in the clinical research unit (CRU) for at least 48 hours after each dosing.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of lasmiditan is to be found in the Investigator’s Brochure (IB).


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4. Objectives and Endpoints
Table LAIG 1 shows the objectives and endpoints of the study.
Table LAIG 1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To test whether each oral dose of lasmiditan (100 and 
200 mg) is noninferior to placebo with regard to 
increasing blood pressure in healthy elderly subjects 
(≥65 years of age).

Systolic blood pressure obtained via ambulatory 
blood pressure monitoring (ABPM)
Secondary
To determine the PK of lasmiditan in healthy elderly 
subjects (≥65 years of age) following single 100- and 
200-mg oral doses of lasmiditan.
To assess the safety and tolerability of 100- and 200-mg 
oral doses of lasmiditan in healthy elderly subjects.

PK parameters:  maximum observed drug 
concentration (Cmax), time of Cmax (tmax), and 
the area under the concentration versus time 
curve from zero to infinity (AUC[0-∞])

A summary of the number of treatment-emergent 
adverse events (TEAEs) and serious adverse 
events (SAEs)


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5. Study Design
5.1.
Overall Design
This is a randomized, subject- and investigator-blind, crossover study with 3 treatment periods in 
healthy elderly subjects.  The treatments are as follows:

Treatment A: Lasmiditan 200 mg

Treatment B: Lasmiditan 100 mg

Treatment C: Placebo
Each subject will be randomized to 1 of 6 treatment sequences in a Williams design, as outlined 
in Table 5.1.
Study governance considerations are described in detail in Appendix 3.
Table 5.1.
Sequences in Study LAIG
Sequence
Period 1
Period 2
Period 3
1
Lasmiditan 200 mg
Lasmiditan 100 mg
Placebo
2
Lasmiditan 100 mg
Placebo
Lasmiditan 200 mg
3
Placebo
Lasmiditan 200 mg
Lasmiditan 100 mg
4
Placebo
Lasmiditan 100 mg
Lasmiditan 200 mg
5
Lasmiditan 200 mg
Placebo
Lasmiditan 100 mg
6
Lasmiditan 100 mg
Lasmiditan 200 mg
Placebo
Screening Period: 
All subjects will participate in a screening visit up to 28 days prior to study drug dosing.
Dosing Period:
Subjects will participate in 1 inpatient period involving 3 dosing periods.  Subjects will be 
admitted on Day -1 and will be randomized to 1 of 6 treatment sequences to receive lasmiditan 
or placebo on Days 1, 3, and 5.  There will be a washout period of approximately 48 hours 
between each dosing day.  Subjects may be discharged on Day 7 based on investigators’
discretion.
All subjects will be discharged from the study approximately 2 days after their final dose of 
lasmiditan.
5.2.
Number of Participants
Up to 36 subjects may be enrolled to ensure 30 subjects complete the study.  Subjects will be 
aged ≥65 years.  Attempts will be made to enroll at least 6 subjects who are aged ≥75 years.  


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Subjects who discontinue from the study prior to completion may be replaced at the discretion of 
the sponsor.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
A randomized, subject- and investigator-blind, placebo-controlled design is being used to 
minimize bias on the safety and tolerability objective.  A crossover design improves the 
sensitivity for detecting any safety/tolerability signals in elderly subjects, particularly in relation 
to vital signs (as described in Section 5.1).
The washout period of approximately 48 h between each dose is adequate based on the half-life 
of lasmiditan.
The nonclinical and clinical data enable conducting clinical pharmacology studies in elderly 
healthy subjects.  The single-dose design of this study limits exposure of subjects to lasmiditan 
and is appropriate to address the study objectives.
5.5.
Justification for Dose
The upper dose level of 200 mg lasmiditan has been well tolerated in previous studies of healthy 
subjects and in elderly patients enrolled in the completed Phase 3 program.  This dose level is in 
the therapeutic dose range and is expected to be the highest potential recommended single dose 
for lasmiditan. A lower dose of 100 mg lasmiditan will also be evaluated in the current study to 
explore any cardiovascular effect.


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to Day 1.  Subjects who are not enrolled within 28 days
of screening may be subjected to an additional medical assessment and/or clinical measurements 
to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, 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 and enrollment (Day 1):
[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 non-childbearing potential, i.e. postmenopausal or permanently sterile 
following hysterectomy, bilateral salpingectomy or confirmed tubal occlusion 
(not tubal ligation), as determined through medical history.  Postmenopausal is 
defined as spontaneous amenorrhea for at least 12 months, and a plasma 
follicle-stimulating hormone level greater than 40 mIU/mL, unless the subject 
is taking hormone replacement therapy.
[2] are aged ≥65 years.
[3] have a body mass index (BMI) of 19.0 to 35.0 kg/m2, inclusive, at the time of 
screening.
[4] have clinical laboratory test results within normal reference range for the population 
or investigator site, or results with acceptable deviations that are judged to be not 
clinically significant by the investigator.
[5] have venous access sufficient to allow for blood sampling as per the protocol.
[6] are reliable and willing to make themselves available for the duration of the study 
and are willing to follow study procedures.
[7] have given written informed consent approved by Lilly and the ethical review board 
(ERB) governing the site.


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6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment (Day 1):
[8] are investigator site personnel directly affiliated with this study and their immediate 
families.  Immediate family is defined as a spouse, parent, child or sibling, whether 
biological or legally adopted.
[9] are Lilly or Covance employees.
[10] are currently enrolled in a clinical study involving an investigational product or any 
other type of medical research judged not to be scientifically or medically 
compatible with this study.
[11] have known allergies to lasmiditan, related compounds, or any components of the 
formulation.
[12] are persons who have previously received lasmiditan.
[13] have a history of, or ECG findings of, clinically significant bradycardia, heart block, 
tachy or brady arrhythmias, or have any other abnormality in the 12-lead ECG that, 
in the opinion of the investigator, increases the risks associated with participating in 
the study.
[14] have significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; of
constituting a risk when taking the study medication; or of interfering with the 
interpretation of data.  Appendectomy, splenectomy, and cholecystectomy are 
considered as acceptable.
[15] show evidence of significant active neuropsychiatric disease (e.g. manic depressive 
illness, schizophrenia, depression) considered as clinically significant by the 
investigator.
[16] show a history of central nervous system (CNS) conditions such as strokes, transient 
ischemic attacks, significant head trauma, seizures, CNS infections, migraines, brain 
surgery, or any other neurological conditions that, in the opinion of the investigator, 
increase the risk of participating in the study.
[17] show evidence of active renal disease (e.g. diabetic renal disease, polycystic kidney 
disease) or estimated glomerular filtration rate <60 mL/min/1.73 m2.
[18] currently use, or within the past 1 year used recreational drug use, or showed 
evidence of substance dependence within the past 6 months based on history at 
screening visit.
[19] show evidence of human immunodeficiency virus (HIV) infection and/or positive 
human HIV antibodies/antigens.
[20] show evidence of hepatitis C and/or positive hepatitis C antibody.


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[21] show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[22] intend to use over-the-counter or prescription medication, dietary supplements, or 
strong inhibitors or inducers of cytochrome P450 (CYP)1A and CYP3A activities 
within 14 days prior to dosing of lasmiditan.  Exceptions allowable for subjects on a 
stable dose of hormone replacement therapy, thyroid replacement therapy, 
prophylactic anti-platelet drugs, angiotensin-converting enzyme (ACE) inhibitors, 
angiotensin receptor blockers (ARBs), thiazides, statins, or protein pump inhibitors 
(PPIs) for at least 3 months prior to admission; medications falling into the 
exceptions listed above, and/or others that may be considered not to impact study 
integrity may be allowed following discussion with the Lilly clinical research 
physician (CRP)/CP or designee.
[23] have donated blood of more than 500 mL within 2 months prior to the screening 
visit.
[24] have an average weekly alcohol intake that exceeds 14 units per week or are 
unwilling to stop alcohol consumption 48 hours prior to admission until the 
completion of the study (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 
1.5 oz or 45 mL of distilled spirits).
[25] have a history of syncope, presyncopy, uncontrolled vertigo, postural dizziness, or at 
risk for falls, as judged to be clinically significant by the investigator.
[26] are unwilling to refrain from tobacco- or nicotine-containing products while in the 
CRU or are unable to abide by CRU restrictions.
[27] have orthostatic hypotension with or without dizziness and/or syncope at screening
(or upon repeat) or a history of it.
[28] have a history of, show evidence of, or are undergoing treatment for significant 
active neuropsychiatric disease (e.g. manic depressive illness, schizophrenia, 
depression), have a recent history of a suicide attempt (30 days within screening 
visit and any time between screening visit and baseline); or are clinically judged by 
the investigator to be at risk for suicide.
[29] 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
The use of lasmiditan in elderly patients is anticipated, thus this study will specifically examine 
the PK, safety, and tolerability in an elderly population.  Criterion 2 defines the elderly 
population for the purposes of this study.
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.


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6.3.1. Meals and Dietary Restrictions
Lasmiditan or placebo will be administered after an overnight fast of at least 8 hours.  Subjects 
will be given a snack prior to bedtime.  Subjects will abstain from water 1 hour before and after 
dosing (except for water given with the dose).  Subjects may be permitted to consume a light 
breakfast (e.g. cereal, toast) at 1 hour postdose at the discretion of the investigator; with the 
exception of this light breakfast, subjects will remain fasting for 3 hours postdose at which time a 
meal will be served.
6.3.2. Caffeine, Alcohol, Tobacco, and Grapefruit
Caffeine – Subjects will refrain from consuming xanthine- or caffeine-containing food and 
drinks from 48 hours prior to admission, and while resident at the CRU.
Alcohol – Subjects will not consume alcohol for 48 hours prior to admission, and while resident 
at the CRU.
Tobacco – Subjects will refrain from using tobacco- or nicotine-containing products while 
resident at the CRU.
Grapefruit – Subjects will refrain from consuming grapefruit and grapefruit-containing products 
from 7 days prior to Day 1, and while resident at the CRU.
6.3.3. Activity
No strenuous exercise will be allowed for 48 hours prior to admission until after follow-up visit.
6.4.
Screen Failures
Individuals may be re-screened once.  The interval between re-screenings should be at least 
1 week.  When 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
Investigational products used in this study are shown in Table 7.1.
Tablets of lasmiditan and/or placebo will be administered orally in the fasted state with 
approximately 240 mL of room temperature water in the morning of Days 1, 3, and 5, while 
subjects are in a sitting position.  Subjects will not be allowed to lie supine for 2 hours after 
dosing, unless clinically indicated or for study procedures.
Table 7.1.
Treatments Administered
Treatment Name
Lasmiditan
Placebo
Dosage Formulation
Film-coated tablet
Film-coated tablet 
(matching to lasmiditan)
Unit Dose Strength
100-mg tablet
--
Route of Administration
Oral
Oral
Dosing Instructionsa
1 or 2 x tablet taken in the morning of 
each dosing day
1 or 2 x tablet taken in the morning of 
each dosing day
a
All subjects will receive 2 tablets at each dosing occasion, i.e. 1 x 100-mg tablet plus 1 matching placebo tablet, 
or 2 x 100 mg tablet, or 2 matching placebo tablets.
The investigator or designee is responsible for

explaining the correct use of the investigational product(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.
7.1.1. Packaging and Labeling
Each tablet of lasmiditan contains 100 mg of active ingredient and is provided as bulk supply in 
bottles.  Placebo tablets look identical but contain no active ingredient and will be provided in 
similar bulk bottles.
The investigational product will be labeled according to the country’s regulatory requirements.


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7.2.
Method of Treatment Assignment
All subjects will participate in 3 treatment periods.  The treatments are as follows:

Treatment A: Lasmiditan 200 mg

Treatment B: Lasmiditan 100 mg

Treatment C: Placebo
Each subject will be randomized to one of 6 treatment sequences in a Williams design (i.e. ABC, 
BCA, CAB, CBA, ACB, BAC) using a computer-generated allocation schedule.
7.2.1. Selection and Timing of Doses
Subjects will receive study drugs on Days 1, 3, and 5.
The actual time of all dose administrations will be recorded in the subject’s case report form 
(CRF).
7.3.
Blinding
This study will be subject- and investigator-blind.  The investigator, site staff (except unblinded 
pharmacy staff), and subjects will be blinded to study treatment.
Emergency codes will be available to the investigator.  A code, which reveals the treatment for a 
specific study subject, may be opened during the study only if the subject’s well-being requires 
knowledge of the subject’s treatment assignment.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist (CP) 
or CRP for the study participant to continue in the study.  During the study, emergency 
unblinding should occur only by accessing the study subject’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
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 all investigational product was received in good 
condition, and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product.  All 


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investigational product should be stored in an environmentally controlled and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as 
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
Concomitant medications are to be avoided during the study unless required to treat an AE or for 
the treatment of an ongoing medical problem.
Acetaminophen may be allowed at the investigator’s discretion, up to 2 g in a 24-hour period, 
without prior consultation with the sponsor.
Stable doses of hormone replacement therapy, thyroid replacement therapy, prophylactic 
antiplatelet drugs, ACE inhibitors, ARBs, thiazides, statins, or PPIs for at least 3 months prior to 
admission. Medications falling into the exceptions listed above, and/or others that may be 
considered not to impact study integrity may be allowed following discussion with the Lilly 
CRP/CP or designee.
If the need for concomitant medication (other than acetaminophen) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator after consultation with a 
Lilly CP, CRP, or designee.  Any medication used during the course of the study must be 
documented.
7.8.
Treatment after the End of the Study
This section is not applicable to this study.


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8. Discontinuation Criteria
Subjects discontinuing from the study prematurely for any reason must complete adverse event 
(AE) and discharge procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

alanine aminotransferase (ALT), aspartate aminotransferase (AST) >5X upper limit of 
normal (ULN)

ALT or AST >3X ULN and total bilirubin >2X ULN or international normalized ratio 
(INR) >1.5

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and total bilirubin >2X ULN

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 CP/CRP or designee and the 
investigator to determine if the patient may continue in the study.  If both agree it is medically 
appropriate to continue, the investigator must obtain documented approval from the Lilly 
CP/CRP or designee to allow the inadvertently enrolled patient 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, or legal representative, requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she fails to return for a scheduled visit 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 electronic case report form (eCRF), 
the occurrence and nature of each subject’s preexisting conditions, including clinically 
significant signs and symptoms of the disease under treatment in the study.  Additionally, site 
personnel will record any change in the condition(s) and the occurrence and nature of any AEs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the concomitant 
treatment or pathologies.
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product 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 patient or may require intervention to prevent 1 
of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
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 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances.


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9.2.2. 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 lasmiditan so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of lasmiditan is considered any dose higher than the 
dose assigned through randomization. There is no specific antidote for lasmiditan. In the event 
of overdose, the subject should receive appropriate supportive care and AEs should be 
documented. 
Refer to the IB.
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).
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the subject receives the first dose of investigational product should be reported to Lilly or 
its designee as an AE via eCRF.
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 (PR) 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 (nondominant 
arm will be used for ambulatory blood pressure monitoring [ABPM]).
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 2 minutes; no longer than 
3 minutes.
If the subject feels unable to stand, supine vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.4.2.1.
Ambulatory Blood Pressure Monitoring
For each subject, ABPM will be performed according to the Schedule of Activities (Section 2).


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Site investigative personnel should be trained on the correct positioning of the ABPM monitor, 
use of correct cuff size, and monitor calibration prior to the start of the study.  Subjects should be
trained on the ABPM device on the evening of Day -1 to maximize the collection of valid 
measurements, and to alleviate any concerns about inconvenience due to the continuous 24-hour 
monitoring.
The ABPM device should be attached to the subject’s nondominant arm and will record 
ambulatory BP and PR every 20 minutes during awake hours (e.g. 0700 hours to 2200 hours) and 
every 30 minutes throughout the night (2200 hours to 0700 hours).  On Days 1, 3, and 5 when 
dosing occurs, the BP and PR recording will be initiated approximately 2 hours prior to the 
planned dosing time and will continue for approximately 26 hours. Subjects will be encouraged 
to keep the same routine without strenuous activity during the ABPM recording days.
The ABPM device should be removed from each subject prior to their discharge from the CRU.
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 single 12-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 
investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/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 CP or CRP/scientist will monitor safety data throughout the course of the study.


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Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes

adverse events.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.4.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, total bilirubin (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 CP 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 

patient/subject discontinued from 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.
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.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.


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Concentrations of lasmiditan will be assayed using a validated liquid chromatography with 
tandem mass spectrometry method.  Analyses of samples collected from subjects who received 
placebo are not planned.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.
9.6.
Pharmacodynamics
This section is not applicable for this study.
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 ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee. This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of lasmiditan or after lasmiditan is commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.
9.8.
Biomarkers
This section is not applicable for this study.
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 36 subjects may be enrolled to ensure 30 subjects complete the study. Assuming a 1-sided 
significance level of 0.05, a standard deviation for the within-subject change in SBP of 
6.0 mmHg (a slightly larger estimate than that seen in Study LAHA), and a noninferiority margin 
of 10 mmHg, this sample size will result in at least 90% power to detect a true increase of 
5 mmHg in the mean within-subject change for lasmiditan 200 mg compared with placebo.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study.
10.2.2. Study Participant Characteristics
The subjects’ age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized using descriptive statistics.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Cardiovascular analyses will be conducted on data from subjects who complete at least 1 dosing 
period.
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least 1 dose 
of the investigational products and have evaluable PK.
Pharmacokinetic/pharmacodynamic analyses will be conducted on data from subjects who have 
evaluable data in both PK and cardiovascular datasets.
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  
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 


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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, vital signs, DBP,
and pulse rate obtained via ABPM, and AEs.  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
Pharmacokinetic parameter estimates for lasmiditan will be calculated using standard 
noncompartmental methods of analysis.  The primary parameters for analysis will be Cmax and 
AUC of lasmiditan.  Other noncompartmental parameters, such as half-life, apparent clearance, 
and apparent volume of distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Analysis
The parameters will be listed, and summarized using standard descriptive statistics, including
estimates of intra-subject variability as appropriate.
10.3.3. Cardiovascular Analyses
10.3.3.1. Cardiovascular Parameter Estimation
The primary parameters for the cardiovascular analyses will be peak hourly mean values of SBP, 
and will be determined using ABPM.  For each subject, the mean SBP will be calculated for each 
hour within the dosing period.  The highest mean value across the 24 calculated means will be 
considered the peak hourly mean value.  Baseline value will be defined as the mean value during 
the 2 hours pre-dose for each period.
10.3.3.2. Statistical Inference of Cardiovascular Parameters
Cardiovascular parameters will be listed, and summarized using descriptive statistics, as 
appropriate.
As a primary analysis, changes from baseline in peak hourly mean values of SBP will be 
analyzed to test whether each dose of lasmiditan (100 mg, 200 mg) is noninferior to placebo, 
assuming a noninferiority margin of 10 mmHg.  Specifically, these changes from baseline will be 
analyzed to test the null hypotheses that the difference in mean baseline change between 
lasmiditan at each dose and placebo is at least 10 mmHg versus the alternative hypotheses that 
this difference is less than 10 mmHg.
A linear mixed-effects model with baseline as a covariate, fixed effects for treatment, period (1, 
2, or 3), and treatment sequence, and a random effect for subject will be used to test the
hypotheses at a 1-sided significance level of 0.05. Least squares (LS) means and treatment 


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differences (lasmiditan 200 mg – placebo, lasmiditan 100 mg - placebo) will be calculated and 
presented with their corresponding 95% CIs.
The following gatekeeping procedure will be used to adjust for multiplicity when conducting the
hypothesis tests.  The null hypothesis that the difference in mean baseline change between 
lasmiditan 100 mg and placebo is at least 10 mmHg will first be tested against the alternative 
hypothesis that this difference is less than 10 mmHg.  If the p-value for this test is less than 0.05, 
then there is significant evidence that lasmiditan 100 mg is non-inferior to placebo and these 
hypotheses will be re-tested using lasmiditan 200 mg.  Otherwise, if the p-value is at least 0.05, 
then there is no significant evidence that lasmiditan 100 mg is noninferior to placebo, in which 
case the null and alternative hypotheses will not be re-tested using lasmiditan 200 mg.
A sensitivity analysis will be performed on subjects who complete all 3 dosing periods. The 
same mixed-effects model as that was used in the primary analysis will be implemented.
A repeated measures analysis will also be conducted in which changes from baseline in hourly 
mean values of SBP will be analyzed to test whether each dose of lasmiditan (100 mg, 200 mg) 
is noninferior to placebo at each time point (hour), assuming a noninferiority margin of 10 
mmHg.  A repeated measures linear mixed-effects model with baseline as a covariate, fixed 
effects for time point, treatment, period, treatment sequence, and the treatment by time point
interaction, and a random effect for subject will be used to conduct the tests at a 1-sided 
significance level of 0.05.  At each time point, LS means and treatment differences (lasmiditan 
200 mg – placebo, lasmiditan 100 mg – placebo) will be calculated and presented with their
corresponding 95% CIs, from which noninferiority of lasmiditan (100 mg, 200 mg) to placebo 
will be determined if the upper confidence limit is less than 10 mmHg.
10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
The relationship between PK and cardiovascular effects will be explored initially in a graphical 
manner.  Additional modeling approaches or graphical analyses may be used, if warranted.
10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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11.
References
Färkkilä M, Diener HC, Géraud G, Láinez M, Schoenen J, Harner N, Pilgrim A, Reuter U; COL 
MIG-202 Study Group. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor 
agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, 
parallel-group, dose-ranging study. Lancet Neurol. 2012;11(5):405-413.
Victor TW, Hu X, Campbell JC, Buse DC, Lipton RB. Migraine prevalence by age and sex in 
the United States: a life span study. Cephalalgia. 2010;30(9):1065-1072.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
5-HT
5-hydroxytryptamine
ABPM
ambulatory blood pressure monitoring
ACE
angiotensin-converting enzyme 
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
ARB
angiotensin receptor blocker
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
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
CI
confidence interval
Cmax
maximum observed drug concentration
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.


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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.
CP
clinical pharmacologist
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
clinical research unit
CYP
cytochrome P450
DBP
diastolic blood pressure
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.
ERB
ethical review board
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
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.
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.
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.
LS
least squares


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PK
pharmacokinetic(s)
PPI
protein pump inhibitor
PR
pulse rate
randomize
The process of assigning subjects/patients to an experimental group on a random basis.
SAE
serious adverse event
SBP
systolic blood pressure
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
tmax
time of maximum observed drug concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Total CO2
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC)
Glucose random
Platelets
Blood urea nitrogen (BUN)
Differential WBC absolute counts and/or % of:
Total protein
Neutrophils
Albumin
Lymphocytes
Total bilirubin
Monocytes
Alkaline phosphatase (ALP)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Alanine aminotransferase (ALT)
Urinalysis
Creatinine
Specific gravity
Ethanol testinga
pH
Urine drug screena,b
Protein
Hepatitis B surface antigenb
Glucose
Hepatitis C antibodyb
Ketones
HIVb
Bilirubin
FSHc
Urobilinogen
Blood
Nitrite
Leukocytes 
Urine microscopic (if positive result for blood)
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Performed on admission.
b
Performed at screening.
c
Performed at screening only for confirmation of postmenopausal status.


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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.
Ethical Review
The investigator or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Council for Harmonization (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
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 


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3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.


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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/patient personal information collected will be provided in a 
written document to the subject/patient 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 patients 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 cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol H8H-MC-LAIG 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
Pharmacokinetics 
2
40
80
Pharmacogenetics
10
1
10
Total
134.5
Total for clinical purposes rounded up to the nearest 10 mL
140
a
Additional samples may be drawn if needed for safety purposes.


Leo Document ID = 502f8e55-244d-4fd3-a3b6-6adc0b36f2ca
Approver:
Approval Date & Time: 19-Dec-2017 16:58:13 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 19-Dec-2017 17:01:03 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan H8H-MC-LAIG
A Study to Investigate the Cardiovascular Effects of Lasmiditan in Healthy Elderly Subjects
NCT03406260  
Approval Date: 08-Feb-2018 


Final, 06 Feb 2018
             Page 1 of 16
STATISTICAL ANALYSIS PLAN
A Study to Investigate the Cardiovascular Effects of Lasmiditan in Healthy Elderly 
Subjects
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  06-February-2018
Study Drug: Lasmiditan (LY573144)
Sponsor Reference:  H8H-MC-LAIG
Covance CRU Study: 1000071-8381132
Clinical Phase I
Approval Date: 08-Feb-2018 GMT


Final, 06 Feb 2018
             Page 2 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8381132
Sponsor Reference H8H-MC-LAIG
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objectives .............................................................................................. 5
5.
STUDY DESIGN........................................................................................................... 5
6.
TREATMENTS............................................................................................................. 6
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 6
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 7
9.1
General.................................................................................................................... 7
9.2
Demographics and Subject Disposition.................................................................... 8
9.3
Pharmacokinetic Assessment................................................................................... 8
9.3.1
Pharmacokinetic Analysis............................................................................... 8
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 11
9.4
Cardiovascular Assessment ................................................................................... 12
9.4.1
Cardiovascular Analysis ............................................................................... 12
9.4.2
Cardiovascular Statistical Methodology........................................................ 12
9.5
Safety and Tolerability Assessments...................................................................... 14
9.5.1
Adverse events ............................................................................................. 14
9.5.2
Concomitant medication............................................................................... 14
9.5.3
Clinical laboratory parameters...................................................................... 14
9.5.4
Vital signs .................................................................................................... 15
9.5.5
Electrocardiogram (ECG)............................................................................. 15
9.5.6
Hepatic Monitoring ...................................................................................... 15
9.5.7
Columbia Suicide Severity Rating Scale (C-SSRS)....................................... 15
9.5.8
Other assessments......................................................................................... 15
9.5.9
Safety and Tolerability Statistical Methodology............................................ 15
10. INTERIM ANALYSES ............................................................................................... 15
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 15
12. REFERENCES ............................................................................................................ 16
13. DATA PRESENTATION ............................................................................................ 16
13.1 Derived Parameters ............................................................................................... 16
13.2 Missing Data ......................................................................................................... 16
13.3 Insufficient Data for Presentation .......................................................................... 16


Final, 06 Feb 2018
             Page 3 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8381132
Sponsor Reference H8H-MC-LAIG
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
ABPM
Ambulatory blood pressure monitoring
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
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(tlast-∞)
Percentage of AUC(0-∞) extrapolated
BQL
Below the quantifiable lower limit of the assay
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular 
administration
Clast
Last measurable drug concentration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantification
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
PD
Pharmacodynamic


Final, 06 Feb 2018
             Page 4 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8381132
Sponsor Reference H8H-MC-LAIG
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SD
Standard deviation 
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after extra-
vascular administration
WHO
World Health Organization


Final, 06 Feb 2018
             Page 5 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8381132
Sponsor Reference H8H-MC-LAIG
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
19 December 2017).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as 
the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective

To test whether each oral dose of lasmiditan (100 and 200 mg) is non-inferior to placebo 
with regard to increasing blood pressure in healthy elderly subjects (≥65 years of age).
4.2
Secondary Objectives

To determine the PK of lasmiditan in healthy elderly subjects (≥65 years of age) 
following single 100 and 200 mg oral doses of lasmiditan.

To assess the safety and tolerability of 100 and 200 mg oral doses of lasmiditan in 
healthy elderly subjects.
5. STUDY DESIGN
This is a randomized, subject- and investigator-blind, crossover study with 3 treatment periods in
healthy elderly subjects. 


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The treatments are as follows:

Treatment A: Lasmiditan 200 mg

Treatment B: Lasmiditan 100 mg

Treatment C: Placebo
Each subject will be randomized to 1 of 6 treatment sequences in a Williams design, as outlined
in Table 1.
Table 1. Sequences in Study LAIG
Sequence
Period 1
Period 2
Period 3
1
Lasmiditan 200 mg
Lasmiditan 100 mg
Placebo
2
Lasmiditan 100 mg
Placebo
Lasmiditan 200 mg
3
Placebo
Lasmiditan 200 mg
Lasmiditan 100 mg
4
Placebo
Lasmiditan 100 mg
Lasmiditan 200 mg
5
Lasmiditan 200 mg
Placebo
Lasmiditan 100 mg
6
Lasmiditan 100 mg
Lasmiditan 200 mg
Placebo
Screening Period
All subjects will participate in a screening visit up to 28 days prior to study drug dosing.
Dosing Period
Subjects will participate in 1 inpatient period involving 3 treatment periods. Subjects will be 
admitted on Day -1 and will be randomized to 1 of 6 treatment sequences to receive lasmiditan
or placebo on Days 1, 3, and 5. There will be a washout period of approximately 48 hours
between each dosing day. Subjects may be discharged on Day 7 based on investigators’
discretion.
All subjects will be discharged from the study approximately 2 days after their final dose of
lasmiditan or placebo.
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
100 mg Lasmiditan
1
200 mg Lasmiditan
2
Placebo
3
7. SAMPLE SIZE JUSTIFICATION
Up to 36 subjects may be enrolled to ensure 30 subjects complete the study. Assuming a 1-sided
significance level of 0.05, a standard deviation (SD) for the within-subject change in systolic 
blood pressure (SBP) of 6.0 mmHg (a slightly larger estimate than that seen in Study LAHA), 
and a non-inferiority margin of 10 mmHg, this sample size will result in at least 90% power to 


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detect a true increase of 5 mmHg in the mean within-subject change for lasmiditan 200 mg 
compared with placebo.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data.  Subjects may be excluded from the PK summary 
statistics and statistical analysis if a subject has an adverse event (AE) of vomiting that occurs at 
or before 2 times median time of maximum observed drug concentration (tmax).
Cardiovascular analyses will be conducted on data from subjects who complete at least 1 dosing 
period.
PK/pharmacodynamics (PD) analyses will be conducted on data from subjects who have 
evaluable data in both PK and cardiovascular datasets.
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. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic SD, median, min, max and N; 
for log-normal data (e.g. the PK parameters: are under the concentration versus time curve 
[AUCs] and maximum observed drug concentration [Cmax]) the geometric mean and geometric 
coefficient of variation (CV%) will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.


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9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized and listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
PK parameter estimates will be determined using non-compartmental procedures in validated 
software program (Phoenix WinNonlin Version 6.4 or later).  For the calculation of the PK 
parameter estimates, the samples collected at predose of Days 3 and 5 will also be used as 48 h 
postdose samples of the Day 1 and 3 PK profiles, respectively.
Plasma concentrations of lasmiditan (LY573144) will be used to determine the following PK 
parameters, when possible:  
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
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration 
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the CSR. 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.


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General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. 

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. 

AUC(0-) values where the percentage of the total area extrapolated is more than 20% 
will be flagged. Any AUC(0-) value excluded from summary statistics will be noted in 
the footnote of the summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
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 predicted last measurable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.


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Covance Clinical Study No. 8381132
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o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.


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Covance Clinical Study No. 8381132
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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.
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.
9.3.2 Pharmacokinetic Statistical Methodology
The PK parameters will be listed, and summarized using standard descriptive statistics, including
estimates of intra-subject variability as appropriate. Arithmetic mean (+/- 1 SD) plasma 


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concentration profiles, as well as individual subject profiles, will be presented graphically by 
treatment over time.
9.4
Cardiovascular Assessment
9.4.1 Cardiovascular Analysis
The primary parameter for the cardiovascular analyses will be peak hourly mean values of SBP, 
and will be determined using ambulatory blood pressure monitoring (ABPM).  For each subject, 
the mean SBP value will be calculated for each hour within the dosing period.  The highest mean 
value across the 24 calculated means will be considered the peak hourly mean value. Baseline 
value will be defined as the mean value during the 2 hours pre-dose for each period.
Additional analysis will be performed if warranted upon review of the data.
9.4.2 Cardiovascular Statistical Methodology
Observed values, as well as change from baseline, for all cardiovascular parameters (including 
peak hourly mean SBP and mean hourly SBP values), will be listed and summarized by 
treatment using descriptive statistics.  Mean hourly SBP values will be plotted over time,
together with changes from baseline. In addition, mean hourly SBP and peak hourly mean SBP 
values will be plotted against plasma concentrations of lasmiditan to explore the relationship 
between PK and cardiovascular effects.
As a primary analysis, changes from baseline in peak hourly mean values of SBP will be
analyzed to test whether each dose of lasmiditan (100 mg, 200 mg) is non-inferior to placebo,
assuming a non-inferiority margin of 10 mmHg. Specifically, these changes from baseline will 
be analyzed to test the null hypothesis that the difference in mean baseline change between
lasmiditan at each dose and placebo is at least 10 mmHg versus the alternative hypothesis that
this difference is less than 10 mmHg.
A linear mixed-effects model with baseline as a covariate, fixed effects for treatment, period 
(1, 2, or 3), and treatment sequence, and a random effect for subject will be used to test the
hypotheses at a 1-sided significance level of 0.05. Least squares (LS) means and treatment
differences (lasmiditan 200 mg – placebo, lasmiditan 100 mg – placebo) will be calculated and
presented with their corresponding 95% confidence intervals (CIs).


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Covance Clinical Study No. 8381132
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An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
    class trtmnt period sequence subject;
    model cardiochg = baseline trtmnt period sequence / alpha=0.05 cl ddfm=kr;
    random subject;
    lsmeans trtmnt;
    lsestimate trtmnt ‘Ltn100 – Placebo’ 1 0 -1 / lower testvalue=10 cl alpha=0.05;
    lsestimate trtmnt ‘Ltn200 – Placebo’ 0 1 -1 / lower testvalue=10 cl alpha=0.05;    
run;
where cardiochg is the change from baseline in peak hourly mean values of SBP, trtmnt is the 
treatment, and seq is the treatment sequence.
The following gatekeeping procedure will be used to adjust for multiplicity when conducting the
hypothesis tests. The null hypothesis that the difference in mean baseline change between
lasmiditan 100 mg and placebo is at least 10 mmHg will first be tested against the alternative
hypothesis that this difference is less than 10 mmHg. If the p-value for this test is less than 0.05,
then there is significant evidence that lasmiditan 100 mg is non-inferior to placebo and these
hypotheses will be re-tested using lasmiditan 200 mg. Otherwise, if the p-value is at least 0.05,
then there is no significant evidence that lasmiditan 100 mg is non-inferior to placebo, in which
case the null and alternative hypotheses will not be re-tested using lasmiditan 200 mg.
A sensitivity analysis will be performed on subjects who complete all 3 dosing periods. In 
addition, sensitivity analyses will be conducted where baseline value is the mean SBP value 
during the 1 hour pre-dose for each period.   These analyses will be performed separately on 
subjects who complete at least 1 dosing period and on subjects who complete all 3 dosing 
periods.  The same mixed-effects model as that was used in the primary analysis will be 
implemented.
A repeated measures analysis will also be conducted in which changes from baseline in hourly
mean values of SBP will be analyzed to test whether each dose of lasmiditan (100 mg, 200 mg)
is non-inferior to placebo at each time point (hour), assuming a non-inferiority margin of 
10 mmHg. A repeated measures linear mixed-effects model with baseline as a covariate, fixed
effects for time point, treatment, period, treatment sequence, and the treatment by time point
interaction, and a random effect for subject will be used to conduct the tests at a 1-sided
significance level of 0.05. An unstructured covariance structure will be applied.  If the model 
fails to converge, alternative structures shall be examined using Akaike’s criteria. At each time 
point, LS means and treatment differences (lasmiditan 200 mg – placebo, lasmiditan 
100 mg - placebo) will be calculated and presented with their corresponding 95% CIs, from 
which non-inferiority of lasmiditan (100 mg, 200 mg) to placebo will be determined if the upper 
confidence limit is less than 10 mmHg.


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Covance Clinical Study No. 8381132
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An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
    class trtmnt time period seq subject;
    model cardiochg = base time trtmnt period seq trtmnt*time / alpha=0.05 cl ddfm=kr;
    repeated time / type=un subject=subject;
    random subject;
    lsmeans trtmnt*time / alpha=0.05 cl pdiff=controll(‘reftrt’);
run;
where cardiochg is the change from baseline in hourly mean values of SBP, trtmnt is the 
treatment, seq is the treatment sequence, and reftrt is the reference treatment of the comparison.
9.5
Safety and Tolerability Assessments
9.5.1 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 20.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.5.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017).
Concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
All clinical chemistry, hematology and 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.


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Covance Clinical Study No. 8381132
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9.5.4 Vital signs
Supine vital signs data will be summarized by treatment together with changes from baseline, 
where baseline is defined as predose of each period. Figures of supine mean vital signs and 
mean changes from baseline profiles by treatment will be presented by treatment. 
Furthermore, values for individual subjects will be listed.
9.5.5 Electrocardiogram (ECG)
For each subject, ECGs will be performed for safety purposes only, and will not be reported.
9.5.6 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.
9.5.7 Columbia Suicide Severity Rating Scale (C-SSRS)
Data from the C-SSRS and self-harm questionnaire will be listed for individual subjects.
9.5.8 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed.
9.5.9
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.


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Covance Clinical Study No. 8381132
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12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 7fdb12ee-585f-4303-baa1-52675bd3e9cc
Approver: 
Approval Date & Time: 07-Feb-2018 19:33:38 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 07-Feb-2018 20:09:26 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 07-Feb-2018 21:31:07 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 08-Feb-2018 09:11:55 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD