Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: yes

Brief summary:
This study will assess the safety, tolerability and blood concentrations of lasmiditan and topiramate together compared to lasmiditan and topiramate separately. Information about any side effects that may occur will be collected.

Participants will be admitted to the Clinical Research Unit (CRU) one day prior to the start of the study and will remain through Day 14.

This study is expected to last approximately 25 days, not including screening. Screening is required within 28 days prior to the start of the study.

Detailed description:

Arms:
arm 1: Lasmiditan administered orally, alone arm 2: Placebo administered orally, alone arm 3: Topiramate administered orally, alone, and co-administered with oral lasmiditan arm 4: Topiramate administered orally, alone, and co-administered with oral placebo

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

Protocol document:
Prot_000.pdf: 
Protocol H8H-MC-LAHT(c) 
Safety, Tolerability, and Pharmacokinetics of Lasmiditan when Co-administered with 
Topiramate in Healthy Subjects 
 
NCT03308669 
Approval Date: 20-Oct-2017 


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Protocol H8H-MC-LAHT(c)
Safety, Tolerability, and Pharmacokinetics of Lasmiditan 
when Co-administered with Topiramate 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 
lasmiditan (LY573144), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Lasmiditan (LY573144)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 
03 August 2017
Amendment (a) Electronically Signed and Approved by Lilly: 05 September 2017
Amendment (b) Electronically Signed and Approved by Lilly: 11 October 2017
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 20-Oct-2017 GMT


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Table of Contents
Safety, Tolerability, and Pharmacokinetics of Lasmiditan 
when Co-administered with Topiramate in Healthy Subjects
Section
Page
Protocol H8H-MC-LAHT(c) Safety, Tolerability, and Pharmacokinetics of 
Lasmiditan when Co-administered with Topiramate in Healthy 
Subjects ..............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
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 ...................................................................................................21
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................24
6.3.
Lifestyle and/or Dietary Requirements .........................................................................25
6.3.1.
Meals and Dietary Restrictions.............................................................................25
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.3.
Activity................................................................................................................25
6.4.
Screen Failures.............................................................................................................25
7.
Treatment..........................................................................................................................26
7.1.
Treatment Administered...............................................................................................26
7.1.1.
Packaging and Labeling .......................................................................................27
7.2.
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................27
7.3.
Blinding .......................................................................................................................27


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7.4.
Dose Modification........................................................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................28
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
9.3.1.
Overdose of Lasmiditan .......................................................................................33
9.3.2.
Overdose of Topiramate.......................................................................................33
9.4.
Safety...........................................................................................................................33
9.4.1.
Laboratory Tests ..................................................................................................33
9.4.2.
Vital Signs ...........................................................................................................33
9.4.3.
Electrocardiograms ..............................................................................................34
9.4.4.
Columbia Suicide Severity Rating Scale...............................................................34
9.4.5.
Neurological Examinations ..................................................................................35
9.4.6.
Safety Monitoring ................................................................................................35
9.4.6.1.
Hepatic Safety................................................................................................35
9.5.
Pharmacokinetics .........................................................................................................36
9.5.1.
Bioanalysis...........................................................................................................36
9.6.
Pharmacodynamics ......................................................................................................36
9.7.
Genetics .......................................................................................................................36
9.8.
Biomarkers...................................................................................................................37
9.9.
Health Economics ........................................................................................................37
10.
Statistical Considerations and Data Analysis.....................................................................38
10.1. Sample Size Determination ..........................................................................................38
10.2. Populations for Analyses..............................................................................................38
10.2.1.
Study Participant Disposition ...............................................................................38
10.2.2.
Study Participant Characteristics ..........................................................................38


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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
11.
References ........................................................................................................................40


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List of Tables
Table
Page
Table LAHT.1.
Objectives and Endpoints .......................................................................18
Table LAHT.2.
Treatments Administered........................................................................26


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List of Figures
Figure
Page
Figure LAHT.1.
Illustration of study design for Protocol H8H-MC-LAHT.......................20


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................41
Appendix 2.
Clinical Laboratory Tests........................................................................45
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................46
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............49
Appendix 5.
Blood Sampling Summary......................................................................50
Appendix 6.
Neurological Examinations.....................................................................51
Appendix 7.
Protocol Amendment H8H-MC-LAHT(c)  Summary Safety, 
Tolerability, and Pharmacokinetics of Lasmiditan when Co-
administered with Topiramate in Healthy Subjects .................................53


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1. Protocol Synopsis
Title of Study:
Safety, Tolerability, and Pharmacokinetics of Lasmiditan when Co-administered with Topiramate in Healthy 
Subjects
Rationale: 
Topiramate is indicated for prophylaxis of migraine and may be used concomitantly with lasmiditan in the intended
patient population.  Study H8H-MC-LAHT (LAHT) is being conducted to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of lasmiditan when co-administered with topiramate in healthy subjects.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To evaluate the safety and tolerability of 
a single dose of lasmiditan in 
combination with topiramate in healthy 
subjects.
A summary of the number of treatment-emergent 
adverse events and serious adverse events.
Secondary
To evaluate the PK of lasmiditan alone 
and in combination with topiramate in 
healthy subjects.
To evaluate the PK of topiramate alone 
and in combination with lasmiditan.
Maximum observed drug concentration (Cmax), time of 
Cmax (tmax), area under the concentration versus time 
curve from zero to last, and zero to infinity
Cmax, tmax, and area under the concentration versus time 
curve during 1 dosing interval
Summary of Study Design:  
Study LAHT is a parallel, placebo-controlled, fixed-sequence study that assesses the safety, tolerability, and 
potential for PK interaction between investigator- and subject-blind lasmiditan/placebo and open-label topiramate.
A single dose of lasmiditan (200 mg) or placebo will be administered on the morning of Day 1. Topiramate 25 mg 
once daily (Day 3), 25 mg twice daily (BID) (Days 4 to 7), 50 mg BID (Days 8 to 13), followed by a single 50-mg 
dose on the morning of Day 14 will be administered. A single dose of lasmiditan (200 mg) or placebo will be 
co-administered with topiramate (50 mg) on the morning of Day 14.
Treatment Arms and Planned Duration for Subjects:  
Screening Period: All subjects will participate in a screening visit of up to 28 days.  
Treatment period: The subjects will be admitted to the clinical research unit (CRU) on the day before dosing 
(Day -1).  Subjects will be discharged from CRU on Day 16 when all study procedures have been completed.
Follow-up period: Subjects will be discharged from the study approximately 10 days after the last dose of 
topiramate.


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Number of subjects:
Approximately 30 subjects may be enrolled so that at least 21 complete the study.
Statistical Analysis:
Safety parameters that will be assessed include safety laboratory parameters, vital signs, neurological examination, 
Columbia Suicide Severity Rating Scale, and 12-lead electrocardiogram parameters.  The parameters will be listed, 
and summarized using standard descriptive statistics, as appropriate.  
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and topiramate will be calculated using
standard noncompartmental methods of analysis.  The parameters will be listed, and summarized using standard 
descriptive statistics, as appropriate.
Pharmacokinetic parameters will be evaluated to determine the impact of topiramate co-administration on the PK of 
a single dose of lasmiditan and its metabolites.  Log-transformed Cmax and area under the concentration versus time 
curve parameters will be evaluated in a linear mixed-effects model with fixed effects for treatment (lasmiditan co-
administered with topiramate [Day 14; test treatment] versus lasmiditan alone [Day 1; reference treatment]), and a 
random effect for subject.  The treatment differences will be back-transformed to present the ratios of geometric 
means and the corresponding 90% confidence interval (CI).
A similar analysis will be performed to determine the impact of co-administration of a single dose of lasmiditan on 
the steady-state PK of topiramate.  The model will include the following treatments:  topiramate co-administered 
with lasmiditan (Day 14; test treatment) versus topiramate alone (Day 13; reference treatment).
The tmax will be analyzed using the Wilcoxon signed rank test.  Estimates of the median difference based on the 
observed medians, 90% CIs, and p-values from the Wilcoxon test will be calculated.


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2. Schedule of Activities


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Study Schedule Protocol H8H-MC-LAHT
Screening
Study Days
Discharg
e
Follow-
up/ED
Comments
Procedure
-28 to -2 
days 
prior to 
Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Day 16
~10 
days 
after 
last 
dose
Informed Consent
X
Subject Admission 
to CRU
X
Subject Discharge 
from CRU
X
Lasmiditan/Placebo 
Administration
X
Day 1, 
indicates 
Time = 
0
X
Topiramate 
Administration
X
X
X
X
X
X
X
X
X
X
X
X
25 mg QD on 
Day 3, 25 mg 
BID from Day 4 
to 7, 50 mg BID 
from Day 8 to 
13, a single 50-
mg dose on the 
morning of Day 
14
Neurological
Examination
X
X
X
X
X
X
X
X
On dosing days, 
all time points
predose and 4-
hour postdose
for morning 
dose only.  Day 
3 is predose 
only. Non-


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Screening
Study Days
Discharg
e
Follow-
up/ED
Comments
Procedure
-28 to -2 
days 
prior to 
Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Day 16
~10 
days 
after 
last 
dose
dosing days at 
single time 
point. 
C-SSRS/Self-Harm
X
X
X
X
Medical History
X
Height
X
Weight
X
X
X
Body weight 
should be 
recorded on Day 
-1 of all study 
periods.  
Vital Signs 
(supine)
X
X
0, 2, 4, 
8 h
24
h
0 & 2 h
0 
& 
2
h
0 
& 
2
h
0, 2, 4, 
8 h
0, 2, 4, 
8 h
24 h
X
X
On dosing days, 
time points 
correspond to 
morning dose 
only.  Day 3 
time points at 
evening dose.
Time points 
may be added 
for each study 
period, if 
warranted and 
agreed upon 
between Lilly 
and the 
investigator.


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Screening
Study Days
Discharg
e
Follow-
up/ED
Comments
Procedure
-28 to -2 
days 
prior to 
Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Day 16
~10 
days 
after 
last 
dose
Triplicate BP 
monitoring
Orthostatic Blood 
Pressure
X
0, 2, & 4 
h
0, 2, & 
4 h
0, 2, & 
4 h
Day 13 time 
points at 
morning dose 
only.
Clinical Laboratory
Tests
X
X
X
X
X
See Appendix 2, 
Clinical 
Laboratory 
Tests, for 
details.
Pregnancy Test 
X
X
X
Serum 
pregnancy test 
will be 
performed at 
screening.  
Urine 
pregnancy test 
will be 
performed at 
every admission 
period and at 
poststudy, if 
applicable.


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Screening
Study Days
Discharg
e
Follow-
up/ED
Comments
Procedure
-28 to -2 
days 
prior to 
Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Day 16
~10 
days 
after 
last 
dose
Physical 
Examination
X
X
Predose
X
After screening, 
medical 
assessment is 
performed  only 
to include 
medical review 
and targeted 
examination, as 
appropriate.
12-Lead ECG
X
Predose
X
X
X
X
X
X
Single; all at 
predose for 
morning dose 
only.
AE/Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lasmiditan and 
Metabolite PK 
Samples
Predose, 
0.5, 1, 
1.5, 2, 3, 
4, 6, 8, 
12 h
24, 
36
h
48 h
Predose, 
0.5, 1, 
1.5, 2, 
2.5, 3, 
4, 6, 8, 
12 h
24, 
36 h
48 h
Topiramate PK 
Samples
Predose, 
0.5, 1, 
1.5, 2, 
3, 4, 6, 
8, 12 h
Predose, 
0.5, 1, 
1.5, 2, 
3, 4, 6, 
8, 12 h
Time points at 
morning dose 
only.
Genetic Sample
X


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Abbreviations: BID = twice daily; BP = blood pressure; CRU = clinical research unit; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; h = 
hour; min = minutes; PK = pharmacokinetics; QD = once daily. 
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.


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3. Introduction
3.1.
Study Rationale
Lasmiditan is a small molecule serotonin (5- hydroxytryptamine1F) receptor agonist being 
developed for the acute treatment of migraine.
Topiramate taken daily is indicated for prophylaxis of migraine and may be used concomitantly
with lasmiditan in the intended patient population. As such, it is important to understand 
potential interactions between drugs commonly used in treating migraine, specifically, whether 
co-administration of such agents results in an increased safety risk or any change in the exposure 
to either (or both). Very common adverse events (AEs) (≥1/10) associated with topiramate 
include dizziness, somnolence, paresthesia, nausea, and fatigue (Topiramate US Prescribing 
Information [https://www.topamax.com/files/topamax.pdf]).  Given the occurrence of similar 
AEs observed following administration of single doses of lasmiditan as documented in 
Section 3.2, it is important to understand the tolerability when both are co-administered.
Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine.  
Six metabolites have been identified in humans, none of which constitutes more than 5% of an 
administered dose.  The metabolites are formed via hydroxylation, hydrolysis, and 
glucuronidation.  In vitro studies indicate that topiramate does not inhibit enzyme activity for 
cytochrome P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 
isozymes.  In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild 
inducer of CYP3A4 (Topiramate US Prescribing Information 
[https://www.topamax.com/files/topamax.pdf]). 
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.  Ketone 
reduction 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.
Although the probability of a pharmacokinetic (PK) drug-drug interaction between lasmiditan 
and topiramate is considered very low based on the low inhibitory potential of both drugs and 
their diverse elimination pathways, a study of their PK interaction is being conducted as a 
secondary endpoint to the safety and tolerability of both drugs because of the likelihood for 
concomitant use in clinical practice.
3.2.
Background
Across the completed Phase 1, 2, and 3 clinical studies, doses of 0.1 to 400 mg of lasmiditan 
were evaluated in healthy subjects or patients with migraine.  To date, lasmiditan has been 
administered to 230 healthy subjects and to 1632 patients with migraine.  Compared with 
placebo, the most frequently reported lasmiditan treatment-emergent adverse events (TEAEs) 
included dizziness, paresthesia, somnolence, fatigue, lethargy, and nausea. The majority of these 


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TEAEs were mild or moderate in severity and none led to subject withdrawal.  One patient 
experienced a serious adverse event (SAE) of dizziness that was moderate in severity (lasmiditan 
200 mg).
Oral tablet doses of lasmiditan up to 400 mg 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 in healthy subjects, no clinically 
significant changes in blood pressure, heart rate, or 12-lead ECG were observed at the 100- or 
400-mg single-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 
intersubject variability in exposure was observed across doses (% coefficient of variation up to 
61% and 45% for maximum observed drug concentration [Cmax] and area under the concentration 
versus time curve [AUC], respectively).  Co-administration of lasmiditan with a high-fat diet led 
to a delay in median time of maximum observed drug concentration (tmax) value by 
approximately 1 hour and a modest (~20%) increase in lasmiditan Cmax and AUC values, relative 
to that under fasted conditions.
3.3.
Benefit/Risk Assessment
The primary objective of this study is to evaluate the safety and tolerability of a single dose of 
lasmiditan in combination with topiramate in healthy subjects. There is no anticipated 
therapeutic benefit for the subjects.
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).  Dosing of lasmiditan in this 
study will be conducted in an inpatient setting, and subjects will be monitored in the clinical 
research unit (CRU) for at least 48 hours after dosing.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of lasmiditan is to be found in the Investigator’s Brochure (IB).  
Topiramate is a marketed drug and will be administered within a dose titration regimen that has 
been tolerated in previous PK studies in healthy subjects (e.g. Bialer et al. 2013; Manitpisitkul 
et al. 2014a,b).
More detailed information about the known and expected benefits and risks of topiramate may be 
found in the following:  2017 US Prescribing Information.


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4. Objectives and Endpoints
Table LAHT.1 shows the objectives and endpoints of the study.
Table LAHT.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the safety and tolerability of a single dose 
of lasmiditan in combination with topiramate in healthy 
subjects. 
A summary of the number of treatment-emergent 
adverse events and serious adverse events
Secondary
To evaluate the pharmacokinetics of lasmiditan alone 
and in combination with topiramate in healthy subjects.
To evaluate the pharmacokinetics of topiramate alone 
and in combination with lasmiditan.
Cmax, tmax, AUC(0-tlast) and AUC(0-∞)
Cmax, tmax, and AUC
Exploratory
To evaluate the pharmacokinetics of lasmiditan 
metabolites alone and in combination with topiramate 
in healthy subjects.
Cmax, tmax, AUC(0-tlast), and AUC(0-∞)
Abbreviations:  AUC(0-tlast) = area under the concentration versus time curve from time zero to time t, where t is 
the last time point with a measurable concentration; AUC(0-∞) = area under the concentration versus time curve
from zero to infinity; AUC= area under the concentration versus time curve during 1 dosing interval; Cmax = 
maximum observed drug concentration; tmax = time to Cmax.


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5. Study Design
5.1.
Overall Design
This is a Phase 1, parallel, placebo-controlled, fixed-sequence study with open-label 
administration of topiramate and investigator- and subject-blind administration of 
lasmiditan/placebo conducted in healthy subjects.
Subjects will be admitted to the CRU on Day -1 and are expected to remain a resident until all 
assessments are completed on Day 16; however, subjects may be allowed to leave the CRU at 
the discretion of the investigator. 
Study governance considerations are described in detail in Appendix 3.
Lasmiditan and topiramate doses will be administered at the CRU. Subjects will be randomly 
assigned in a 2:1 ratio to receive lasmiditan or placebo on both lasmiditan dosing days (Days 1 
and 14).  A single oral dose of study drug (200-mg lasmiditan or placebo) will be administered in 
the morning on Day 1. After lasmiditan wash-out, topiramate will be titrated up to 100 mg on 
Days 3 to 13. On Day 14, 1 oral dose of lasmiditan 200 mg or placebo will be co-administered
with the final topiramate dose (50 mg) in the morning.
Blood sampling for PK assessment will be conducted predose and at time points up to 48 hours 
postdose on Days 1 and 14 for the measurement of plasma concentrations of lasmiditan and its 
metabolites.  Blood samples will also be collected predose and up to 12 hours postdose on Days 
13 and 14 for the measurement of plasma concentrations of topiramate.
A follow-up visit will take place at least 10 days following co-administration of lasmiditan and 
topiramate (Day 14).
Figure LAHT.1 illustrates the study design.


H8H-MC-LAHT(c) Clinical Pharmacology Protocol
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Abbreviations: LY = lasmiditan (200 mg); n = number of subjects in each group; P = 
placebo.
Symbols: “25” inside a circle = one 25-mg tablet of topiramate; gray pentagon =
lasmiditan dose or placebo.
Figure LAHT.1.
Illustration of study design for Protocol H8H-MC-LAHT.
5.2.
Number of Participants
Approximately 30 subjects may be enrolled so that at least 21 subjects complete the study.  For 
purposes of this study, a subject completes the study when all scheduled procedures shown in the 
Schedule of Activities have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
Subjects will be randomly assigned to 1 of 2 treatment arms.  Treatment arms run in parallel and 
both receive the same topiramate dosing schedule. One treatment arm will receive lasmiditan 
(200 mg) on Days 1 and 14 when the other receives a lasmiditan placebo to control for observed 
AEs.
The study has a double-blind (subject- and investigator-blind), fixed-sequence design in which 
each subject receives lasmiditan or placebo alone, topiramate alone, and lasmiditan or placebo 
co-administered with topiramate, allowing each subject to act as his/her own control for safety 
and PK comparisons. A single 200-mg dose of lasmiditan was selected as it is the highest 


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potential recommended dose for lasmiditan.  The washout period between lasmiditan doses of 
14 days is considered sufficient based on the half-life of lasmiditan of approximately 4 to 
6 hours. Topiramate will be administered using a titration schedule over a period of 12 days to 
aid tolerability, with a single dose of lasmiditan or placebo co-administered on the final day, to 
ensure that topiramate concentrations are at steady state at the time of lasmiditan or placebo 
dosing.
5.5.
Justification for Dose
The dose level of 200-mg lasmiditan has been well tolerated in previous studies of healthy 
subjects; 200 mg is expected to be the highest recommended single dose of lasmiditan. 
As described in the label, topiramate is initiated at 25 mg/day (Day 3), increased to 50 mg/day 
(Days 4 to 7), and maintained at 100 mg/day (Days 8 to 13). The recommended dosage for 
migraine prophylaxis is 100 mg/day (Topiramate US Prescribing Information 
[https://www.topamax.com/files/topamax.pdf]). Similar topiramate titration schedules to reach
steady state in healthy subjects demonstrate acceptable safety profiles (Bialer et al. 2013; 
Manitpisitkul et al. 2014a) and are generally well tolerated (Manitpisitkul et al. 2014b).


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG. 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening:
[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 non-childbearing potential, i.e., postmenopausal or permanently sterile 
following hysterectomy, bilateral salpingectomy, or confirmed tubal 
occlusion (not tubal ligation), as determined by written or spoken medical 
history.  Postmenopausal is defined as spontaneous amenorrhea for at least 
12 months, and a plasma follicle-stimulating hormone level greater than 
40 mIU/mL, unless the subject is taking hormone replacement therapy 
(HRT). 
[2]
are aged 18 to 65 years at the time of screening. 
[3]
have a body mass index (BMI) of 19.0 to 35.0 kg/m2, inclusive, at the time of 
screening.
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.
[5]
have venous access sufficient to allow for blood sampling as per the protocol.
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[7]
have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site.


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6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8] are CRU 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 
(IP) or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[11]
have known allergies to lasmiditan, topiramate, related compounds or any 
components of the formulation of lasmiditan or topiramate.
[12]
are persons who have previously received the IP in this study, withdrawn from 
this study, or received lasmiditan in any other study investigating lasmiditan.
[13]
have participated (dosed with IP [lasmiditan or placebo]), within the past
30 days, in a clinical study involving an IP.  If the previous IP has a long 
half-life, 5 half-lives or 30 days (whichever is longer) should have passed.
[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 an abnormal supine blood pressure, defined as systolic blood pressure 
<90 or >140 mmHg or diastolic blood pressure <60 or >90 mmHg at 
screening.  Repeat assessments may be performed to confirm eligibility.
[16]
have a significant history of or current cardiovascular, respiratory (including 
bronchospasm or bronchial asthma, or chronic obstructive airways disease), 
hepatic, renal, gastrointestinal, endocrine, hematological, or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs; of constituting a risk when taking the study medication; 
or of interfering with the interpretation of data.  Appendectomy, splenectomy, 
and cholecystectomy are considered as acceptable.
[17]
show a history of central nervous system (CNS) conditions such as strokes, 
transient ischemic attacks, significant head trauma, CNS infections, migraines, 
brain surgery, or any other neurological conditions that, in the opinion of the 
investigator, increases the risk of participating in the study.
[18]
have known or ongoing psychiatric disorders considered clinically significant 
by the investigator or demonstrate suicidal ideation on the Columbia Suicide 
Severity Rating Scale (C-SSRS).


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[19]
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 screening visit.
[20]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[21]
show evidence of hepatitis C and/or positive hepatitis C antibody.
[22]
show evidence of hepatitis B and/or positive hepatitis B surface antigen. 
[23]
are women with a positive pregnancy test or women who are lactating.
[24]
intend to use over-the-counter or prescription medication, dietary supplements 
within 14 days prior to dosing and until study discharge (apart from 
occasional acetaminophen or HRT).
[25]
have donated blood of more than 500 mL within 1 month prior to the 
screening visit. 
[26]
have an average weekly alcohol intake that exceeds 21 units per week (males 
up to the age of 65 years) and 14 units per week (females), or are unwilling to 
stop alcohol consumption 48 hours prior to dosing until the completion of the 
study (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 
mL of distilled spirits).
[27]
have a clinically significant abnormality in the neurological examination.
[28]
have current or a history of orthostatic hypotension (>20-mmHg drop in 
systolic blood pressure, or >10-mmHg drop in diastolic blood pressure) with 
or without dizziness and/or syncope at screening or admission to the CRU 
upon repeat testing.
[29]
are unwilling to refrain from tobacco- or nicotine-containing products while in 
the CRU or are unable to abide by CRU restrictions.
[30]
have an estimated glomerular filtration rate using Modification of Diet in 
Renal Disease <60 mL/min/1.73 m2.
[31]
have a history of glaucoma.
[32]
have a history of galactose intolerance, Lapp lactase deficiency, or 
glucose-galactose malabsorption.
[33]
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 [33] 
predominantly exclude medical conditions, medication intolerance, and concomitant medication 
use that may confound the assessment of study endpoints.


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6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Meals and Dietary Restrictions
On intensive PK sampling days (Days 1, 13, and 14), subjects will abstain from water 1 hour 
before and after dosing (except for water given with the dose). Subjects will fast on these 
mornings for a minimum of 8 hours predose. Subjects will remain fasting for 3 hours postdose, 
at which time a meal will be served.
Subjects may be permitted to consume a light breakfast at 1 hour postdose at the discretion of the 
investigator on all other days.
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, and while resident at the CRU.
Alcohol – Subjects will not consume alcohol for 48 hours prior to dosing, and while resident at 
the CRU.
Tobacco – Subjects will refrain from using tobacco- or nicotine-containing products while 
resident at the CRU.
6.3.3. Activity
No strenuous exercise will be allowed for 48 hours prior to admission 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
Table LAHT.2 shows the treatment regimens for lasmiditan and topiramate.
Tablets of lasmiditan and topiramate will be administered orally with approximately 240 mL of 
room temperature water in the morning of each dosing day in a sitting position. Subjects will not 
be allowed to lie supine for 2 hours after dosing, unless clinically indicated or for study 
procedures.
Table LAHT.2.
Treatments Administered
Treatment Name
Lasmiditan
LY573144
Lasmiditan Placebo
Topiramate
Dosage Formulation
Film-coated tablet
Film-coated tablet
Tablet
Unit Dose 
Strength(s)/Dosage 
Level(s)
(1 200-mg) tablet/
200-mg lasmiditan
NA
(1 25-mg) tablet/
25-mg topiramate
(2 25-mg) tablet/
50-mg topiramate
Route of Administration
Oral
Oral
Oral
Abbreviation:  NA = not applicable.
The dosing schedule is as follows:

Day 1: 1 oral dose of lasmiditan (1 × 200-mg tablet or placebo) in the morning
Two days following the initial lasmiditan dose, subjects in the CRU will be administered the 
following topiramate doses:

Day 3: starting dose of a single 25-mg tablet

Days 4 to 7: 2 oral doses of a single 25-mg tablet separated by approximately 12 hours

Days 8 to 13: 2 oral doses of 50 mg (2 × 25-mg tablets) each separated by approximately 
12 hours

Day 14: Final topiramate dosing (2 × 25-mg tablets) will be co-administered with 1 oral
dose of lasmiditan (1 × 200-mg tablet or placebo) in the morning 
The investigator or designee is responsible for

explaining the correct use of the IP(s) to the subject

verifying that instructions are followed properly

maintaining accurate records of IP dispensation and collection

and returning all unused medications to Lilly or its designee at the end of the study


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Note: In some cases, the CRU 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.
The study site will obtain topiramate. 
The IP will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
The sponsor (or designee) will be responsible for generating each of the randomization schedules 
and distributing them directly to the CRU pharmacist.
7.2.1. Selection and Timing of Doses
Doses of topiramate will be administered at approximately the same times on each dosing day 
(every 12 hours) except for Day 3 and Day 14 when only 1 dose is administered.  On Day 14, 
topiramate (50 mg) should be co-administered with lasmiditan (200 mg). The actual time of all 
dose administrations will be recorded in the subject’s electronic case report form (eCRF).
7.3.
Blinding
Investigator and subject blinding of lasmiditan will be maintained throughout the conduct of the 
study as described in the separate Blinding Plan. Topiramate will be administered open-label.
Emergency codes will be available to the pharmacy.  A code, which reveals the lasmiditan 
treatment group 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. 


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7.5.
Preparation/Handling/Storage/Accountability
Only participants enrolled in the study may receive IP or study materials, and only authorized 
CRU staff may supply or administer IP. All IPs 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 CRU 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 IP will be administered at the CRU, and documentation of treatment administration will 
occur at the CRU.
7.7.
Concomitant Therapy
In general, concomitant medication should be avoided; however, acetaminophen (1 g, maximum 
4 g/24 hours) may be administered at the discretion of the investigator for treatment of headache,
etc.  If the need for concomitant medication (other than acetaminophen) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator after consultation with a 
Lilly clinical pharmacologist or CRP.  Hormone replacement therapy is allowed per the inclusion 
criteria. 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.
8.1.
Discontinuation from Study Treatment
Discontinuation of the IP for abnormal liver test results should be considered by the investigator 
when a subject meets 1 of the following conditions after consultation with the Lilly-designated 
medical monitor:

alanine aminotransferase (ALT), aspartate aminotransferase (AST) >5X upper limit of 
normal (ULN)

ALT or AST >3X ULN sustained for more than 2 weeks or

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or international 
normalized ratio >1.5 or

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist/CRP
and the investigator to determine if the patient may continue in the study.  If both agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist/CRP to allow the inadvertently enrolled patient to continue in the 
study with or without continued treatment with IP.
8.2.
Discontinuation from the Study
Subjects will be discontinued under the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study


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o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the CRU.  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 IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
After the informed consent form (ICF) is signed, CRU personnel will record, via eCRF, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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


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will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
9.3.
Treatment of Overdose
9.3.1. Overdose of Lasmiditan
For the purposes of this study, an overdose of lasmiditan is considered any dose higher than the 
dose assigned through randomization. There is no specific antidote for lasmiditan.  In the event 
of overdose, the subject should receive appropriate supportive care and AEs should be 
documented.
Refer to the IB.
9.3.2. Overdose of Topiramate
In the event of a topiramate overdose, the subject should receive appropriate supportive care 
according to the approved product label for advice on overdose.
Refer to the 2017 US Prescribing Information (Topiramate US Prescribing Information 
[https://www.topamax.com/files/topamax.pdf]). 
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
9.4.2. Vital Signs
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).
Blood pressure and pulse rate should be measured after at least 5 minutes supine.  All supine 
blood pressure and pulse rate measurements will be done in triplicates at approximately 1-minute 
intervals.  The last triplicate vital sign can be used as the supine vital sign for the calculation of 
orthostatic changes.  Vital sign measurements should be taken from the nondominant and 
opposite arm as used for PK sampling, and for each individual subject the same cuff size should 
be used throughout the study for measurements of blood pressure.


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Where orthostatic measurements are required, subjects should be supine for at least 5 minutes 
and stand for at least 2 minutes.
If the subject feels unable to stand, supine vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.4.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP, should be reported to Lilly, or its designee, as an AE via 
eCRF. 
For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities.  Electrocardiograms must be recorded before collecting any blood samples.  Subjects
must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but 
awake during ECG collection.  Electrocardiograms may be obtained at additional times, when 
deemed clinically necessary.  All ECGs recorded should be stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed, and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an
AE.
9.4.4. Columbia Suicide Severity Rating Scale
The C-SSRS (Posner 2007; Posner et al. 2007a,b) captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviors during the assessment period. The C-SSRS 
and a corresponding Self-Harm Supplement Form will be administered according to the 
Schedule of Activities by appropriately trained site personnel. Any significant change would 
need to be referred to a psychiatrist.
If the investigator determines that suicide-related behaviors have occurred, the Lilly self-harm
follow-up form will be used to collect additional information to allow for a more complete
assessment of these behaviors. As noted above, subjects with any clinically significant change,
as determined by the investigator, will be referred to a psychiatrist.


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9.4.5. Neurological Examinations
Neurological examinations will be performed as indicated in the Schedule of Activities. 
The neurological examination will include observation for tremors and testing of ocular 
movements, finger-to-nose and heel-to-shin testing, rapid alternating movements, tandem 
walking, strength testing, and muscle stretch (deep) reflexes.  An experienced clinician will 
conduct the neurological examination.  Please see Appendix 6 for a description of the techniques 
used.
Positive significant findings (such as nystagmus, dystaxia, ataxia, irregular alternating 
movements, and hyperreflexia) on neurological examination of oculomotor testing, tandem 
walking, heel-to-shin, rapid alternating movements, finger-nose coordination, and muscle stretch 
(deep) reflexes will be recorded as preexisting conditions or AEs.  A clinically significant change 
from baseline or clinically significant new findings should be a consideration for discontinuation 
of study drug.
9.4.6. 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.
9.4.6.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatinine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator based on 
consultation with the Lilly clinical pharmacologist or CRP.  Monitoring should continue until 
levels normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests 


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
patient/subject discontinued from treatment due to a hepatic event or abnormality 
of liver tests

hepatic event considered to be a SAE.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of 
approximately 3 mL each will be collected to determine the plasma concentrations of lasmiditan
and its metabolites.  Similarly, at times specified in the Schedule of Activities, 2 mL of venous 
blood samples will be collected to determine the plasma concentrations of topiramate. 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 tandem-mass spectrometry (LC-MS/MS) method.  Analyses of samples 
collected from subjects who received placebo are not planned.
Concentrations of topiramate will be assayed using a validated LC-MS/MS method.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
2 years following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses.
9.6.
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 or topiramate 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 


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selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of lasmiditan or after lasmiditan is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 30 subjects will be enrolled, so that at least 21 subjects complete the study.  
Subjects will be randomized in a 2:1 ratio of lasmiditan 200 mg:placebo.  The sample size is 
customary for Phase 1 studies evaluating safety and tolerability, and is not powered on the basis 
of statistical hypothesis testing.
Subjects who are randomized but who do not complete Day 14 treatment may be replaced to 
ensure that enough subjects complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The subjects’ age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least 1 dose 
of lasmiditan or topiramate and have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post hoc analyses and incomplete disclosures of analyses.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to enrollment will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.
The number of IP-related SAEs will be reported.


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10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs,
neurological examinations, and C-SSRS.  The parameters will be listed, and summarized using 
standard descriptive statistics.  Additional analysis will be performed if warranted upon review 
of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for lasmiditan and its metabolites, and topiramate will be 
calculated using standard noncompartmental methods of analysis and summarized using 
descriptive statistics.
The primary parameters for analysis will be Cmax, tmax, AUC(0-tlast) and AUC from zero to 
infinity for lasmiditan and its metabolites on Days 1 and 14, and Cmax, tmax, and AUC during 1 
dosing interval for topiramate on Days 13 and 14.  Other noncompartmental parameters, such as 
half-life, apparent clearance, and apparent volume of distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to determine the impact of topiramate 
co-administration on the PK of a single dose of lasmiditan and its metabolites.  Log-transformed 
Cmax and AUC parameters will be evaluated in a linear mixed-effects model with fixed effects for 
treatment (lasmiditan co-administered with topiramate [Day 14; test treatment] versus lasmiditan 
alone [Day 1; reference treatment]), and a random effect for subject.  The treatment differences 
will be back-transformed to present the ratios of geometric means and the corresponding 90% 
confidence interval (CI).
A similar analysis will be performed to determine the impact of co-administration of a single 
dose of lasmiditan on the steady-state PK of topiramate.  The model will include the following 
treatments:  topiramate co-administered with lasmiditan (Day 14; test treatment) versus 
topiramate alone (Day 13; reference treatment).
The tmax will be analyzed using the Wilcoxon signed rank test.  Estimates of the median 
difference based on the observed medians, 90% CIs, and p-values from the Wilcoxon test will be 
calculated.
Additional analyses may be performed, as warranted.


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11.
References
Bialer M, Shekh-Ahmad T, Braun T, Halorsen M. Comparative steady-state pharmacokinetic 
evaluation of immediate-release topiramate and USL255, a once-daily extended-release 
topiramate formulation. Epilepsia. 2013;54(8):1444-1452.
Manitpisitkul P, Curtin CR, Shalayda K, Wang S, Ford L, Heald D. Pharmacokinetic interactions 
between topiramate and diltiazem, hydrochlorothiazide, or propranolol. Clin Pharmacol Drug 
Dev. 2014a;3(5):378-387.
Manitpisitkul P, Curtin CR, Shalayda K, Wang S, Ford L, Heald D. Pharmacokinetic interactions 
between topiramate and pioglitazone and metformin. Epilepsy Res. 2014b;108(9):1519-1532.
Posner K. State of the science: measurement of suicidal adverse events and the Columbia suicide 
severity rating scale. Boca Raton, FL: NCDEU; 2007.
Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007a;12(2):156-162.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007b;165(7):1035-1043.
Topiramate US Prescribing Information resource page. Topomax web site. May 2017. Available 
at: https://www.topamax.com/files/topamax.pdf. Accessed June 15, 2017.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
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
BMI
body mass index
CI
confidence interval
Cmax
maximum observed drug concentration
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be re-tested at some defined time point, depending on the steps required to obtain 
confirmed results.
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
clinical research unit
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450
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.


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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
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate. Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
LC-MS/MS
liquid chromatography tandem-mass spectrometry
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.
non-
investigational 
product (non-IP)
A product that is not being tested or used as a reference in the clinical study, but is provided 
to subjects and used in accordance with the protocol, such as concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PK
pharmacokinetic(s)
QTc
corrected QT interval
randomize
The process of assigning subjects/patients to an experimental group on a random basis.
SAE
serious adverse event


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


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Total CO2
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC) 
Glucose (random)
Platelets
Blood urea nitrogen (BUN)
Differential WBC absolute counts and % of
Total protein
Neutrophils
Albumin
Lymphocytes
Reflex total bilirubin
Monocytes
Alkaline phosphatase (ALP)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Alanine aminotransferase (ALT)
Creatinine
Gamma-glutamyl transferase (GGT)
Urinalysis
Specific gravity
pH
Protein
Glucose
Ethanol testingb
Ketones
Urine drug screenb
Urine pregnancy test
Bilirubin
Hepatitis B surface antigena
Urobilinogen
Hepatitis C antibodya
Blood
HIVa
Nitrite
Serum pregnancy test (females only)a
Urine microscopic (if positive result for blood)
FSH (females only, if applicable)c
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Performed at screening only.
b
Urine drug screen and ethanol level will be performed locally at screening and may be repeated prior to 
admission to the clinical research unit and at other times indicated in the Schedule of Activities (Section 2).  
c
Performed at screening only, for confirmation of postmenopausal status.


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Appendix 3.
Study Governance, Regulatory, and Ethical 
Considerations
Informed Consent
The investigator is responsible for

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject or legal representative.  This
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of IP.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
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 and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines
3) applicable laws and regulations


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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.
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 CRU, 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.
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.


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Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.
The purpose and use of subject/patient personal information collected will be provided in a 
written document to the subject/patient by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol H8H-MC-LAHT Sampling Summary
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume (mL)
Screening testsa
45
1
45
Clinical laboratory testsa
12.5
5
62.5
Lasmiditan and metabolite 
pharmacokineticsb
3
27
81
Topiramate pharmacokineticsb
2
20
40
Pharmacogenetics
10
1
10
Total
238.5
Total for clinical purposes rounded up to the nearest 10 mL
240
a
Additional samples may be drawn if needed for safety purposes.
b
Includes a potential 3 additional samples.


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Appendix 6.
Neurological Examinations
Tests for Dysfunction on Neurological Examination
Abnormality
Method of Examination
Gait dystaxia
Free walking for broad-based gait
Tandem walking
Nystagmus
Have patient follow your finger through fields of gaze
Irregular alternating movements
Thigh slapping test
Arm dystaxia
Finger-to-nose
Leg dystaxia
Heel-to-shin
Scapular winging
Strength testing
Hyperreflexia
Muscle stretch (deep) reflexes
Dystaxia = incoordination of intentional movements
Neurological Examination
1) Test station (stance) and gait:

Inspect the patient for swaying when standing and for dystaxia of gait.

Ask the patient to stand with feet together.

Ask the patient to take 6 steps along a straight line, walking heel to toe (tandem 
walking).
2) Test eye movements:

Observe spontaneous eye movements.

Observe the patient’s eyes as they pursue the examiner’s finger as it moves from 
side-to-side and up and down through the full range of ocular movements.
3) Test rapid alternating movements:

Thigh-slapping test.  Test each hand separately.

Demonstrate the action to the patient by lightly slapping your own thigh, 
alternating first with the palm and then with the back of the hand as rapidly and 
rhythmically as possible, making an audible sound with each slap.

Instruct the patient to make actions that sound exactly like yours.
4) Test arm movement:

Finger-to-nose test.  Ask the patient to extend his arms out in front.

Instruct him to place his index finger on the tip of his nose by moving his finger 
in slowly, and placing the tip of his finger exactly on the tip of his nose, trying not 
to miss.


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
Inspect for intention tremor of the movement in progress, and the precision with 
which the patient touches the tip of his nose.

If uncertain of the result, have the patient alternatively touch his nose, your finger, 
and his nose several times.
5) Test leg movement:

Heel-to-shin test.  The patient is sitting or supine.

Instruct the patient to place one heel precisely on the opposite knee and run the 
heel in a straight line precisely down the shin.
6) Strength testing:

Shoulder girdle.  Try to press the patient’s arms down after he or she abducts
them to shoulder height.  Look for scapular winging.

Upper extremities.  Test the biceps, triceps, wrist dorsiflexors, and grip.  Test 
strength of finger abduction and extension.

Lower extremities.  Test hip flexors, abductors and adductors, knee flexors, foot 
dorsiflexors, invertors, and evertors.  Have patient do a deep knee bend to test 
knee extension.

Grade strength on a 0 to 5 scale.
7) Muscle stretch (deep) reflexes:
Biceps
Triceps
Quadriceps (knee reflex)
Triceps surae (ankle jerk)
Grade 0 to 4+
Positive significant findings (such as nystagmus, dystaxia, ataxia, and irregular alternating 
movements*) on neurological examination of oculomotor testing, tandem walking, heel-to-shin, 
rapid alternating movements, finger-nose coordination and muscle stretch (deep) reflexes will be 
recorded as pre-existing conditions or adverse events.  Increase in severity from baseline or new 
findings should be a consideration for discontinuation of study drug.
* Enter “clumsiness” for irregular alternating movements on the eCRF as the pre-existing 
condition or adverse event.


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Appendix 7.
Protocol Amendment H8H-MC-LAHT(c) 
Summary Safety, Tolerability, and Pharmacokinetics of 
Lasmiditan when Co-administered with Topiramate in 
Healthy Subjects
Overview
Protocol H8H-MC-LAHT, Safety, Tolerability, and Pharmacokinetics of Lasmiditan when Co-
administered with Topiramate 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.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Protocol Synopsis
Statistical Analysis:
Safety parameters that will be assessed include safety laboratory parameters, vital signs, neurological examination, 
Columbia Suicide Severity Rating Scale, and 12-lead electrocardiogram parameters.  The parameters will be listed, 
and summarized using standard descriptive statistics, as appropriate.  
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and topiramate will be calculated using
standard noncompartmental methods of analysis.  The parameters will be listed, and summarized using standard 
descriptive statistics, as appropriate.
Pharmacokinetic parameters will be evaluated to determine the impact of topiramate co-administration on the PK of 
a single dose of lasmiditan and its metabolites.  Log-transformed Cmax and area under the concentration versus time 
curve parameters will be evaluated in a linear mixed-effects model with fixed effects for treatment (lasmiditan co-
administered with topiramate [Day 14; test treatment] versus lasmiditan alone [Day 1; reference treatment]), and a 
random effect for subject.  The treatment differences will be back-transformed to present the ratios of geometric 
means and the corresponding 90% confidence interval (CI).
A similar analysis will be performed to determine the impact of co-administration of a single dose of lasmiditan on 
the steady-state PK of topiramate.  The model will include the following treatments:  topiramate co-administered 
with lasmiditan (Day 14; test treatment) versus topiramate alone (Day 13; reference treatment).
The tmax will be analyzed using the Wilcoxon signed rank test.  Estimates of the median difference based on the 
observed medians, 90% CIs, and p-values from the Wilcoxon test will be calculated.


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2. Schedule of Activities
Study Schedule Protocol H8H-MC-LAHT
Screening
Study Days
Discharg
e
Follow-
up/ED
Comments
Procedure
-28 to -2 
days 
prior to 
Day 1
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Day 16
~10 
days 
after 
last dose
Lasmiditan and 
Metabolite PK 
Samples
Predose, 
0.5, 1, 
1.5, 2, 3, 
4, 6, 8, 
12 h
24, 
36
h
48
h
Predose, 
0.5, 1, 
1.5, 2, 
2.5, 3, 
4, 6, 8, 
12 h
24, 
36 h
48 h


H8H-MC-LAHT(c) Clinical Pharmacology Protocol
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LY573144
4. Objectives and Endpoints
Table LAHT.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the safety and tolerability of a single dose 
of lasmiditan in combination with topiramate in healthy 
subjects. 
A summary of the number of treatment-emergent 
adverse events and serious adverse events
Secondary
To evaluate the pharmacokinetics of lasmiditan alone 
and in combination with topiramate in healthy subjects.
To evaluate the pharmacokinetics of topiramate alone 
and in combination with lasmiditan.
Cmax, tmax, AUC(0-tlast) and AUC(0-∞)
Cmax, tmax, and AUC
Exploratory
To evaluate the pharmacokinetics of lasmiditan 
metabolites alone and in combination with topiramate 
in healthy subjects.
Cmax, tmax, AUC(0-tlast), and AUC(0-∞)
Abbreviations:  AUC(0-tlast) = area under the concentration versus time curve from time zero to time t, where t is 
the last time point with a measurable concentration; AUC(0-∞) = area under the concentration versus time curve
from zero to infinity; AUC= area under the concentration versus time curve during 1 dosing interval; Cmax = 
maximum observed drug concentration; tmax = time to Cmax.
5.1. Overall Design
This is a Phase 1, parallel, placebo-controlled, fixed-sequence study with open-label 
administration of topiramate and investigator- and subject-blind administration of 
lasmiditan/placebo conducted in healthy subjects.
Subjects will be admitted to the CRU on Day -1 and are expected to remain a resident until all 
assessments are completed on Day 16; however, subjects may be allowed to leave the CRU at 
the discretion of the investigator. 
Study governance considerations are described in detail in Appendix 3.
Lasmiditan and topiramate doses will be administered at the CRU. Subjects will be randomly 
assigned in a 2:1 ratio to receive lasmiditan or placebo on both lasmiditan dosing days (Days 1 
and 14).  A single oral dose of study drug (200-mg lasmiditan or placebo) will be administered in 
the morning on Day 1.  After lasmiditan wash-out, topiramate will be titrated up to 100 mg on 
Days 3 to 13.  On Day 14, 1 oral dose of lasmiditan 200 mg or placebo will be co-administered
with the final topiramate dose (50 mg) in the morning.
Blood sampling for PK assessment will be conducted predose and at time points up to 48 hours 
postdose on Days 1 and 14 for the measurement of plasma concentrations of lasmiditan and its 
metabolites.  Blood samples will also be collected predose and up to 12 hours postdose on Days 
13 and 14 for the measurement of plasma concentrations of topiramate.


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LY573144
A follow-up visit will take place at least 10 days following co-administration of lasmiditan and 
topiramate (Day 14).
9.5. Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of 
approximately 3 mL each will be collected to determine the plasma concentrations of lasmiditan
and its metabolites.  Similarly, at times specified in the Schedule of Activities, 2 mL of venous 
blood samples will be collected to determine the plasma concentrations of topiramate.  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 tandem-mass spectrometry (LC-MS/MS) method.  Analyses of samples 
collected from subjects who received placebo are not planned. 
Concentrations of topiramate will be assayed using a validated LC-MS/MS method.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
2 years following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses.
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for lasmiditan and its metabolites, and topiramate will be 
calculated using standard noncompartmental methods of analysis and summarized using 
descriptive statistics.
The primary parameters for analysis will be Cmax, tmax, AUC(0-tlast) and AUC from zero to 
infinity for lasmiditan and its metabolites on Days 1 and 14, and Cmax, tmax, and AUC during 1 
dosing interval for topiramate on Days 13 and 14.  Other noncompartmental parameters, such as 
half-life, apparent clearance, and apparent volume of distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to determine the impact of topiramate 
co-administration on the PK of a single dose of lasmiditan and its metabolites.  Log-transformed 
Cmax and AUC parameters will be evaluated in a linear mixed-effects model with fixed effects for 
treatment (lasmiditan co-administered with topiramate [Day 14; test treatment] versus lasmiditan 
alone [Day 1; reference treatment]), and a random effect for subject.  The treatment differences 
will be back-transformed to present the ratios of geometric means and the corresponding 90% 
confidence interval (CI).


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Appendix 5. Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol H8H-MC-LAHT Sampling Summary
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume (mL)
Screening testsa
45
1
45
Clinical laboratory testsa
12.5
5
62.5
Lasmiditan and metabolite
pharmacokineticsb
3
27
81
Topiramate pharmacokineticsb
2
20
40
Pharmacogenetics
10
1
10
Total
238.5
Total for clinical purposes rounded up to the nearest 10 mL
240
a
Additional samples may be drawn if needed for safety purposes.
b
Includes a potential 3 additional samples.


Leo Document ID = 9147c1ba-6644-46bd-a6c6-a9340b641595
Approver: 
Approval Date & Time: 19-Oct-2017 17:11:26 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 20-Oct-2017 08:36:56 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan H8H-MC-LAHT 
Safety, Tolerability, and Pharmacokinetics of Lasmiditan when Co-administered with 
Topiramate in Healthy Subjects 
 
NCT03308669 
Approval Date: 01-Nov-2017 


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             Page 1 of 16
STATISTICAL ANALYSIS PLAN
Safety, Tolerability, and Pharmacokinetics of Lasmiditan when Co-administered with 
Topiramate in Healthy Subjects  
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  30-October-2017
Study Drug: LY573144 (Lasmiditan)
Sponsor Reference: H8H-MC-LAHT
Covance CRU Study: 1000071-8370359
Clinical Phase I
Approval Date: 01-Nov-2017 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370359
Sponsor Reference H8H-MC-LAHT
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objectives .............................................................................................. 5
4.3
Exploratory Objectives ............................................................................................ 5
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS............................................................................................................. 7
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
Safety and Tolerability Assessments...................................................................... 14
9.4.1
Adverse events ............................................................................................. 14
9.4.2
Concomitant medication............................................................................... 14
9.4.3
Clinical laboratory parameters...................................................................... 14
9.4.4
Hepatic Monitoring ...................................................................................... 14
9.4.5
Vital signs .................................................................................................... 15
9.4.6
Electrocardiogram (ECG)............................................................................. 15
9.4.7
Columbia Suicide Severity Rating Scale (C-SSRS)....................................... 15
9.4.8
Neurological Examination ............................................................................ 15
9.4.9
Other assessments......................................................................................... 15
9.4.10
Safety and Tolerability Statistical Methodology............................................ 15
10. INTERIM ANALYSES ............................................................................................... 16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 16
12. REFERENCES ............................................................................................................ 16
13. DATA PRESENTATION ............................................................................................ 16
13.1 Derived Parameters ............................................................................................... 16
13.2 Missing Data ......................................................................................................... 16
13.3 Insufficient Data for Presentation .......................................................................... 16


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370359
Sponsor Reference H8H-MC-LAHT
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC
Area under the concentration versus time curve during one dosing interval
AUC(0-tlast)
Area under the concentration versus time curve from time zero to time t, 
where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from time zero to infinity
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
bid 
Twice daily
BQL
Below the lower limit of quantification
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
CRU
Clinical research unit
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MR
Metabolic ratio
MRE
Magnetic resonance elastography


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370359
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qd
Once daily
QTc
QT correction; QT interval corrected for heart rate
QTcB
QTc calculated using the Bazett correction
QTcF
QTc calculated using the Fridericia correction
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SD
Standard deviation 
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-compartmental
analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after extra-vascular
administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370359
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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated
03 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 evaluate the safety and tolerability of a single dose of lasmiditan in combination 
with topiramate in healthy subjects.
4.2
Secondary Objectives

To evaluate the PK of lasmiditan alone and in combination with topiramate in healthy 
subjects.

To evaluate the PK of topiramate alone and in combination with lasmiditan.
4.3
Exploratory Objectives

To evaluate the PK of lasmiditan metabolites alone and in combination with 
topiramate in healthy subjects.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370359
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5. STUDY DESIGN
This is a Phase 1, parallel, placebo-controlled, fixed-sequence study with open-label
administration of topiramate and investigator- and subject-blind administration of
lasmiditan/placebo conducted in healthy subjects.
Subjects will be admitted to the Clinical Research Unit (CRU) on Day -1 and are expected to 
remain a resident until all assessments are completed on Day 16; however, subjects may be 
allowed to leave the CRU at the discretion of the investigator.
Study governance considerations are described in detail in Appendix 3 of the protocol.
Lasmiditan and topiramate doses will be administered at the CRU. Subjects will be randomly
assigned in a 2:1 ratio to receive lasmiditan or placebo on both lasmiditan dosing days (Days 1
and 14). A single oral dose of study drug (200 mg lasmiditan or placebo) will be administered in
the morning on Day 1. After lasmiditan wash-out, topiramate will be titrated up to 100 mg on
Days 3 to 13. On Day 14, 1 oral dose of lasmiditan 200 mg or placebo will be co-administered
with the final topiramate dose (50 mg) in the morning.
Blood sampling for PK assessment will be conducted predose and at time points up to 48 hours
postdose on Days 1 and 14 for the measurement of plasma concentrations of lasmiditan and its 
metabolites. Blood samples will also be collected predose and up to 12 hours postdose on Days 
13 and 14 for the measurement of plasma concentrations of topiramate.
A follow-up visit will take place at least 10 days following co-administration of lasmiditan and
topiramate (Day 14).
Figure 1 illustrates the study design.


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Covance Clinical Study No. 8370359
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Abbreviations: LY = lasmiditan (200 mg); n = number of subjects in each group; P = placebo.
Symbols: “25” inside a circle = one 25 mg tablet of topiramate; gray pentagon = lasmiditan dose or placebo
Figure 1. Illustration of study design
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
2
25 mg topiramate QD
3
25 mg topiramate BID
4
50 mg topiramate BID
5
50 mg topiramate + placebo
6
50 mg topiramate + 200 mg lasmiditan
7
D = Day; QD = once daily; BID = twice daily


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370359
Sponsor Reference H8H-MC-LAHT
The following treatment sequences may be displayed across some outputs.
Sequence
Treatment Sequence Description
1
Placebo / 25 mg topiramate QD / 25 mg topiramate BID / 25 mg topiramate BID / 
50 mg topiramate BID / 50 mg topiramate + placebo
2
200 mg lasmiditan / 25 mg topiramate QD / 25 mg topiramate BID / 25 mg 
topiramate BID / 50 mg topiramate BID / 50 mg topiramate + 200 mg lasmiditan 
7. SAMPLE SIZE JUSTIFICATION
Approximately 30 subjects will be enrolled, so that at least 21 subjects complete the study.
Subjects will be randomized in a 2:1 ratio of lasmiditan 200 mg : placebo. The sample size is 
customary for Phase 1 studies evaluating safety and tolerability, and is not powered on the basis 
of statistical hypothesis testing.
Subjects who are randomized but who do not complete Day 14 treatment may be replaced to 
ensure that enough subjects complete the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “PK” population will consist of all subjects who received at least one dose of lasmiditan or 
topiramate and have evaluable PK data.  Subjects may be excluded from the PK summary 
statistics and statistical analysis if a subject has an adverse event (AE) of vomiting that occurs at 
or before 2 times median time of maximum observed concentration (tmax). 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration 
versus time curve [AUCs] and maximum observed drug concentration [Cmax]) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
subjects included in the relevant analysis population. For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 


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


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370359
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Plasma concentrations of topiramate will be used to determine the following PK parameters, 
when possible:  
Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUCτ
ng.h/mL
area under the concentration versus time curve during one dosing 
interval
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the CSR. Any exceptions or special handling of data will 
be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. AUC(0-) values where the 
percentage of the total area extrapolated is more than 20% will be flagged. Any 
AUC(0-) value excluded from summary statistics will be noted in the footnote of the 
summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370359
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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
o
Individual concentrations will be plotted utilizing actual sampling times.
o
The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles
o
The average concentration profiles will be graphed using scheduled (nominal) 
sampling times.
o
The average concentration profiles will be graphed using arithmetic average 
concentrations.
o
The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will 
be used to calculate average concentrations.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370359
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o
Concentrations at a sampling time exceeding the sampling time window specified 
in the protocol, or ± 10%, will be excluded from the average concentration 
profiles.
o
Concentrations excluded from the mean calculation will be documented in the 
final study report.
o
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 ± X%. An average 
concentration estimated with less than 2/3 but more than 3 data points may be 
displayed on the mean concentration plot if determined to be appropriate and will 
be documented within the final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed
values and exclude that value from the dataset.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370359
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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 parameters will be evaluated to determine the impact of topiramate co-administration on the 
PK of a single dose of lasmiditan and its metabolites.  Log-transformed Cmax, AUC(0-), and
AUC(0-tlast) parameters will be evaluated in a linear mixed-effects model with fixed effects for 
treatment and a random effect for subject.  The treatment differences will be back-transformed to 
present the ratios of geometric means and the corresponding 90% confidence interval (CI).The 
comparison of interest is:
Lasmiditan co-administered with topiramate (Day 14; test treatment) versus Lasmiditan alone 
(Day 1; reference treatment)
An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
    class trtmnt subject;
    model l_pk = trtmnt / alpha=0.1;
    random subject;
    lsmeans trtmnt / pdiff;
run;
where l_pk is the log-transformed (base e) PK parameter.
A similar analysis will be performed to determine the impact of co-administration of a single 
dose of lasmiditan on the steady-state PK of topiramate.  This analysis shall evaluate the log-
transformed Cmax and AUCτ using a similar model to the one described above.  The comparison 
of interest will be:
Topiramate co-administered with lasmiditan (Day 14; test treatment) versus Topiramate alone  
(Day 13; reference treatment)   


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370359
Sponsor Reference H8H-MC-LAHT
The tmax will be analyzed using the Wilcoxon signed rank test.  Estimates of the median 
difference based on the observed medians, 90% CIs and p-values from the Wilcoxon test will be 
calculated.
Additional analyses may be performed, as warranted.
9.4
Safety and Tolerability Assessments
9.4.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose. 
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.
9.4.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017
Enhanced Dictionary B2 Format). Concomitant medication will be listed.
9.4.3 Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. Urinalysis data will be listed. Additionally clinical chemistry, hematology and urinalysis 
data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.4.4 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 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370359
Sponsor Reference H8H-MC-LAHT
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, if available.
All hepatic chemistry, hematology, coagulation, and serology data will be summarized by
parameter and treatment, and listed. Values outside the reference ranges will be flagged on the 
individual subject data listings.
9.4.5 Vital signs
Where supine blood pressure and pulse rate are measured in triplicate, the mean value will be
calculated and used in all subsequent calculations. When triplicate blood pressure or pulse rate
measurements precede a standing measurement, the last supine blood pressure or pulse rate
measurement will be used for orthostatic calculations. Orthostatic will be calculated as the
standing value, minus the last supine value taken prior to the standing value.
Vital signs data will be summarized together with changes from baseline, where baseline is 
defined as the mean of the triplicate measurement on Day 1 predose for supine vital signs, and 
the last measurement on Day 1 predose for standing and orthostatic vital signs. Figures of mean 
vital signs and mean changes from baseline profiles will be presented by period over time. 
Furthermore, values for individual subjects will be listed.
9.4.6 Electrocardiogram (ECG)
For each subject, ECGs will be performed for safety purposes only, and will not be reported.
9.4.7 Columbia Suicide Severity Rating Scale (C-SSRS)
Data from the C-SSRS and self-harm questionnaire will be listed for individual subjects.
9.4.8 Neurological Examination
Data from the neurological examination questionnaire will be summarized in frequency tables 
and listed for individual subjects.
9.4.9 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.10
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370359
Sponsor Reference H8H-MC-LAHT
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious AE’s occurred for this study.”


Leo Document ID = 88462d58-9184-419b-9f38-0b09141455ae
Approver: 
Approval Date & Time: 31-Oct-2017 11:31:54 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 31-Oct-2017 13:07:43 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 01-Nov-2017 13:10:28 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 01-Nov-2017 16:46:40 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD