Clinical trial NCT03310411
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2017-10-17; Completion date: 2017-12-23
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess whether taking lasmiditan and sumatriptan together will have any additional effects on heart rate and blood pressure compared to taking lasmiditan and sumatriptan individually. This study will also 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 when these two drugs are taken together.

This study will last about 21 days, not including the screening. Participants will spend 16 days/15 nights in the clinical research unit (CRU) followed by follow-up. Screening is required within 28 days prior to the start of the study.

Detailed description:

Arms: arm 1: Single oral dose of 200 milligram (mg) lasmiditan tablet and single oral dose of 100 mg sumatriptan tablet in one of four treatment periods. arm 2: Single oral dose of 200 mg lasmiditan tablet and single oral dose of placebo tablet in one of four treatment periods. arm 3: Single oral dose of 100 mg sumatriptan tablet and single oral dose of placebo tablet in one of four treatment periods. arm 4: Oral doses of placebo tablets in one of four treatment periods.
Interventions: intervention 1: Lasmiditan intervention 2: Sumatriptan intervention 3: Placebo for Lasmiditan intervention 4: Placebo for Sumatriptan
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally intervention 4: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol (c) H8H-MC-LAHU 
 
 
A Randomized, Double-Blind, Four-Period, Crossover Study to Evaluate the Cardiovascular 
Effect of Single Oral Doses of Lasmiditan when Coadministered with Single Oral Doses of 
Sumatriptan in Healthy Subjects 
 
NCT03310411 
 
Approval Date: 20-Oct-2017 
 
 
 


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Protocol H8H-MC-LAHU(c)
A Randomized, Double-Blind, Four-Period, Crossover 
Study to Evaluate the Cardiovascular Effect of Single Oral 
Doses of Lasmiditan when Coadministered with Single 
Oral Doses of Sumatriptan in Healthy Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY573144, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act Exemption 4 and 
may not be reproduced or otherwise disseminated without the written approval of Eli Lilly 
and Company or its subsidiaries.
Approval Date: 20-Oct-2017 GMT
Lasmiditan(LY573144)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:  
17August2017.
Amendment (a) Electronically Signed and Approved by Lilly: 26 September 2017
Amendment (b) Electronically Signed and Approved by Lilly: 10 October 2017
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below.


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Table of Contents
A Randomized, Double-Blind, Four-Period, Crossover Study 
to Evaluate the Cardiovascular Effect of Single Oral Doses of 
Lasmiditan when Coadministered with Single Oral Doses of 
Sumatriptan in Healthy Subjects
Section
Page
Protocol H8H-MC-LAHU(c) A Randomized, Double-Blind, Four-Period, 
Crossover Study to Evaluate the Cardiovascular Effect of Single Oral 
Doses of Lasmiditan when Coadministered with Single Oral Doses 
of Sumatriptan in Healthy Subjects .....................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
5.2.
Number of Participants.................................................................................................20
5.3.
End of Study Definition ...............................................................................................20
5.4.
Scientific Rationale for Study Design...........................................................................20
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................21
6.1.
Inclusion Criteria..........................................................................................................21
6.2.
Exclusion Criteria ........................................................................................................22
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................24
6.3.
Lifestyle and/or Dietary Requirements .........................................................................24
6.3.1.
Meals and Dietary Restrictions.............................................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................24
6.3.3.
Activity................................................................................................................25
6.4.
Screen Failures.............................................................................................................25
7.
Treatment..........................................................................................................................26
7.1.
Treatment Administered...............................................................................................26
7.1.1.
Packaging and Labeling .......................................................................................26


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7.2.
Method of Treatment Assignment ................................................................................26
7.2.1.
Timing of Doses...................................................................................................27
7.3.
Blinding .......................................................................................................................27
7.4.
Dose Modification........................................................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................28
7.7.
Concomitant Therapy...................................................................................................28
7.8.
Treatment After the End of the Study...........................................................................28
8.
Discontinuation Criteria ....................................................................................................29
8.1.
Discontinuation from Study Treatment.........................................................................29
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................29
8.2.
Discontinuation from the Study....................................................................................29
8.3.
Subjects Lost to Follow-Up..........................................................................................30
9.
Study Assessments and Procedures ...................................................................................31
9.1.
Efficacy Assessments...................................................................................................31
9.2.
Adverse Events ............................................................................................................31
9.2.1.
Serious Adverse Events........................................................................................32
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................32
9.2.2.
Complaint Handling.............................................................................................33
9.3.
Treatment of Overdose.................................................................................................33
9.4.
Safety...........................................................................................................................33
9.4.1.
Laboratory Tests ..................................................................................................33
9.4.2.
Vital Signs ...........................................................................................................33
9.4.2.1.
Supine and Orthostatic Vital Signs..................................................................33
9.4.2.2.
Ambulatory Blood Pressure Monitoring..........................................................34
9.4.3.
Electrocardiograms ..............................................................................................34
9.4.4.
Safety Monitoring ................................................................................................35
9.4.4.1.
Hepatic Safety................................................................................................35
9.5.
Pharmacokinetics .........................................................................................................35
9.5.1.
Bioanalysis...........................................................................................................36
9.6.
Pharmacodynamics ......................................................................................................36
9.7.
Genetics .......................................................................................................................36
9.8.
Biomarkers...................................................................................................................36
9.8.1.
Creatinine Clearance ............................................................................................36
9.8.2.
Renal Biomarker Samples....................................................................................37
9.9.
Health Economics ........................................................................................................37
10.
Statistical Considerations and Data Analysis.....................................................................38
10.1. Sample Size Determination ..........................................................................................38


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10.2. Populations for Analyses..............................................................................................38
10.2.1.
Study Participant Disposition ...............................................................................38
10.2.2.
Study Participant Characteristics ..........................................................................38
10.3. Statistical Analyses ......................................................................................................38
10.3.1.
Safety Analyses....................................................................................................38
10.3.1.1.
Clinical Evaluation of Safety..........................................................................38
10.3.1.2.
Statistical Evaluation of Safety.......................................................................39
10.3.2.
Pharmacokinetic Analyses....................................................................................39
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................39
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................39
10.3.3.
Cardiovascular Analyses ......................................................................................39
10.3.3.1.
Cardiovascular Parameter Estimation .............................................................39
10.3.3.2.
Statistical Inference of Cardiovascular Parameters..........................................39
10.3.4.
Biomarker Analyses.............................................................................................40
10.3.5.
Interim Analyses..................................................................................................40
11.
References ........................................................................................................................41


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List of Tables
Table
Page
Table LAHU.1.
Objectives and Endpoints .......................................................................18
Table LAHU.2.
Sequences in Study LAHU .....................................................................19
Table LAHU.3.
Treatments Administered........................................................................26


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................42
Appendix 2.
Clinical Laboratory Tests........................................................................46
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................47
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............50
Appendix 5.
Blood Sampling Summary......................................................................51
Appendix 6.
Protocol Amendment H8H-MC-LAHU(c) Summary:  A 
Randomized, Double-Blind, Four-Period, Crossover Study to 
Evaluate the Cardiovascular Effect of Single Oral Doses of 
Lasmiditan when Coadministered with Single Oral Doses of 
Sumatriptan in Healthy Subjects.............................................................52


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1. Protocol Synopsis
Title of Study:
A Randomized, Double-Blind, Four-Period, Crossover Study to Evaluate the Cardiovascular Effect of Single Oral 
Doses of Lasmiditan when Coadministered with Single Oral Doses of Sumatriptan in Healthy Subjects
Rationale: 
The study will assess the cardiovascular effects of coadministration of single doses of sumatriptan 100 mg and 
single doses of lasmiditan 200 mg as measured by vital signs using 24-hour ambulatory blood pressure (ABP) 
monitoring (ABPM).  Pharmacokinetics (PK), safety, and tolerability will also be reported.  Sumatriptan is known to 
cause a transient increase in blood pressure (BP) and is contraindicated in patients with moderate and severe 
hypertension and mild uncontrolled hypertension.  Initial studies with lasmiditan have identified mild effects on 
cardiovascular parameters (pulse rate [PR] and BP). In clinical practice, lasmiditan may be coadministered with 
sumatriptan.  Therefore, Study H8H-MC-LAHU is being conducted to evaluate the cardiovascular effects and PK 
impact of coadministration of lasmiditan with sumatriptan in healthy subjects.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To compare and contrast the cardiovascular effects of 
lasmiditan 200 mg and sumatriptan 100 mg administered 
together to the cardiovascular effects of single doses of 
either drug administered alone.
Systolic BP (SBP), diastolic BP (DBP), mean arterial 
pressure (MAP), and PR per 24-hour ABPM.
Secondary

To evaluate PK of lasmiditan 200 mg and 
sumatriptan 100 mg administered either alone 
or together.

To evaluate the safety and tolerability of 
lasmiditan 200 mg and sumatriptan 100 mg.

Maximum observed drug concentration (Cmax), 
time of maximum observed drug concentration 
(tmax), area under the concentration versus time 
curve (AUC) from time 0 extrapolated to 
infinity (AUC)[0-∞]), and AUC from time 0 to 
time t, where t is the last time point with a 
measurable concentration (AUC[0-tlast]).

A summary of the number of 
treatment-emergent adverse events (TEAEs) 
and serious adverse events (SAEs).
Summary of Study Design:
Study H8H-MC-LAHU is a randomized, double-blind (subject- and investigator-blinded), crossover study with 
4 study periods in healthy subjects to investigate the cardiovascular effects, PK, and safety and tolerability of oral 


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doses of lasmiditan alone, sumatriptan alone, and sumatriptan in combination with lasmiditan.  All subjects will 
participate in 4 treatment periods.  The treatments are as follows:

Treatment A:  lasmiditan 200 mg + sumatriptan 100 mg

Treatment B:  lasmiditan 200 mg + placebo

Treatment C:  sumatriptan 100 mg + placebo

Treatment D:  placebo + placebo
Each subject will be randomized to one of 4 treatment sequences in a William’s square design (i.e. ABCD, BCDA, 
CDAB, and DABC).
Treatment Arms and Planned Duration for Individual Subjects:  
Screening Period:
All subjects will participate in a screening visit up to 28 days prior to Period 1 study drug dosing.
Treatment Periods:
All subjects will participate in 4 treatment periods.  Subjects will be randomized to 1 of 4 treatment sequences.  
They will be admitted to the clinical research unit (CRU) the day prior to dosing (Day -1) in Period 1, and will be 
dosed on Day 1 of each treatment period according to their assigned treatment sequence. Subjects will be 
discharged from the CRU on Day 3 of Period 4, following the collection of all ABP measurements and 
pharmacokinetic (PK) blood samples.  There will be a washout of at least 4 days between each dosing day.
All subjects will be discharged from the study at least 5 days after discharge from Period 4.
Number of Subjects:
Up to 40 subjects may be enrolled to ensure 30 subjects complete the study.
Statistical Analysis:
Cardiovascular parameters that will be assessed by ABPM include peak hourly mean values of SBP, DBP, and 
MAP, and nadir hourly mean value of PR.  The parameters will be listed, and summarized using descriptive 
statistics, as appropriate. Changes from baseline in cardiovascular parameters SBP, DBP, MAP, and PR will be 
analyzed to determine the impact of a single dose of sumatriptan 100 mg on the cardiovascular parameters of 
lasmiditan. A repeated measures linear mixed-effects model with baseline as a covariate, fixed effects for time 
point, treatment, period (1, 2, 3, or 4), treatment sequence and the treatment by time point interaction, and a random 
effect for subject will be used. Least squares (LS) means and treatment differences ([lasmiditan + sumatriptan] -
[lasmiditan + placebo]) will be calculated and presented with the corresponding confidence intervals (CIs). The 
same model will be used to assess the impact of a single dose of lasmiditan 200 mg on the cardiovascular parameters
of sumatriptan.
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and sumatriptan will be calculated by standard 
noncompartmental methods of analysis.  Pharmacokinetic parameter estimates will be evaluated to determine the 
impact of a single dose of sumatriptan 100 mg on the PK of lasmiditan and its metabolites.  Log-transformed Cmax
and AUC parameters will be evaluated using a linear effects model with fixed effects for treatment, period (1, 2, 3, 


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or 4), and treatment sequence, and a random effect for subject.  From this model, the 90% CIs of the ratios of 
geometric means from Treatment A (lasmiditan + sumatriptan) will be determined and presented versus those of 
Treatment B (lasmiditan + placebo).  The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the 
median difference based on the observed medians, 90% CIs, and the p-value from the Wilcoxon test will be 
calculated.  The same model will be independently used to assess the impact of a single dose of lasmiditan 200 mg 
on the PK of sumatriptan.
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and 12-lead 
electrocardiogram (ECG) parameters.  The parameters will be listed, and summarized using descriptive statistics, as 
appropriate.


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2. Schedule of Activities


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Study Schedule Protocol H8H-MC-LAHU
Screening
Periods 1, 2, 3, and 4
Early Discontinuation
Follow-
Up
Comments
Procedure
-28 to -2 days 
prior to 
Day 1/Period 1
Day -1
Day 1
Day 2
Day 3
At least
5 days 
after 
discharge 
from 
Period 4
Informed Consent
X
Subject Admission to 
CRU
X
Subject admission will take 
place in Period 1 only; 
subjects should remain 
inpatient until Day 3 of 
Period 4.
Subject Discharge 
from CRU
X
Subject discharge from the 
CRU will take place in 
Period 4 only.
Randomization
Period 1 
only
Investigational 
Product 
Administration
Day 1, 
indicates 
Time = 0
Subjects will fast 8 hours 
before and 3 hours after 
study drug administration.
Medical History
X
X
After screening, medical 
history should include 
interim medical history.
Concomitant 
Medication
X
X
X
X
X
X
X
Adverse Event 
Review
X
X
X
X
X
X
X
Height
X
Weight
X


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Screening
Periods 1, 2, 3, and 4
Early Discontinuation
Follow-
up
Comments
Procedure
-28 to -2 days 
prior to Day 
1/Period 1
Day -1
Day 1
Day 2
Day 3
At least
5 days 
after 
discharge 
from 
Period 4
Vital Signs (Supine)
X
X
Predose, 1, 
2 and 4 h
24 h
X
Time points may be added 
for each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.
ABPM
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.
ABPM Training
X
Subjects should be trained 
on the ABPM device on the 
evening of Day -1 in 
Period 1 only.  Data from 
this acclimation period will 
not be stored or analyzed.
Orthostatic Vital 
Signs
X
Time points may be added if 
warranted and agreed upon 
between Lilly and the 
investigator.
Clinical Lab Tests
X
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for details.


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Screening
Periods 1, 2, 3, and 4
Early Discontinuation
Follow-up
Comments
Procedure
-28 to -2 days 
prior to Day 
1/Period 1
Day -1
Day 1
Day 2
Day 3
At least
5 days after 
discharge 
from 
Period 4
Pregnancy Test 
X
X
X
X
Serum pregnancy test will 
be performed at screening.  
Urine or serum pregnancy 
test will be performed at 
admission to Period 1 and at 
follow-up.
12-Lead ECG
X
Predose
24 h
X
Single ECGs will be taken.
Physical Exam
X
X
X
X
X
Full medical assessment 
(including neurological 
examination) will be 
performed at screening.  
After screening, medical 
assessment only performed 
to include medical review 
and targeted examination, as 
appropriate.
Genetic Sample
X
Single sample for 
pharmacogenetic analysis 
taken prior to dosing on 
Day 1 of Period 1.
Lasmiditan and 
Metabolite PK 
Samples
Predose, 
0.5, 1, 1.5, 
2, 2.5, 3, 4, 
6, 8, 12 h
24 and
36 h
48 h
Sampling times are relative 
to the time of study 
treatment administration 
(0 min).
Sumatriptan PK 
Samples
Predose, 
0.5, 1, 1.5, 
2, 2.5, 3, 4, 
6, 8, 12 h
24 h
Sampling times are relative 
to the time of study 
treatment administration 
(0 min).


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Screening
Periods 1, 2, 3, and 4
Early Discontinuation
Follow-up
Comments
Procedure
-28 to -2 days 
prior to Day 
1/Period1
Day -1
Day 1
Day 2
Day 3
At least
5days after 
discharge 
from 
Period 4
Urine Samplefor 
CrCl
0-6, 6-12, 
and 
12-18h
18-24, 
24-30 and 
30-36h
36-42 
and 
42-48h
Urine collection for the 
determination of CrCl.
Renal Biomarker 
Samples
Predose, 
0.5, 1, 1.5, 
2, 2.5, 3, 4, 
6, 8, 12h
24and
36h
48 h
Sampling times are relative 
to the time of study 
treatmentadministration 
(0min).
Abbreviations:  ABPM = ambulatory blood pressure monitoring; CrCl = creatinine clearance; CRU = clinical research unit; ECG = electrocardiogram; h=hours; 
min=minutes; PK = pharmacokinetics. 
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used: ECG,vital signs, and venipuncture.Where 
venipuncture and other procedures take place at the same time point, the following time windows for obtaining blood samplesshould be maintained: 
>0to2hours postdose: ±5 minutes; 2.5to 6 hours postdose: ±10 minutes; 7 to 12 hours postdose: ±20 minutes; >12 hours postdose:±30 minutes. Where 
repeats of supine 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 serotonin (5-hydroxytryptamine; 5-HT)1F receptor agonist being 
developed for the acute treatment of migraine.  Triptans, which are 5-HT1B and 5-HT1D 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 >450-fold higher affinity for the 5-HT1F receptor than for 
5-HT1B and 5-HT1D receptors (Capi et al. 2017).  Lasmiditan is under development as a neurally 
acting treatment for migraine without the vasoconstrictor liability of triptans.
Sumatriptan is a synthetic triptan used for the treatment of migraine and cluster headaches, 
known to cause a transient increase in blood pressure (BP), and is contraindicated in patients 
with moderate and severe hypertension, and mild uncontrolled hypertension.
Sumatriptan has an oral bioavailability of approximately 15%, partially attributable to the 
presystemic metabolism of sumatriptan via monoamine oxidase (MAO).  Due to the 
predominance of this metabolism pathway, the potential for MAO inhibitors to cause clinically 
significant drug-drug interactions is high.  In vitro studies suggest that lasmiditan is not a 
monoamine oxidase inhibitor, and it is expected that the likelihood of lasmiditan affecting 
sumatriptan pharmacokinetics (PK) is low.  In clinical practice, lasmiditan may be 
coadministered with sumatriptan; it is therefore pertinent to determine the potential for 
pharmacodynamic (PD) or PK drug interactions. This study will assess the effect of single doses 
of sumatriptan 100 mg on the cardiovascular effects of single doses of lasmiditan 200 mg; the 
effect of single doses of lasmiditan 200 mg on the cardiovascular parameters of sumatriptan, and 
the cardiovascular effects of either drug alone, as measured by vital signs using 24-hour 
ambulatory blood pressure (ABP) monitoring (ABPM).  Pharmacokinetics, safety and 
tolerability will also be reported.
3.2.
Background
Two Phase 2 studies have been completed with lasmiditan in the acute treatment of migraine, 
using doses of up to 45 mg over 20 minutes of the intravenous (IV) formulation (Study COL 
MIG-201), and up to 400 mg of the oral tablet formulation (COL MIG-202).  One Phase 3 
randomized, double-blind, placebo-controlled trial has been completed in the United States 
(COL MIG-301 [SAMURAI]), where 1856 patients were randomized to 100 mg lasmiditan 
(630 subjects), 200 mg (609 subjects), or placebo (617 subjects), respectively. In the SAMURAI 
study, both 100 and 200 mg doses of orally administered lasmiditan achieved superior 2-hour 
pain free rate and the relief of most bothersome migraine symptoms (nausea, phonophobia, and 
photophobia) compared to placebo.


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Five Phase 1 studies of lasmiditan have been completed and methods of administration included 
IV, oral, and sublingual.  Lasmiditan was tolerated by healthy subjects when administered IV up 
to 180 mg over 20 or 60 minutes (H8H-BD-LACA; 40 subjects), as a solution formulation 
administered orally or sublingually up to doses of 400 and 32 mg, respectively (COL MIG-102; 
60 subjects), as oral tablets or a solution formulation up to doses of 400 and 200 mg, respectively 
(COL MIG-103; 44 subjects), and as oral tablets of 200 mg (COL MIG-104; 30 subjects) and up 
to 400 mg (COL MIG-105; 55 subjects).
Across the completed Phase 1, 2, and 3 clinical studies, doses of 0.1 mg to 400 mg of lasmiditan 
were evaluated in healthy subjects or patients with migraine; methods of administration included 
IV, oral, and sublingual.  Compared with placebo, the most frequently reported lasmiditan 
treatment-emergent adverse events (TEAEs) across all studies included somnolence, fatigue, 
dizziness, paresthesia, and hot flashes.  The majority of these TEAEs were mild or moderate in 
severity and none led to subject withdrawal.  One patient in the Phase 2 dose-ranging study in 
migraineurs experienced a serious adverse event (SAE) of dizziness that was moderate in 
severity, occurred approximately 30 minutes after dosing, and was considered related to 
lasmiditan.  The subject was admitted to hospital for overnight observation following review by 
the hospital emergency room physician.
When administered IV at the highest dose of 180 mg (H8H-MC-LACA), lasmiditan produced a 
statistically significant but small dose-related decrease in pulse rate (PR) and increase in BP, 
although the magnitude of these effects was considered unlikely to be of clinical significance in 
this group of healthy subjects.  Following oral administration at doses of up to 400 mg
(COL MIG-102), PR again was slightly reduced, but there were no consistent effects on BP.  The 
effects on vital signs were transient, not dose-related, and unlikely to be clinically significant 
given the intended intermitten7t use of lasmiditan.
Oral tablet doses of lasmiditan up to 400 mg (COL MIG-103) did not result in any clinically 
relevant changes in electrocardiograms (ECGs) (including QT interval/corrected QT interval 
[QTc]) following administration to healthy subjects.  In the thorough QT study (COL MIG-105) 
in healthy subjects, no clinically significant changes in BP, PR, or 12-lead ECG were observed at 
the 100 or 400 mg dose levels.  Lasmiditan caused no significant QT prolongation at either dose.
In healthy subjects, peak plasma concentrations of lasmiditan were observed approximately 1 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 to 6 hours.  Lasmiditan exhibited dose-linear PK; low to moderate 
inter-subject variability in exposure was observed across doses (coefficient of variation [%CV]
up to 61% and 45% for maximum observed drug concentration [Cmax] and area under the curve 
[AUC], respectively; COL MIG-102).  Co-administration of lasmiditan with a high fat diet 
(COL MIG-104) 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 Cmax and AUC 
values, relative to that under fasted conditions.    
Following exploratory analysis of human plasma samples from adult subjects receiving oral 
lasmiditan, 3 major human metabolites (M7, M8, and [S,R]-M18) were observed.  Ketoreduction 


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of lasmiditan to M8 (alcohol) appears to be the major metabolic pathway, presumably via non-
CYP enzymes.  In human liver microsomes, CYP1A2 and CYP3A4 appear to be involved to a 
minor extent in lasmiditan metabolism.  Unchanged lasmiditan comprises approximately 2% of 
the dose excreted in urine.  Lasmiditan is a very weak inhibitor of CYP3A4, CYP2D6, and 
P-glycoprotein.
3.3.
Benefit/Risk Assessment
The primary objective for this study is to compare and contrast the cardiovascular effects of 
lasmiditan and sumatriptan, in relation to vital signs following a single oral dose alone or when 
coadministered in healthy subjects.  There is no anticipated therapeutic benefit for the subjects.
Lasmiditan has been well tolerated by healthy subjects as single oral doses up to 400 mg.  No 
clinically significant safety or tolerability concerns have been identified in subjects to date for 
lasmiditan up to the highest single oral dose given (400 mg).  
Sumatriptan is a marketed drug and will be administered within the recommended dose regimen 
for clinical use (100 mg).  Sumatriptan is known to cause transient increases in blood pressure at 
this dose.  This dose regimen has been tolerated in previous PK/PD studies in healthy subjects 
(for example Nappi et al. 1994). Similar to the adverse events (AEs) observed following dosing 
with lasmiditan, AEs observed following dosing with sumatriptan include, but are not limited to, 
fatigue, dizziness, paresthesia, and hot flashes.
Dosing of lasmiditan and sumatriptan in this study will be conducted in an inpatient setting and 
subjects will be monitored in-house for at least 24 hours after dosing.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of lasmiditan are to be found in the investigator's brochure (IB).
More detailed information about the known and expected benefits and risks of sumatriptan may 
be found in the following:  Patient Information Leaflet or Summary of Product Characteristics.


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4.Objectivesand Endpoints
TableLAHU.1shows the objectives and endpoints of the study.
TableLAHU.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare and contrast the cardiovascular effectsof 
lasmiditan 200mg and sumatriptan 100mg administered 
together to the cardiovascular effectsof single doses of 
either drug administered alone.
Systolic BP(SBP), diastolic BP(DBP), mean arterial 
pressure (MAP), and PRper 24-hour ABPM.
Secondary
To evaluatethe PKof lasmiditan 200mg and 
sumatriptan 100mg administered either alone 
or together.
To evaluate the safety and tolerability of 
lasmiditan 200mg and sumatriptan 100mg.
Cmax, t
max,area under the concentration versus 
time curve (AUC) from time 0 extrapolated to 
infinity (AUC[0-∞]), and AUCfrom time 0 to 
time t, where t is the last time point with a 
measurable concentration (AUC[0-tlast]).
A summary of the number of TEAEsand 
SAEs.
Exploratory
To evaluatethe effect of lasmiditan on renal function 
biomarkers in serum and urine.
To evaluate the PK of lasmiditan metabolites alone and 
in combination with sumatriptan in healthy subjects.
Cystatin C, creatinine,and creatinineclearance
Cmax, t
max, AUC(0-tlast) and AUC(0-∞).


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5. Study Design
5.1.
Overall Design
This is a randomized, double-blind, crossover study with 4 study periods in healthy subjects.  All 
subjects will participate in 4 treatment periods.  The treatments are as follows:

Treatment A:  lasmiditan 200 mg + sumatriptan 100 mg

Treatment B:  lasmiditan 200 mg + placebo

Treatment C:  sumatriptan 100 mg + placebo

Treatment D:  placebo + placebo
Each subject will be randomized to one of 4 treatment sequences in a William’s square design as 
outlined in Table LAHU.2.
Table LAHU.2.
Sequences in Study LAHU
Sequence
Period 1
Period 2
Period 3
Period 4
1
Lasmiditan + 
sumatriptan
Lasmiditan + 
placebo
Sumatriptan + 
placebo
Placebo + placebo
2
Lasmiditan + 
placebo
Sumatriptan + 
placebo
Placebo + placebo
Lasmiditan + 
sumatriptan
3
Sumatriptan + 
placebo
Placebo + placebo
Lasmiditan + 
sumatriptan
Lasmiditan + 
placebo
4
Placebo + placebo
Lasmiditan + 
sumatriptan
Lasmiditan + 
placebo
Sumatriptan + 
placebo
Screening Period:
All subjects will participate in a screening visit up to 28 days prior to Period 1 study drug dosing.
Treatment Periods:
All subjects will participate in 4 treatment periods.  Subjects will be randomized to one of 
4 treatment sequences.  They will be admitted to the clinical research unit (CRU) the day prior to 
dosing (Day -1) in Period 1, and will be dosed on Day 1 of each treatment period according to 
their assigned treatment sequence (Table LAHU.2).  Subjects will be discharged from the CRU 
on Day 3 of Period 4 following the collection of all ABP measurements and PK blood samples.  
There will be a washout of at least 4 days between each dosing day.
All subjects will be discharged from the study at least 5 days after discharge from Period 4.


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5.2.
Number of Participants
Up to 40 subjects may be enrolled to ensure 30 subjects complete the study.
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 double-blind (subject- and investigator-blinded), randomized, and placebo-controlled design is 
being used to minimize bias on the primary objective of this study.  
The study blind will be maintained by either use of a blindfold, or placement of the tablets in an 
amber vial to disguise their appearance; the sumatriptan tablets to be used in this study will be 
similar in shape and size to both lasmiditan and lasmiditan placebo (round and approximately 
10 mm in diameter), therefore lasmiditan placebo will also be used as the placebo for 
sumatriptan.
A crossover design improves the sensitivity for detecting any cardiovascular signals by means of
vital signs (as are described in Section 3.2).  Conducting the study in healthy subjects mitigates 
the potential confounding effects of the disease state and concomitant medications.
The washout period is at least 4 days, which is adequate based on the half-life of lasmiditan.
The nonclinical and clinical data enable conducting clinical pharmacology studies in healthy 
subjects.  The single dose design of this study limits exposure of subjects to lasmiditan and is 
appropriate to address the study objectives.
Preliminary data suggest that lasmiditan may inhibit renal transporters involved in the active 
secretion of creatinine into the urine, which can lead to a decrease in the renal clearance of 
creatinine in vivo and subsequent increase in serum creatinine.  The change in creatinine renal 
clearance is often delayed and transient.  Hence, frequent sampling with urine collection is
necessary for capturing temporal changes in creatinine disposition. The inclusion of serum 
cystatin C, which provides a more precise measure of glomerular filtration rate (GFR), enables 
differentiation between changes in creatinine transport versus change in renal function.
5.5.
Justification for Dose
The dose level of 200 mg lasmiditan has been well tolerated in previous studies of healthy 
subjects.  This dose level is expected to be the highest recommended single dose for lasmiditan.
The dose of sumatriptan (100 mg) is within the range used in clinical practice.  More detailed 
information can be found in the Sumatriptan Package Insert.


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests and ECG. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment (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, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination  
[1a] male subjects:
are not required to adhere to contraceptive requirements.
[1b] female subjects:
of childbearing potential, must test negative for pregnancy at screening, and 
agree to use a reliable method of birth control during the study and for 
1 week following the last dose of lasmiditan.  Reliable methods of 
contraception for female subjects of childbearing potential include the use of 
stable hormonal contraception, bilateral tubal ligation, intrauterine device, or 
diaphragm with spermicide along with male partner’s use of male condom 
with spermicide.
of non-childbearing potential, i.e., postmenopausal or permanently sterile 
following hysterectomy, bilateral salpingectomy, or confirmed tubal 
occlusion (not tubal ligation), as determined by medical history.  
Postmenopausal is defined as spontaneous amenorrhea for at least 
12 months, and a plasma follicle-stimulating hormone (FSH) level greater 
than 40 mIU/mL, unless the subject is taking hormone replacement therapy 
(HRT). 
[2]
are aged 18 to 65 years old, inclusive, at the time of screening.
[3]
have a body mass index (BMI) of 19.0 to 35.0 kg/m2, inclusive, at screening.
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator


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[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.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[9] are Lilly or Covance employees.
[10] are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[11]
have known allergies to lasmiditan, sumatriptan, related compounds, or any 
components of the formulations of lasmiditan and sumatriptan.
[12]
are persons who have previously received the investigational product in this 
study, who have been withdrawn from this study, or who have received 
lasmiditan in any other study investigating lasmiditan within the 3 months 
prior to screening.
[13]
have participated (dosed with any investigational product), within the 30 days
prior to Day -1, in a clinical study involving an investigational product.  If the 
previous investigational product has a long half-life, 5 half-lives or 30 days
(whichever is longer) should have passed.
[14]
have a history of, or ECG findings of, clinically significant bradycardia, heart 
block, 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.
[15]
have a history, signs, or symptoms of arrhythmia or Wolff Parkinson White
syndrome that could affect the subject’s safety.
[16]
have an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2
as determined by the CKD-EPI equation:
GFR = 141 × minimum(Scr/ĸ, 1)α × maximum(Scr/ĸ, 1)-1.209 × 0.993Age × 
(1.018 if female) × (1.159 if black).

Scr is serum creatinine; ĸ is 0.7 for females and 0.9 for males; 
α is -0.329 for females and -0.411 for males.


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
Minimum indicates the minimum of Scr/ĸ or 1; maximum indicates 
the maximum of Scr/or 1.
[17]
have a resting SBP >135 mmHg and DBP >85 mmHg at screening.  
Additional assessments may be performed to confirm eligibility.
[18]
have a history of syncope, presyncope, uncontrolled vertigo, postural 
dizziness, or being at risk for falls, as judged to be clinically significant by the 
investigator, or have orthostatic decreases in SBP of >20 mmHg, or have 
orthostatic decreases in DBP of >10 mmHg at screening.  May be repeated on 
1 occasion if asymptomatic.
[19]
have a supine PR of <50 or >90 bpm at screening.  Additional assessments 
may be performed to confirm eligibility.
[20]
have significant history of or current cardiovascular, respiratory (including 
bronchospasm or bronchial asthma, or chronic obstructive airways disease), 
hepatic, renal, gastrointestinal, endocrine, hematological, or neurological 
disorder, or a condition 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.
[21]
have a history, signs, or symptoms of vasospastic coronary artery disease.
[22]
a history of allergic reactions to medications or food products.
[23]
have known or ongoing neuropsychiatric disorders (for example, manic 
depressive illness, schizophrenia, depression) considered as clinically 
significant by the Investigator.
[24]
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.
[25]
have a clinically significant abnormality in the neurological examination.
[26]
have a history, signs, or symptoms of Raynaud’s phenomenon, hypertension, 
ischemic bowel disease, or peripheral vascular disease.
[27]
have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65), and 14 units per week (females), or are unwilling to stop 
alcohol consumption 48 hours prior to admission in Period 1, and whilst 
resident at the CRU.  At all other times, subjects must agree to consume no 
more than 2 units per day (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL 
of wine; 1.5 oz or 45 mL of distilled spirits).
[28]
currently use, or within the past 1 year used recreational drugs, or showed 
evidence of substance dependence within the past 6 months based on history 
at the screening visit.


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[29]
are unwilling to refrain from tobacco- or nicotine-containing products from 
3 months prior to screening until discharge from the study.
[30]
have received centrally active drugs or those affecting peripheral cholinergic 
transmission within the 3 months prior to Day -1.
[31]
use of monoamine oxidase-A inhibitors and other drugs associated with 
serotonin syndrome (i.e. selective serotonin reuptake inhibitors, selective 
serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and 
5-HT1 agonists) within the 3 months prior to the first dosing occasion.
[32]
intend to use over-the-counter or prescription medication, including dietary 
supplements, within 14 days prior to dosing and until study discharge (apart 
from occasional acetaminophen, hormonal contraception, or HRT).
[33]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[34]
show evidence of hepatitis C and/or positive hepatitis C antibody.
[35]
show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[36]
are women with a positive pregnancy test or who are lactating.
[37]
have donated blood of more than 500 mL within 1 month prior to the 
screening visit.
[38]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in 
the study.
6.2.1. Rationale for Exclusion of Certain Study Candidates
Criteria [1] through [7] define a healthy population suitable for evaluation in a Phase 1 study.  
Criteria [8] and [9] prevent conflict of interest in study participants.  Criteria [10] through [38] 
predominantly exclude medical conditions, medication intolerance, and concomitant medication 
use that may confound the assessment of study endpoints.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Lasmiditan and sumatriptan will be administered after an overnight fast of at least 8 hours.  On 
Day 1 of each treatment period, subjects will abstain from water 1 hour before and after dosing 
(except for water given with the dose).  Subjects will remain fasting for approximately 3 hours 
postdose, at which time a meal will be served.
6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine – Subjects will refrain from consuming xanthine- or caffeine-containing food and 
drinks from 48 hours prior to admission in Period 1, and whilst resident at the CRU.


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Alcohol – Subjects will not consume alcohol for 48 hours prior to admission in Period 1, and 
whilst resident at the CRU.  At all other times, subjects must consume no more than 2 units per 
day (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled 
spirits).
Tobacco – Subjects will refrain from smoking from 3 months prior to screening until discharge 
from the study.  
Grapefruit – Subjects will refrain from consuming grapefruit and grapefruit-containing products 
from 7 days prior to Day 1 in Period 1, and until study discharge.
6.3.3. Activity
No strenuous exercise will be allowed for 48 hours prior to admission in each treatment period 
until after the follow-up visit.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened. 


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7. Treatment
7.1.
Treatment Administered
Investigational products used in this study are shown in Table LAHU.3.
Tablets of lasmiditan and sumatriptan will be administered orally with approximately 240 mL of 
room temperature water, in a sitting position.  Tablets of lasmiditan and sumatriptan will be
administered in the morning of Day 1 of each treatment period.  Subjects will not be allowed to 
lie supine for 2 hours after dosing, unless clinically indicated or for study procedures.
Table LAHU.3.
Treatments Administered
Treatment Name
Lasmiditan
Sumatriptan
Placebo (lasmiditan)
Dosage Formulation
film-coated tablet
film-coated tablet
film-coated tablet
Unit Dose 
Strength/Dosage Level
(1 200-mg) tablets/
200 mg lasmiditan
(1 100-mg) tablets/ 
100 mg sumatriptan
--
Route of Administration
Oral
Oral
Oral
Dosing Instructions
1 tablet taken in the morning 
of Day 1
1 tablet taken in the morning
of Day 1
1 tablet taken in the morning 
of Day 1
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 200 mg of active ingredient and is provided as bulk supplies in 
bottles.  Sumatriptan will be sourced by the investigative site.
Both lasmiditan and sumatriptan tablets are round and 10 mm in diameter.  Placebo tablets look 
similar to both lasmiditan and sumatriptan tablets, but contain no active ingredient.  Placebo 
tablets will be provided in similar bulk bottles as lasmiditan.
The investigational product will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
All subjects will participate in 4 treatment periods.  The treatments are as follows:


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
Treatment A:  lasmiditan 200 mg + sumatriptan 100 mg

Treatment B:  lasmiditan 200 mg + placebo

Treatment C:  sumatriptan 100 mg + placebo

Treatment D:  placebo + placebo
Each subject will be randomized to one of 4 treatment sequences in a William’s square design 
(i.e., ABCD, BCDA, CDAB, and DABC) using a computer-generated allocation schedule.
7.2.1. Timing of Doses
The doses will be administered at approximately the same time on Day 1 of each treatment 
period.  The actual time of all dose administrations will be recorded in the subject’s electronic 
case report form (eCRF).
7.3.
Blinding
Each subject will either be blindfolded at each dosing occasion, or will receive the study drug in 
an amber vial, to maintain the study blind.  Blinding will also be maintained throughout the 
conduct of the study as described in the separate Blinding Plan.
Emergency codes will be available to the investigator.  A code, which reveals the treatment 
sequence for a specific study subject, may be opened during the study only if the subject’s 
well-being requires knowledge of the subject’s treatment assignment.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist or 
clinical research physician (CRP) for the study participant to continue in the study.  During the 
study, emergency unblinding should occur only by accessing the study subject’s emergency 
code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
Dose modification will not be allowed during the study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm all investigational product was received in good 
condition, and any discrepancies are reported and resolved before use of the study treatment.


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Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational product should be stored in an environmentally controlled and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
In general, concomitant medication should be avoided; however, acetaminophen (maximum 
2 g/24 hours) may be administered at the discretion of the investigator for treatment of headaches 
etc.  Contraceptive medication is permitted as per the inclusion criteria.  Hormone replacement 
therapy is also allowed.
If the need for concomitant medication (other than acetaminophen, hormonal contraception, or 
HRT) arises, inclusion or continuation of the subject may be at the discretion of the investigator 
after consultation with a Lilly clinical pharmacologist, CRP, or designee.  Any medication used 
during the course of the study must be documented.
7.8.
Treatment After the End of the Study
Not applicable.


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8. Discontinuation Criteria
Subjects discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 2 of this protocol.
Subjects who do not complete the study will not be replaced.
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 clinical pharmacologist/CRP or 
designee and the investigator to determine if the subject may continue in the study.  If both agree 
it is medically appropriate to continue, the investigator must obtain documented approval from 
the Lilly clinical pharmacologist/CRP or designee to allow the inadvertently enrolled subject to 
continue in the study with or without continued treatment with investigational product.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator decision
o
the investigator decides that the subject should be discontinued from the study

Subject decision


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


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


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9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly clinical pharmacologist/CRP, or its designee, of any 
SAE as soon as practically possible.
All AEs occurring after signing the ICF are recorded in the case report forms and assessed for 
serious criteria.  The SAE reporting to the sponsor begins after the subject has signed the ICF 
and has received investigational product.  However, if an SAE occurs after signing the ICF, but 
prior to receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
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 eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an adverse event.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
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.
Complaints pertaining to lasmiditan in this study will be collected.  As sumatriptan will be 
commercially supplied, Lilly will not collect product complaints on sumatriptan in this study.
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 or sumatriptan is considered any dose 
higher than the dose assigned through randomization.  There is no specific antidote for 
lasmiditan or sumatriptan.  In the event of overdose, the subject should receive appropriate 
supportive care and AEs should be documented.
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
9.4.2.1.
Supine and Orthostatic Vital Signs
For each subject, supine and orthostatic vital signs measurements should be conducted according 
to the Schedule of Activities (Section 2).  
Blood pressure and 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.
Where orthostatic measurements are required, subjects should be supine for at least 5 minutes 
and then subjects will stand, and standing blood pressure 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 treatment period if warranted.


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9.4.2.2.
Ambulatory Blood Pressure Monitoring
For each subject, ABPM will be performed according to the Schedule of Activities (Section 2).
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 before the predose measurement in the first treatment period 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 (for example, 0700 hours to 
2200 hours) and every 30 minutes throughout the night (2200 hours to 0700 hours).  On Day 1 of 
each treatment period, 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, single 12-lead digital safety ECGs should be collected according to the 
Schedule of Activities (Section 2).  Electrocardiograms may be obtained at additional times, 
when deemed clinically necessary.
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the investigational, should be reported to Lilly, or its designee, 
as an AE via eCRF.
Electrocardiograms must be recorded before collecting any blood samples.  Subjects must be 
supine for at least 5 to 10 minutes before ECG collection and remain supine but awake during 
ECG collection.  All ECGs 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 whilst 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 quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the subject can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in subject management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point.


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9.4.4. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes 

AEs
When appropriate, the Lilly clinical pharmacologist 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, direct bilirubin, gamma-glutamyl transferase (GGT), and 
creatinine kinase to confirm the abnormality and to determine if it is increasing or decreasing.  If 
the abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator based on consultation with the Lilly clinical pharmacologist or CRP.  Monitoring 
should continue until levels normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum total bilirubin to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests 

subject discontinued from 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, venous blood samples of 
approximately 2 mL each will be collected to determine the plasma concentrations of lasmiditan, 
and its metabolites, and 3 mL each to determine the plasma concentrations of sumatriptan.  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.


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9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of lasmiditan and its metabolites will be assayed using a validated liquid 
chromatography with tandem mass spectrometric detection (LC-MS/MS) method.  
Concentrations of sumatriptan will be assayed using a validated LC-MS/MS method.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
lasmiditan and to investigate genetic variants thought to play a role in migraine.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or 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
9.8.1. Creatinine Clearance
Urine samples (relative to the dosing time of lasmiditan) will be collected according to the 
Schedule of Activities (Section 2) to determine creatinine clearance. The collection will start at 


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the time of dosing on Day 1 and will be completed on Day 3 of each treatment period.  The 
actual volume of urine collected and the time of each collection will be recorded.
Creatinine urine samples, together with the serum creatinine measurements, will be used to 
assess creatinine clearance.
The sample(s) will be stored per institutional standards at a facility selected by the sponsor.  
During this time, remaining samples may be used for exploratory analyses.
9.8.2. Renal Biomarker Samples
Analysis will be performed on renal function biomarkers, including, but not limited to, creatinine 
and cystatin C, to evaluate any changes from baseline (predose) following lasmiditan dosing.  
Venous blood samples will be collected as specified in the Schedule of Activities (Section 2) for 
determination of serum concentrations of creatinine and cystatin C.
The samples will be identified by subject numbers and stored for a maximum of 2 years after the 
last subject visit for the 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 SizeDetermination
Up to 40 subjects may be enrolled to ensure 30 subjects complete the study.Assuming standard 
deviation for the change, within-subject, in SBPof 12.7 mmHg (based on results from study 
), this will result in a 90% probability that the half-width of the 90% confidence 
interval (CI) about the mean within-subject change between periods is no larger than 4.6 mmHg.
10.2.Populations for Analyses
10.2.1.Study Participant Disposition
A detailed description of subject disposition will be providedat 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 analyseswill be conducted on data from all subjects who have the relevant test 
and reference treatment measurements.
Pharmacokinetic analyses will be conducted on data from all subjects who receiveat least one 
dose of lasmiditan or sumatriptanand have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects,whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PKanalysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1.Safety Analyses
10.3.1.1.Clinical Evaluation of Safety
CCI
All investigational productand 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 productas perceived by the investigator.  Symptoms reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study.  Each symptom will be classified by the most suitable term from the medical regulatory 
dictionary.


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The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Clinical laboratory and vital signs 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, its metabolites, and sumatriptan will be 
calculated by standard noncompartmental methods of analysis and summarized using descriptive 
statistics.
The primary parameters for analysis will be Cmax, tmax, AUC(0-tlast), and AUC(0-∞) of 
lasmiditan, its metabolites, and sumatriptan.  Other noncompartmental parameters, such as half-
life, apparent clearance, and apparent volume of distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameter estimates will be evaluated to the impact of a single dose of 
sumatriptan 100 mg on the PK of lasmiditan and its metabolites.  Log-transformed Cmax and 
AUC parameters will be evaluated using a linear effects model with fixed effects for treatment, 
period (1, 2, 3, or 4) and treatment sequence, and a random effect for subject.  From this model, 
the 90% CIs of the ratios of geometric means from Treatment A (lasmiditan + sumatriptan) will 
be determined and presented versus those of Treatment B (lasmiditan + placebo).  
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CIs, and the p-value from the Wilcoxon test will be 
calculated.  
The same model will be independently used to assess the impact of a single dose of lasmiditan 
200 mg on the PK of sumatriptan.
Additional analyses may be performed, as warranted.
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, 
DBP, and MAP, and nadir hourly mean value of PR, and will be determined by ABPM.
10.3.3.2. Statistical Inference of Cardiovascular Parameters
Cardiovascular parameters will be listed, and summarized using descriptive statistics, as 
appropriate.  
Baseline value will be defined as the mean value during the 2 hours pre-dose for each period.  
Changes from baseline in cardiovascular parameters SBP, DBP, MAP, and PR will be analyzed 
to determine the impact of a single dose of sumatriptan 100 mg on the cardiovascular parameters


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of lasmiditan. A repeated measures linear mixed-effects model with baseline as a covariate, 
fixed effects for time point, treatment, period (1, 2, 3, or 4), treatment sequence, and the 
treatment by time point interaction, and a random effect for subject will be used. Least squares 
(LS) means and treatment differences ([lasmiditan + sumatriptan] - [lasmiditan + placebo]) will 
be calculated and presented with the corresponding CIs. The same model will be used to assess 
the impact of a single dose of lasmiditan 200 mg on the cardiovascular parameters of 
sumatriptan.
10.3.4. Biomarker Analyses
Exploratory biomarkers such as creatinine clearance, as well as creatinine and cystatin C levels 
may be listed, and summarized using descriptive statistics.
Additional analysis may be performed if warranted upon review of the data.
10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, 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
Capi M, de Andrés F, Lionetto L, Gentile G, Cipolla F, Negro A, Borro M, Martelletti P, 
Curto M.  Lasmiditan for the treatment of migraine.  Expert Opin Investig Drugs.  2017 
Feb;26(2):227-234.
Nappi G, Sicuteri F, Byrne M, Roncolato M, Zerbini O. Oral sumatriptan compared with placebo 
in the acute treatment of migraine. J Neurol. 1994;241(3):138-144.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
5-HT
5-hydroxytryptamine
ABP
ambulatory blood pressure
ABPM
ambulatory blood pressure monitoring
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve extrapolated from time 0 to infinity
AUC(0-tlast)
area under the concentration versus time curve from time 0 to time t, where t is the last time 
point with a measurable concentration
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received
BMI
body mass index
BP
blood pressure
CI
confidence interval
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.


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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 retested at some defined time point, depending on the steps required to obtain 
confirmed results.
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
DBP
diastolic blood pressure
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IND
Investigational New Drug:  An application to the Food and Drug Administration to allow 
testing of a new drug in humans.
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate. Informed consent is documented by means of a 
written, signed and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
Investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.


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investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
intravenous
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.
MAP
mean arterial pressure
randomize
the process of assigning subjects/patients to an experimental group on a random basis
PK/PD
pharmacokinetic/pharmacodynamic
PR
pulse rate
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.  
SUSARs
suspected unexpected serious adverse reactions
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
Differential WBC absolute counts and % of:
Total protein
Neutrophils
Albumin
Lymphocytes
Total bilirubin
Monocytes
Alkaline phosphatase
Eosinophils
Aspartate aminotransferase
Basophils
Alanine aminotransferase
Creatinine
Urinalysis
Ethanol testinga
Specific gravity
Urine drug screena
pH
Hepatitis B surface antigenb
Protein
Hepatitis C antibodyb
Glucose
HIVb
Ketones
FSHc
Bilirubin
Urobilinogen
Blood
Nitrite
Urine microscopic (if positive result for blood)
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Urine drug screen and ethanol level will be performed locally at screening and admission to the CRU, and may 
be repeated at other times indicated in the Schedule of Activities (Section 2).
b
Performed at screening only.
c
Performed at screening only for confirmation of post-menopausal 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 Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB

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 (CIOMS) 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 eCRFs, 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 eCRF 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 personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline phosphatase isoenzymesa
GGT
CK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatinine kinase; 
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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LY573144
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-LAHU 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
5
62.5
Serum pregnancy test
5
3
15
Lasmiditan and metabolite 
pharmacokinetics
2
56
112
Sumatriptan pharmacokinetics
3
45
135
Renal biomarkers
2.5
56
140
Pharmacogenetics
10
1
10
Total
494
Total for clinical purposes (rounded up to the nearest 10 mL)
500
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Protocol Amendment H8H-MC-LAHU(c) 
Summary:  A Randomized, Double-Blind, Four-Period, 
Crossover Study to Evaluate the Cardiovascular Effect 
of Single Oral Doses of Lasmiditan when 
Coadministered with Single Oral Doses of Sumatriptan 
in Healthy Subjects
Overview
Protocol H8H-MC-LAHU, A Randomized, Double-Blind, Four-Period, Crossover Study to 
Evaluate the Cardiovascular Effect of Single Oral Doses of Lasmiditan when Coadministered 
with Single Oral Doses of Sumatriptan in Healthy Subjects, has been amended.  The new 
protocol is indicated by Amendment (c) and will be used to conduct the study in place of any 
preceding version of the protocol.
Following feedback from the FDA from the Type C meeting on 12 October 2017, the protocol 
was amended to include an assessment on lasmiditan metabolites. In addition, language was 
added to clarify the definitions of peak, nadir, and baseline for ABPM.


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LY573144
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Protocol Synopsis
Statistical Analysis:
Cardiovascular parameters that will be assessed by ABPM include peak hourly mean values of SBP, DBP, and 
MAP, and nadir hourly mean value of PR.  The parameters will be listed, and summarized using descriptive 
statistics, as appropriate. Changes from baseline in cardiovascular parameters SBP, DBP, MAP, and PR will be 
analyzed to determine the impact of a single dose of sumatriptan 100 mg on the cardiovascular parameters of 
lasmiditan. A repeated measures linear mixed-effects model with baseline as a covariate, fixed effects for time 
point, treatment, period (1, 2, 3, or 4), treatment sequence and the treatment by time point interaction, and a random 
effect for subject will be used. Least squares (LS) means and treatment differences ([lasmiditan + sumatriptan] -
[lasmiditan + placebo]) will be calculated and presented with the corresponding confidence intervals (CIs). The 
same model will be used to assess the impact of a single dose of lasmiditan 200 mg on the cardiovascular parameters
of sumatriptan.
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and sumatriptan will be calculated by standard 
noncompartmental methods of analysis.  Pharmacokinetic parameter estimates will be evaluated to determine the 
impact of a single dose of sumatriptan 100 mg on the PK of lasmiditan and its metabolites.  Log-transformed Cmax
and AUC parameters will be evaluated using a linear effects model with fixed effects for treatment, period (1, 2, 3, 
or 4), and treatment sequence, and a random effect for subject.  From this model, the 90% CIs of the ratios of 
geometric means from Treatment A (lasmiditan + sumatriptan) will be determined and presented versus those of 
Treatment B (lasmiditan + placebo).  The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the 
median difference based on the observed medians, 90% CIs, and the p-value from the Wilcoxon test will be 
calculated.  The same model will be independently used to assess the impact of a single dose of lasmiditan 200 mg 
on the PK of sumatriptan.
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and 12-lead 
electrocardiogram (ECG) parameters.  The parameters will be listed, and summarized using descriptive statistics, as 
appropriate.


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LY573144
Study Schedule Protocol H8H-MC-LAHU
Screening
Periods 1, 2, 3, and 4
Early 
Discontinuation
Follow-
Up
Comments
Procedure
-28 to -2 days 
prior to 
Day 1/Period 1
Day -1
Day 1
Day 
2
Day 
3
At least
5 days 
after 
discharge 
from 
Period 4
Lasmiditan
and 
Metabolite
PK 
Samples
Predose, 
0.5, 1, 
1.5, 2, 
2.5, 3, 
4, 6, 8, 
12 h
24
and
36 h
48 h
Sampling 
times are 
relative to the 
time of study 
treatment
administration 
(0 min).
4. Objectives and Endpoints
Table LAHU.1.
Objectives and Endpoints
Exploratory
To evaluate the effect of lasmiditan on renal function 
biomarkers in serum and urine.
To evaluate the PK of lasmiditan metabolites alone and 
in combination with sumatriptan in healthy subjects.
Cystatin C, creatinine, and creatinine clearance.
Cmax, tmax, AUC(0-tlast) and AUC(0-∞).
9.5. Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of 
approximately 2 mL each will be collected to determine the plasma concentrations of lasmiditan
and its metabolites, and 3 mL each to determine the plasma concentrations of sumatriptan.  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.
Concentrations of lasmiditan and its metabolites will be assayed using a validated liquid 
chromatography with tandem mass spectrometric detection (LC-MS/MS) method.  
Concentrations of sumatriptan will be assayed using a validated LC-MS/MS method.


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LY573144
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and sumatriptan will be 
calculated by standard noncompartmental methods of analysis and summarized using descriptive 
statistics.
The primary parameters for analysis will be Cmax, tmax, AUC(0-tlast), and AUC(0-∞) of 
lasmiditan, its metabolites, and sumatriptan.  Other noncompartmental parameters, such as half-
life, apparent clearance, and apparent volume of distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameter estimates will be evaluated to the impact of a single dose of 
sumatriptan 100 mg on the PK of lasmiditan and its metabolites.  Log-transformed Cmax and 
AUC parameters will be evaluated using a linear effects model with fixed effects for treatment, 
period (1, 2, 3, or 4) and treatment sequence, and a random effect for subject.  From this model, 
the 90% CIs of the ratios of geometric means from Treatment A (lasmiditan + sumatriptan) will 
be determined and presented versus those of Treatment B (lasmiditan + placebo).
10.3.3.1. Cardiovascular Parameter Estimation
The primary parameters for the cardiovascular analyses will be peak hourly mean values of SBP, 
DBP, and MAP, and nadir hourly mean value of PR, and will be determined by ABPM.
10.3.3.2. Statistical Inference of Cardiovascular Parameters
Cardiovascular parameters will be listed, and summarized using descriptive statistics, as 
appropriate.
Baseline value will be defined as the peak mean value during the 2 hours pre-dose for each 
period.  Changes from baseline in cardiovascular parameters SBP, DBP, MAP, and PR will be 
analyzed to determine the impact of a single dose of sumatriptan 100 mg on the cardiovascular 
parameters of lasmiditan. A repeated measures linear mixed-effects model with baseline as a 
covariate, fixed effects for time point, treatment, period (1, 2, 3, or 4), treatment sequence, and 
the treatment by time point interaction, and a random effect for subject will be used. Least 
squares (LS) means and treatment differences ([lasmiditan + sumatriptan] -
[lasmiditan + placebo]) will be calculated and presented with the corresponding CIs. The same 
model will be used to assess the impact of a single dose of lasmiditan 200 mg on the 
cardiovascular parameters of sumatriptan.
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.  


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Protocol H8H-MC-LAHU 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
5
62.5
Serum pregnancy test
5
3
15
Lasmiditan and metabolite 
pharmacokinetics
2
56
112
Sumatriptan pharmacokinetics
3
45
135
Renal biomarkers
2.5
56
140
Pharmacogenetics
10
1
10
Total
494
Total for clinical purposes (rounded up to the nearest 10 mL)
500
a
Additional samples may be drawn if needed for safety purposes.


PPD
Leo Document ID = d90b545b-bf55-413e-bff8-e4fb2b5a9925
Approver: 
Approval Date & Time: 19-Oct-2017 17:16:34 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 20-Oct-2017 08:36:25 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan version 2 H8H-MC-LAHU 
 
 
 
A Randomized, Double-Blind, Four-Period, Crossover Study to Evaluate the Cardiovascular 
Effect of Single Oral Doses of Lasmiditan when Coadministered with Single Oral Doses of 
Sumatriptan in Healthy Subjects 
 
NCT03310411 
 
Approval Date: 22-Nov-2017 
 
 
 


Final v2, 02Nov2017
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STATISTICAL ANALYSIS PLAN
A Randomized, Double-Blind, Four-Period, CrossoverStudy to Evaluate the 
Cardiovascular Effect of Single OralDoses of Lasmiditan when Coadministeredwith 
SingleOral Doses of Sumatriptan in Healthy Subjects
Approval Date: 22-Nov-2017 GMT
Statistical Analysis Plan Status:  Finalv2
Statistical Analysis Plan Date:  02-Nov-2017
Study Drug:LY573144(Lasmiditan)
Sponsor Reference:  H8H-MC-LAHU
Covance CRU Study: 1000071-8370358
Clinical Phase I


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370358
Sponsor Reference H8H-MC-LAHU
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary Objective..........................................................................................................6
4.2
Secondary Objectives ....................................................................................................6
4.3
Exploratory Objective....................................................................................................6
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENTS...................................................................................................................8
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................8
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................8
9.
STATISTICAL METHODOLOGY .....................................................................................8
9.1
General..........................................................................................................................8
9.2
Demographics and Subject Disposition..........................................................................9
9.3
Pharmacokinetic Assessment.........................................................................................9
9.3.1
Pharmacokinetic Analysis.....................................................................................9
9.3.2
Pharmacokinetic Statistical Methodology ...........................................................13
9.4
Cardiovascular Assessment .........................................................................................14
9.4.1
Cardiovascular Analyses.....................................................................................14
9.4.2
Cardiovascular Statistical Methodology..............................................................14
9.5
Safety and Tolerability Assessments............................................................................15
9.5.1
Adverse events ...................................................................................................15
9.5.2
Concomitant medication.....................................................................................16
9.5.3
Clinical laboratory parameters............................................................................16
9.5.4
Hepatic Monitoring ............................................................................................16
9.5.5
Vital signs ..........................................................................................................16
9.5.6
Electrocardiogram (ECG)...................................................................................17
9.5.7
Other assessments...............................................................................................17
9.5.8
Safety and Tolerability Statistical Methodology..................................................17


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Covance Clinical Study No. 8370358
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9.6
Biomarker Analyses ....................................................................................................17
10. INTERIM ANALYSES .....................................................................................................17
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............17
12. REFERENCES ..................................................................................................................17
13. DATA PRESENTATION ..................................................................................................17
13.1 Derived Parameters .....................................................................................................17
13.2 Missing Data ...............................................................................................................17
13.3 Insufficient Data for Presentation ................................................................................18


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370358
Sponsor Reference H8H-MC-LAHU
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
ABP
Ambulatory blood pressure
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
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 lower limit of quantitation
CI
Confidence interval
Cmax
Maximum observed drug concentration
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
DBP
Diastolic blood pressure
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantification
LS
Least square
MAP
Mean arterial pressure
MedDRA
Medical Dictionary for Regulatory Activities


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370358
Sponsor Reference H8H-MC-LAHU
MRE
Magnetic resonance elastography 
PK
Pharmacokinetic
PR
Pulse rate
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SD
Standard deviation 
SOP
Standard Operating Procedure
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


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370358
Sponsor Reference H8H-MC-LAHU
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
17 August 2017) and Protocol Amendment (c) (final version dated 20 October 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 compare and contrast the cardiovascular effects of lasmiditan 200 mg and sumatriptan
100 mg administered together to the cardiovascular effects of single doses of either drug 
administered alone.
4.2
Secondary Objectives

To evaluate the PK of lasmiditan 200 mg and sumatriptan 100 mg administered either 
alone or together.

To evaluate the safety and tolerability of lasmiditan 200 mg and sumatriptan 100 mg.
4.3
Exploratory Objective

To evaluate the effect of lasmiditan on renal function biomarkers in serum and urine.

To evaluate the PK of lasmiditan metabolites alone and in combination with sumatriptan 
in healthy subjects.


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Statistical Analysis Plan 
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5. STUDY DESIGN
This is a randomized, double-blind, crossover study with 4 study periods in healthy subjects. All
subjects will participate in 4 treatment periods. The treatments are as follows:

Treatment A: lasmiditan 200 mg + sumatriptan 100 mg

Treatment B: lasmiditan 200 mg + placebo

Treatment C: sumatriptan 100 mg + placebo

Treatment D: placebo + placebo
Each subject will be randomized to one of 4 treatment sequences in a William’s square design as
outlined in Table 1.
Table 1. Sequences in Study LAHU
Sequence
Period 1
Period 2
Period 3
Period 4
1
Lasmiditan + 
sumatriptan
Lasmiditan + 
placebo
Sumatriptan + 
placebo
Placebo + 
placebo
2
Lasmiditan + 
placebo
Sumatriptan + 
placebo
Placebo + 
placebo
Lasmiditan + 
sumatriptan
3
Sumatriptan + 
placebo
Placebo + 
placebo
Lasmiditan + 
sumatriptan
Lasmiditan + 
placebo
4
Placebo + 
placebo
Lasmiditan + 
sumatriptan
Lasmiditan + 
placebo
Sumatriptan + 
placebo
Screening Period:
All subjects will participate in a screening visit up to 28 days prior to Period 1 study drug dosing.
Treatment Periods:
All subjects will participate in 4 treatment periods. Subjects will be randomized to one of 4 
treatment sequences. They will be admitted to the clinical research unit (CRU) the day prior to 
dosing (Day -1) in Period 1, and will be dosed on Day 1 of each treatment period according to 
their assigned treatment sequence (Table 1). Subjects will be discharged from the CRU on 
Day 3 of Period 4 following the collection of all ambulatory blood pressure (ABP) measurements 
and PK blood samples.
There will be a washout of at least 4 days between each dosing day.
All subjects will be discharged from the study at least 5 days after discharge from Period 4.


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Covance Clinical Study No. 8370358
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6.TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
Placebo
1
200 mg lasmiditan + 100 mg sumatriptan
2
200 mg lasmiditan + placebo
3
100 mg sumatriptan + placebo
4
7.SAMPLE SIZE JUSTIFICATION
Up to 40 subjects may be enrolled to ensure 30 subjects complete the study. Assuming standard
deviation for the change, within-subject, in systolic blood pressure (SBP)of 12.7 mmHg (based 
on results from study
), this will result in a 90% probability that the half-width of 
the 90% confidenceinterval (CI) about the mean within-subject change between periods is no 
larger than 4.6 mmHg.
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 
lasmiditan or sumatriptanandhave evaluable PKdata.  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 mediantime of maximum observed drug concentration(t
max). 
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 alldatathat isdatabased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include thearithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration 
versus time curve [AUCs]and maximum observed drug concentration [Cmax
CCI
]) 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 


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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 9.3 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index 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).
Plasma concentrations of lasmiditan (LY573144), its metabolites, and sumatriptan will be used 
to determine the following PK parameters, when possible:  


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370358
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Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration (LY573144 and sumatriptan only)
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration (LY573144 and sumatriptan only)
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration (LY573144 and sumatriptan only)
MR
Metabolic ratioa
a = no molar correction will be applied since the metabolites are very similar in molecular weight  
and within 5% of the molecular weight for lasmiditan.
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the 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.
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 


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370358
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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 Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.


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Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during 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.  


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Covance Clinical Study No. 8370358
Sponsor Reference H8H-MC-LAHU
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
PK parameter estimates will be evaluated to determine the impact of a single oral dose of 
sumatriptan 100 mg on the PK of lasmiditan and its metabolites.  Log-transformed Cmax,
AUC(0-), and AUC(0-tlast) will be evaluated using a linear effects model with fixed effects for 
treatment, period (1, 2, 3, or 4) and treatment sequence, and a random effect for subject.  From 
this model, the 90% CI of the ratio of geometric means from Treatment A 
(lasmiditan + sumatriptan) will be determined and presented versus those of Treatment B 
(lasmiditan + placebo).
An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
by analyte;
    class trtmnt period seq subject;
    model l_pk = trtmnt period seq / alpha=0.1;
    random subject;
    lsmeans trtmnt / pdiff;
run;
where l_pk is the log-transformed (base e) PK parameter.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370358
Sponsor Reference H8H-MC-LAHU
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CIs, and the p-values from the Wilcoxon test will be 
calculated.
The same model will be independently used to assess the impact of a single oral dose of 
lasmiditan 200 mg on the PK of single oral dose of sumatriptan 100 mg.
Additional analyses may be performed, as warranted.
9.4
Cardiovascular Assessment
9.4.1
Cardiovascular Analyses
The primary parameters for the cardiovascular analyses will be peak hourly mean values of SBP, 
diastolic blood pressure (DBP), and mean arterial pressure (MAP), and nadir hourly mean values 
for pulse rate (PR), and will be determined by ambulatory blood pressure monitoring (ABPM). 
These data will be listed and summarized by treatment. 
Mean hourly SBP, DBP, MAP, and PR values will be calculated, summarized by treatment, and 
plotted, together with changes from baseline.  Baseline value will be defined as the mean value 
during the 2 hours pre-dose for each period.  
Finally, descriptive statistics will be used to summarize the mean values of SBP, DBP, MAP, 
and PR parameters over the intervals 0-4 h, 4-8h, 8-12 h, and 12-24 h.
9.4.2
Cardiovascular Statistical Methodology
Primary analysis
Changes from baseline in peak hourly mean values of cardiovascular parameters SBP, DBP, and 
MAP, and nadir hourly mean values of PR will be analysed to determine the impact of a single 
dose of sumatriptan 100 mg on the peak/nadir hourly mean values of the cardiovascular 
parameters of lasmiditan. A linear mixed-effects model with baseline as a covariate, fixed 
effects for treatment, period (1, 2, 3, or 4), and treatment sequence, and a random effect for 
subject will be used. Least squares (LS) means and treatment differences ([lasmiditan + 
sumatriptan] - [lasmiditan + placebo]) will be calculated and presented with the corresponding 
CIs. 
Primary cardiovascular parameters may be log-transformed prior to the statistical analysis if a 
review of the data indicates that the assumption of normality is violated. 
The same model will be used to assess the impact of a single dose of lasmiditan 200 mg on the 
peak/nadir hourly mean values of the cardiovascular parameters of sumatriptan.


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Covance Clinical Study No. 8370358
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An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
    class trtmnt period seq subject;
    model primcard = base trtmnt period seq / alpha=0.1 cl ddfm=kr;
    random subject;
    lsmeans trtmnt / alpha=0.1 cl pdiff;
run;
where ‘primcard’ is the change from baseline in the peak/nadir hourly mean values of the 
primary cardiovascular parameters SBP, DBP, MAP/PR respectively.
Repeated measures analysis:
Changes from baseline in cardiovascular parameters will be evaluated to determine the impact of 
a single oral dose of sumatriptan 100 mg on the cardiovascular parameters of single oral dose of 
lasmiditan 200 mg.
A repeated measures linear mixed-effects model with baseline as a covariate, fixed effects for 
time point, treatment, period (1, 2, 3, or 4), treatment sequence, and the treatment by time point 
interaction, and a random effect for subject will be used.  LS means and treatment differences 
([lasmiditan + sumatriptan] – [lasmiditan + placebo]) will be calculated and presented with the 
corresponding 90% CIs.  
An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
    class trtmnt subject time period seq;
    model cardio = base time trtmnt period seq trtmnt*time / alpha=0.1 cl ddfm=kr;
    repeated time / type=un subject=subject;
    random subject;
    lsmeans trtmnt*time / alpha=0.1 cl pdiff;
run;
where ‘cardio’ is the change from baseline in the cardiovascular parameter.
Cardiovascular parameters may be log-transformed prior to the statistical analysis if a review of 
the data indicates that the assumption of normality is violated. 
The same model will be used to assess the impact of a single dose of lasmiditan 200 mg on the 
cardiovascular parameters of sumatriptan.
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 


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370358
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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 
Enhanced Dictionary B2 Format). 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.
9.5.4
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.
9.5.5
Vital signs
Supine vital signs data will be summarized by treatment together with changes from baseline, 
where baseline is defined as Day 1 predose. Furthermore, values for individual subjects will be 
listed.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370358
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9.5.6
Electrocardiogram (ECG)
For each subject, ECGs will be performed for safety purposes only, and will not be reported.
9.5.7
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.5.8
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
9.6
Biomarker Analyses
Exploratory biomarkers such as creatinine clearance and renal biomarkers, including, but not 
limited to, creatinine and cystatin C levels, will be summarized by treatment and listed.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.


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Covance Clinical Study No. 8370358
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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.”


PPD
Leo Document ID = 0aca3db4-3fe8-4725-b16a-552cce8ea5e1
Approver: 
Approval Date & Time: 13-Nov-2017 10:31:51 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-Nov-2017 13:19:29 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-Nov-2017 13:36:27 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 22-Nov-2017 13:20:12 GMT
Signature meaning: Approved
PPD
PPD
PPD