Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 70
Healthy volunteers: yes

Brief summary:
The purpose of this study is to look at how much lasmiditan, study drug, gets into the blood stream and how long it takes the body to get rid of it.

When drugs are taken together, one or all of the drugs used in combination may be affected. This study will also evaluate the concentrations in the blood of a probe drug cocktail taken alone and in combination with lasmiditan. Information about any side effects that may occur will also be collected.

The study has two parts. Participants will only enroll in one part. This study will last about 25 days for group 1 and 22 days for group 2, not including screening. Screening is required within 28 days prior to the start of the study.

This study is for research purposes only and is not intended to treat any medical condition.

Detailed description:

Arms:
arm 1: Probe Drug Cocktail administered orally on Day -3. arm 2: 200 mg lasmiditan administered alone, orally, on Days 1-6 and concurrently with probe drug cocktail on Day 7. arm 3: Placebo administered alone, orally, on Days 1-6 and concurrently with probe drug cocktail on Day 7. arm 4: 400 mg lasmiditan administered orally for 7 days. arm 5: Placebo administered orally for 7 days.

Interventions: intervention 1: Probe Drug Cocktail intervention 2: Lasmiditan intervention 3: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally

Protocol document:
Prot_000.pdf: 
Protocol Protocol H8H-MC-LAHE(b) 
Multiple-Ascending Dose, Safety, Tolerability, 
Pharmacokinetic, and Drug-Drug Interaction Study of 
Lasmiditan 
 
NCT03252015 
 
Approval Date: 31-Aug-2017 


H8H-MC-LAHE(b) Clinical Pharmacology Protocol 
Page 1 
LY573144 
 
Protocol H8H-MC-LAHE(b) 
Multiple-Ascending Dose, Safety, Tolerability, 
Pharmacokinetic, and Drug-Drug Interaction Study of 
Lasmiditan 
 
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: 29 June 
2017. 
Amendment (a) Electronically Signed and Approved by Lilly: 25 July 2017 
Approval Date: 31-Aug-2017 GMT
Amendment(b) Electronically Signed and Approved by Lilly 
on approval date provided below. 


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LY573144
Table of Contents
Multiple-Ascending Dose, Safety, Tolerability, 
Pharmacokinetic, and Drug-Drug Interaction Studyof 
Lasmiditan
Section
Page
Protocol H8H-MC-LAHE(b) Multiple-Ascending Dose, Safety, 
Tolerability, Pharmacokinetic, and Drug-Drug Interaction Study of 
Lasmiditan..........................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities.........................................................................................................9
3.
Introduction......................................................................................................................19
3.1. Study Rationale............................................................................................................19
3.2. Background..................................................................................................................19
3.3. Benefit/Risk Assessment..............................................................................................21
4.
Objectives and Endpoints..................................................................................................22
5.
Study Design.....................................................................................................................23
5.1. Overall Design.............................................................................................................23
5.1.1. 
Exploratory Assessments.....................................................................................24
5.2. Number of Participants.................................................................................................24
5.3. End of Study Definition...............................................................................................24
5.4. Scientific Rationale for Study Design...........................................................................24
5.5. Justification for Dose...................................................................................................25
5.5.1.
Lasmiditan...........................................................................................................25
5.5.2.
Probe Drug Cocktail.............................................................................................25
6.
Study Population...............................................................................................................26
6.1. Inclusion Criteria..........................................................................................................26
6.2. Exclusion Criteria........................................................................................................27
6.3. Lifestyle and/or Dietary Requirements.........................................................................29
6.3.1.
Meals and Dietary Restrictions.............................................................................29
6.3.2.
Caffeine, Alcohol, and Tobacco...........................................................................29
6.3.3.
Activity................................................................................................................29
6.4. Screen Failures.............................................................................................................29
7.
Treatment..........................................................................................................................30
7.1. Treatment Administered...............................................................................................30
7.1.1.
Packaging and Labeling.......................................................................................30


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7.2. Method of Treatment Assignment................................................................................31
7.2.1.
Selection and Timing of Doses.............................................................................31
7.3. Blinding.......................................................................................................................31
7.4. Dose Modification........................................................................................................31
7.4.1.
Dose Decision......................................................................................................31
7.5. Preparation/Handling/Storage/Accountability...............................................................32
7.6. Treatment Compliance.................................................................................................33
7.7. Concomitant Therapy...................................................................................................33
7.8. Treatment after the End of the Study............................................................................33
8.
Discontinuation Criteria....................................................................................................34
8.1. Discontinuation from Study Treatment.........................................................................34
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................34
8.2. Discontinuation from the Study....................................................................................34
8.3. Subjects Lost to Follow-up...........................................................................................35
9.
Study Assessments and Procedures...................................................................................36
9.1. Efficacy Assessments...................................................................................................36
9.2. Adverse Events............................................................................................................36
9.2.1.
Serious Adverse Events........................................................................................37
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................37
9.2.2.
Complaint Handling.............................................................................................38
9.3. Treatment of Overdose.................................................................................................38
9.4. Safety...........................................................................................................................38
9.4.1.
Laboratory Tests..................................................................................................38
9.4.2.
Vital Signs...........................................................................................................38
9.4.3.
Electrocardiograms..............................................................................................38
9.4.4.
Colombia-Suicide Severity Rating Scale..............................................................39
9.4.5.
Safety Monitoring................................................................................................40
9.4.5.1.
Hepatic Safety................................................................................................40
9.5. Pharmacokinetics.........................................................................................................40
9.5.1.
Lasmiditan...........................................................................................................40
9.5.2. 
Probe Drug Cocktail.............................................................................................41
9.5.3.
Bioanalysis...........................................................................................................41
9.6. Pharmacodynamics......................................................................................................41
9.7. Exploratory Assessments..............................................................................................41
9.7.1.
Bioanalysis...........................................................................................................42
9.8. Genetics.......................................................................................................................42
9.9. Biomarkers...................................................................................................................42
9.10. Health Economics........................................................................................................43


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LY573144
10. Statistical Considerations and Data Analysis.....................................................................44
10.1. Sample Size Determination..........................................................................................44
10.1.1. Cohort 1...............................................................................................................44
10.1.1.1. Caffeine..........................................................................................................44
10.1.1.2. Midazolam.....................................................................................................44
10.1.1.3. Tolbutamide...................................................................................................44
10.1.1.4. Benzodiazepine Withdrawal Symptom Questionnaire.....................................44
10.1.2. Cohort 2...............................................................................................................45
10.2. Populations for Analyses..............................................................................................45
10.2.1. Study Participant Disposition...............................................................................45
10.2.2. Study Participant Characteristics..........................................................................45
10.3. Statistical Analyses......................................................................................................45
10.3.1. Safety Analyses....................................................................................................45
10.3.1.1. Clinical Evaluation of Safety..........................................................................45
10.3.1.2. Statistical Evaluation of Safety.......................................................................46
10.3.2. Pharmacokinetic Analyses....................................................................................46
10.3.2.1. Pharmacokinetic Parameter Estimation...........................................................46
10.3.2.2. Pharmacokinetic Statistical Inference.............................................................46
10.3.3. Pharmacodynamic Evaluations.............................................................................47
10.3.3.1. Pharmacodynamic Parameter Estimation........................................................47
10.3.3.2. Pharmacodynamic Statistical Inference...........................................................47
10.3.4. Exploratory Assessment Evaluations....................................................................47
10.3.4.1. Exploratory Parameter Estimation..................................................................47
10.3.4.2. Exploratory Parameter Statistical Inference....................................................47
10.3.5. Data Review During the Study.............................................................................47
10.4. Interim Analyses..........................................................................................................48
11. References........................................................................................................................49


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List of Tables
Table
Page
TableLAHE.1.
Objectives and Endpoints.......................................................................22


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions................................................................50
Appendix 2.
Clinical Laboratory Tests........................................................................54
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................55
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality............58
Appendix 5.
Blood Sampling Summary......................................................................59
Appendix 6.
Protocol Amendment H8H-MC-LAHE(b) Summary: Multiple-
Ascending Dose, Safety, Tolerability, Pharmacokinetic, and Drug-
Drug Interaction Study of Lasmiditan.....................................................60


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1.Protocol Synopsis
Title of Study:  
Multiple-Ascending Dose, Safety, Tolerability, Pharmacokinetic, and Drug-Drug Interaction Study of Lasmiditan 
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
The primary objective of this study is to explore the 
safety and tolerability of multipledoses of 200mg and 
400mg lasmiditan in healthy subjects.
Incidence of serious adverse events (SAEs) and 
treatment-emergent adverse events (TEAEs).
Secondary
To evaluate the plasma pharmacokinetics
(PK) of multiple doses of lasmiditan and its 
major metabolites.
To evaluate the effect of multiple doses of 
lasmiditan on CYP1A2, CYP2C9, and 
CYP3A activity.  
To evaluate any potential withdrawal 
symptoms following once-daily dosing of 
lasmiditan.
Maximum observed drug concentration (Cmax),time of 
maximum observed drug concentration (tmax), area 
under the concentration versus time curve (AUC) over 
one dosing interval(AUC
).
Cmax, T
max, AUCfrom time zero to infinity(0-∞), and 
AUC from time zero to last observable concentration
AUC(0-t
last)of probe drugs.
Responses to the benzodiazepine withdrawal symptom 
questionnaireand physician withdrawal checklist.
Summary of Study Design:  
This is a Phase 1, randomized, subjectandinvestigator-blinded, placebo-controlled, multiple-ascending dose study, 
conducted in 2 cohorts of healthy subjects.  The study will evaluate the safety, tolerability and PK of lasmiditan 
following once-daily dosing of 200 and 400 mg.  The potential effects of lasmiditan upon cytochrome P450 (CYP) 
induction will be evaluated through the PK of components of a coadministeredcocktail of CYP substrate drugs
(Cohort1) and measurement ofCYP3A-mediated cortisol metabolism (Cohorts1 and 2).  
Treatment Arms and Planned Durationfor an Individual Subject:  
All subjects will participate in a screening visit up to 28 days prior to study drug dosing.
Subjects will participate in 1 dosing period.  Subjects in Cohort1willbe admitted to the clinical research unit 
(CRU)on Day-4.  Each subject will receivea single dose of probe drug cocktail on Day-3 and Day7 relative to the 
first dose of lasmiditan.  Subjects will receive a once-daily dose of 200mg lasmiditan or placebo on Days1 to 7of 
the study.  Subjects will be dischargedfrom the CRUon Day9of the dosing period, based on investigator 
discretion.
Subjects in Cohort2 will be admitted to the CRU on Day-1.  Subjects will receive a once-daily dose of 400mg 
lasmiditan or placebo on Days1 to 7of the study.  Subjects will be discharged from theCRU on Day9 of the dosing 
period, based on investigator discretion.


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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LY573144
All subjects will attend a follow-up visit and be discharged from the study approximately14days post their final 
dose of lasmiditan.
The planned studyduration for each subject will beup to 55days in Cohort1, and 52days in Cohort2, including 
screening and follow-up visits.  
Number of Subjects:  
Up to 40subjects may be enrolled in Cohort1in order that 30complete the study.  Up to 30subjects may be 
enrolled in Cohort2 in order that 24complete the study.  Up to 70 subjects may be enrolled in total.
Statistical analysis:
Safety parameters that will be assessed include safety lab parameters, vital signs, Colombia-Suicide Severity Rating 
Scale(C-SSRS) scores and electrocardiogram (ECG) parameters.  The parameters will be listed, and summarized 
using standard descriptive statistics.  
Pharmacokinetic parameter estimates for lasmiditan and its metabolites and the probe drugs will be calculated by 
standard noncompartmental methods of analysis.  Trough concentrations of lasmiditan and its metaboliteswill be 
evaluated graphically and/or descriptively for achievement of steady-state.  Pharmacokinetic parameter estimates for 
each probe drug will be evaluated to delineate the effects of drug interaction in Cohort1.  Probe drugs administered 
in the absence of lasmiditan will represent reference treatments and will be analyzed separately.  Probe drugs 
administered with lasmiditan will represent the test treatments and will be analyzed separately.  Log-transformed 
Cmax, and AUC(0-∞) estimates of each probe drugwill be evaluated in a linear mixed-effects analysis of variance 
model with a fixed effect for treatment and a random effect for subject.  The treatment differences will be 
back-transformed to present ratios of geometric least squares means and the corresponding 90% confidence intervals 
(CIs).  
The tmaxof each probe drug will be analyzed using a 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. 


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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2.Scheduleof Activities


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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Study Schedule Protocol H8H-MC-LAHE Cohort 1
Screening
Days
FU/ED
Comments
Procedure
Days 
-32
to -4
-4 
-3 
-2 
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days 
post final dose
Informed 
Consent
X
Subject 
Admission to 
CRU
X
Subject 
Discharge from 
CRU
X
Randomization
X
Lasmiditan or 
Placebo 
Administration
X 
X 
X
Probe Drugs 
Administration
X
X
Medical History
X 
X
AEs and 
Medication 
Review
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
AE and medication review 
will be ongoing from 
Day-4
Height & 
Weight
X 
X
Height recorded only at 
Screening


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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LY573144
Screening
Days
FU/ED
Comments
Procedure
Days 
-32
to -4
-4 
-3 
-2 
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days 
post final dose
Orthostatic Vital 
Signs
X 
X
Predose, 
0.5, 1, 
2h
Day2 
Predose
Predose
, 0.5, 1,
2h
Last triplicate vital sign can 
be used as the supine vital 
sign for calculation of 
orthostatic changes.  
Timepoints may be added 
for each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.  
Vital Signs
(supine)
X 
X
Predose 
2, 4h
Predose, 
0.5, 1, 2, 
2.5, 3, 4, 
6, 8, 12h 
Day2 
predose 
Predose
, 0.5 1, 
2, 2.5, 
3, 4, 6, 
8, 12h
24h
X
Timepoints may be added 
for each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.  All vitals 
should be taken in triplicate 
apart from follow-up and 
screening visitswhere a 
single measurement will be 
taken.   
Screening 
Laboratory 
Tests
X
Clinical Lab 
Tests
X
X
Day2, 
Day6
X
X
See Appendix 2for details.  
HIV/Hepatitis 
Tests
X


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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Screening
Days
FU/ED
Comments
Procedure
Days 
-32
to -4
-4 
-3 
-2 
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days 
post final dose
Urine Drug 
Screen and 
Ethanol Test
X 
X
FSH Test
X
Females only to confirm 
menopausal status.
Pregnancy Test
X 
X
X
Serum pregnancy test will be 
performed at all timepoints. 
Females of childbearing 
potential only. 
12-lead Safety 
ECG
X 
X
X
Predose, 
1, 2, 4h 
Day2 
Predose 
Predose
,1, 2, 
4h 
24
h
Single ECG readings will be 
taken.   Timepoints relative 
to lasmiditan dosing on 
Days1 and 7. 
Physical Exam
X 
X
X
Day2 
Day6
Predose
X
X
After screening, medical 
assessment only performed 
to include targeted 
examination, as appropriate.
Plasma PK 
Samples 
(lasmiditan)
0.5, 1.0, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 
12h
Day 
2(24h), 
Predose 
(Days 
3-5)
Predose
, 0.5, 
1.0, 1.5, 
2, 2.5, 
3, 4, 6, 
8, 12 h
24 
h
Timepoints relative to dosing 
on Days1 and 7. Predose 
samples to be taken on Days 
3, 4 and 5 for assessment of 
steady-state. 


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Screening
Days
FU/ED
Comments
Procedure
Days 
-32 
to -4
-4 
-3 
-2 
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days 
post final dose
Plasma PK 
Samples
(probe)
Predose
0.5, 
1.0, 
1.5, 2, 
2.5, 3, 
4, 6, 8, 
12h
24h
48 h
Predose
, 0.5, 
1.0, 1.5, 
2, 2.5, 
3, 4, 6, 
8, 12 h
24 
h
48 
h
Timepoints relative to dosing 
on Days-3 and 7.
Exploratory 
PlasmaSample
(Cortisol)
Predose
Predose
Urine Sample
for 2 
Exploratory 
Analyses
(lasmiditan
metabolitesand
6-βOHC)
X
X
0 to 24h urine collection on 
Days1 and 7 (timepoints 
relative tolasmiditan dosing 
on Day1 and7)
Pharmaco-
genetics sample
X
The 
Benzodiazepine 
Withdrawal 
Symptom 
Questionnaire
X 
X 
X 
X 
X 
X
Questionnaire to be 
administered daily via phone 
by a member of CRU staff 
following discharge from the 
CRU on Day9until the 
follow-up visit.
Physician 
Withdrawal 
Checklist
Predose
X
C-SSRS and 
Self-Harm 
X 
X
X
“Baseline”questionnaire to 
be used at screening, all 


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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LY573144
Supplement
other timepoints use “Since 
Last Visit”questionnaire
Abbreviations:  6 βOHC = 6-beta hydroxycortisol;AE = Adverse event; CRU = Clinical Research Unit;C-SSRS =Columbia-Suicide Severity Rating Scale; 
ECG= electrocardiogram;ED = early discharge;FSH = follicle stimulating hormone, FU= follow-up visit;h = hours; HIV = human immunodeficiency virus; 
PK=pharmacokinetic.
Note:  Ifmultiple procedures take place at the same timepoint, the following order of the procedure should be:  ECG,supine vitalsigns, orthostatic vital signs,
and venipuncture.  Where venipuncture and other procedures take place at the same timepoint, the following time windows for obtaining blood samples 
should be maintained:  0 to 2.5hours postdose:  ±5 minutes; 3 to 6 hours postdose:  ±10 minutes; 7 to 12 hours postdose:  ±20 minutes; >12 hours postdose:  
±30 minutes.


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Study Schedule Protocol H8H-MC-LAHE Cohort 2
Screening
Days
FU/ED
Comments
Procedure
Days 
-29
to -1
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days post 
final dose
Informed Consent
X
Subject Admission 
to CRU
X
Subject Discharge
from CRU
X
Randomization
X
Lasmiditan or 
Placebo 
Administration
X
X
X
Medical History
X 
X
AEs and 
Medication review
X 
X
X
X 
X 
X 
X 
X
AE and medication review will 
be ongoing from Day-1.
Height & weight
X 
X
Height recorded only at 
Screening.
Vital Signs 
(supine)
X
Predose, 0.5, 
1, 2, 2.5, 3, 
4, 6, 8, 12h
Day2 Predose
Predose, 
0.5, 1, 2, 
2.5, 3, 4, 6, 
8, 12h
24h
X
Timepoints may be added for 
each study period, if warranted 
and agreed upon between Lilly 
and the investigator.  All vitals 
should be in triplicate, apart 
from screening and follow-up 
visitswhere a single 
measurement will be taken. 


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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Screening
Days
FU/ED
Comments
Procedure
Days 
-29
to -1
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days post 
final dose
Orthostatic Vital 
Signs
X 
X
Predose, 
0.5, 1, 2h
Day2 
Predose 
Predose, 
0.5, 1,
2h
Last triplicate vital sign can be 
used as the supine vital sign for 
calculation of orthostatic 
changes.  Timepoints may be 
added for each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.  
Screening 
Laboratory Tests
X
Clinical Lab Tests
X
Day2, Day6
X
X
HIV/Hepatitis 
Tests
X
Urine Drug Screen 
and Ethanol Test
X 
X
FSH Test
X
Females only to confirm 
menopausal status.
Pregnancy Test 
X 
X
X
Serum pregnancy test will be 
performed at all timepoints.
Females of childbearing 
potential only.  
12-lead Safety 
ECG
X 
X
Predose, 1, 
2, 4h 
Day2 
Predose
Predose, 1, 
2, 4h 
24h
Single ECG readings will be 
taken. Timepoints relative to 
lasmiditan dosing on Days1 and 
7. 
Physical Exam
X 
X
X
X
X
After screening, medical 
assessment only performed to 
include targeted examination, as 
appropriate.


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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Abbreviations:  6-βOHC =6-betahydroxycortisol, AE= Adverse event; CRU = Clinical Research Unit; C-SSRS =Columbia-Suicide Severity Rating Scale; 
ECG= electrocardiogram;ED = early discharge;FSH = follicle stimulating hormone;FU = follow-upvisit;h = hours; HIV = human immunodeficiency 
virus; PK= pharmacokinetic.
Screening
Days
FU/ED
Comments
Procedure
Days 
-29 
to -1
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days post 
final dose
Plasma PK 
Samples 
(lasmiditan)
0.5, 1.0, 1.5, 
2, 2.5, 3, 4, 
6, 8, 12 h
Day2 (24h), 
Predose 
(Days3 to 5)
Predose, 
0.5, 1.0, 
1.5, 2, 2.5, 
3, 4, 6, 8, 
12 h
24 h
Timepoints relative to dosing on 
Days1and 7.  Predose samples 
to be taken on Days 3, 4 and 5 
for assessment of steady-state.
Exploratory 
PlasmaSample
(Cortisol)
Predose
Predose
UrineSamplefor 
2 Exploratory 
Analyses
(lasmiditan
metabolitesand 
6-βOHC)
X
X
0 to 24h urine collection on 
Days1 and 7 (timepoints 
relative tolasmiditan dosing on 
Day1 and7)
Pharmacogenetics 
Sample
X
The 
Benzodiazepine 
Withdrawal 
Symptom 
Questionnaire
X
X 
X 
X 
X 
X
Questionnaire to be 
administered daily via phone by 
a member of CRUstaff 
following discharge from the 
CRU on Day9until the follow-
up visit.
Physician 
Withdrawal 
Checklist
Predose
X
C-SSRS and Self-
Harm 
Supplement
X 
X
X
“Baseline”questionnaire to be 
used at Screening , all other 
timepoints use “Since Last 
Visit”questionnaire


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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Note:  If multiple procedures take place at the same timepoint, the following order of the procedure should be:  ECG, supine vital signs, orthostatic vital signs,
and venipuncture.  Where venipuncture and other procedures take place at the same timepoint, the following time windows for obtaining blood samples 
should be maintained:  0 to 2.5hours postdose:  ±5 minutes; 3 to 6 hours postdose:  ±10 minutes; 7 to 12 hours postdose:  ±20 minutes; >12 hours postdose:  
±30 minutes.


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3.Introduction
3.1. Study Rationale
Lasmiditan is a small molecule5-HT1F receptor agonistbeing developed for the acute treatment 
of migraineat doses up to 200mg.
Triptans, which are 5-HT1B/1D receptor agonists, are well established as an acute therapy for 
migraine, though they are not effective in all patients.  Triptans were developed as cerebral 
vasoconstrictors, mediated via their affinity for 5-HT1B receptors located on vascular smooth 
muscle.  Inherent in this mechanism of action is a liability for coronary vasoconstriction, and 
therefore, triptans are contraindicated in patients with cardiovascular disease.  
Unlike triptans, lasmiditan is a highly selective and potent agonist atthe 5-HT1F receptor with 
>470-fold higher affinity for the 5-HT1F receptor than for 5-HT1B/1D receptors.  
Lasmiditan is under development as a neurally acting treatment for migraine without the 
vasoconstrictor liability of triptans.  Lasmiditan has beenshown to be well-tolerated at single 
doses up to 400mgin healthy subjects and migrainepatients;however,safety, tolerability,and 
pharmacokinetics(PK) have not been assessed after multiple dosingat any dose level.  
This study aims to evaluate the safety, tolerability, PK,and potential withdrawal symptoms 
followingonce-dailydosing of lasmiditan.  Preclinical studies have indicated that lasmiditan and 
some of its metabolites may induce, but not inhibit,the expression and activity of cytochrome 
P450 (CYP) 1A2, CYP2C9,and CYP3A enzymes.  Cohort1of the study aims to examine the 
effect of multiple doses of lasmiditan upon CYP1A2, CYP2C9,and CYP3A activity via 
concomitant administration and PK monitoring of a probe drug cocktailincluding caffeine 
(CYP1A2 substrate), tolbutamide (CYP2C9 substrate) and midazolam (CYP3A4/5 substrate).  
Cytochrome P450 3A induction will also be assessed inboth cohorts by evaluation of
concentrations of 6-beta hydroxycortisol (6-βOHC) excreted in urine relative to plasma 
concentrations of cortisol. 
3.2. Background
Two Phase 2 studies have been completed with lasmiditan in the acute treatment of migraine, 
usingdoses of up to 45 mg over 20 minutes of theintravenous (IV)andup to 400mg of the oral
tablet formulation.  One Phase 3 randomized, double-blind, placebo-controlled trial has been 
completed in the United States (COL MIG-301 [SAMURAI]), where 1856subjects were 
randomizedto 100 mg lasmiditan (630 subjects), 200 mglasmiditan(609 subjects),or placebo 
(617 subjects), respectively.  In the SAMURAI study, both 100 mg and 200 mg doses of orally 
administered lasmiditan achieved superior 2-hour headache pain free rate and the most relief of 
bothersome migraine symptoms (nausea, phonophobia, and photophobia) compared to placebo.  
Across the completed Phase 1, 2, and 3clinical studies, doses of 0.1mg to 400mg of lasmiditan 
were evaluated in healthy subjects or patients with migraine.  Lasmiditan has been administered 
to 230healthy subjects in 5Phase 1 studies:  as IV doses ranging from 0.1 to 180mg 
(H8H-BD-LACA; 40 subjects); as an oral or sublingual solution with doses ranging from 25 to 


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400mg and 1to32mg, respectively (COLMIG-102; 60 subjects); as an oral solution at a dose 
of 200mg oras oral tablets at doses of 50 or 200mg (COLMIG-103; 44 subjects); as oral 
tablets at a dose of 200mg (COLMIG-104; 30 subjects); and as oral tablets at doses of 100 or 
400mg (COL MIG-105; 56 subjects).  Two Phase 2 studies have been completed, evaluating IV
doses ranging from 2.5 to 45mg (COL MIG-201) and oral tablets ranging from 50 to 400mg 
(COL MIG-202).  In the Phase 3 SAMURAI (COL MIG-301) study, 1856 subjectsaged 18to 79 
years received at least 1 dose of lasmiditan or placebo, with 1239 subjectsreceiving oral tablets 
of 100 or 200mg lasmiditan.  
Compared with placebo, the most frequently reported treatment-emergent adverse events 
(TEAEs) after receiving lasmiditan included somnolence, fatigue, dizziness, paresthesia, and hot 
flush.  The majority of these TEAEs were mild or moderate in severity and none led to subject 
withdrawal.  One subject experienced aserious adverse event (SAE)of dizziness that was 
moderate in severity (lasmiditan 200 mg, COLMIG-202)
Oral doses of lasmiditan up to 400mg (COLMIG-103) did not demonstrateany clinically 
relevant changes in electrocardiograms (ECGs),including QT interval/corrected QT interval,
following administration to healthy subjects.  In the thorough QT study (COLMIG-105) in 
healthy subjects, no clinically significant changes in blood pressure, heart rate, or 12-lead ECG 
were observed at the 100 or 400mg dose levels.  Lasmiditan caused no significant QT 
prolongation at either dose.
In healthy subjects, peak plasma concentrations of lasmiditan were observed approximately 1 to 
2.5hours after a single oral doseranging from 25 to 400 mg, and the geometric mean terminal 
half-life was approximately 4 to 6hours.  The maximum observed drug concentration (Cmax)and 
area under the concentration versus time curve (AUC)valuesfollowing a 400mg oral dose 
(COLMIG-102) were comparable to that following a 180mg IV dose infused over 60 minutes
(H8H-BD-LACA).  Lasmiditan exhibited dose-linear PK; lowto moderate inter-subject 
variability in exposure was observed across doses (%coefficient of variance)up to 61% and 
45% for Cmaxand AUC, respectively[COLMIG-102]).  Co-administration of lasmiditan with a 
high fat diet led to a delay in median time of C
max(tmax)value by approximately 1hour and a 
modest (~20%) increase in lasmiditan C
maxand AUC values, relative to that under fasted 
conditions.Pharmacokinetics of lasmiditan following repeated daily administration hasnot been 
previously evaluated.  However, accumulation of lasmiditan is not expected,based on the short 
terminal half-life observed following a single oral dose.
Human metabolism has been investigated using liquid chromatography-tandem mass 
spectrometry (LC-MS/MS)following dosing with lasmiditan, where up to 11 metabolites were 
detected in plasma and urine, including 3 major metabolites (M7, M8, and M18).  The relative 
proportions of metabolites to parent drugremained reasonably constant throughout the oral dose 
range studied and their PK were approximately linear.  The half-lifeof the metabolites ranged 
from ~4.5 hours to ~12 hours.


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3.3. Benefit/Risk Assessment
The primary objective for this study is to explore the safetyand tolerability of lasmiditan after 
multipleoral dosesat potential therapeutic dose levels.  Current Phase 3 studies have allowed 
subjectsto self-administer a repeat dose of 200mg lasmiditan at least 2 hours after the first dose 
and therefore the maximum daily dose to be evaluated in this study is 400mg.  There is no 
anticipated therapeutic benefit for the subjectsin this study.
In healthy male and female subjects single oral doses of lasmiditan up to 400 mg were not 
associated with drug related SAEs orstudywithdrawals due to adverse events (AEs).  Multiple
once-dailydoses of 200mg and 400mghave not been administered previously in humans.  The 
incidence of central nervous systemAEs has been correlated with increases in dose; however the 
AEs observed havebeen transient.  The probe drugs selected for use in this study are commonly 
used in studies of drug-drug interactions, and the planned doses are expected to be well-tolerated.  
Data suggests that lasmiditan is an inducer of CYPenzymes;therefore probe drug exposures are 
expected to decrease following exposure to lasmiditan.  Dosing in this study will be conducted in 
an inpatient setting, and subjects will be monitored in house for at least 48hours after the final 
dose of lasmiditanand/or probe drug cocktail.  
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of lasmiditanare to be found in the 
Investigator’s Brochure (IB).  More information about the risks, SAEs and reasonable anticipated 
AEs of the probe drug cocktail are to be found in the respective package inserts and reference 
labels. 


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4.Objectivesand Endpoints
TableLAHE.1shows the objectives and endpoints of the study.
TableLAHE.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective of this study is to explore the 
safety and tolerability of multiple doses of 200mg and 
400mg lasmiditan in healthy subjects.
Incidence of serious adverse events (SAEs) and 
treatment-emergent adverse events(TEAEs).
Secondary
Toevaluate the plasma PK of multiple doses 
of lasmiditan and its major metabolites.
To evaluate the effect of multiple doses of 
lasmiditan on CYP1A2, CYP2C9, and 
CYP3A activity.  
To evaluate any potential withdrawal 
symptoms following once-daily dosing of 
lasmiditan.
Cmax, t
max, AUC over one dosing interval(AUC
).
Cmax, T
max, AUC from time zero toinfinity
(AUC[0-∞]), and AUC from time zero to last 
observable concentration (AUC[0-t
last])of probe drugs.
Responses to the benzodiazepine withdrawal symptom 
questionnaireand physician withdrawal checklist.
Exploratory
To evaluate concentrations of 6-beta 
hydroxycortisol (6-βOHC) excreted in urine 
relative to plasma concentrationsof cortisol as 
an indicator of CYP3A induction before and 
after treatment with200 and 400mg 
lasmiditan for 7 days.
Toprofile urine for lasmiditan metabolites 
after multiple doses.
Ratio of urinary 6-βOHC and plasma cortisol 
concentrations.




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5.1.1. Exploratory Assessments
The effect of lasmiditan upon CYP3A-mediated cortisol metabolism will be assessed in 
Cohorts1 and2.  To this end, plasma levels of cortisol and urinary concentrations of 6-βOHC
will be determined on Day1 and Day7.  Urine samples will also be collected for future 
exploratory analysis, and may be used for lasmiditan metabolite identification and analysis.
5.2. Number of Participants
Up to 40and 30subjects may be enrolled to Cohort1and Cohort2respectively, so that 30 and 
24 subjectscomplete the studyin each cohort, respectively.  
5.3. End of Study Definition
End of the studyis the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities(Section2) for the last subject.
5.4. Scientific Rationale for Study Design
A subject and investigator-blinded, randomized and placebo-controlled designis being used for 
this study to minimize the effect of bias on the safety and tolerability objectives.  Conducting the 
study in healthy subjects mitigates the potential confounding effects of the disease state and 
concomitant medications.  The benzodiazepine withdrawal symptom questionnaire (Tyrer et al.
1990) and physician withdrawal checklist (Rickels et al. 2008) will be completed to assess any 
potential withdrawal symptoms following repeated dosing of lasmiditan.  Subjects in Cohort1 
will receive 2 single doses of midazolam, a benzodiazepine, during the study. The doses of 
midazolam will however be low and separated by a period of 9 days;therefore the impact on 
results of the benzodiazepine withdrawal symptom questionnaire is likely to be negligible. 
Regulatory agencies recommend conducting clinical drug interaction studies using a drug 
cocktail approach where interactions with multiple CYPs are investigated (European Medicines 
Agency [EMA] Guideline 2012; Federal Drug Administration [FDA]2012).  The drugs should 
be selective for specific CYP enzyme isotypes, should not interact with each other, and should be 
safe when administered.  Many such drug cocktails exist, with differing CYP isotype 
specificities:  one such cocktail includes midazolam, caffeine, tolbutamide, chlorzoxazone, and
debrisoquine, which has been administeredin previous studies(Sharma etal. 2004).  The 
cocktail was modifiedfor this protocolto consist of the required probes for CYP3A 
(midazolam),CYP1A2 (caffeine),and CYP2C9 (tolbutamide) to specifically target the CYP 
isoforms of interest.  The drug cocktail will be administeredon Day -3before the initiation of 
lasmiditanon Day 1, and on Day 7concurrently with dosing of lasmiditan, when steady-state 
concentrations of lasmiditan should be achieved.  Probe drug administration will be open-label, 
as the PK endpoints of the study are objective. 


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5.5. Justification for Dose
5.5.1. Lasmiditan
To date, single dosesof 400mg lasmiditan have been well-tolerated in healthy volunteers and
patients.  Single and doubledoses, separated by 2 hours, of 100mg and 200mg lasmiditan were
well-tolerated and effective in patients enrolled in the Phase 3 SAMURAI study.  In preclinical 
toxicology studies absorption was similar between the first and final doses in a variety of 
preclinical species.  A dose dependent and linear increase in exposure of lasmiditan was
observed inanimal and human studiesat dose levels similar to those planned in this study.  
Once-daily dosing up to 400mg for 7 days is expected to achieve steady state, and provide 
sufficient exposure to lasmiditan to evaluate potential CYP induction.  Dosing in Cohort2 of the 
study will only occurafter careful review of the safety data from subjectsin Cohort1 (including 
data from the follow-up visit).
5.5.2. Probe Drug Cocktail 
The doses used in the drugcocktail (100mg caffeine, 500mg tolbutamide and 2mg midazolam) 
are clinically relevant doses considered safe to administer and have been used concomitantly in 
previous drug cocktail clinical studies.  
The rationale for the drug-drug interaction arm of the study is that lasmiditan may induce the 
expression of CYP enzymes in humans.  It is therefore likely that if lasmiditan affects CYP 
expression the systemic exposure to the probe drug cocktail will be reduced due to increased 
drug clearance.  


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6.Study Population
Eligibilityof 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 28 days prior to Day-4 in Cohort1, and 28 days prior to Day-1in 
Cohort2.  Subjects who are not enrolled within 28 days of screening may be subjected to an 
additional medical assessment and/or clinical measurements to confirm theireligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1. Inclusion Criteria
Subjects areeligible for inclusion in the study only if they meet all of the following criteria at 
screening and admission to the study:
[1] are healthy males or females, as determined by medical history and physical 
examination  
[1a]  male subjectswill not be subject to any specific contraception requirements. 
[1b]  female subjects:
of childbearing potential, must test negative for pregnancy at screening, and 
agree to use a reliable method of birth control during the study and for 1 week
following the final dose of lasmiditan.  Reliable methods of contraception for 
female subjects of childbearing potential include the use of stable oral, 
implanted, or injected contraceptive hormones, bilateral tubal ligation, 
intrauterine device, or diaphragm with spermicide along with male partner’s 
use of male condom with spermicide.
of non-child-bearing potential, i.e.  postmenopausal or permanently sterile 
following hysterectomy, bilateral salpingectomy or confirmed tubal occlusion 
(not tubal ligation), as determined by medical history.  Postmenopausal is 
defined as spontaneous amenorrhea for at least 12 months, and a serum 
folliclestimulating hormone (FSH) level greater than 40mIU/mL, unless the 
subject is taking hormone replacement therapy.
[2] Subjects mustbe aged 18 to 65years, inclusiveat the time of screening. 
[3] have abody mass index (BMI) of 19to 35kg/m2, inclusiveat the time of 
screening.
[4] have clinical laboratory test results within normal reference range for the 
population or investigativesite, or results withinacceptable 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.


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[6] are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[7] have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site.  
6.2. Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8]are investigativesite personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological, or
legal guardian, child, or sibling, whether biological or legally adopted.
[9] are Lilly employees 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 participated, within the last 30 daysina clinical study involving an IP.  
[12] have previously completed or withdrawn from this study or any other study 
investigating lasmiditan, and have previously received lasmiditan.
[13] have known allergies to lasmiditan, midazolam, caffeine, tolbutamide, related 
compounds, orany components of the formulations used.
[14] have aclinically significantabnormality in the 12-lead ECG,  including 
corrected QT (QTc) interval with Fridericia’s correction(QTcF)>450msec 
for men or >470msec for women or any abnormality that in the opinion of the 
investigator increases the risk of participating in the study (not limited to 
significant bradycardia or heart block). 
[15] any history of prolonged QT interval, family history of QT interval 
prolongation or sudden death, or history of unexplained loss of consciousness.
[16] have significant history of or current cardiovascular disorders including any 
history of clinically significant arrhythmia, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, orelimination of drugs; 
of constituting a risk when taking the study drug, or of interfering with the 
interpretation of data.  Appendectomy, splenectomy, and cholecystectomy are 
considered as acceptable.
[17] In the opinion of the investigator, has history of syncope, presyncopy, vertigo, 
postural dizziness, or at risk for falls.


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[18] have current or history of orthostatic hypotension (>20mmHg drop in systolic 
blood pressure, or >10mmHg drop in diastolic blood pressure) with or without 
dizziness and/or syncope at screening or admission to the CRU upon repeat 
testing.
[19] history of, showevidence of, or are undergoing treatment forsignificant 
activeneuropsychiatric disease (for example, manic depressive illness, 
schizophrenia, depression), have a recent history of a suicide attempt (30 days 
within screening visit and any timebetween screening visit and baseline); or 
are clinically judged by the investigator to be at risk for suicide.
[20] show a history of CNS conditions such as strokes, transient ischemicattacks, 
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.
[21] history of hypoglycemia.
[22] known history of glucose-6-phosphate dehydrogenase deficiency.
[23] have anestimated glomerular filtrationrate(eGFR)of < 60 mL/min(as 
measured by the CKD-EPIequation).
[24] are taking a concomitant medication or a dietary substance that affects 
CYP1A2, CYP2C9,and/or CYP3A isotypeswithin 14 days of screening. 
[25] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[26] show evidence of hepatitis C and/or positive hepatitis C antibody.
[27] show evidence of hepatitis B and/or positive hepatitis B surface antigen.  
[28] are women with a positive pregnancy test or women who are lactating.
[29] intend to use over-the-counter or prescription medication within 14 days prior 
to dosing of lasmiditan.
[30] have donated a bloodor plasmavolume of more than 500 mL within 1month
prior to the screening visit.
[31] have an average weekly alcohol intake that exceeds 21 units per week (males) 
or 14 units per week(females),or are unwilling to stop alcohol consumption 
48 hours prior to admission and throughoutthe duration of the study(1 unit = 
12 oz.or 360 mL of beer; 5 oz.or 150 mL of wine; 1.5 oz.or 45 mL of 
distilled spirits).
[32] currently use, or have ahistory of drug or alcohol abusewithin the past 2 
years.
[33] have a clinically significant abnormality in the neurological examination.
[34] are current smokers.


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[35] drink more than 5caffeinated drinks/per day, and are unwilling /unable to
abstain from caffeineor xanthine containing productsfrom72hours prior to
admissionto the end of the study.
[36] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
6.3. Lifestyle and/or Dietary Requirements
Throughoutthe study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Mealsand Dietary Restrictions
Lasmiditan, placeboand probe drugswill be administered after an overnight fast of at least 
10hours.  Subjects will abstain from water 1hour before and after dosing (except for water 
given with the dose).  Subjects will remain fasting for 3hours postdose on Days1and 7 (and 
Day -3 in Cohort 1)at which time a meal will be served.  On Days 2to6in both cohorts, a light 
breakfast will be allowed 1 hourpostdose. 
6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine –Subjects will refrain from consuming xanthine-or caffeine-containing food and 
drinks from 72 hours prior to admission until the end of the study period.  
Alcohol –Subjects will not consume alcohol for 48 hours prior to admission and for the duration 
of the study. 
Tobacco –Subjects will be non-smokersand thuscannot smoke throughout the study.  
6.3.3. Activity
No strenuous exercise will be allowed for 48hours 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 
rescreened.  


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7.Treatment
7.1. Treatment Administered
Subjects in Cohort1willbe administered 200 mg lasmiditan (1 x 200 mg film-coated tablet)or 
placeboon Days 1 through 7, following an overnight fast.  Subjects in Cohort1will also receive 
a probe drug cocktail on Day -3 and Day 7of the treatment period.  The drug cocktail will 
consist of:
a 100 mg oral dose of caffeine (as caffeine base) in tablet form
a 500 mg oral dose of tolbutamide in tablet form
a 2mg dose of midazolam oral syrup.  
The study site will obtain the cocktail drugs.  Administration of each cocktail drug will be 
according to the respective instructions for use.  Cocktail drugs will be administered on Day-3 
with approximately 240mL of room-temperature water to the subject in a sittingposition.  On 
Day7, lasmiditan and probe drugs will be administered orally with 240mL of room-temperature 
water. On all other dosing days, lasmiditan will be administered orally with 240mL of 
room-temperaturewater.  Additional water may be given on an individual basis if needed and 
amount will be recorded.
Subjects in Cohort2will be administered 400 mg lasmiditan (as 2 x 200mg film-coated tablets)
or placeboon Days 1 through 7, following an overnight fast.  Tablets of lasmiditan or placebo 
will be administered orally with approximately 240 mL of room-temperature water.  Additional 
water may be given on an individual basis if needed and amount will be recorded.
All doses in both cohorts will be given in the morning of each day, whilst in a sitting position.  
Subjects will not be allowed to lie supine for approximately 2 hours after dosing, unless 
clinically indicated, or for study procedures.
The investigator or designee is responsible for:
explaining the correct use of the IP(s) and other study treatments to the site personnel
verifying that instructions are followed properly
maintaining accurate records of IPdispensing and collection
and returning all unused medication to Lilly or its designee at the end of the study. 
Note: In some cases, sites may destroy the material if, during the investigativesite 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 200mg of active ingredient and is provided as bulk supply in 
bottles.  Placebo tablets look identical but contain no active ingredient and will be provided in 
similar bulk bottles.


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The IPwill be labeled according to the country’s regulatoryrequirements.
7.2. Method of Treatment Assignment
Subjects will be randomizedto lasmiditan or placebo treatment using a computer generated 
allocation schedule.  
7.2.1. Selection and Timing of Doses
Subjects in Cohort1and 2 will receive oral doses of 200mgor 400mgof lasmiditan or placebo
respectively,once-daily for 7days.  Subjectsin Cohort1will receive single oral dosesof the 
probe drug cocktail on Day-3,and Day7of the studyperiodrelative to lasmiditan 
administration.  On Day7, probe drugs will be administered concurrently withlasmiditan.  The 
actual time of all dose administrations will berecorded in the subject’s clinical report form 
(CRF).
7.3. Blinding
The study will be subject-and investigator-blindfor lasmiditan.  The investigator, site staff 
(apart from unblindedpharmacy staff) and subjects will be blinded to the administration of 
lasmiditan or placebo in Cohorts1 and 2.  Administration of the probe drugs will be open-label, 
as the PK endpoints in the study are considered objective.  
Emergency codes will be available to the investigator.  A code, which reveals the treatment for a 
specific study subject, may be opened during the study only if the subject’s well-being requires 
knowledge of the subject’s treatment assignment.  
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist or 
clinical research physician for the study participant to continue in the study.  During the study, 
emergency unblinding should occur only byaccessing the study subject’s emergency code.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’streatment assignment is warranted for medical management of the event.  The 
subject’ssafety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted,it is the responsibility of theinvestigator 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 modificationfor individual subjectswill not be allowed during the study.  
7.4.1. Dose Decision
Safety and tolerability data collected fromCohort1of the study will be assessed prior to
lasmiditan administration in Cohort2.  No decision can occur without prior discussion and 
agreement between the investigator and the Lilly clinical pharmacologist/clinical research 
physicianor designee.


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Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator, and will be considered related to lasmiditan or the 
probe drug cocktailunless there is clear evidence that the event is not related.  Safety data from 
at least 18 subjects in Cohort1 will be required prior to the dose decisionfor Cohort 2.  After 
review of these data, an agreement on whether to dose Cohort2will be made by the investigator 
and sponsor.  If escalation to 400mg is not deemed appropriate for Cohort2 an intermediate 
dose of 300mg may be considered.  In the case of disagreement, the decision of the investigator 
will be followed, except in a situation where Lilly’s proposal is the more conservative action (for 
example, where the investigator wishes to escalate and the Lilly clinical pharmacologist/clinical 
research physician does not) in which case, the Lilly proposal will be followed.
If any of the following scenarios occurin Cohort1, dosing in Cohort2will be halted or delayed 
until thorough review by the investigator, sponsorrepresentative, and medical consultants as 
appropriate.  Pharmacokinetic data may also be requested and considered in dose decision:  
1)
a single subject experiences a SAE that is related to lasmiditan administration
2)
2 or more subjects show QTcF >500 msec or increases of QTcF values of >60 
msec above the QTcF baseline value, sustained for two consecutive timepoints.  
The QTcF baseline value is defined as the Day1 predose ECG of the 
corresponding period.  If a subject shows QTcF >500 msec or increases of QTcF 
values of >60 msec above the QTcF baseline value, two additional ECGs will be 
obtained within 10 minutes and the 3 ECGs will be averaged to see if the 
QTcF>500 or increases of QTcF values are >60 msec above the QTcF baseline 
value.
3)
if a suicide-related thought or behavior is identified at any time during the study 
or if during the study a subject givesthe following responses after lasmiditan 
exposure:  
a "yes" answer to Question 4 (Active Suicidal Ideation with Some Intent to 
Act, Without Specific Plan) on the "Suicidal Ideation" portion of the C-SSRS; 
a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the "Suicidal Ideation" portion of the C-SSRS 
a "yes" answer to any of the suicide-related behaviors (actual attempt, 
interrupted attempt, aborted attempt, preparatory act, or behavior) on the 
"Suicidal Behavior" portion of the C-SSRS.  
7.5. Preparation/Handling/Storage/Accountability
The investigator or designee must confirm all IPwas received in good condition, and any 
discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IPor study materials, and only authorized 
site staff may supply or administer IP.All IPshould be stored in anenvironmentally controlled 


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and monitored (manual or automated) area in accordance with thelabeled storage conditions 
with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, andfinal disposition records).
7.6. Treatment Compliance
The IPwill be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7. Concomitant Therapy
Concomitantmedications are to be avoided during the study unless required to treat an AE or for 
the treatment of an ongoing medical problem.
Up to 2 grams of acetaminophen may be allowedper 24hour periodat the investigator’s 
discretion.
If the need for any other concomitant medication arises, inclusion or continuation of the subject 
may be at the discretion of the investigator after consultation with a Lilly clinical 
pharmacologist, clinical research physician (CRP), or designee.  Any medication used during the 
course of the study must be documented.
7.8. Treatment after the End of the Study
This section is not applicable to this study.


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8.DiscontinuationCriteria
8.1. Discontinuation from Study Treatment
Subjects discontinuing from the IPprematurely for any reason must complete adverse event and 
follow-up procedures per Section2of this protocol.
Discontinuation of the investigational product for abnormal liver tests should be consideredby 
the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly designated medical monitor:
ALT (alanine aminotransferase ) AST (aspartate aminotransferase) >5X ULN (upper 
limit of normal)
ALT or AST >3X ULN sustained for more than 2 weeks 
ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or INR >1.5 orALT or 
AST >3X ULN 
the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%)
ALP (alkaline phosphatase) >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 subjectwho did not meet enrollment criteria and was 
inadvertently enrolled,thesubject must be discontinued from the study.
8.2. Discontinuationfrom the Study
Subjectswill be discontinued in the following circumstances:
Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study
Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)
Investigator Decision
o the investigator decides that the subject should be discontinuedfrom the study
Subject Decision
o the subject, ortheirlegal representative, requests to be withdrawn from the study.


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If a suicide-related thought or behavioris identified at any time during the study, or if 
during the study a subject gives:
o A“yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the “Suicidal Ideation” portion of the C-SRSS; or
o A “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent)  on the “Suicidal Ideation” portion of the C-SSRS
o A “yes” answer to any of the suicide-related behaviors(actual attempt, interrupted 
attempt, aborted attempt, preparatory act, or behavior) on the “Suicidal Behavior” 
portion of the C-SSRS.
Asubject showsQTcF >500 msec or increases of QTcF values of >60 msec above the 
QTcF baseline value, sustained across two consecutive timepoints.  The QTcF baseline 
value is defined as the Day1 predose ECG of the corresponding period.  If a subject 
shows QTcF >500 msec or increases ofQTcF values of >60 msec above the QTcF 
baseline value, two additional ECGs will be obtained within 10 minutes and the 3 ECGs 
will be averaged to see if the QTcF>500 or increases of QTcF values are >60 msec above 
the QTcF baseline value.
In addition, a subject will also be evaluated for discontinuation if they have self-injurious 
behavior that would be classified as non-suicidal self-injurious behavior.  It is recommended that 
a subject be assessed by a psychiatrist or appropriately trained professional to assist the 
investigator in deciding whether the subject should be discontinued from the study.
8.3. Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9.Study Assessments and Procedures
Section2lists the Schedule of Activities, detailingthe study procedures and their timing 
(including tolerance limits for timing).
Appendix 2lists the clinical laboratory tests that will be performed for this study.
Appendix 5provides 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, orotherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizeswith 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the ICF is signed, study site personnel will record,via CRF,the occurrence and nature of 
each subject’s preexisting conditions, including clinically significant signs, andsymptoms 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 anAE has a reasonablepossibility 
of being related to study treatmentor a study procedure, taking into account the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility”means that there is a potential cause and effect relationship between 
the IP, study 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, study site personnel must report this to Lilly 
or its designee via CRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:
death
initial or prolonged inpatient hospitalization
a life-threatening experience (that is, immediate risk of dying)
persistent or significant disability/incapacity
congenital anomaly/birth defect
important medical events that may not be immediately life-threatening or result in death 
or hospitalizationbut may jeopardizethe subjector may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnelmust alert the Lilly CRP/CP, ortheir designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert LillyGlobal 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 
studyspecific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.  
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.  
Pregnancy (maternal or paternal exposure to IP) does not meet the definition of an adverse event.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
9.2.1.1. 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 reportsas related to IPor procedure.  Lilly has procedures that 
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.


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9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Subjects should be instructed to contact the investigator as soon as possibleif he or she has a 
complaint or problem with the IPso that the situation can be assessed.
9.3. Treatment of Overdose
For the purposes of this study, an overdose of lasmiditanis considered any dose higher than the 
planned study dose.  There is no specific antidote for lasmiditan.  In the event of overdose, the 
subject should receive appropriate supportive care and AEs should be documented.
No drug interaction studies in humans have yet been performed with lasmiditan.  In the event of 
probe drug overdose, the package inserts should be referred to for further information on 
antidotes or supportive care.  
9.4. Safety
9.4.1. Laboratory Tests
For each subject,laboratory tests detailed in Appendix 2should be conducted according to the 
Schedule of Activities (Section2). 
9.4.2. Vital Signs
For eachsubject,vital signs measurements should be conducted according to the Schedule of 
Activities (Section2).  
Blood pressure and pulse rate should be measured after at least5 minutes supine.  All supine 
blood pressure and pulse rate except for screeningand follow-up 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.
Where orthostatic measurements are required, subjectsshould be supine for at least 5minutes 
and stand for 2 minutes and no more than3minutes.
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).


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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 single12-lead digital ECGwill be collected according to the Schedule of 
Activities.  Electrocardiograms must be recorded before collecting any blood samples.  Subjects 
must be supine for at least 5minutes 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. Colombia-Suicide Severity Rating Scale
Any occurrence of suicide-related thoughts and behaviors will be assessed as indicated in the 
Schedule of Activities (Section2)using the C-SSRS.  The C-SSRS is administered by an 
appropriately trained healthcare professional with at least 1 year of patient care/clinical 
experience.  
Adverse event collection should occur prior to the collection of the C-SSRS.  If a suicide-related 
event is discovered during the C-SSRS, but was not captured during AE collection, sites should 
not change the AE form.  If an event is serious or leads to discontinuationfrom study treatment, 
this is an exception where the SAE and/or AE leading to discontinuationfrom study treatment
should be included on the AE form and the process for reporting SAEs should be followed.  
Terms captured by the use of the C-SSRS can be mapped to the Columbia Classification 
Algorithm of Suicide Assessment(Posner et al. 2007) to facilitate future pooling of data.  
The first time the scale is administered in this study, the C-SSRS “Baseline” version will be 
used, and the findings will constitute the baseline assessment.  The C-SSRS “Since Last Visit” 
scale will be used for all subsequent assessments.  If a suicide-related thought or behavior is 
identified at any time during the study(including follow-up), a thorough evaluation will be 
performed by a study physician, and appropriate medical care will be provided.  It is 
recommended that a subject be assessed by a psychiatrist or appropriately trained professional to 
assist in deciding whether the subject should be discontinued from study treatment.  A subject 
does not necessarily have to be discontinued if they have self-injurious behavior that would be 


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classified as non-suicidal self-injurious behavior.  If this situation arises, the subjectwillbe 
referred to a psychiatrist or appropriately trained professional.
The Lilly Self-Harm Supplement should be completed every time the C-SSRS is administered.  
If, based on administration of the C-SSRS, it is determined that suicide-related behaviors have 
occurred, then the Lilly Self-Harm Follow-Up form will be used to collect additional information 
to allow for a more complete assessment of these behaviors.  
9.4.5. 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
9.4.5.1. Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, liver tests (Appendix 4)should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatinine 
kinase to confirm the abnormality and to determine if it is increasing or decreasing.  If the 
abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator based on consultation with the Lilly clinical pharmacologist or CRP.  Monitoring 
should continue until levelsnormalize 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 two or more consecutive blood tests
elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome)
elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests 
subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests
hepatic event considered to be a SAE.
9.5. Pharmacokinetics
9.5.1. Lasmiditan
At the visits and times specified in the Scheduleof Activities,venous bloodsamples of 
approximately 2mL each will be collected to determine the plasmaconcentrations of lasmiditan 
and its major metabolites(M7, M8, and M18).  A maximum of 3samples may be collected at 


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additional timepoints 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.
9.5.2. Probe Drug Cocktail
At the visits and times specified in the Schedule of Activitiesfor Cohort 1, 2venous blood 
samples of approximately 2 mL each will be collected to determine the plasma concentrations of 
caffeine,tolbutamide,and midazolam.  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.
9.5.3. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsorand stored at a facility 
designated by the sponsor.
Plasma concentrations oflasmiditanand its major metabolites will be assayed using a validated 
LC-MS/MS method.  Plasma concentrations ofeach analyte in the drug cocktail (caffeine, 
tolbutamide, and midazolam) will be assayed using respective validated LC-MS/MS methods.  
Plasma remaining after the analyses may be used for exploratory work to further understand the 
disposition and metabolism of lasmiditanor the probe substrates.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after thebioanalyses may be used for exploratory analyses.  
9.6. Pharmacodynamics
The benzodiazepine withdrawal symptom questionnaire (Tyrer et al. 1990) will be completed
dailyby subjectsfrom Day2 of lasmiditan or placebo dosing until 14days following thefinal 
dose of lasmiditanor placebo.  Whilst resident at the CRU, subjects will be administeredthe 
questionnaireby CRU staff.  Subjects will be administered the questionnaire via phone by a 
member of CRU staff each day following discharge from the CRU on Day9 until the follow-up 
visit in both cohorts. The physician withdrawal checklist (Rickels et al. 2008) will be completed 
by qualified CRU staff predose on Day 7 and follow-up.
9.7. Exploratory Assessments
At the visits and times specified in the Schedule of Activities, venous bloodsamples of 
approximately 2mL each will be collected for the determination of plasma concentrations of 
cortisol.  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.
Beginning from the time of lasmiditan dosing on Days 1 and 7 of Cohort1 and Cohort2, 
24-hour urine samples will be collected.  The actual volume of urine collected and the time of 
each collection will be recorded.


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Oneurine aliquot from the 24-hour urine collections will be takento determine urinary 
concentrations of 6-βOHC.  
A secondurine aliquot from the 24-hour urine collections willbe usedfor exploratory metabolite 
profiling.
The urine aliquot(s)will be stored for upto a maximum of2yearsafter last subject visit for the 
study at a facility selected by the sponsor.During this time, samples remaining after the 
bioanalyses may be used for other exploratory analyses.
9.7.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsorand stored at a facility 
designated by the sponsor.
Plasma concentrations of cortisol will be determinedusing a validated LC-MS/MS method.  
Urine concentrations of 6-βOHC concentrations will be determined usinga validated 
LC-MS/MS method.
9.8. Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, where local regulations allow.  
Samples will notbe used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to lasmiditanand to 
investigate genetic variants thought to play a role in migraine.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of lasmiditanor after lasmiditanis commercially available.  
Molecular technologies are expected to improve during the 15 year storage period andtherefore 
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. 
9.9. Biomarkers
This section is not applicable for this study.


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9.10.Health Economics
Thissection is not applicable for this study.


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10. Statistical Considerations and Data Analysis
10.1.Sample SizeDetermination
10.1.1.Cohort 1
Up to 40subjects may be enrolled in Cohort1in order that 30subjects complete the study.  
Subjects will be randomized at a ratio of 7:3lasmiditan: placeboin order that 21 completing 
subjects are exposed to lasmiditanand 9 to placebo.  Subjects who do not complete the study for 
non-drug related reasons may be replaced, and replacement subjects will be assigned the same 
treatment group as the subject being replaced.
10.1.1.1.Caffeine
For caffeine AUC the intrasubjectCV was estimated to be 21.0% (Blanchard and Sawers 1983).  
Based on this assumption, 21subjectswill provide a precision(i.e.  half-width of the 90% 
confidence interval)of 0.13on the log scale, with 90% power, which corresponds to 12.4% on 
the natural scale.  For caffeine C
maxthe intrasubjectCV was estimated to be 23.4% (Turpault et 
al.  2009).  Based on this assumption, 21subjectswill provide a precision of 0.15 on the log 
scale, with 90% power, which corresponds to 13.7% on the natural scale.
10.1.1.2.Midazolam
For midazolam AUC the intrasubjectCV was estimated to be 40.0% (derived fromLY2484595 
study I1V-MC-EIAB).  Based on this assumption, 21subjectswill provide a precision of 0.24on 
the log scale, with 90% power, which corresponds to 21.7% on the natural scale.  For midazolam 
Cmaxthe intrasubject CV was estimated to be 38.0% (derived from LY2484595study 
I1V-MC-EIAB).  Based on this assumption, 21subjectswill provide a precision of 0.23on the 
log scale, with 90% power, which corresponds to 20.8% on the natural scale.
10.1.1.3.Tolbutamide 
For tolbutamide AUC the intrasubject CV was estimated to be 39.7% (derived fromLY2409021 
study I1R-FW-GLBD).  Based on this assumption, 21subjectswill provide a precision of 
0.24on the log scale, with 90% power, which corresponds to 21.6% on the natural scale.  For 
tolbutamide C
maxthe intrasubject CV was estimated to be 26.8% (derived from LY2409021
study I1R-FW-GLBD).  Based on this assumption, 21subjectswill provide a precision of 0.17
on the log scale, with 90% power, which corresponds to 15.4% on the natural scale.  
10.1.1.4.Benzodiazepine Withdrawal Symptom Questionnaire
For the Benzodiazepine Withdrawal Symptom Questionnairetotal scores, assuming a mean of 9 
in the lasmiditan group, a mean of 1 in the placebo group, and 7.3common standard deviation 
(assumptions based on results in Tyrer et al.1990), 21 lasmiditan subjects and 9 placebo subjects 
will provide 85% power to detect a significant difference between lasmiditan and placebo (t-test 
with 2-sided alpha of 0.10).


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10.1.2.Cohort 2
Up to 30subjects may be enrolled in Cohort2in order that 24subjects complete the study.  
Subjects will be randomized at a ratio of 1:1 lasmiditan: placebo.  Subjects who do not complete 
the studyfor non-drug related reasonsmay be replaced, and replacement subjects will be 
assigned the same treatment group as the subject being replaced.  For the Benzodiazepine 
Withdrawal Symptom Questionnairetotal scores, assuming a mean of 9 in the lasmiditan group, 
a mean of 1 in the placebo group, and 7.3 common standard deviation (assumptions based on 
results in Tyrer et al.1990), 12 lasmiditan subjects and 12 placebo subjects will provide 83% 
power to detect a significant difference between lasmiditan and placebo (t-test with 2-sided alpha 
of 0.10).
10.2.Populations for Analyses
10.2.1.Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study.  
10.2.2.Study Participant Characteristics
The subjects’ age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized using descriptive statistics.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on the full analysis set.  For drug cocktail PK, the 
full analysis set includesall data from all subjects receiving at least one dose of drug cocktail
with evaluable PK data, according to the treatment the subjects actually received.  For lasmiditan 
PK, the full analysis set includes all data from all subjects receiving at least one dose of 
lasmiditan with evaluable PK data.  
Safety analyses will be conducted for all enrolledsubjects,whether or not they completed all 
protocol requirements.  Baseline for safety analyses will be the predosemeasurement on Day 1.
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 treatment 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 IPand/or with probe drugas perceived by the investigator.  Symptoms reported to occur 


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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.
10.3.1.2.Statistical Evaluation of Safety
Safety parameters that will be assessed include safety lab parameters, vital signs, ECG 
parameters, and C-SRSS scores.  The parameters will be listed, and summarized using standard 
descriptive statistics.  
To assess the impact of lasmiditan on pulse rate, descriptive statistics such as the mean, median, 
and standard deviation will be calculated for each timepointby dose level.  Summary statistics 
for baseline-corrected pulse rates will also be calculated and presented.  The corresponding box 
plots for the pulse rate and baseline-corrected heart rate will be presented as well.
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 lasmiditanand its major metabolites as well ascaffeine, 
midazolam, and tolbutamide will be calculated by standard noncompartmental methods of 
analysis and will be listed and summarized for each group of subjects using descriptive statistics.  
The primary parameters foranalysiswill be C
max, AUC(0-∞),AUC(0-tlast)and t
maxof
midazolam, tolbutamide, andcaffeine.  Additionally, Cmax, t
max,andAUCwill be reported for 
plasma concentrations of lasmiditan, and metabolites(M7, M8, and M18).  Other 
noncompartmental parameters, such ashalf-life, apparent clearance,apparentvolume of 
distribution, metabolite ratio, and accumulation ratiomay be reported.  AUC(0-tlast)and 
AUC(0-∞)may be assessedfor lasmiditanand its metabolitesto determine temporal linearity.  
10.3.2.2.Pharmacokinetic Statistical Inference
Trough concentrations of lasmiditan and its metabolites will be evaluated graphically and/or 
descriptively for achievement of steady-state.  No formal analysis willbe performed for 
attainment of steady-state.
Pharmacokinetic parameter estimates of cocktail drugs will be evaluated to delineate the effects 
of drug interaction in Cohort1of the study.  Midazolam, tolbutamide, and caffeine administered 
in the absence of lasmiditan will represent the reference treatments and will be analyzed 
separately.  Each drug administered with lasmiditan will represent the test treatments and will be 
analyzed separately.
For the primary analysis, log-transformed C
max, andAUC(0-∞)estimates of probe drugs will be 
evaluated in a linear mixed-effects analysis of variance model with a fixed effect for treatment 
and a random effect for subject.  The treatment differences will be back-transformed to present 
ratios of geometric least squares means and the corresponding 90%CIs.  The AUC(0-t
last) will be 


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analyzed using the same method described above.  The tmax will be analyzed using a Wilcoxon 
signed rank test.  Estimates of the median difference based on the observed medians, 90% CI, 
and p-valuesfrom the Wilcoxon testwill be calculated.  
Additional analysis will be performed if warranted upon review of the data.
10.3.3.PharmacodynamicEvaluations
10.3.3.1.PharmacodynamicParameter Estimation
A benzodiazepine withdrawal symptom questionnaire will be completed by all subjectsfrom 
Day2 of lasmiditanor placebodosing until14days following the final dose of lasmiditan or 
placebo,inboth cohorts.  The physician withdrawal checklist will be completed predose on 
Day7 and at follow-up.
10.3.3.2.Pharmacodynamic Statistical Inference
Benzodiazepine withdrawal symptom questionnaire scores and physician withdrawal checklist 
will be listed, and summarized using standard descriptive statistics.  Total score at each time 
point will be averaged for each treatment group in each cohortbased upon the available data, and
the lasmiditan group will be compared with the placebo group via t-test at each time point within 
each cohort.  
10.3.4.Exploratory Assessment Evaluations
10.3.4.1.Exploratory Parameter Estimation
Plasma levels of cortisol and urinary 6-βOHC will be measured on Days 1 and 7 in Cohort 1 
and2.  Twenty-four hour urine collections will beginprior to dosing on Days 1 and 7 in Cohort 1 
and 2.  Levels of plasma cortisol relative to urinary 6-βOHC (mean concentration over 24 hour 
period) will be calculated for both days in bothcohorts.  
10.3.4.2.Exploratory Parameter Statistical Inference
Exploratory parameters may be listed and summarized using standard descriptive statistics.  
Additional analysis will be performed if warranted upon review of the data.
10.3.5.Data Review During the Study
Interim access to the data is scheduled to occur after Cohort 1as described in Section 7.4.1.  The 
purpose of this interim review is to review the safety data and determine the dose for the next 
cohort.  The investigator and the Lilly study teamwill make the determination regarding dose 
escalation based upon their review of the safety and tolerability data.  The investigator will 
remain blinded and the Lilly study teammay be unblinded during this interim review.  If 
available, summary PK data may also be reviewed, but is not required for selecting the Cohort 2 
dose level.


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10.4.Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.


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11. References
Blanchard J, Sawers SJ.  The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol.  
1983;24(1):93-98.
EMA CPMP/EWP/560/95/Rev.  1 Corr 2.  Guideline on the investigation of drug interactions.  
2012.
FDA Center for Drug Evaluation and Research.  Guidance for Industry –Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations.  2012.
Rickels K, Schweizer E, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. 
Effects of abrupt discontinuation. Arch Gen Psychiatry. 1990;47(10):899–907.
Rickels K, Garcia-Espana F, Mandos L,CaseGW. Physician Withdrawal Checklist (PWC-20). J 
Clin Psychopharmacol. 2008;28:447-451. 
Sharma A, Pilote S, Bèlanger PM, Arsenault M, Hamelin BA. A convenient five-drug cocktail 
for the assessment of major drug metabolizing enzymes:  a pilot study. Br J Clin Pharmacol. 
2004;58(3):288–297.
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.2007;164(7):1035-1043.
Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donazzolo Y, Boulenc X. 
Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. 
Br J Clin Pharmacol.  2009;68(6):928-935.
TyrerP, MurphyS, Riley, P.The Benzodiazepine Withdrawal Symptom Questionnaire. J Affect
Disord. 1990;9(1):53-61.


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Appendix 1.
Abbreviations and Definitions
Term
Definition
6-βOHC
6-β-hydroxycortisol
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
AUC
area under the concentration versus time curve over one dosing interval
AUC(0-∞)
area under the concentration versus time curve from zero to infinity
AUC(0-t
last)
area under the concentration versus time curve from time zero to time t, where t is the last 
timepoint with a measurable concentration
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received.
BMI
body mass index
CI
confidence interval
CIOMS
CouncilforInternationalOrganizationsofMedical Sciences
CNS
central nervous system
CV
coefficient of variance
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.


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compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined timepoint, depending on the steps required to obtain 
confirmed results.
CP
Clinical Pharmacologist
CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
Clinical Research Unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
eCRF
electronic case report form
ED
early discharge
eGFR
estimated glomerular filtration rate as measured by the CKD-EPI equation
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EMA
European Medicines Agency
ERB
ethical review board
FDA
Food andDrug Administration
FSH
follicle stimulating hormone
FU
follow-up visit
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization


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IND
Investigational New Drug:  An application to the FDA to allow testing of a new drug in 
humans.
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
Investigational 
product (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 studyat a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
intravenous
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’sparticipation in the clinical study.
MTD
maximum tolerated dose
randomize
the process of assigning subjects/patients to an experimental group on a random basis
PK
pharmacokinetic
QTc
corrected QT interval
QTcF
QT interval with Friederica’s correction
SAE
serious adverse event
screen
The act of determining if an individual meetsminimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions 
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period,having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment
t
max
time to maximum drug concentration


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ULN
upper limit of normal
WBC
white blood cell


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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) 
Magnesium
Platelets
Glucose (fasting)
   Differential WBC absolute counts and % of:
Blood urea nitrogen (BUN)
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase (ALP)
Basophils
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Urinalysis
Creatinine
eGFR
Microscopic
Specific gravity
pH
Protein
Glucose
Urine drug and ethanol screen
Ketones
Hepatitis B surface antigena
Bilirubin
Hepatitis C antibodya
Urobilinogen
HIVa
Blood
Pregnancy test 
Nitrite
FSH 
a
Abbreviations:  eGFR= estimated glomerular filtration rate, assessed by CKD-EPI equation; FSH = follicle
stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
a Performed at screening only, as applicable


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:
ensuring that the subjectunderstands the nature of the study,the potential risks and 
benefits of participating in the study, and that their participation is voluntary.
ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.
answering any questions the subjectmayhave throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’swillingness to 
continue his or her participation in the study.
providing a copy of the ICFto the participant or the participant’s legal representativeand 
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 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 withthe protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 


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


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Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject/patient personal information collected will be provided in a 
written document to the subject/patient by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinuedif Lilly or its designee, the investigator, or the ERB 
of the study sitejudges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes forall 
blood sampling (screening, safety laboratories, and bioanalytical assays) during thestudy.  
Protocol H8H-MC-LAHE Sampling Summary 
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples 
(Cohort1/Cohort2)
Total Volume (mL)
(Cohort1/Cohort2)
Screening testsa
19.5
1/1
19.5/19.5
Clinical laboratory testsa
12.5
6/5
75/62.5
Serum pregnancy test 
5
3/3
15/15
Exploratory cortisol assessment
2
2/2
4/4
Lasmiditan pharmacokinetics
2
29/29
58/58
Probe drug pharmacokinetics
2x 2
26/NA
104/NA
Pharmacogenetics
10
1/1
10/10
Total
285.5/169
Total for clinical purposes rounded up to nearest 10 mL
290/170
a Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Protocol Amendment H8H-MC-LAHE(b) 
Summary: Multiple-Ascending Dose, Safety, Tolerability, 
Pharmacokinetic, and Drug-Drug Interaction Study of 
Lasmiditan
Overview
Protocol H8H-MC-LAHE, Multiple-Ascending Dose, Safety, Tolerability, Pharmacokinetic, and 
Drug-Drug Interaction Study of Lasmiditan, has been amended. The new protocol is indicated 
by Amendment (b) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changeand rationale made to this protocol are to comply with FDA feedback 
received via email on 24 August 2017. Details of the changeareas follows:
Physician Withdrawal Checklist will be administered on Day 7 and at follow-up to 
further assess the potential symptoms of withdrawal. 


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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
Title of Study:  
Multiple-Ascending Dose, Safety, Tolerability, Pharmacokinetic, and Drug-Drug Interaction Study of Lasmiditan 
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
The primary objective of this study is to explore the 
safety and tolerability of multipledoses of 200mg and 
400mg lasmiditan in healthy subjects.
Incidence of serious adverse events (SAEs) and 
treatment-emergent adverse events (TEAEs).
Secondary
To evaluate the plasma pharmacokinetics 
(PK) of multiple doses of lasmiditan and its 
major metabolites.
To evaluate the effect of multiple doses of 
lasmiditan on CYP1A2, CYP2C9, and 
CYP3A activity.  
To evaluate any potential withdrawal 
symptoms following once-daily dosing of 
lasmiditan.
Maximum observed drug concentration (Cmax), time of 
maximum observed drug concentration (tmax), area 
under the concentration versus time curve (AUC) over 
one dosing interval (AUC).
Cmax, T
max, AUC from time zero to infinity (0-∞), and 
AUC from time zero to last observable concentration
AUC(0-t
last) of probe drugs.
Responses to the benzodiazepine withdrawal symptom 
questionnaireand physician withdrawal checklist.


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2.
Schedule of Activities
Study Schedule Protocol H8H-MC-LAHE Cohort 1
Screening
Days
FU/ED
Comments
Procedure
Days 
-32
to -4
-4 
-3 
-2 
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days 
post final dose
Informed 
Consent
X
Subject 
Admission to 
CRU
X
Subject 
Discharge from 
CRU
X
Randomization
X
Lasmiditan or 
Placebo 
Administration
X 
X 
X
Probe Drugs 
Administration
X
X
Medical History
X 
X
AEs and 
Medication 
Review
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
AE and medication review 
will be ongoing from 
Day-4
Height & 
Weight
X 
X
Height recorded only at 
Screening


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Screening
Days
FU/ED
Comments
Procedure
Days 
-32
to -4
-4 
-3 
-2 
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days 
post final dose
Orthostatic Vital 
Signs
X 
X
Predose, 
0.5, 1, 
2h
Day2 
Predose
Predose
, 0.5, 1,
2h
Last triplicate vital sign can 
be used as the supine vital 
sign for calculation of 
orthostatic changes.  
Timepoints may be added 
for each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.  
Vital Signs 
(supine)
X 
X
Predose 
2, 4h
Predose, 
0.5, 1, 2, 
2.5, 3, 4, 
6, 8, 12h 
Day2 
predose 
Predose
, 0.5 1, 
2, 2.5, 
3, 4, 6, 
8, 12h
24h
X
Timepoints may be added 
for each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.  All vitals 
should be taken in triplicate 
apart from follow-up and 
screening visitswhere a 
single measurement will be 
taken.   
Screening 
Laboratory 
Tests
X
Clinical Lab 
Tests
X
X
Day2, 
Day6
X
X
See Appendix 2for details.  
HIV/Hepatitis 
Tests
X


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Screening
Days
FU/ED
Comments
Procedure
Days 
-32
to -4
-4 
-3 
-2 
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days 
post final dose
Urine Drug 
Screen and 
Ethanol Test
X 
X
FSH Test
X
Females only to confirm 
menopausal status.
Pregnancy Test
X 
X
X
Serum pregnancy test will be 
performed at all timepoints. 
Females of childbearing 
potential only. 
12-lead Safety 
ECG
X 
X
X
Predose, 
1, 2, 4h 
Day2 
Predose 
Predose
,1, 2, 
4h 
24
h
Single ECG readings will be 
taken.   Timepoints relative 
to lasmiditan dosing on 
Days1 and 7. 
Physical Exam
X 
X
X
Day2 
Day6
Predose
X
X
After screening, medical 
assessment only performed 
to include targeted 
examination, as appropriate.
Plasma PK 
Samples 
(lasmiditan)
0.5, 1.0, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 
12h
Day 
2(24h), 
Predose 
(Days 
3-5)
Predose
, 0.5, 
1.0, 1.5, 
2, 2.5, 
3, 4, 6, 
8, 12 h
24 
h
Timepoints relative to dosing 
on Days1 and 7. Predose 
samples to be taken on Days 
3, 4 and 5 for assessment of 
steady-state. 


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Screening
Days
FU/ED
Comments
Procedure
Days 
-32 
to -4
-4 
-3 
-2 
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days 
post final dose
Plasma PK 
Samples
(probe)
Predose
0.5, 
1.0, 
1.5, 2, 
2.5, 3, 
4, 6, 8, 
12h
24h
48 h
Predose
, 0.5, 
1.0, 1.5, 
2, 2.5, 
3, 4, 6, 
8, 12 h
24 
h
48 
h
Timepoints relative to dosing 
on Days-3 and 7.
Exploratory 
PlasmaSample
(Cortisol)
Predose
Predose
Urine Sample
for 2 
Exploratory 
Analyses 
(lasmiditan
metabolites and
6-βOHC)
X
X
0 to 24h urine collection on 
Days1 and 7 (timepoints 
relative tolasmiditan dosing 
on Day1 and7)
Pharmaco-
genetics sample
X
The 
Benzodiazepine 
Withdrawal 
Symptom 
Questionnaire
X 
X 
X 
X 
X 
X
Questionnaire to be 
administered daily via phone 
by a member of CRU staff 
following discharge from the 
CRU on Day9 until the 
follow-up visit.
Physician 
Withdrawal 
Checklist
Predose
X
C-SSRS and 
Self-Harm 
X 
X
X
“Baseline”questionnaire to 
be used at screening, all 


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Supplement
other timepoints use “Since 
Last Visit”questionnaire
Abbreviations:  6 βOHC = 6-beta hydroxycortisol; AE = Adverse event; CRU = Clinical ResearchUnit; C-SSRS =Columbia-Suicide Severity Rating Scale; 
ECG= electrocardiogram; ED = early discharge; FSH = follicle stimulating hormone, FU= follow-up visit; h = hours; HIV = human immunodeficiency virus; 
PK =pharmacokinetic.
Note:  If multiple procedures take place at the same timepoint, the following order of the procedure should be:  ECG, supine vital signs, orthostatic vital signs, 
and venipuncture.  Where venipuncture and other procedures take place at the same timepoint, the following time windows for obtaining blood samples 
should be maintained:  0 to 2.5 hours postdose:  ±5 minutes; 3 to 6 hours postdose:  ±10 minutes; 7 to 12 hours postdose:  ±20 minutes; >12 hours postdose:  
±30 minutes.


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Study Schedule Protocol H8H-MC-LAHE Cohort 2
Screening
Days
FU/ED
Comments
Procedure
Days 
-29
to -1
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days post 
final dose
Informed Consent
X
Subject Admission 
to CRU
X
Subject Discharge
from CRU
X
Randomization
X
Lasmiditan or 
Placebo 
Administration
X
X
X
Medical History
X 
X
AEs and 
Medication review
X 
X
X
X 
X 
X 
X 
X
AE and medication review will 
be ongoing from Day-1.
Height & weight
X 
X
Height recorded only at 
Screening.
Vital Signs 
(supine)
X
Predose, 0.5, 
1, 2, 2.5, 3, 
4, 6, 8, 12h
Day2 Predose
Predose, 
0.5, 1, 2, 
2.5, 3, 4, 6, 
8, 12h
24h
X
Timepoints may be added for 
each study period, if warranted 
and agreed upon between Lilly 
and the investigator.  All vitals 
should be in triplicate, apart 
from screening and follow-up 
visitswhere a single 
measurement will be taken. 


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Screening
Days
FU/ED
Comments
Procedure
Days 
-29
to -1
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days post 
final dose
Orthostatic Vital 
Signs
X 
X
Predose, 
0.5, 1, 2h
Day2 
Predose 
Predose, 
0.5, 1,
2h
Last triplicate vital sign can be 
used as the supine vital sign for 
calculation of orthostatic 
changes.  Timepoints may be 
added for each study period, if 
warranted and agreed upon 
between Lilly and the 
investigator.  
Screening 
Laboratory Tests
X
Clinical Lab Tests
X
Day2, Day6
X
X
HIV/Hepatitis 
Tests
X
Urine Drug Screen 
and Ethanol Test
X 
X
FSH Test
X
Females only to confirm 
menopausal status.
Pregnancy Test 
X 
X
X
Serum pregnancy test will be 
performed at all timepoints.
Females of childbearing 
potential only.  
12-lead Safety 
ECG
X 
X
Predose, 1, 
2, 4h 
Day2 
Predose
Predose, 1, 
2, 4h 
24h
Single ECG readings will be 
taken. Timepoints relative to 
lasmiditan dosing on Days1 and 
7. 
Physical Exam
X 
X
X
X
X
After screening, medical 
assessment only performed to 
include targeted examination, as 
appropriate.


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LY573144
Abbreviations:  6-βOHC =6-beta hydroxycortisol, AE = Adverse event; CRU = Clinical Research Unit; C-SSRS =Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; ED = early discharge;FSH = follicle stimulating hormone; FU = follow-up visit; h = hours; HIV = human immunodeficiency 
virus; PK = pharmacokinetic.
Screening
Days
FU/ED
Comments
Procedure
Days 
-29 
to -1
-1 
1
2 to 6
7 
8 
9
10 to 
FU
FU approximately 14days post 
final dose
Plasma PK 
Samples 
(lasmiditan)
0.5, 1.0, 1.5, 
2, 2.5, 3, 4, 
6, 8, 12 h
Day2 (24h), 
Predose 
(Days3 to 5)
Predose, 
0.5, 1.0, 
1.5, 2, 2.5, 
3, 4, 6, 8, 
12 h
24 h
Timepoints relative to dosing on 
Days1and 7.  Predose samples 
to be taken on Days 3, 4 and 5 
for assessment of steady-state.
Exploratory 
PlasmaSample
(Cortisol)
Predose
Predose
UrineSamplefor 
2 Exploratory 
Analyses
(lasmiditan
metabolites and 
6-βOHC)
X
X
0 to 24h urine collection on 
Days1 and 7 (timepoints 
relative tolasmiditan dosing on 
Day1 and7)
Pharmacogenetics 
Sample
X
The 
Benzodiazepine 
Withdrawal 
Symptom 
Questionnaire
X
X 
X 
X 
X 
X
Questionnaire to be 
administered daily via phone by 
a member of CRUstaff 
following discharge from the 
CRU on Day9 until the follow-
up visit.
Physician 
Withdrawal 
Checklist
Predose
X
C-SSRS and Self-
Harm 
Supplement
X 
X
X
“Baseline”questionnaire to be 
used at Screening , all other 
timepoints use “Since Last 
Visit”questionnaire


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Note:  If multiple procedures take place at the same timepoint, the following order of the procedure should be:  ECG, supine vital signs, orthostatic vital signs, 
and venipuncture.  Where venipuncture and other procedures take place at the same timepoint, the following time windows for obtaining blood samples 
should be maintained:  0 to 2.5 hours postdose:  ±5 minutes; 3 to 6 hourspostdose:  ±10 minutes; 7 to 12 hours postdose:  ±20 minutes; >12 hours postdose:  
±30 minutes. 


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4. Objectives and Endpoints
Table LAHE.1shows the objectives and endpoints of the study.
TableLAHE.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective of this study is to explore the 
safety and tolerability of multiple doses of 200mg and 
400mg lasmiditan in healthy subjects.
Incidence of serious adverse events (SAEs) and 
treatment-emergent adverse events (TEAEs).
Secondary
To evaluate the plasma PK of multiple doses 
of lasmiditan and its major metabolites.
To evaluate the effect of multiple doses of 
lasmiditan on CYP1A2, CYP2C9, and 
CYP3A activity.  
To evaluate any potential withdrawal 
symptoms following once-daily dosing of 
lasmiditan.
Cmax, t
max, AUC over one dosing interval (AUC
).
Cmax, T
max, AUC from time zero to infinity
(AUC[0-∞]), and AUC from time zero to last 
observable concentration (AUC[0-t
last])of probe drugs.
Responses to thebenzodiazepine withdrawal symptom 
questionnaireand physician withdrawal checklist.
Exploratory
To evaluate concentrations of 6-beta 
hydroxycortisol (6-βOHC) excreted in urine 
relative to plasma concentrations of cortisol as 
an indicator of CYP3A induction before and 
after treatment with 200 and 400mg 
lasmiditan for 7 days.
Toprofile urine for lasmiditan metabolites 
after multiple doses.
Ratio of urinary 6-βOHC and plasma cortisol 
concentrations.
5. Study Design
5.1. Overall Design
This studyis a Phase 1, investigator and subject-blinded, randomized, placebo-controlled 
multiple-ascending dose study to assess the effect of once-daily oral dosing of lasmiditan in 
2cohorts of healthy subjects.  Cohort 1will also assess the effects of lasmiditanand its 
circulating metabolites upon CYP activity by evaluating effects on the PK of components of a 
coadministered cocktail of CYP substrate drugs.  
All subjects will participate in a screening visit up to 28 days prior to admission to the study.


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Subjects in Cohort1will be admitted to the CRU on Day-4, and will receive a dose of the probe 
drug cocktail (100 mg caffeine, 500 mg tolbutamide and 2 mg midazolam) on Day-3 with serial 
blood samples taken at the times listed in the Schedule of Activities up to 48hours postdose for 
assessment of probe drug PK.  Subjects will begin receiving oral doses of 200mg lasmiditan or 
placebo (at a ratio of 7:3lasmiditan: placebo) on Day1, and will be dosed once per day until 
Day7 (inclusive).  The probe drug cocktail will be coadministered with lasmiditan on Day7 and 
serial blood samples will be taken up to 48hours post dose for the assessment of probe drug PK.  
Serial blood samples for lasmiditan will be collected up to 24hours postdose on Day1 and 
Day7;also, blood samples will be taken predose at Days3, 4, and 5 to assess the steady-state PK 
of lasmiditan.  
Subjects will be discharged from the CRU on Day9 at the discretion of the investigator.  
Subjects in Cohort2 will be admitted to the CRU on Day-1.  Subjects will begin receiving oral 
doses of 400 mg lasmiditan or placebo on Day 1 (at a ratio of 1:1lasmiditan to placebo) and will 
be dosed once per day until Day7 (inclusive).  Subjects will be discharged from the CRU on 
Day9 at the discretion of the investigator.  Serial blood samples will be taken at times listed in 
the Schedule of Activities up to 24 hours postdose on Days1 and 7 for the assessment of 
lasmiditan PK.  Blood samples will be taken predose at Days3, 4, and 5 to assess steady-state 
PK of lasmiditan.  The potential for withdrawal symptoms following multiple dosing of 
lasmiditan will be assessed by daily completion of a benzodiazepine withdrawal questionnaire 
(Tyrer et al. 1990) by subjects in both cohorts from Day2 of lasmiditan or placebo dosing until 
14days following the final dose of lasmiditan or placebo. Whilst resident at the CRU, subjects 
will complete the questionnaire under supervision of CRU staff.  Subjects will be administered 
the questionnaire via phone by a member of CRU staff each day following discharge from the 
CRU on Day9 until the follow-up visit in both cohorts.Additionally, the potential for 
withdrawal symptoms will be assessed usingthe physician withdrawal checklist (i.e. Rickels et 
al. 1990,2008) on Day7 and at follow-up.
Subjects in each cohort will return to the CRU for a follow-up visit 14days after the final dose of 
lasmiditan.  Subjects will be resident at the CRU for 13 days (Cohort1) and 10days (Cohort2) 
respectively.  The planned study duration for each subject will to 55daysin Cohort1, and 52 
days in Cohort2, including screening and follow-up visits.  
5.4. Scientific Rationale for Study Design
A subject and investigator-blinded, randomized and placebo-controlled design is being used for
this study to minimize the effect of bias on the safety and tolerability objectives.  Conducting the 
study in healthy subjects mitigates the potential confounding effects of the disease state and 
concomitant medications.  The benzodiazepine withdrawal symptom questionnaire (Tyrer et al. 
1990) and physician withdrawal checklist (Rickels et al. 2008) will be completed by subjects to 
assess any potential withdrawal symptoms following repeated dosing of lasmiditan.  Subjects in 
Cohort1 will receive 2 single doses of midazolam, a benzodiazepine, during the study
.  The 
doses of midazolam will however be low and separated by a period of 9 days; therefore the 


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
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LY573144
impact on results of the benzodiazepine withdrawal symptom questionnaire is likely to be 
negligible. 
Regulatory agencies recommend conducting clinical drug interaction studies using a drug 
cocktail approach where interactions with multiple CYPs are investigated (European Medicines 
Agency [EMA] Guideline 2012; Federal Drug Administration [FDA] 2012).  The drugs should 
be selective for specific CYP enzyme isotypes, should not interact with each other, and should be 
safe when administered.  Many such drug cocktails exist, with differing CYP isotype 
specificities:  one such cocktail includes midazolam, caffeine, tolbutamide, chlorzoxazone, and 
debrisoquine, which has been administered in previous studies (Sharma et al. 2004).  The 
cocktail was modified for this protocol to consist of the required probes for CYP3A 
(midazolam), CYP1A2 (caffeine), and CYP2C9 (tolbutamide) to specifically
 target the CYP 
isoforms of interest.  The drug cocktail will be administered on Day -3 before the initiation of 
lasmiditan on Day 1, and on Day 7 concurrently with dosing of lasmiditan, when steady-state 
concentrations of lasmiditan should be achieved.  Probe drug administration will be open-label, 
as the PK endpoints of the study are objective. 
9.6. Pharmacodynamics
The benzodiazepine withdrawal symptom questionnaire (Tyrer et al. 1990) will be completed
dailyby subjectsfrom Day2 of lasmiditan or placebo dosing until 14days following thefinal 
dose of lasmiditanor placebo.  Whilst resident at the CRU, subjects will be administered the 
questionnaire by CRU staff.  Subjects will be administered the questionnaire via phone by a 
member of CRU staff each day following discharge from the CRU on Day9 until the follow-up 
visit in both cohorts. The physician withdrawal checklist (Rickels et al. 2008) will be completed 
by qualified CRU staff predose on Day 7 and follow-up.
10.3.3. Pharmacodynamic Evaluations
10.3.3.1. Pharmacodynamic Parameter Estimation
A benzodiazepine withdrawal symptom questionnaire will be completed by all subjects from 
Day2 of lasmiditan or placebo dosing until 14days following the final dose of lasmiditan or 
placebo, in both cohorts.  The physician withdrawal checklist will be completed predose on Day 
7 and at follow-up.
10.3.3.2. Pharmacodynamic Statistical Inference
Benzodiazepine withdrawal symptom questionnaire scores and physician withdrawal checklist 
will be listed, and summarized using standard descriptive statistics.  Totalscore at each time 
point will be averaged for each treatment group in each cohort based upon the available data, and 
the lasmiditan group will be compared with the placebo group via t-test at each time point within 
each cohort.  
11. References
Blanchard J, Sawers SJ.  The absolute bioavailability of caffeine in man.  Eur J Clin Pharmacol.  
1983;24(1):93-98.


H8H-MC-LAHE(b)Clinical Pharmacology Protocol
Page 74
LY573144
EMA CPMP/EWP/560/95/Rev.  1 Corr 2.  Guideline on the investigation of drug interactions.  
2012.
FDA Center for Drug Evaluation and Research.  Guidance for Industry –Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations.  2012.
Rickels K, Schweizer E, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. 
Effects of abrupt discontinuation. Arch Gen Psychiatry. 1990;47(10):899–907.
Rickels K, Garcia-Espana F, Mandos L, Case GW. Physician Withdrawal Checklist (PWC-20). J 
Clin Psychopharmacol. 2008;28:447-451. 
Sharma A, Pilote S, Bèlanger PM, Arsenault M, Hamelin BA. A convenient five-drug cocktail 
for the assessment of major drug metabolizing enzymes:  a pilot study. Br J Clin Pharmacol. 
2004;58(3):288–297.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M.Columbia Classification Algorithm of 
Suicide Assessment (C-CASA):  classification of suicidal eventsin the FDA’s pediatric 
suicidal risk analysis of antidepressants.  Am J Psychiatry.2007;164(7):1035-1043.
Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donazzolo Y, Boulenc X. 
Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. 
Br J Clin Pharmacol.  2009;68(6):928-935.
Tyrer P, Murphy S, Riley, P. The Benzodiazepine Withdrawal Symptom Questionnaire. J Affect
Disord. 1990;9(1):53-61.


PPD
Leo Document ID = e2f9a714-dde5-4552-92e9-e488ef7e31e3
Approver: 
Approval Date & Time: 31-Aug-2017 16:53:03 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 31-Aug-2017 17:01:13 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Final, 18 Aug 2017
             Page 1 of 20
STATISTICAL ANALYSIS PLAN
Multiple-Ascending Dose, Safety, Tolerability, Pharmacokinetic, and Drug-Drug 
Interaction Study of Lasmiditan
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  18-August-2017
Study Drug: LY573144 (Lasmiditan)
Sponsor Reference:  H8H-MC-LAHE
Covance CRU Study: 1000071-8366191
Clinical Phase I
Approval Date: 11-Sep-2017 GMT


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             Page 2 of 20
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366191
Sponsor Reference H8H-MC-LAHE
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Primary objective .................................................................................................... 6
4.2
Secondary objectives ............................................................................................... 6
4.3
Exploratory objective .............................................................................................. 7
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 8
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 8
7.1
Cohort 1 .................................................................................................................. 8
7.2
Cohort 2 .................................................................................................................. 9
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 9
9.
STATISTICAL METHODOLOGY ............................................................................. 10
9.1
General.................................................................................................................. 10
9.2
Demographics and Subject Disposition.................................................................. 10
9.3
Pharmacokinetic Assessment................................................................................. 10
9.3.1
Pharmacokinetic Analysis............................................................................. 10
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 15
9.4
Pharmacodynamic Assessment .............................................................................. 16
9.4.1
Pharmacodynamic Analysis.......................................................................... 16
9.4.2
Pharmacodynamic Statistical Methodology .................................................. 16
9.5
Exploratory Assessment ........................................................................................ 17
9.5.1
Exploratory Analysis .................................................................................... 17
9.5.2
Exploratory Statistical Methodology............................................................. 17
9.6
Safety and Tolerability Assessments...................................................................... 17
9.6.1
Adverse events ............................................................................................. 17
9.6.2
Concomitant medication............................................................................... 17
9.6.3
Clinical laboratory parameters...................................................................... 17
9.6.4
Hepatic Monitoring ...................................................................................... 18
9.6.5
Vital signs .................................................................................................... 18
9.6.6
Electrocardiogram (ECG)............................................................................. 18
9.6.7
Columbia-Suicide Severity Rating Scale (C-SSRS) / Self-Harm Supplement 18
9.6.8
Other assessments......................................................................................... 18
9.6.9
Safety and Tolerability Statistical Methodology............................................ 19


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Statistical Analysis Plan 
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Sponsor Reference H8H-MC-LAHE
10. INTERIM ANALYSES ............................................................................................... 19
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 19
12. REFERENCES ............................................................................................................ 19
13. DATA PRESENTATION ............................................................................................ 19
13.1 Derived Parameters ............................................................................................... 19
13.2 Missing Data ......................................................................................................... 19
13.3 Insufficient Data for Presentation .......................................................................... 20


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Statistical Analysis Plan 
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Covance Clinical Study No. 8366191
Sponsor Reference H8H-MC-LAHE
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
Ae
Amount of drug excreted
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AR
Accumulation ratio
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
BQL
Below the quantifiable lower limit of the assay
6-OHC
6-beta hydroxycortisol
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation


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Covance Clinical Study No. 8366191
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LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MR
Metabolic ratio 
MRE
Magnetic Resonance Elastography
NA
Not applicable
PD
Pharmacodynamic
PK
Pharmacokinetic
QD
Once daily
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula
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  
 
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Covance Clinical Study No. 8366191 
 
Sponsor Reference H8H-MC-LAHE 
3. INTRODUCTION 
This SAP has been developed after review of the Clinical Study Protocol (final version dated 29 
June 2017 and Protocol Amendment (b) (final version dated 31 August 2017). 
This SAP describes the planned analysis of the safety, tolerability,  pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study.  A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document. 
The intent of this document is to provide guidance for the statistical and PK analyses of data.  In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company 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 
The primary objective of this study is to explore the safety and tolerability of multiple doses of 
200 mg and 400 mg lasmiditan in healthy subjects. 
4.2 
Secondary objectives 
The secondary objectives of this study are: 
 To evaluate the PK of multiple doses of lasmiditan and its major metabolites. 
 To evaluate the effect of multiple doses of lasmiditan on CYP1A2, CYP2C9, and CYP3A 
activity. 
 To evaluate any potential withdrawal symptoms following once-daily dosing of 
lasmiditan. 


 
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Statistical Analysis Plan  
 
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Covance Clinical Study No. 8366191 
 
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4.3 
Exploratory objective 
The exploratory objectives of this study are: 
 To evaluate concentrations of 6-beta hydroxycortisol (6-βOHC) excreted in urine relative 
to plasma concentrations of cortisol as an indicator of CYP3A induction before and after 
treatment with 200 and 400 mg lasmiditan for 7 days. 
 To profile urine for lasmiditan metabolites after multiple doses. 
5. STUDY DESIGN 
This study is a Phase 1, investigator and subject-blinded, randomized, placebo-controlled 
multiple-ascending dose study to assess the effect of once-daily oral dosing of lasmiditan in 2 
cohorts of healthy subjects. Cohort 1 will also assess the effects of lasmiditan and its circulating 
metabolites upon CYP activity by evaluating effects on the PK of components of a 
coadministered cocktail of CYP substrate drugs. 
All subjects will participate in a screening visit up to 28 days prior to admission to the study. 
Subjects in Cohort 1will be admitted to the Clinical Research Unit (CRU) on Day -4, and will 
receive a dose of the probe drug cocktail (100 mg caffeine, 500 mg tolbutamide and 2 mg 
midazolam) on Day -3 with serial blood samples taken at the times listed in the Schedule of 
Activities up to 48 hours postdose for assessment of probe drug PK. Subjects will begin 
receiving oral doses of 200 mg lasmiditan or placebo (at a ratio of 7:3 lasmiditan: placebo) on 
Day 1, and will be dosed once per day until Day 7 (inclusive). The probe drug cocktail will be 
coadministered with lasmiditan on Day 7 and serial blood samples will be taken up to 48 hours 
post dose for the assessment of probe drug PK. Serial blood samples for lasmiditan will be 
collected up to 24 hours postdose on Day 1 and Day 7; also, blood samples will be taken predose 
at Days 3, 4, and 5 to assess the steady-state PK of lasmiditan.  Subjects will be discharged from 
the CRU on Day 9 at the discretion of the investigator.  
Subjects in Cohort 2 will be admitted to the CRU on Day -1. Subjects will begin receiving oral 
doses of 400 mg lasmiditan or placebo on Day 1 (at a ratio of 1:1 lasmiditan to placebo) and will 
be dosed once per day until Day 7 (inclusive). Subjects will be discharged from the CRU on Day 
9 at the discretion of the investigator. Serial blood samples will be taken at times listed in the 
Schedule of Activities of the protocol up to 24 hours postdose on Days 1 and 7 for the 
assessment of lasmiditan PK. Blood samples will be taken predose at Days 3, 4, and 5 to assess 
steady-state PK of lasmiditan. The potential for withdrawal symptoms following multiple dosing 
of lasmiditan will be assessed by daily completion of a benzodiazepine withdrawal questionnaire 
(Tyrer et. al 1990) by subjects in both cohorts from Day 2 of lasmiditan or placebo dosing until 
14 days following the final dose of lasmiditan or placebo. Whilst resident at the CRU, subjects 
will complete the questionnaire under supervision of CRU staff. Subjects will be administered 
the questionnaire via phone by a member of CRU staff each day following discharge from the 
CRU on Day 9 until the follow-up visit in both cohorts.  Additionally, the potential for 
withdrawal symptoms will be assessed using the physician withdrawal checklist on Day 7 and at 
follow-up. 
Subjects in each cohort will return to the CRU for a follow-up visit 14 days after the final dose of 
lasmiditan. Subjects will be resident at the CRU for 13 days (Cohort 1) and 10 days (Cohort 2) 


 
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Statistical Analysis Plan  
 
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Covance Clinical Study No. 8366191 
 
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respectively. The planned study duration for each subject will to 55 days in Cohort 1, and 52 
days in Cohort 2, including screening and follow-up visits. 
6. TREATMENTS 
The following is a list of the study treatment abbreviations that will be used in the TFLs. 
Cohort 
Study Treatment Name 
Abbreviation 
Treatment  
order in TFL 
1 
100 mg caffeine + 500 mg tolbutamide  +  
2 mg midazolam 
Probe drug cocktail 
1 
 
Placebo QD 
Placebo QD 
2 
 
200 mg lasmiditan QD 
200 mg lasmiditan QD 
3 
 
Placebo + 100 mg caffeine +  
500 mg tolbutamide  + 2 mg midazolam 
Placebo QD +  
Probe drug cocktail 
4 
 
200 mg lasmiditan +100 mg caffeine +  
500 mg tolbutamide  + 2 mg midazolam 
200 mg lasmiditan QD + 
Probe drug cocktail 
5 
2 
Placebo QD 
Placebo QD 
6 
 
400 mg lasmiditan QD 
400 mg lasmiditan QD 
7 
7. SAMPLE SIZE JUSTIFICATION 
7.1 
Cohort 1 
Up to 40 subjects may be enrolled in Cohort 1 in order that 30 subjects complete the study. 
Subjects will be randomized at a ratio of 7:3 lasmiditan: placebo in order that 21 completing 
subjects are exposed to lasmiditan and 9 to placebo. Subjects who do not complete the study for 
non-drug related reasons may be replaced, and replacement subjects will be assigned the same 
treatment group as the subject being replaced. 
Caffeine 
For caffeine area under the concentration versus time curve (AUC) the intrasubject coefficient of 
variance (CV) was estimated to be 21.0% 3. Based on this assumption, 21 subjects will provide a 
precision (i.e. half-width of the 90% confidence interval [CI]) of 0.13 on the log scale, with 90% 
power, which corresponds to 12.4% on the natural scale. For caffeine the maximum observed 
drug concentration  (Cmax) the intrasubject CV was estimated to be 23.4% 4. Based on this 
assumption, 21 subjects will provide a precision of 0.15 on the log scale, with 90% power, which 
corresponds to 13.7% on the natural scale. 


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Midazolam
For midazolam AUC the intrasubject CV was estimated to be 40.0% (derived from LY2484595 
study I1V-MC-EIAB). Based on this assumption, 21 subjects will provide a precision of 0.24 on 
the log scale, with 90% power, which corresponds to 21.7% on the natural scale. For midazolam 
Cmax the intrasubject CV was estimated to be 38.0% (derived from LY2484595 study 
I1V-MC-EIAB). Based on this assumption, 21 subjects will provide a precision of 0.23 on the 
log scale, with 90% power, which corresponds to 20.8% on the natural scale.
Tolbutamide
For tolbutamide AUC the intrasubject CV was estimated to be 39.7% (derived from LY2409021 
study I1R-FW-GLBD). Based on this assumption, 21 subjects will provide a precision of 0.24 on 
the log scale, with 90% power, which corresponds to 21.6% on the natural scale. For tolbutamide 
Cmax the intrasubject CV was estimated to be 26.8% (derived from LY2409021 study 
I1R-FW-GLBD). Based on this assumption, 21 subjects will provide a precision of 0.17 on the 
log scale, with 90% power, which corresponds to 15.4% on the natural scale.
Benzodiazepine Withdrawal Symptom Questionnaire
For the Benzodiazepine Withdrawal Symptom Questionnaire total scores, assuming a mean of 9 
in the lasmiditan group, a mean of 1 in the placebo group, and 7.3 common standard deviation 
(assumptions based on results in Tyrer et al. 19905), 21 lasmiditan subjects and 9 placebo 
subjects will provide 85% power to detect a significant difference between lasmiditan and 
placebo (t-test with 2-sided alpha of 0.10).
7.2
Cohort 2
Up to 30 subjects may be enrolled in Cohort 2 in order that 24 subjects complete the study. 
Subjects will be randomized at a ratio of 1:1 lasmiditan: placebo. Subjects who do not complete 
the study for non-drug related reasons may be replaced, and replacement subjects will be 
assigned the same treatment group as the subject being replaced. For the Benzodiazepine 
Withdrawal Symptom Questionnaire total scores, assuming a mean of 9 in the lasmiditan group, 
a mean of 1 in the placebo group, and 7.3 common standard deviation (assumptions based on 
results in Tyrer et al, 1990), 12 lasmiditan subjects and 12 placebo subjects will provide 83% 
power to detect a significant difference between lasmiditan and placebo (t-test with 2-sided alpha 
of 0.10).
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data.  For drug cocktail PK, the PK population will include all 
data from all subjects receiving at least one dose of drug cocktail with evaluable PK data, 
according to the treatment the subjects actually received. For lasmiditan PK, the PK population 
will include all data from all subjects receiving at least one dose of lasmiditan with evaluable PK 
data.


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Subjects may be excluded from the PK summary statistics and statistical analysis if a subject has 
an adverse event of vomiting that occurs at or before 2 times median time of maximum observed 
study drug concentration (tmax). 
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
study drug or placebo and have evaluable PD data.
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: AUCs and Cmax) the geometric 
mean and geometric CV% will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.3 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
Plasma concentrations of lasmiditan (LY573144) and its metabolites (M7, M8 and M18) will be 
used to determine the following PK parameters, when possible:  


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Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUCτ
ng.h/mL
area under the concentration versus time curve during one 
dosing interval
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)
RA
Accumulation ratio based upon AUCτ  and Cmax
MR
metabolic ratioa
Ae
mg
amount of drug excreted (LY573144 only)
fe
%
fraction of dose excreted unchanged (LY573144 only)
CLR
L/h
renal clearance (LY573144 only)
a: no molar correction will be applied since the metabolites are very similar in molecular weight  and within 5% of 
the molecular weight for lasmiditan.
Trough (predose) plasma concentrations of LY573144 and its metabolites will be listed and 
summarised.
Plasma concentrations of caffeine, tolbutamide and midazolam will be used to determine the 
following PK parameters, when possible:  


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Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time 
zero to infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time 
zero to time t, where t is the last time point with a 
measurable concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase 
after extra-vascular administration 
Vss/F
L
apparent volume of distribution at steady state after extra-
vascular administration 
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the clinical study report. Any exceptions or special 
handling of data will be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

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 


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AUC(0-) value excluded from summary statistics will be noted in the footnote of the 
summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve.

The parameters based on predicted Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 

The compound is non-endogenous.

The samples are from the initial dose period for a subject or from a 
subsequent dose period following a suitable wash-out period.

The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.


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
The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all pharmacokinetic 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 pharmacokinetic 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 pharmacokinetic 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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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
Trough concentrations of lasmiditan and its metabolites will be evaluated graphically and/or
descriptively for achievement of steady-state. No formal analysis will be performed for
attainment of steady-state.
The PK parameter estimates of cocktail drugs will be evaluated to delineate the effects of drug 
interaction in Cohort 1 of the study. Midazolam, tolbutamide, and caffeine administered in the 
absence of lasmiditan will represent the reference treatments and will be analysed separately. 
Each drug administered with lasmiditan will represent the test treatments and will be analyzed 
separately. The comparisons made will be the following:

Lasmiditan + Probe drug cocktail (Day 7 [Test]) vs Probe drug cocktail (Day -3 
[Reference]) – Midazolam PK Parameters

Lasmiditan + Probe drug cocktail (Day 7 [Test]) vs Probe drug cocktail (Day -3 
[Reference]) – Tolbutamide PK Parameters

Lasmiditan + Probe drug cocktail (Day 7 [Test]) vs Probe drug cocktail (Day -3 
[Reference]) – Caffeine PK Parameters
For the primary analysis, log-transformed Cmax, AUC(0-tlast), and AUC(0-∞) estimates of all 
probe drugs (midazolam, tolbutamide, and caffeine) will be evaluated in a linear mixed-effects 
analysis of variance model (ANOVA) with a fixed effect for treatment and a random effect for 
subject. The treatment differences will be back-transformed to present ratios of geometric least 
squares means and the corresponding 90% CIs. 


 
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Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Clinical Study No. 8366191 
 
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An example of the SAS code that will be used is as follows: 
 proc mixed data=xxx; 
by analyte; 
 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. 
The tmax will be analyzed using a Wilcoxon signed rank test. Estimates of the median difference 
based on the observed medians, 90% CI, and p-values from the Wilcoxon test will be calculated.  
The 200 mg and 400 mg lasmiditan log-transformed PK parameters Cmax and AUC will be 
analyzed using an ANOVA model.  The model will include treatment as a fixed effect.  Least 
squares mean for each dose level and 90% CIs will be calculated from model. P-values for the 
treatment comparison will be presented.  These values will be back-transformed to give 
geometric least squares means, a point estimate and 90% CI for the ratio between the two dose 
levels.   
Additional analysis will be performed if warranted upon review of the data. 
9.4 
Pharmacodynamic Assessment 
9.4.1 
Pharmacodynamic Analysis 
A benzodiazepine withdrawal symptom questionnaire will be completed by all subjects from 
Day 2 of lasmiditan or placebo dosing until 14 days following the final dose of lasmiditan or 
placebo, in both cohorts.  The physician withdrawal checklist will be completed predose on Day 
7 and follow-up. 
9.4.2 
Pharmacodynamic Statistical Methodology 
Benzodiazepine withdrawal symptom questionnaire scores and physician withdrawal checklist 
will be listed, and summarized by cohort and treatment. Total score at each time point will be 
averaged for each treatment in each cohort based upon the available data, and the lasmiditan 
group will be compared with the placebo group via t-test at each time point within each cohort.  
Days 7 and 21 are of main interinterest and analysis of other days will be performed if 
appropriate.  An example of the SAS code that will be used is as follows: 
proc ttest data=xxxx; 
by cohort day; 
class trtmnt; 
var score; 
run; 
 
where score is the average total score for each cohort, treatment, and time point. 


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Covance Clinical Study No. 8366191
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9.5
Exploratory Assessment
9.5.1
Exploratory Analysis
Plasma levels of cortisol and urinary 6-βOHC will be measured on Days 1 and 7 in Cohort 1 
and 2.  Twenty-four hour urine collections will begin prior to dosing on Days 1 and 7 in Cohort 1 
and 2.  Levels of plasma cortisol relative to urinary 6-βOHC (mean concentration over 24 hour 
period) will be calculated for both days in both cohorts.
9.5.2
Exploratory Statistical Methodology
Exploratory parameters may be listed and summarized by cohort and treatment.  Additional 
analysis will be performed if warranted upon review of the data.
9.6
Safety and Tolerability Assessments
9.6.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (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. Adverse events by day of onset will be presented.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of adverse events, the number of 
subjects experiencing an adverse event and the percentage of subjects experiencing an adverse 
event) of treatment-emergent adverse events will be summarized by treatment, Medical 
Dictionary for Regulatory Activities (MedDRA) version 20.0 system organ class and preferred 
term. The summary and frequency adverse event tables will be presented for all causalities and 
those considered related to the study drug. Any serious adverse events will be tabulated.
9.6.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017
Enhanced Dictionary B2 Format). Concomitant medication will be listed.
9.6.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. Urinalysis data will be listed. Additionally clinical chemistry, hematology and urinalysis 
data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.


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9.6.4
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 a 
magnetic resonance elastography (MRE) scan and 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 age group and 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.
9.6.5
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 orpulse rate 
measurement will be used for orthostatic calculations. Orthostatic changes will be calculated as 
the standing value, minus the last supine value taken prior to the standing value.
Vital signs data will be summarized by cohort and treatment, together with changes from 
baseline, where baseline is defined as the mean of the triplicate measurement on Day 1 predose 
for each treatment for supine vital signs, and the last measurement on Day 1 predose for each 
treatment for standing and orthostatic vital signs. Figures of mean vital signs and mean changes 
from baseline profiles by treatment will be presented by treatment and cohort over time. 
Furthermore, values for individual subjects will be listed.
Summary statistics for baseline-corrected pulse rates will also be calculated and presented. The 
corresponding box plots for the pulse rate and baseline-corrected heart rate will be presented as 
well.
9.6.6
Electrocardiogram (ECG)
For each subject, ECGs will be performed for safety purposes only, and will not be reported. 
9.6.7
Columbia-Suicide Severity Rating Scale (C-SSRS) / Self-Harm Supplement
Data from the C-SSRS questionnaire and Self-Harm Supplement will be listed.
9.6.8
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 


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9.6.9
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
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.
3. Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin 
Pharmacol. 1983;24(1):93-98
4. Turpault S, Brian Q, Van Horn R, Santoni A, Poitiers F, Donazzolo Y, Boulene X. 
Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. 
Br J Clin Pharmacol. 2009;68(6):928-935
5. Tyrer, P, Murphy S., and Riley, P. The Benzodiazepine Withdrawal Symptom Questionnaire. 
J Affect.Discord. 19 (1):53-61, 1990
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.


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13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”