Clinical trial NCT03286218
Conditions: Recreational Drug Use Prescription Drug Abuse (Not Dependent)
Sponsor: Eli Lilly and Company
Start date: 2017-09-15; Completion date: 2017-11-20
Enrollment: 96 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the abuse potential of study drug lasmiditan.

Lasmiditan will be compared to a marketed benzodiazepine, alprazolam (positive control), as well as to placebo (dummy substance that looks like lasmiditan or alprazolam without any active drug) to determine the potential for drug abuse. The dosages will be in tablet form and will be taken orally (by mouth).

This study will last about 55 days, including screening. Screening will occur within 28 days prior to qualification phase.

Detailed description:

Arms: arm 1: Placebo was administered orally in one of five treatment periods arm 2: 2 mg of alprazolam was administered orally in one of five treatment periods arm 3: 100 mg of lasmiditan was administered orally in one of five treatment periods arm 4: 200 mg of lasmiditan was administered orally in one of five treatment periods arm 5: 400 mg of lasmiditan was administered orally in one of five treatment periods
Interventions: intervention 1: Lasmiditan intervention 2: Alprazolam intervention 3: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally

Protocol documents:
Prot_000.pdf: 
H8H-MC-LAHB Protocol 
 
A Randomized, Subject- and Investigator-Blind, Placebo and Active-Controlled Study to Assess the 
Abuse Potential of Lasmiditan   
 
NCT03286218 
 
Approval Date:   05-Sep-2017 


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Protocol H8H-MC-LAHB(c)
A Randomized, Subject- and Investigator-Blind, Placebo-
and Active-Controlled Study to Assess the Abuse Potential 
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:
24 July 2017
Amendment(a) Electronically Signed and Approved by Lilly: 14 August 2017
Amendment(b) Electronically Signed and Approved by Lilly: 31 August 2017
Amendment (c) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 05-Sep-2017 GMT


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Table of Contents
Section
Page
Protocol H8H-MC-LAHB(c) A Randomized, Subject- and Investigator-
Blind, Placebo- and Active-Controlled Study to Assess the Abuse 
Potential of Lasmiditan .......................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
2.1.
Qualification Phase ......................................................................................................10
2.2.
Treatment Phase...........................................................................................................11
3.
Introduction ......................................................................................................................12
3.1.
Study Rationale............................................................................................................12
3.2.
Background..................................................................................................................12
3.3.
Benefit–Risk Assessment .............................................................................................13
4.
Objectives and Endpoints..................................................................................................14
5.
Study Design.....................................................................................................................15
5.1.
Overall Design .............................................................................................................15
5.2.
Number of Participants.................................................................................................16
5.3.
End of Study Definition ...............................................................................................16
5.4.
Scientific Rationale for Study Design...........................................................................16
5.4.1.
Study Population..................................................................................................16
5.4.2.
Selection of Positive Control................................................................................17
5.4.3.
Overall Study Design ...........................................................................................17
5.5.
Justification for Dose ...................................................................................................17
5.5.1.
Lasmiditan ...........................................................................................................17
5.5.2.
Alprazolam ..........................................................................................................18
6.
Study Population...............................................................................................................19
6.1.
Inclusion Criteria..........................................................................................................19
6.1.1.
Qualification Criteria ...........................................................................................21
6.2.
Exclusion Criteria ........................................................................................................21
6.3.
Lifestyle and/or Dietary Requirements .........................................................................23
6.3.1.
Meals and Dietary Restrictions.............................................................................23
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................23
6.3.2.1.
Caffeine and Alcohol......................................................................................23
6.3.2.2.
Tobacco..........................................................................................................23
6.3.3.
Activity................................................................................................................23


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6.3.4.
Contraception Requirement..................................................................................23
6.3.5.
Use of Drugs of Abuse.........................................................................................23
6.4.
Screen Failures.............................................................................................................24
7.
Treatment..........................................................................................................................25
7.1.
Treatment Administered...............................................................................................25
7.1.1.
Packaging and Labeling .......................................................................................26
7.2.
Method of Treatment Assignment ................................................................................26
7.2.1.
Selection and Timing of Doses.............................................................................26
7.3.
Blinding .......................................................................................................................26
7.4.
Dose Modification........................................................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................27
7.7.
Concomitant Therapy...................................................................................................27
7.8.
Treatment after the End of the Study............................................................................28
8.
Discontinuation Criteria ....................................................................................................29
8.1.
Discontinuation from Study Treatment.........................................................................29
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................29
8.2.
Discontinuation from the Study....................................................................................29
8.3.
Subjects Lost to Follow-up...........................................................................................30
9.
Study Assessments and Procedures ...................................................................................31
9.1.
Efficacy Assessments...................................................................................................31
9.2.
Adverse Events ............................................................................................................31
9.2.1.
Serious Adverse Events........................................................................................32
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................32
9.2.2.
Complaint Handling.............................................................................................33
9.3.
Treatment of Overdose.................................................................................................33
9.4.
Safety...........................................................................................................................33
9.4.1.
Laboratory Tests ..................................................................................................33
9.4.2.
Physical Examination...........................................................................................33
9.4.3.
Vital Signs ...........................................................................................................33
9.4.4.
Electrocardiograms ..............................................................................................33
9.4.5.
Columbia Suicide Severity Rating Scale and Self-Harm 
Form....................................................................................................................34
9.4.6.
Safety Monitoring ................................................................................................34
9.4.6.1.
Hepatic Safety................................................................................................35
9.5.
Pharmacokinetics .........................................................................................................35
9.5.1.
Bioanalysis...........................................................................................................35
9.6.
Pharmacodynamics – Abuse Potential Assessments......................................................36


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9.6.1.
Drug Effects and Drug Similarity Visual Analog Scale 
Battery.................................................................................................................36
9.7.
Genetics .......................................................................................................................36
9.8.
Biomarkers...................................................................................................................37
9.9.
Health Economics ........................................................................................................37
10.
Statistical Considerations and Data Analysis.....................................................................38
10.1. Sample Size Determination ..........................................................................................38
10.2. Populations for Analyses..............................................................................................39
10.2.1.
Study Participant Disposition ...............................................................................39
10.2.2.
Study Participant Characteristics ..........................................................................39
10.3. Statistical Analyses ......................................................................................................39
10.3.1.
Safety Analyses....................................................................................................40
10.3.1.1.
Clinical Evaluation of Safety..........................................................................40
10.3.1.2.
Statistical Evaluation of Safety.......................................................................40
10.3.2.
Pharmacokinetic Analyses....................................................................................40
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................40
10.3.3.
Abuse Potential Analyses.....................................................................................40
10.3.4.
Interim Analyses..................................................................................................41
11.
References ........................................................................................................................42


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List of Tables
Table
Page
Table LAHB.1.
Objectives and Endpoints .......................................................................14
Table LAHB.2.
Treatments Administered........................................................................25


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List of Figures
Figure
Page
Figure LAHB.1.
Illustration of study design for Protocol H8H-MC-LAHB.......................16


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................44
Appendix 2.
Clinical Laboratory Tests........................................................................49
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................50
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............53
Appendix 5.
Blood Sampling Summary......................................................................54
Appendix 6.
Protocol Amendment H8H-MC-LAHB(c) Summary:  A 
Randomized, Subject- and Investigator-Blind, Placebo- and 
Active-Controlled Study to Assess the Abuse Potential of 
Lasmiditan..............................................................................................55


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1. Protocol Synopsis
Title of Study:
A Randomized, Subject- and Investigator-Blind, Placebo- and Active-Controlled Study to Assess the Abuse 
Potential of Lasmiditan
Rationale: 
Lasmiditan is being developed for the acute treatment of migraine.  Because lasmiditan penetrates the central 
nervous system and adverse events possibly related to abuse have been reported in completed clinical studies, the 
risk of abuse should be evaluated in accordance with the United States Food and Drug Administration’s Guidance 
for Industry: Assessment of Abuse Potential of Drugs (2017).
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To assess the abuse potential of lasmiditan compared to 
the positive control alprazolam and placebo
The difference in the maximal effect score (Emax) 
during the 24 hours after dosing of the at-the-moment 
100-mm bipolar Drug Liking Visual Analog Scale 
(VAS) scores for:

alprazolam versus placebo

lasmiditan versus alprazolam

lasmiditan versus placebo
Secondary

Further characterize the abuse potential of 
lasmiditan with additional Drug Effects and 
Drug Similarity VAS measures

Safety evaluations

Pharmacokinetics of lasmiditan

Assessing additional Drug Effects and Drug 
Similarity VAS measures in addition to the 
time course of the assessments: overall drug 
liking, take drug again, any effects, good 
effects, bad effects, alertness/drowsiness, 
agitation/relaxation, high, hallucination, and 
similarity.

Treatment-emergent adverse event profiles

Pharmacokinetic parameters: area under the 
concentration versus time curve (AUC) and 
maximum observed drug concentration (Cmax)
Summary of Study Design:
Study H8H-MC-LAHB is a Phase 1, randomized, subject- and investigator-blind, placebo- and active-controlled, 
crossover clinical trial in adult subjects who are recreational poly-drug users.  This study includes 4 phases:
Screening Phase:  A screening phase will determine the eligibility of subjects for the study based on the results of 
screening medical history, physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG).  
Subjects who meet the screening criteria will enter the Qualification Phase.
Qualification Phase: This will be a subject- and investigator-blind, placebo-controlled, 2-period crossover study 
designed to identify subjects who are able to discriminate an alprazolam test dose from placebo. Only subjects who 
meet alprazolam qualification criteria will be eligible to enter the Treatment Phase.


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Treatment Phase:  This will be a subject- and investigator-blind, placebo- and active-controlled, 5-period crossover 
study to evaluate the abuse potential of placebo, alprazolam, and 100-mg, 200-mg, and 400-mg lasmiditan.
Follow-up Phase: Subjects will enter a follow-up phase after their last dose of study drug.
Treatment Arms and Planned Duration for an Individual Subject:  
For the Qualification Phase, subjects will be randomized to a test dose of 1-mg alprazolam and placebo in a 
crossover manner with a washout period of at least 3 days (72 hours) between each dose.
For the Treatment Phase, subjects will be randomized to 1 of 10 dosing sequences; each dosing sequence consists of 
5 dosing periods that evaluate the abuse potential of 1 of the 5 study treatments: placebo, 2-mg alprazolam, 100-mg
lasmiditan, 200-mg lasmiditan, and 400-mg lasmiditan.  The washout period between each dose of at least 3 days
(72 hours).  A follow-up visit will occur approximately 1 week after the last dose of study drug.
Number of Subjects:
An appropriate number of subjects will be screened to allow for approximately 130 subjects to enter into the 
Qualification Phase so that approximately 60 subjects are randomized in the Treatment Phase and approximately 50 
subjects complete the study. Subjects will be randomly assigned to 1 of 10 treatment sequences, determined by the 
repeated Williams square design.  This will lead to 90% or more power for testing each of the hypotheses of primary 
interest regarding the Drug Liking Visual Analog Scale (VAS) endpoints.
Statistical Analysis:
Subjects who complete all 5 periods of the Treatment Phase will comprise the completers population; this will be the 
population used for analyzing the Drug Effects VAS Battery.  Descriptive statistics for continuous variables will 
include mean, standard error, minimum, first quartile, median, third quartile, and maximum.  Descriptive statistics 
for categorical variables include count and percent.
Descriptive statistics for the Drug Liking VAS will be reported for each treatment and for each paired difference 
among treatments.  A linear mixed-effects model, which includes period, sequence, and treatment as fixed effects, 
and subject as a random effect will be used to evaluate the hypothesis tests of primary interest at the peak of drug 
response effects (Emax) at a significance level of 0.05 (1-sided).
Descriptive statistics for other measures in the Drug Effects and Drug Similarity VAS Battery, adverse events, 
safety laboratory parameters, vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS), ECG, and 
pharmacokinetic parameters will be reported by treatment.


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2.
Schedule of Activities
2.1.
Qualification Phase
Study Schedule Protocol H8H-MC-LAHB: Qualification Phase
Procedure
Screening 
Phase
Qualification Phase: Periods 1-2
Comment
Study Day
-28 to -2
-1
1
2
D/C or ET
Minimum of 3 days = 72 h washout between doses
Informed Consent
X
Visits
O
I
I
I
O
I: inpatient; O: outpatient
Medical History
X
Drug History
X
Height
X
Weight
X
X
X
Weight will be collected at screening, Qualification Phase Period 1, and D/C or 
ET.
ECG
X
X
Screening Labs
X
Study Drug Dosing
X
Study drug will be administered on Day 1 after an overnight fast.
AE/Medication Review
X
X
X
X
X
PE
X
X
Full PE at screening and first CRU admission. Symptom-driven PE at all other 
time points as deemed necessary by PI. 
BP/Pulse
X
X
0, 1, 2, 4, 6
24
X
Single supine BP and pulse rate. 
Urine Drug Screen and 
Alcohol Screen
X
X
Urine Drug and Alcohol screen will be collected at screening and Qualification 
Phase Period 1 (additional test may be performed at Period 2 if subject
discharged between periods).
Pregnancy Test
X
X
Serum test at screening. Serum or urine tests thereafter.  Pregnancy test will be 
collected at screening and Qualification Phase Period 1 (additional test will be 
performed at Period 2 if subject discharged between periods).
CBC and Chemistry
X
X
X
Performed as a fasting sample on Day -1 of Period 1 only.
VAS training
X
VAS training to occur on Day -1 of each Period
Drug Effects VAS Battery
0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 
3.5, 4, 4.5, 5, 6, 8, 12
24
Overall Drug Liking and Take Drug Again assessed at 12 and 24 hours 
postdose only.
Drug Similarity VAS Battery
24
Drug Familiarity VAS, a subset of Drug Similarity VAS, will be administered 
at Day 2 Qualification Phase Period 1 only.
C-SSRS/Self Harm
X
X
X
A self-harm form may be administered at time of C-SSRS.  
C-SSRS/Self Harm will be administered at screening, Day -1 Qualification 
Phase of Period 1, and D/C or ET (additional test will be performed at Period 2 
if subject was discharged between periods).
Abbreviations:  AE = adverse event; BP = blood pressure; CBC = complete blood counts; CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; D/C = discontinuation; ECG 
= electrocardiogram; ET = early termination; h = hour; labs = laboratory tests; mins = minutes; PE = physical examination; PI = principle investigator; VAS = visual analogue scale. 
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used:  ECG, vital signs, and venipuncture.
a
Should be taken in the following order: ECG ± 15 mins, BP/Pulse ± 15 mins, and VAS ± 15 mins at nominal time point.


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2.2.
Treatment Phase
Study Schedule Protocol H8H-MC-LAHB: Treatment Phase
Procedure
Treatment Phase: Periods 1-5
Follow-up 
Phase
Comment
Study Day
-1
1
2
D/C or ET
20
Minimum of 3 days = 72 h washout between doses
Visits
I
I
I
O
I: inpatient; O: outpatient; Follow-up = approximately 1 week after last dose of study 
drug.
Weight
X
X
X
Weight will be collected at Treatment Phase Period 1, D/C or ET, and Follow-up.
ECG
X
0, 2, 4
24
X
X
Study Drug Dosing
X
Study drug will be administered on Day 1 after an overnight fast.
AE/Medication Review
X
X
X
X
X
PE
X
Full PE at first CRU admission. Symptom-driven PE at all other time points as deemed 
necessary by PI. 
BP/Pulse
X
0, 1, 2, 4, 6
24
X
X
Single supine BP and pulse rate. Follow same window as PK.
Urine Drug Screen and 
Alcohol Screen
X
X
Urine Drug and Alcohol screen will be collected at Treatment Phase Period 1 and 
Follow-up (additional test will be performed at Periods 2-5 if subject discharged between 
periods).
Pregnancy Test
X
X
Pregnancy test will be collected at Treatment Phase Period 1 only and Follow-up 
(additional test will be performed at Periods 2-5 if subject discharged between periods). 
CBC and Chemistry
X
X
Fasting samples on Days -1 of all periods.
VAS training
X
VAS training to occur on Day -1 of each Period
Drug Effects Battery
0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 
3.5, 4, 4.5, 5, 6, 8, 12
24
Overall Drug Liking and Take Drug Again assessed at 12 and 24 hours postdose only.
Drug Similarity VAS Battery
24
C-SSRS/ Self-Harm
X
X
X
A self-harm form may be administered at time of C-SSRS.  C-SSRS/Self Harm will be 
administered on Day -1 Treatment Phase Period 1, D/C or ET, and Follow-up (additional 
test will be performed at Periods 2-5 if subject discharged between periods).
PK
0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 
8, 12
24
Genetic Sample
X
Genetic samples will be collected at the first period of Treatment Phase only.
Abbreviations:  AE = adverse event; BP = blood pressure; CBC = complete blood counts; CRU = clinical research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; D/C = discontinuation; ECG 
= electrocardiogram; ET = early termination; h = hour; PE = physical examination; PI = principle investigator; PK = pharmacokinetics; VAS = visual analogue scale. 
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used:  ECG, vital signs, and venipuncture.
a
Should be taken in the following order: ECG ± 15 mins, BP/Pulse ± 15 mins, PK ± 5 mins, and VAS ± 15 mins at nominal time point.


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3. Introduction
3.1.
Study Rationale
Lasmiditan is a centrally penetrant, potent, and selective small-molecule 5-hydroxytryptamine
(5-HT)1F receptor agonist.  Lasmiditan is being developed by Eli Lilly and Company (Lilly) for 
the acute treatment of migraine.  This molecule has been developed by Lilly as LY573144 and 
by CoLucid Pharmaceuticals, Inc. (CoLucid) as COL-144. 
Because lasmiditan penetrates the central nervous system (CNS) and adverse events (AEs) 
possibly related to abuse have been reported in completed clinical studies, the risk of abuse will
be evaluated in accordance with the United States (US) Food and Drug Administration’s
(FDA’s) Guidance for Industry: Assessment of Abuse Potential of Drugs (FDA 2017 ).
3.2.
Background
Two Phase 2 studies have been completed with lasmiditan in the acute treatment of migraine, 
using intravenous (IV) and tablet formulations, respectively.  One Phase 3 randomized, double-
blind, placebo-controlled trial has been completed in the US (COL MIG-301 [SAMURAI]). In 
the SAMURAI study, both 100- and 200-mg doses of orally administered lasmiditan achieved 
superior 2-hour pain-free rate and a relief for the most bothersome migraine symptoms compared 
to baseline.
Five Phase 1 studies of lasmiditan have been completed using IV, sublingual, and oral 
formulations of lasmiditan in healthy subjects. Single doses of lasmiditan up to 400 mg were
tolerated by healthy subjects.
In healthy subjects, peak plasma concentrations of lasmiditan were observed approximately 
1 hour to 2.5 hours after a single oral dose, and the geometric mean terminal half-life was 
approximately 4 to 6 hours. Lasmiditan exhibited dose-linear pharmacokinetics (PK); low to 
moderate intersubject variability in exposure was observed across doses (percent coefficient of 
variation [%CV] up to 61% and 45% for maximum observed drug concentration [Cmax] and area 
under the curve [AUC], respectively. Renal clearance of lasmiditan was low, with 
approximately 2% of the parent dose recovered by 24 hours postdose. Coadministration of 
lasmiditan with a high fat diet led to a delay in median time to maximum concentration (Tmax) 
value by approximately 1 hour and a modest (approximately 20%) increase in Cmax and AUC 
values, relative to that under fasted conditions.
Based on the currently available data from in vitro and in vivo studies in humans, lasmiditan 
appears to be eliminated primarily through both non-cytochrome P450 (CYP) and CYP-mediated 
metabolism to form metabolites M8 (keto-reduced metabolite), M7 (carbonyl oxidized 
metabolite), and M18 (keto-reduced, carbonyl oxidized metabolite).  All 3 of these major
metabolites circulate in humans are not considered to be active, and have been quantitated in 
pharmacokinetic (PK) studies. 
Across the completed Phase 1, 2, and 3 clinical studies, doses of 0.1 to 400 mg of lasmiditan 
were evaluated in healthy subjects or patients with migraine; methods of administration included 


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IV, oral, and sublingual.  Compared with placebo, the most frequently reported treatment-
emergent adverse events (TEAEs) that could possibly indicate abuse potential after receiving 
lasmiditan included somnolence, fatigue, dizziness, and hot flash.  Less frequently reported 
TEAEs possibly related to abuse after receiving lasmiditan included euphoric mood, 
hallucination, and feeling abnormal.  A majority of these TEAEs were mild or moderate in 
severity and none led to subjects’ withdrawal.  One subject experienced a serious adverse event 
(SAE) of dizziness that was moderate in severity (lasmiditan 200 mg; COL-MIG 202).
Nonclinical receptor-binding results indicated that with the exception of the 5-HT1F receptor 
subtype, lasmiditan and its major metabolites (M7, M8, and M18) do not demonstrate affinity for 
5-HT1 serotonin receptor subtypes.  Lasmiditan also had poor affinity for the benzodiazepine 
binding site on the gamma-aminobutyric acid (GABA)A ionophore.  Additionally, in a rat drug 
discrimination study, in which lorazepam served as a positive control, none of the lasmiditan 
doses tested (10, 30, and 100 mg/kg) produced a discriminative stimulus similar to lorazepam.
3.3.
Benefit–Risk Assessment
This study compares the abuse potential for lasmiditan versus placebo, and versus alprazolam in 
experienced recreational polydrug users. Thus, there is no anticipated therapeutic benefit for the 
subjects in this study.
To date, lasmiditan has been tolerated by healthy subjects after single dose oral administration up 
to 400 mg. The most frequently reported AEs in clinical studies include somnolence, dizziness, 
fatigue, and hot flash. More information about the known and expected benefits, risks, SAEs,
and reasonably anticipated AEs of lasmiditan are to be found in the Investigator’s Brochure (IB). 
Alprazolam, a short-acting benzodiazepine, has been chosen as a positive control. Potential risks 
from alprazolam include sedation and somnolence. Administration of lasmiditan and alprazolam
will be conducted in inpatient setting, with monitoring of adverse reactions, vital signs, and 
electrocardiograms (ECGs). Adverse events will be managed with supportive care.
Only subjects with a prior history of recreational drug use will be enrolled in this study and a 
maximum of 2 doses within the therapeutic dose range of alprazolam will be administered to 
minimize potential risks, including the risk for dependence. Subjects at risk of adverse reaction 
from alprazolam, including subjects with a prior history of benzodiazepine dependence, seizures, 
or depression and concomitant use of CYP3A inhibitors will be excluded from the study.  
Information about known risks for alprazolam can be found in the package insert for alprazolam.


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4. Objectives and Endpoints
Table LAHB.1 shows the objectives and endpoints of the study.
Table LAHB.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the abuse potential of lasmiditan compared to 
the positive control alprazolam and placebo
The difference in the maximal effect score (Emax) 
during the 24 hours after dosing of the at-the-moment 
100-mm bipolar Drug Liking Visual Analog Scale 
(VAS) scores for:

alprazolam versus placebo

lasmiditan versus alprazolam

lasmiditan versus placebo
Secondary

Further characterize the abuse potential of 
lasmiditan with additional Drug Effects and 
Drug Similarity VAS measures

Safety evaluations

Pharmacokinetics of lasmiditan

Assessing additional drug effects and drug 
similarity VAS measures in addition to the 
time course of the assessments: overall drug 
liking, take drug again, any effects, good 
effects, bad effects, alertness/drowsiness, 
agitation/relaxation, high, hallucination, and 
similarity.

Treatment-emergent adverse event profiles

Pharmacokinetic parameters: area under the 
concentration versus time curve (AUC) and 
maximum observed drug concentration (Cmax)
Tertiary/Exploratory
Pharmacokinetics of alprazolam

Pharmacokinetic parameters: AUC and Cmax


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5. Study Design
5.1.
Overall Design
This study is a Phase 1, randomized, subject- and investigator-blind, placebo- and active-
controlled, crossover clinical trial in adult subjects who are recreational poly-drug users.  This 
study includes 4 phases:
Screening Phase: Subjects will sign informed consent before their entry to the study and 
completion of all screening procedures. Screening visits should be within 28 days of dosing in 
Qualification Phase. Subjects who fail screening may not be rescreened. 
Qualification Phase:  Eligible subjects who meet all inclusion criteria and none of the exclusion 
criteria will enter a subject- and investigator-blind placebo-controlled, 2-period crossover design
Qualification Phase. Subjects will be randomized to a test dose of 1-mg alprazolam and placebo 
in a crossover manner with a washout period of at least 3 days (72 hours) between each dose.
“Drug-liking” response will be assessed before and after alprazolam and placebo administration
using a 100-mm bipolar Drug Liking Visual Analog Scale (VAS). Only subjects who meet 
alprazolam qualification criteria (see Section 6.1.1) will be eligible to enter the Treatment Phase.
Treatment Phase: This will be a subject- and investigator-blind, placebo- and active-controlled, 
5-period crossover design. Subjects will be randomized to 1 of 10 dosing sequences; each 
dosing sequence consists of 5 dosing periods that evaluate the abuse potential of 1 of the 5 study 
treatments: placebo, 2-mg alprazolam, and 100-mg lasmiditan, 200-mg lasmiditan, and 400-mg 
lasmiditan. The washout period between each dose should be at least 3 days (72 hours).
Eligible subjects will be admitted to the clinical research unit (CRU) on Day -1 before the 
planned study drug dosing during each of the dosing periods in both the Qualification Phase and 
Treatment Phase. After verification of subjects’ eligibility, including a urine drug screen at time 
of CRU admission, blinded study drug will be administered on Day 1 after an overnight fast. 
Abuse potential will be assessed using Drug Effects VAS Battery. Adverse events, vital signs,
and ECGs will be monitored, and PK samples will be collected according to the Study Schedule 
(Section 2). 
Follow-up Phase:  Subjects will have a follow-up visit approximately 1 week after their last dose 
of study drug, and will present to the CRU for discharge from the study as deemed appropriate 
by the investigator. Subjects who discontinued from the study before its completion will be 
asked to attend an Early Discontinuation visit (according to the Study Schedule [Section 2])
approximately 1 week after the last dose of study drug dosing.
Study governance considerations are described in detail in Appendix 3.
Figure LAHB.1 illustrates the study design.


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Abbreviations: High = high (400 mg) dose; Las = lasmiditan; Low = low (100 mg) 
dose; Med = medium (200 mg) dose.
Figure LAHB.1.
Illustration of study design for Protocol H8H-MC-LAHB.
5.2.
Number of Participants
An appropriate number of subjects will be screened to allow for approximately 130 subjects to 
enter into the Qualification Phase so that approximately 60 subjects are randomized in the 
Treatment Phase and approximately 50 subjects complete the study.  For the purposes of this 
study, a subject completes the study when all scheduled procedures shown in the Schedule of 
Activities (Section 2) have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
This study is designed based on the FDA’s Guidance for Industry: Assessment of Abuse 
Potential of Drugs (FDA 2017[WWW]).
5.4.1. Study Population
The population for this study is recreational poly-drug users who are able to discriminate 
between alprazolam and placebo. The selection of this population ensures that the subjects are 
familiar with the psychoactive effects of the positive control to improve the sensitivity for 
detecting any abuse potential for lasmiditan. In addition, subjects with prior experience of 
recreational use of sedative medications are more likely to tolerate alprazolam. Lilly or its 
designee will attempt to enroll a comparable number of men and women, where possible.


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5.4.2. Selection of Positive Control
The AE data suggested that the predominant AEs for lasmiditan were sedative effects, including 
somnolence, with occasional subjects/patients also reporting euphoric-related terms, including 
euphoric mood and hallucination. Alprazolam has been shown to be able to produce both 
sedative and euphoric type of symptoms (Zawertailo et al. 1995). 
Furthermore, lasmiditan and alprazolam have similar PK profiles.  Following oral administration, 
alprazolam is readily absorbed. Peak concentrations in the plasma occur in 1 to 2 hours 
following administration. Plasma levels are proportionate to the dose given; over the dose range 
of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. The mean plasma elimination 
half-life of alprazolam is about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults. The 
median Tmax value of lasmiditan was approximately 1 hour to 2.5 hours, and mean terminal half-
life was approximately 4 to 6 hours after oral dosing.
The similarity of both PK and AE profiles of alprazolam and lasmiditan makes alprazolam an 
appropriate positive control for this study.
Alprazolam has demonstrated abuse potential consistent with other drugs in the benzodiazepine 
class of compounds and is scheduled under the Controlled Substance Act as a C-IV.
5.4.3. Overall Study Design
The abuse potential will be assessed using a Drug Effects VAS Battery (Section 9.6.1). Due to 
the subjective nature of these endpoints, the design is subject- and investigator-blind. Subjects 
and the investigator will be informed of the treatments to be tested in the study; they will be 
blind to the treatment assignment at each period, which reduces the expectation bias. The 
crossover design minimizes the inter-individual variability and improves the sensitivity for 
detecting any differences between treatments. Previous studies on alprazolam suggest that the 
drug-liking effects reduced to neutral about 24 hours after a 1-mg to 3-mg dose, indicating that a
3-day washout period for the Qualification Phase will be adequate (Levy-Cooperman et al.
2016). Based on the PK properties of lasmiditan, a washout period of at least 3 days is deemed 
adequate for the Treatment Phase; major metabolites are not considered active. 
5.5.
Justification for Dose
5.5.1. Lasmiditan
Three single doses of 100, 200, and 400 mg lasmiditan have been selected for this protocol.
Lasmiditan is being evaluated in patients with migraine at 50, 100, and 200 mg in the Phase 3 
program. The likely commercial dose levels are 100 and 200 mg based on data from the Phase 2 
study (COL MIG-202) and the concluded Phase 3 study (SAMURAI).  The 400-mg dose level is 
the highest oral dose tested in the lasmiditan clinical program to date. This dose has been 
tolerated by both healthy subjects and patients with acute migraine attacks. It represents 2 times
the highest proposed commercial dose of 200 mg, which is consistent with the recent FDA 
guidance for identifying a supratherapeutic dose for evaluation in a human abuse potential study.  


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At a 400-mg dose, CNS AEs that may suggest abuse potential, including somnolence, dizziness, 
euphoria, and hallucination, have been reported in healthy subjects (thorough QT [TQT] Study 
COL MIG-105) and migraine patients.
5.5.2. Alprazolam
In this single-dose study, a 1-mg dose of alprazolam will be tested in the Qualification Phase and 
2-mg doses of alprazolam will be tested in the Treatment Phase. 
Clinical studies demonstrated the abuse potential of a single dose of immediate-release 
alprazolam between the dose range of 1 to 4 mg (Mumford et al. 1995).  Drug-liking effects of 
alprazolam were numerically higher with a higher dose within the 1- to 4-mg dose range using 
the categorical scale (Evans et al. 1994; Mumford et al. 1995). 
The use of different dose levels between the Qualification Phase and Treatment Phase is 
consistent with precedent (Blanchard et al. 2010) and ensures that the subjects enrolled into the 
Treatment Phase can safely tolerate and are sensitive to the effects of the positive control.  This 
will help to ensure that subjects can perform the tests and that significant liking is detectable in 
this study.  Using bipolar Drug Liking VAS, the drug-liking effects between 1- and 3-mg 
alprazolam was modest (2 to 4 mm) (Blanchard et al. 2010; ClinicalTrials.gov [WWW]). 
Therefore, only 1 dose of 2-mg alprazolam will be evaluated in the Treatment Phase as positive 
control.
The 1- and 2-mg doses are within the therapeutic dose range of alprazolam (Xanax® US package 
insert, 2011).  Risk and severity of dependence appear greater in patients treated with alprazolam 
doses >4 mg/day and for periods of >12 weeks (Xanax US package insert, 2011). Higher doses 
of alprazolam are also associated with other adverse effects, such as more severe sedation and 
somnolence.  Thus, higher doses beyond 2 mg are not proposed for this study.


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG. 
Abnormal screening tests (including, but not limited to physical examination, screening 
laboratory tests, vital signs, and ECG) may be repeated based on the investigator’s judgment.  
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to the Qualification Phase.  Subjects who do not enter 
the Qualification Phase within 28 days of screening may be subjected to an additional medical 
assessment and/or clinical measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination
[1a] female subjects:

Women not of childbearing potential may participate and include those 
who are:
A. infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as Müllerian 
agenesis; or 
B. postmenopausal – defined as either 
i. A woman at least 50 years of age with an intact uterus, not 
on hormone therapy, who has had either: a) cessation of 
menses for at least 1 year, or b) at least 6 months of 
spontaneous amenorrhea with a follicle-stimulating 
hormone >40 mIU/mL; or
ii. A woman 55 years or older not on hormone therapy, who 
has had at least 6 months of spontaneous amenorrhea; or 
iii. A woman at least 55 years of age with a diagnosis of 
menopause prior to starting hormone replacement therapy.

Women of childbearing potential who are abstinent (if this is complete abstinence 
as their preferred and usual lifestyle) or in a same-sex relationship (as part of their 
preferred and usual lifestyle) must agree to either remain abstinent or stay in a 
same-sex relationship without sexual relationships with males.


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
Otherwise, women of childbearing potential (WOCBP) participating must agree 
to use 2 forms of effective contraception, where at least 1 form is highly effective 
(less than 1% failure rate), for the entirety of the study. Contraception must 
continue for 1 month following completion of study drug administration.
a.
WOCBP must test negative for pregnancy prior to initiation of 
treatment as indicated by a negative serum pregnancy test at the 
screening visit followed by a negative pregnancy test (serum or 
urine tests) within 24 hours prior to exposure. Subsequent 
pregnancy testing (urine or serum tests) should be completed 
monthly.
b. Two forms of effective contraception, where at least one form is 
highly effective (such as combination oral contraceptives, 
implanted contraceptives, or intrauterine devices) will be used.
Effective contraception (such as male or female condoms with 
spermicide, diaphragms with spermicide, or cervical sponges) may 
be used as the second therapy. Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable 
method. Thus, each barrier method must include use of a 
spermicide (ie, condom with spermicide, diaphragm with 
spermicide, female condom with spermicide). It should be noted 
that the use of male and female condoms as a double-barrier 
method is not considered acceptable due to the high failure rate 
when these methods are combined.
[2]
are 18 to 55 years of age inclusive at time of consent
[3]
have a body mass index of 18 to 32 kg/m2, inclusive
[4]
have clinical laboratory test results within normal reference range, or results 
with acceptable deviations that are judged to be not clinically significant by 
the investigator
[5]
have venous access sufficient to allow for blood sampling as per the protocol
[6]
are able and willing to give signed informed consent, are reliable and willing 
to make themselves available for the duration of the study and are willing to 
follow study procedures
[7]
Subjects must be recreational drug users defined as follows:

≥10 lifetime non-therapeutic experiences (ie, for psychoactive effects) with 
central nervous system (CNS) depressants (eg., benzodiazepines, 
barbiturates, zolpidem, eszopiclone, propofol/fospropofol, gamma-hydroxy-
butyrate)

≥1 non-therapeutic use of a CNS depressant/sedative drug within the 
12 weeks prior to Screening.

≥1 lifetime non-therapeutic use of another drug class of abuse (eg, opioids, 
stimulants, dissociatives, or hallucinogens).


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[8]
agree not to consume any recreational drugs during the study.
6.1.1. Qualification Criteria
In order to qualify for the Treatment Period of the study, subjects must demonstrate the ability to 
discriminate an alprazolam test dose from placebo, using the 100-mm bipolar Drug Liking VAS,
as defined by:

Acceptable placebo response ranging from 40 to 60 (inclusive) on the 100-mm
bipolar VAS for Drug Liking “at this moment”.

≥15-mm increase in “liking” alprazolam more than placebo.

Subject is able to tolerate the 1-mg dose of alprazolam, as judged by the 
investigator, including the ability to complete all pharmacodynamic assessments 
within 4 hours post-dose.

General behavior suggests that the subject could successfully complete the study, 
as judged by the study site personnel.
On a case-by-case basis, a subject who meets all of the above criteria, with the exception 
of sporadic erroneous responses, may be permitted into the treatment phase, provided that 
the investigator or designee determines that the subject’s response was made in error and 
that the subject can be successfully retrained regarding proper completion of that 
assessment.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[9]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[10]
are Lilly or Covance employees
[11]
are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[12]
have been dosed with an investigational drug within the 30 days prior to 
admission during the Qualification Phase.
[13]
have previously completed or withdrawn from this study or any other study 
investigating lasmiditan, and have previously received the investigational 
product.
[14]
have known allergies to lasmiditan, alprazolam, related compounds, or any 
components of the formulation, or a history of significant atopy.


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[15]
has evidence of drug or alcohol dependence (excluding nicotine and/or 
caffeine) within the past 1 year as defined by the Diagnostic and Statistical 
Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), or has 
a lifetime history of participation in a drug rehabilitation program, excluding 
past participation in tobacco smoking cessation programs or previous court 
mandated treatment.
[16]
are currently seeking or participating in treatment for addiction or 
substance-related disorders, or have recovered from substance abuse disorder.
[17]
have a significant history of or current cardiovascular (including arrhythmia, 
bradycardia, heart block), respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, or neurological disorders capable of significantly 
altering the absorption, metabolism, or elimination of drugs; of constituting a 
risk when taking the investigational product; or of interfering with the 
interpretation of data.
[18]
have a history of significant psychological illness, including any affective 
disorders within the past year, or are currently taking medications for 
psychological illness, including selective serotonin reuptake inhibitors, 
serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, 
or tricyclic antidepressants.
[19]
are currently taking prescription or over-the-counter (OTC) medications other 
than those that are permitted (as outlined in Section 7.7).
[20]
Positive test results for human immunodeficiency virus- (HIV-) 1/HIV-2 
antibodies, Hepatitis B surface antigen (HBsAg) or Hepatitis C virus antibody 
(HCVAb).
[21]
are women who are lactating.
[22]
have a history of significant sleep disorder, including sleep apnea or
narcolepsy.
[23]
have donated blood of more than 500 mL within the previous 4 weeks of 
study screening.
[24]
have an average weekly alcohol intake that exceeds 21 units per week for 
males, and 14 units per week for females, or are unwilling to follow study 
alcohol restrictions (refer to Section 6.3.2).
[25]
have a history of orthostatic hypotension, vertigo, syncopy, or presyncopy
[26]
have a history of brain injury, including a history of concussions.
[27]
take medications or other substances that affect CYP3A activity within 
14 days of screening.


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[28]
in the opinion of the investigator are considered to be a danger to themselves, 
or who have answered “yes” to either Question 4 or Question 5 on the 
Suicidal Ideation portion of the C-SSRS; or answered “yes” to any of the 
suicide-related behaviors on the Suicidal Behavior portion of C-SSRS, and the 
ideation and behavior occurred within the past 6 months.
[29]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Meals and Dietary Restrictions
Subjects are prohibited from consumption of grapefruit, grapefruit juice, and Seville (blood) 
oranges and their juice during the entire duration of the study.  Subjects should only consume 
meals/snacks provided by the CRU during inpatient stays.  Subjects should fast from midnight 
on Day -1 up to the time of dosing.
6.3.2. Caffeine, Alcohol, and Tobacco
6.3.2.1.
Caffeine and Alcohol
Subjects may be allowed 2 servings of a caffeinated beverage during inpatient days.
The use of alcohol is not allowed from 24 hours before all study visits and during the inpatient 
clinic stays. At all other times, alcohol consumption is limited to no more than 2 alcoholic 
beverages or the equivalent per day. Breath alcohol tests or the equivalent will be performed as 
shown in the Schedule of Activities (Section 2).
6.3.2.2.
Tobacco
Subjects must adhere to smoking restrictive rules of CRU during the inpatient stays and at 
outpatient visits.
6.3.3. Activity
Subjects must refrain from strenuous exercise throughout the study. Subjects should not be 
allowed to drive or operate machinery, unless deemed appropriate by the investigator.
6.3.4. Contraception Requirement
See Inclusion Criteria [1] (Section 6.1) for details on the use of contraception during the study.
6.3.5. Use of Drugs of Abuse
Subjects will be instructed to refrain from recreational drug use for the duration of the study 
(from screening through the last treatment period), including cannabinoid use. While a positive 
cannabinoid test may not exclude the subject from further participation, the subject will be 
informed that there is a safety risk of using recreational drugs during the study and that an 


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adverse interaction with a recreational drug is possible. If a subject reports to the clinical 
research facility and has a positive cannabinoid test, the subject will be required to pass a 
Cannabis Intoxication Evaluation to confirm that he/she is not cognitively impaired or 
intoxicated. Following this evaluation, continued eligibility will be at the discretion of the 
Investigator.
A subject with a positive result on the screen for substances of abuse, other than cannabinoids, 
may be rescheduled and retested up to 3 times at the discretion of the Investigator. If the subject 
continues to have positive results, he/she will be discontinued from the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.


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7. Treatment
7.1.
Treatment Administered
This study compares single doses of orally administered lasmiditan at 100, 200, and 400 mg with
placebo and alprazolam.
Table LAHB.2 shows the treatment regimens.
Qualification Phase: 1 tablet of alprazolam or placebo will be administered orally with 
approximately 240 mL of room temperature water in the morning, in a sitting position, after an 
overnight fast.
Treatment Phase:  An appropriate number of lasmiditan, alprazolam, and/or placebo tablets will 
be administered orally with approximately 240 mL of room temperature water, in the morning of 
each dosing day, in a sitting position, after an overnight fast.  The total number of tablets
administered in each of the 5 dosing periods will be the same.
Study drugs (alprazolam, lasmiditan, and/or placebo) will be prepared into individual dispensing 
cups by an unblinded pharmacist and administered by an unblinded staff member who will not 
be involved in any study assessment procedures. Subjects will be blindfolded prior to each 
dosing session for each period during the Qualification and Treatment Phases. The unblinded 
staff member will hand the dispensing cup to each subject, who will then self-administer all 
tablets in the dispensing cup without touching any of the tablets by hand. Neither the 
Investigator nor any nursing staff involved in the subject assessment will be allowed to witness 
the study drug administration.
For both phases, water will be allowed 1 hour after study drug dosing, and meals will be allowed 
approximately 2 hours after study drug dosing. Subjects will not be allowed to lie supine for 
2 hours after dosing, unless clinically indicated or for study procedures.
Table LAHB.2.
Treatments Administered
Treatment Name
Lasmiditan
Placebo
Alprazolam
Dosage Formulation
Tablet
Tablet
Tablet
Unit dose Strength(s)/Dosage 
Level(s)
100-mg, 200-mg tablets
Placebo to match lasmiditan
1-mg or 2-mg tablet
Route of Administration
Oral
Oral
Oral
The investigator or designee is responsible for:

explaining the correct use of the investigational product(s) to the site personnel

verifying that instructions are followed properly


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
maintaining accurate records of investigational product dispensing and collection

returning all unused medications to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.
7.1.1. Packaging and Labeling
Each lasmiditan tablet contains 100 or 200 mg of active ingredient and is provided as bulk 
supply in bottles.  Placebo tablets look identical to 100- or 200-mg lasmiditan, but contain no 
active ingredient, and will be provided in similar bulk bottles.
Alprazolam will be obtained from commercial source.  The details and presentation of 
alprazolam will be provided prior to document finalization.
The investigational product will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Treatment sequences will be determined using a repeated 5×5 Williams square design
(Figure LAHB.1). The study will be conducted at a single study center, so the respective 
randomization schedule can be securely maintained by the study center pharmacist who is 
responsible for dispensing the blinded study medication in accordance with the schedule.  The 
sponsor (or designee) will be responsible for generating each of the randomization schedules and 
distributing them directly to the study center pharmacist.
7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the subject’s case report form (CRF).
7.3.
Blinding
Blinding will be maintained throughout the conduct of the study as described in the separate 
Blinding Plan.
Emergency codes will be available to the investigator.  A code, which reveals the treatment 
assignment 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 
further drug administration, unless the investigator obtains specific approval from a Lilly clinical 
pharmacologist or clinical research physician (CRP) for the study participant to continue in the 
study.  During the study, emergency unblinding should occur only by accessing the study 
subject’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 


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subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all investigational products
received and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational products or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational products should be stored in an environmentally controlled and monitored 
(manual or automated) area, in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
Subjects on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study. Any concomitant medication must be 
documented in the CRF.
Drugs, or supplements that are known inducers, or inhibitors of CYP3A are specifically 
excluded.  Additional drugs are to be avoided during the study unless required to treat an AE or
for the treatment of an ongoing medical problem.
At least 14 days prior to the Qualification Phase and during the course of the entire study, 
subjects should not take any new prescribed medications.  Over the counter (OTC) medications, 
vitamins, or herbal supplements other than those permitted at the time of screening will not be 
permitted for 7 days prior to the Qualification Phase and during the course of the entire study. 
Medications with psychoactive properties include, but are not limited to, anxiolytics, 
antidepressants, anticonvulsants, antipsychotics, medical cannabis, OTC diet or sleep aids, 
histamine antagonists, cough/cold/sinus preparations, steroids, narcotic analgesics, and 


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phosphodiesterase 5 inhibitors.  Medications for weight loss or smoking cessation are 
specifically excluded.
In general, concomitant medication should be avoided; however, acetaminophen (maximum 
2 g/24 hours) may be administered at the discretion of the investigator for treatment of 
headaches, or minor pain or fever, etc.  If the need for concomitant medication (other than
acetaminophen) arises, inclusion or continuation of the subject may be at the discretion of the 
investigator after consultation with a Lilly clinical pharmacologist or CRP or designee.  Any 
medication used during the course of the study must be documented in the CRF.
7.8.
Treatment after the End of the Study
Not applicable.


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8. Discontinuation Criteria
Subjects discontinuing from the treatment prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 of this protocol.
Subjects discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Subjects will be discontinued from the investigational product under the following 
circumstances:

Subjects who experience an SAE, regardless of causality

Subjects who experience a sustained moderate or severe AEs that require medical 
intervention
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist or CRP
and the investigator to determine if the subject may continue in the study.  If both agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist or CRP to allow the inadvertently enrolled subject to continue in 
the study with or without continued treatment with investigational product.
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator or designee decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent
o
Physician decision
o
Protocol violation
o
AE


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o
Death
o
Study terminated by Sponsor
o
Met protocol defined discontinuation criteria
o
Other

Subject Decision
o
the subject requests to be withdrawn from the study
If a subject withdraws from the study, the investigator or designee will complete and report the 
observations as thoroughly as possible up to the date of withdrawal, including the date of last 
treatment and the reason for withdrawal.
If the subject is withdrawn due to an AE, the investigator or designee will follow the subject until 
the AE has resolved or stabilized. All subjects who are withdrawn from the study should 
complete protocol specified withdrawal procedures.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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


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Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via electronic data entry.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization, but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/clinical pharmacologist, or its designee, of any 
SAE as soon as practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
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 the investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB, and that the investigator reports as related to the investigational product or procedure.  
Lilly has procedures that will be followed for the recording and expedited reporting of SUSARs 
that are consistent with global regulations and the associated detailed guidances.


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9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product (or drug delivery system) so that the 
situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of lasmiditan or alprazolam is considered any dose 
higher than the dose assigned through randomization.
Refer to the lasmiditan IB for information on the clinical consequences of an overdose. Refer to 
the alprazolam US Package Insert for information on overdose.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor, if a central vendor is used for the study.
9.4.2. Physical Examination
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities (Section 2) and as clinically indicated.
9.4.3. Vital Signs
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  If orthostatic measurements are required, subjects should be supine 
for at least 5 minutes and stand for at least 2 minutes. If the subject feels unable to stand, supine 
vital signs only will be recorded.
Additional vital signs may be measured during each study period, if warranted.
9.4.4. 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 investigational product, should be reported to Lilly, or its 
designee, as an AE via electronic data entry.
For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 
samples.  Subjects must be supine for at least 5 minutes before ECG collection and remain 
supine, but awake, during ECG collection.  Electrocardiograms may be obtained at additional 
times, when deemed clinically necessary.  
Electrocardiograms will be interpreted by the investigator, or qualified designee, at the site as 
soon after the time of ECG collection as possible, and ideally while the subject is still present, to 
determine whether the subject meets entry criteria at the relevant visit(s) and for immediate 
subject management, should any clinically relevant findings be identified.
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/corrected QT [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.
9.4.5. Columbia Suicide Severity Rating Scale and Self-Harm Form
The Columbia Suicide Severity Rating Scale (C-SSRS) (Posner 2007; Posner et al. 2007a,
Posner et al. 2007b) captures the occurrence, severity, and frequency of suicide-related thoughts 
and behaviors during the assessment period.  The scale includes suggested questions to solicit the 
type of information needed to determine if a suicide-related thought or behavior occurred.  The 
C-SSRS and a corresponding Self-Harm Supplement Form will be administered at the times 
specified in the Schedule of Activities (Section 2).  If a self-harm event is reported, investigators 
will also complete the Self-Harm Follow-Up Form.  If the subject does not attend the 
discontinuation visit, the C-SSRS and Self-Harm Supplement Form should still be completed if 
the site has become aware of a suicide-related thought or behavior by other communications.  If 
a self-harm or suicidal-related event is considered serious by the investigator, it must be reported 
as an SAE via the procedures indicated in Section 9.2. The C-SSRS, Self-Harm Supplement 
Form, and Self-Harm Follow-Up Form must be administered by appropriately trained site 
personnel.  Any significant change would necessitate a referral to a psychiatrist.
9.4.6. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.  Lilly will review SAEs within the time frames mandated by company procedures.  
The Lilly clinical pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes


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
adverse events
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the Blinding Plan.
9.4.6.1.
Hepatic Safety
If a study subject experiences elevated alanine aminotransferase (ALT) ≥3X upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2X ULN, or elevated total bilirubin level (TBL)
≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, 
aspartate aminotransferase (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 levels normalize and/or are returning to approximate baseline 
levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be a SAE.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine the plasma concentrations of lasmiditan and alprazolam.  A 
maximum of 3 samples may be collected at additional time points during the study if warranted 
and agreed upon between both the investigator and sponsor.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and time (24-hour 
clock time) of each sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative
sites or blinded personnel until the study has been unblinded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor, and stored at a facility 
designated by the sponsor.


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Concentrations of lasmiditan and alprazolam will be assayed using validated liquid 
chromatography with tandem mass spectrometric detection (LC/MS/MS) methods.  Samples will 
only be analyzed for the drug administered. Samples collected to maintain the blinding will not 
be analyzed.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following the last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses, such as 
metabolism and/or protein binding work.
9.6.
Pharmacodynamics – Abuse Potential Assessments
9.6.1. Drug Effects and Drug Similarity Visual Analog Scale Battery
Drug Effects VAS Battery lists a series of Drug Effects VAS measures that evaluate different 
subjective effects of the abuse potential of the study drug.
The primary objective of the study is to assess the abuse potential of lasmiditan compared to the 
positive control alprazolam and to placebo using the maximal effect score (Emax) of the at-the-
moment 100-mm bipolar Drug Liking VAS.  The bipolar Drug Liking VAS is consistent with 
FDA Guidance (January 2017) such that placebo should produce a score between 40 and 60 
representing neutral drug-liking (ie, neither like nor dislike); a score of 0 indicates strong 
disliking, and a score of 100 indicates strong liking.
The remaining questions in the Drug Effects VAS Battery and the Drug Similarity VAS Battery
will be assessed as secondary endpoints.
Subjects must draw a point on a 100-mm horizontal line that best represents their response to the 
given question.  The endpoints of each electronic scale are marked with descriptive anchors on a 
scale from 0 to 100 (Fraser et al. 1961; Bond and Lader 1974; Bigelow 1991; Shram et al. 2010).
The VAS measurements should be conducted according to the Schedule of Activities (Section 2). 
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research, either 
now or in the future.  Samples will be used to investigate variable exposure or response to
lasmiditan and to investigate genetic variants thought to play a role in migraine or substance 
abuse.  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 institutional review boards impose shorter time limits, for the 


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


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The study design and analysis methods are as prescribed in “Assessment of Abuse Potential of 
Drugs: Guidance for Industry” published by the US FDA, January 2017 (FDA 2017).  Three 
different hypothesis tests are of primary interest:
1. Validation test of the sensitivity and integrity of the study: Does the positive control (C) 
produce mean responses that show greater abuse potential compared to placebo (P)?
H10: μC – μP ≤ δ1 versus H1a: μC – μP > δ1 where δ1 > 0
2. Does the test drug (T) produce mean responses that show less abuse potential compared 
to positive control?
H20: μC – μT ≤ δ2 versus H2a: μC – μT > δ2 where δ2 ≥ 0
3. Does the test drug produce mean responses that show similar abuse potential, compared 
to placebo? 
H30: μT – μP ≥ δ3 versus H3a: μT – μP < δ3 where δ3 > 0
Approximately 60 subjects will be randomly assigned to 1 of 10 treatment sequences, in order to 
get approximately 50 completers.  Subjects who are randomized but who do not complete all 5 
periods during the Treatment Phase may be replaced. Replacement subjects will enter the same 
treatment sequence as the original subjects to complete all 5 periods. Treatment sequence 
assignment will be determined by the repeated Williams square design, as shown in 
Figure LAHB.1.  This will lead to 90% or more power for testing each of the hypotheses of 
primary interest listed above, with the following assumptions:

standard deviation of differences of 16 for the Drug Liking VAS (estimate based on 
within-subject standard deviation estimate of 11.4 from previous studies [Blanchard et al. 
2010])

actual mean difference between alprazolam and placebo of 22 or more for the Drug 
Liking VAS,

actual mean difference between alprazolam and lasmiditan of 12 or more for the Drug 
Liking VAS,

actual mean difference between lasmiditan and placebo of 7 or less for the Drug Liking 
VAS,

δ1 = 15, δ2 = 5, and δ3 = 14; and

one-sided significance level of 0.05.
The margin for comparing alprazolam with placebo (δ1) is defined as 15 mm, based on the 2017 
FDA guidance , stating that there should be a difference of at least 15 points between placebo 
and positive control response.  The margin for comparing alprazolam with lasmiditan (δ2) is 


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defined as 5 mm, based on the need to show that lasmiditan shows some non-negligible lower 
abuse potential compared to positive control.  The margin for comparing lasmiditan with placebo 
(δ3) is defined as 14 mm. Consistent with FDA advice, the margin for comparing lasmiditan 
with placebo (δ3) is less than the margin for comparing the positive control (alprazolam) to 
placebo (δ1).
10.2. Populations for Analyses
Subjects who complete all 5 periods of the Treatment Phase will comprise the Completers 
population; this will be the population used for analyzing the Drug Effects VAS Battery.  
Pharmacokinetic/Pharmacodynamic (PK/PD) analyses will be conducted on data from all 
subjects who receive at least 1 dose of lasmiditan or alprazolam and have evaluable PK.  All 
subjects who take at least 1 dose of the investigational product will comprise the safety 
population; this will be the population used for all analyses except the Drug Effects VAS Battery
analyses and PK/PD 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 subject’s year of birth, sex, weight, height, and other demographic characteristics will be 
recorded. Age and body mass index will be calculated.  Demographic and baseline 
characteristics will be summarized.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.  A complete list 
of planned tables, figures, and listings will be included in a separate Statistical Analysis Plan.
Descriptive statistics for continuous variables will include mean, standard error, minimum, first 
quartile, median, third quartile, and maximum.  Descriptive statistics for categorical variables 
include count and percent.  Additional exploratory analyses of the data will be conducted, as 
deemed appropriate.
The pattern of missing data will be assessed in the population of patients who entered into the 
treatment phase and took at least 1 dose of study drug in the treatment phase by looking at the 
trend of dropout rates among the first 4 periods, as well as comparing the dropout rates among 
the 5 treatments. 
A sensitivity analysis will be performed on all patients who entered into the treatment phase and 
received at least 1 dose of study drug in the treatment phase, regardless of completion of all the 5
periods. The same mixed model and model diagnosis procedure as the primary analysis will be 
implemented.


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10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed by treatment, and if the 
frequency of events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment period will be presented by severity and by 
association with the investigational product as perceived by the investigator.  Symptoms reported 
to occur prior to study entry will be distinguished from those reported as new or increased in 
severity during the study.  Each symptom will be classified by the most suitable term from the 
Medical Dictionary for Regulatory Activities (MedDRA).
The number of investigational product-related SAEs will be reported by treatment.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, 
C-SSRS, and ECG parameters.  The parameters will be listed and summarized by treatment, 
using standard descriptive statistics.  Additional analyses will be performed, if warranted, upon 
review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Plasma concentrations of lasmiditan and alprazolam will be summarized by nominal time point
and treatment in a graphical or tabular format.
Pharmacokinetic parameter estimates for lasmiditan and alprazolam will be calculated using
standard noncompartmental methods of analysis.  The primary parameters for analysis will be 
Cmax and AUC of lasmiditan and alprazolam.  Other noncompartmental parameters, such as 
half-life, apparent clearance, and apparent volume of distribution may be reported.  The 
parameters will be listed and summarized by treatment using standard descriptive statistics.
Additional analyses may be performed to evaluate whether subjective measures, such as VAS 
and/or AEs, can be correlated with drug levels over time, if warranted.
10.3.3. Abuse Potential Analyses
Descriptive statistics for the Drug Liking VAS will be reported for each treatment and for each 
paired difference among treatments.  A linear mixed-effects model, which includes period, 
sequence, and treatment as fixed effects, and subject as a random effect will be used to evaluate 
the hypothesis tests of primary interest at the peak of drug response effects (Emax) at a 
significance level of 0.05 (1-sided).  The following pairwise comparisons will be made:

alprazolam minus placebo, with null hypothesis that the difference is ≤15 mm;

alprazolam minus each dose of lasmiditan, with the null hypothesis that the difference is 
≤5 mm; and


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
each dose of lasmiditan minus placebo, with the null hypothesis that the difference is ≥14
mm.
Least square mean estimates and 90% confidence intervals will be reported for each treatment 
and for each paired difference among treatments.
The residuals from the mixed-effect model will be investigated for normality using the Q-Q plot.  
If this normality assumption is not met, paired sample t-test or nonparametric test will be 
considered based on actual data distributions.  For nonparametric analyses, pairwise treatment 
comparisons will be assessed using the Wilcoxon signed-rank test on the within-subject 
differences, and median and intraquartile range will be reported.
Descriptive statistics for each other element of the Drug Effects VAS Battery, aside from Drug 
Liking VAS, and for time to peak effect will be reported for each treatment. If the normality 
assumptions of mixed-effects model on the residuals are met, a linear mixed-effects model, 
which includes period, sequence, and treatment as fixed effects, and subject as a random effect
will be used to provide least square mean estimates and 90% confidence intervals for each 
treatment.  The residuals from the mixed-effect model will be investigated for normality using 
the Q-Q plot. If the normality assumptions of mixed-effects model are not met, alternative 
approaches such as paired t-test or non-parametric test may be considered based on the actual 
data distributions. For non-parametric analyses, the median and intra-quartile range will be 
reported for each treatment.
10.3.4. 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
Bigelow GE. Human drug abuse liability assessment: opioids and analgesics. Br J Addict.
1991;86(12):1615-1623.
Blanchard RL, Sun H, McCrea JB, Schoedel K, Ngo P, Li X, Panebianco DL, Rosen LB, Sellers 
E, Murphy MG. A clinical study demonstrates no potential for recreational abuse of 
telcagepant. Headache. 2010;50(Suppl 1):S54.
Bond A, Lader M. The use of analogue scales in rating subjective feeling. Br J Med Psychol. 
1974;47:211-218.
ClinicalTrials.gov. A study to evaluate the abuse potential of single oral doses of dimebon 
(latrepirdine) in healthy recreational polydrug users. 2009. Available at: 
https://www.clinicaltrials.gov/ct2/show/results/NCT00975481?sect=X70156&term=alprazola
m+and+abuse&rank=2. Accessed March 23, 2017.
Evans SM, Troisi JR, Griffiths RR. Tandospirone and alprazolam: comparison of behavioral 
effects and abuse liability in humans. J Pharmacol Exp Ther. 1994;271(2):683-694.
[FDA] Food and Drug Administration. Guidance for Industry: Assessment of Abuse Potential of 
Drugs. January 2017. Available at: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm198650.pdf. Accessed February 16, 2017.
Fraser HF, Van Horn GD, Martin WR, Wolbach AB, Isbell H. Methods for evaluating addiction 
liability. (A) “Attitude” of opiate addicts toward opiate-like drugs. (B) a short-term “direct”
addiction test. J Pharmacol Exp Ther. 1961;133:371-387.
Levy-Cooperman N, Schoedel KA, Chakraborty B, Blum D, Cheng H. Abuse liability 
assessment of eslicarbazepine acetate in healthy male and female recreational sedative users: A
Phase I randomized controlled trial. Epilepsy Behav. 2016;61:63-71.
Mumford GK, Rush CR, and Griffiths RR. Abecarnil and alprazolam in humans: behavioral, 
subjective and reinforcing effects. J Pharmacol Exp Ther. 1995;272(2):570-580.
Posner K. State of the Science: Measurement of Suicidal Adverse Events and the Columbia 
Suicide Severity Rating Scale. Boca Raton, FL: NCDEU; 2007.
Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007a;12(2):156-162.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007b;164(7):1035-1043.
Shram MJ, Sathyan G, Khanna S, Tudor IC, Nath R, Thipphawong J, Sellers EM. Evaluation of 
the abuse potential of extended release hydromorphone versus immediate release
hydromorphone. J Clin Psychopharmacol. 2010;30(1):25-33.
Xanax [package insert]. New York, NY:Pfizer; June 2011. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018276s045lbl.pdf. Accessed on 
March 27 2017.


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Zawertailo LA, Busto U, Kaplan HL, Sellers EM. Comparative abuse liability of sertraline, 
alprazolam, and dextroamphetamine in humans. J Clin Psychopharmacol. 1995;15(2):117-
124.


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Appendix 1. Abbreviations and Definitions


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Term
Definition
5-HT
5-hydroxytryptamine
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the drug plasma concentration versus time curve
blinding
A procedure in which 1 or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his/her 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/or his/her 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
BUN
blood urea nitrogen
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum concentration
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety, effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to verify that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that 
samples be held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results.
Cmax
maximum observed drug concentration
COL-144
lasmiditan (also LY573144)


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Term
Definition
CPK
creatine phosphokinase
CRF
case report form
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
CV
coefficient of variation
CYP
cytochrome P450
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
ECG
electrocardiogram
Emax
maximal effect score
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GABA
gamma aminobutyric acid
GCP
good clinical practice
GGT
gamma glutamyl transferase
HBsAG
hepatitis B surface antigen
HCVAb
hepatitis C virus antibody
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council on Harmonisation


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Term
Definition
Ig
immunoglobulin
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.  
INR
international normalized ratio
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IRB
institutional review board (also ethical review board)
IV
intravenous
LC/MS/MS
liquid chromatography-tandem mass spectrometry
legal representative
An individual or a judicial or other body authorized, under applicable law, to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.
Lilly
Eli Lilly and Company
LY573144
lasmiditan (also COL-144)
MedDRA
Medical Dictionary for Regulatory Activities
OTC
over-the-counter
QTc
corrected QT interval
randomization
The process of assigning subjects/patients to an experimental group on a random basis.
RBC
red blood cell
PK
pharmacokinetic
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin level


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Term
Definition
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship with 
this treatment 
Tmax
time after administration of drug when maximum plasma concentration is reached; rate
of absorption equals the rate of elimination
TQT
thorough QT study
ULN
upper limit of normal
VAS
Visual Analog Scale
WBC
white blood cell
WOCBP
woman/women of childbearing potential


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Appendix 2. Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume
Chloride
Mean cell hemoglobin
Glucose [random and fasting]
Mean cell hemoglobin concentration
Leukocytes (WBC)
Platelets
Differential WBC [absolute counts and %] of:
Blood urea nitrogen (BUN)
Neutrophils
Uric acid
Lymphocytes
Total protein
Monocytes
Albumin
Eosinophils
Total bilirubin
Basophils
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Urinalysisa
Alanine aminotransferase (ALT)
Specific gravity
Creatinine
pH
Protein
Glucose
Ketones
Ethanol testinga,b
Bilirubin
Urine drug screena,b
Urobilinogen
Hepatitis B surface antigena
Blood
Hepatitis C antibodya
Nitrite
HIV
Pregnancy test [if applicable]
FSH [if applicable]a
Thyroid-stimulating hormonea
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell.
a
Performed at screening only.
b
Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other 
times indicated in the Schedule of Activities (Section 2); urine drug screen is not conducted at the clinical 
research unit in Singapore.


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Appendix 3.
Study Governance, Regulatory, and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Lilly or its 
designee will attempt to enroll a comparable number of men and women where possible.
Individual investigators may have additional local requirements or processes.  Study-specific 
recruitment material should be approved by Lilly.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly, or its representatives, must approve the ICF 
before it is used at the investigative site(s). All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, the principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator, or designee, will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.


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In addition, Lilly, or its representatives, will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.
The purpose and use of subject personal information collected will be provided in a written
document to the subject by the Sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly, or its designee, judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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


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Appendix 5. Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol H8H-MC-LAHB Sampling Summary (5 Periods)
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
17.5
1
17.5
Clinical laboratory testsa
9
8
72
Pharmacokinetics for lasmiditan
2
60 (+3)
120 (6)
Pharmacokinetics for alprazolam
2
60 (+3)
120 (6)
Blood discard for cannula patency
1
60
60
Pharmacogenetics
10
1
10
Total
411.5
Total for clinical purposes [rounded up to nearest 10 mL]
420
a
Additional samples may be drawn, if needed, for safety purposes.


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Appendix 6.
Protocol Amendment H8H-MC-LAHB(c) 
Summary: A Randomized, Subject- and Investigator-
Blind, Placebo- and Active-Controlled Study to Assess 
the Abuse Potential of Lasmiditan
Overview
Protocol H8H-MC-LAHB - A Randomized, Subject- and Investigator-Blind, Placebo- and 
Active-Controlled Study to Assess the Abuse Potential of Lasmiditan - has been amended.  The 
new protocol is indicated by Amendment (c) and will be used to conduct the study in place of 
any preceding version of the protocol.
The following change was made to this protocol and rationale is as follows:

Appendix 5 Blood Sampling Summary updated to include blood volumes for items 
previously listed as to be determined to ensure consistency with CRU procedure and 
alignment with the informed consent form.


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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.
Appendix 5. Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol H8H-MC-LAHB Sampling Summary (5 Periods)
Purpose
Blood Volume per Sample 
(mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
TBD17.5
TBD 1
TBD 17.5
Clinical laboratory testsa
TBD 9
TBD 8
TBD 72
Pharmacokinetics for lasmiditan
2
60 (+3)
120 (6)
Pharmacokinetics for alprazolam
2
60 (+3)
120 (6)
Blood discard for cannula patency
1
60
60
Pharmacogenetics
10
1
10
Total
TBD 411.5
Total for clinical purposes [rounded up to nearest 10 mL]
TBD 420
Abbreviations: TBD = to be determined
a
Additional samples may be drawn, if needed, for safety purposes.


Approver: 
Approval Date & Time: 05-Sep-2017 19:17:02 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Sep-2017 20:05:29 GMT
Signature meaning: Approved
PPD
PPD
PPD

SAP_001.pdf: 
H8H-MC-LAHB Statistical Analysis Plan 
 
A Randomized, Subject- and Investigator-Blind, Placebo and Active-Controlled Study to Assess the 
Abuse Potential of Lasmiditan   
 
NCT03286218 
 
Approval Date:  11-Sep-2017 


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             Page 1 of 22
STATISTICAL ANALYSIS PLAN
A Randomized, Subject- and Investigator-Blind, Placebo- and Active-Controlled Study to 
Assess the Abuse Potential of Lasmiditan
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  06-September-2017
Study Drug: LY573144 (Lasmiditan)
Sponsor Reference:  H8H-MC-LAHB
Covance CRU Study: 1000071-8366187
Clinical Phase I
Approval Date: 11-Sep-2017 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366187
Sponsor Reference H8H-MC-LAHB
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
Tertiary/Exploratory Objective ......................................................................................6
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENTS...................................................................................................................9
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................9
8.
DEFINITION OF ANALYSIS POPULATIONS................................................................10
8.1
Populations..................................................................................................................10
9.
STATISTICAL METHODOLOGY ...................................................................................11
9.1
General........................................................................................................................11
9.2
Demographics and Subject Disposition........................................................................11
9.3
Pharmacokinetic Assessment.......................................................................................11
9.3.1
Pharmacokinetic Analysis...................................................................................11
9.3.2
Pharmacokinetic Statistical Methodology ...........................................................15
9.4
Pharmacodynamic Assessment ....................................................................................16
9.4.1
Pharmacodynamic Analysis................................................................................16
9.4.2
Pharmacodynamic Statistical Methodology ........................................................18
9.5
Safety and Tolerability Assessments............................................................................20
9.5.1
Adverse events ...................................................................................................20
9.5.2
Concomitant medication.....................................................................................20
9.5.3
Clinical laboratory parameters............................................................................20
9.5.4
Hepatic Monitoring ............................................................................................21
9.5.5
Vital signs ..........................................................................................................21
9.5.6
Electrocardiogram (ECG)...................................................................................21
9.5.7
Columbia-Suicide Severity rating Scale (C-SSRS)..............................................21
9.5.8
Other assessments...............................................................................................21
9.5.9
Safety and Tolerability Statistical Methodology..................................................21


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366187
Sponsor Reference H8H-MC-LAHB
10. INTERIM ANALYSES .....................................................................................................21
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............22
12. REFERENCES ..................................................................................................................22
13. DATA PRESENTATION ..................................................................................................22
13.1 Derived Parameters .....................................................................................................22
13.2 Missing Data ...............................................................................................................22
13.3 Insufficient Data for Presentation ................................................................................22


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366187
Sponsor Reference H8H-MC-LAHB
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
BQL
Below the quantifiable lower limit of the assay
C
Control 
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CNS
Central nervous system
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)
Emax
Maximal effect score
FDA
Food and Drug Administration
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366187
Sponsor Reference H8H-MC-LAHB
MRE
Magnetic resonance elastography
P
Positive 
PD
Pharmacodynamic
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SD
Standard deviation 
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual Analog Scale
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366187
Sponsor Reference H8H-MC-LAHB
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
24 July 2017 and Protocol Amendment (c) (final version dated 06 September 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 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective

To assess the abuse potential of lasmiditan compared to the positive control alprazolam 
and placebo.
4.2
Secondary Objectives

Further characterize the abuse potential of lasmiditan with additional Drug Effects and 
Drug Similarity Visual Analog Scale (VAS) measures

Safety evaluations

PK of lasmiditan
4.3
Tertiary/Exploratory Objective

PK of alprazolam


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366187
Sponsor Reference H8H-MC-LAHB
5. STUDY DESIGN
This study is a Phase 1, randomized, subject- and investigator-blind, placebo- and 
active-controlled, crossover clinical trial in adult subjects who are recreational poly-drug users. 
This study includes 4 phases:
Screening Phase: Subjects will sign informed consent before their entry to the study and
completion of all screening procedures. Screening visits should be within 28 days of dosing in
Qualification Phase. Subjects who fail screening may not be rescreened.
Qualification Phase: Eligible subjects who meet all inclusion criteria and none of the exclusion
criteria will enter a subject- and investigator-blind placebo-controlled, 2-period crossover design
Qualification Phase. Subjects will be randomized to a test dose of 1 mg alprazolam and placebo
in a crossover manner with a washout period of at least 3 days (72 hours) between each dose. 
“Drug-liking” response will be assessed before and after alprazolam and placebo administration 
using a 100 mm bipolar Drug Liking VAS. Only subjects who meet alprazolam qualification 
criteria as detailed below will be eligible to enter the Treatment Phase.
In order to qualify for the Treatment Period of the study, subjects must demonstrate the ability to 
discriminate an alprazolam test dose from placebo, using the 100 mm bipolar Drug Liking VAS, 
as defined by:

Acceptable placebo response ranging from 40 to 60 (inclusive) on the 100 mm bipolar 
VAS for Drug Liking “at this moment”.

≥ 15 mm increase in “liking” alprazolam more than placebo.

Subject is able to tolerate the 1 mg dose of alprazolam, as judged by the investigator, 
including the ability to complete all PD assessments within 4 hours postdose.

General behavior suggests that the subject could successfully complete the study, as 
judged by the study site personnel. 
On a case-by-case basis, a subject who meets all of the above criteria, with the exception of 
sporadic erroneous responses, may be permitted into the Treatment Phase, provided that the 
investigator or designee determines that the subject’s response was made in error and that the 
subject can be successfully retrained regarding proper completion of that assessment.
Treatment Phase: This will be a subject- and investigator-blind, placebo- and active-controlled,
5-period crossover design. Subjects will be randomized to 1 of 10 dosing sequences; each
dosing sequence consists of 5 dosing periods that evaluate the abuse potential of 1 of the 5 study
treatments: placebo, 2 mg alprazolam, and 100 mg lasmiditan, 200 mg lasmiditan, and 400 mg
lasmiditan. The washout period between each dose should be at least 3 days (72 hours).
Eligible subjects will be admitted to the clinical research unit (CRU) on Day -1 before the
planned study drug dosing during each of the dosing periods in both the Qualification Phase and
Treatment Phase. After verification of subjects’ eligibility, including a urine drug screen at time
of CRU admission, blinded study drug will be administered on Day 1 after an overnight fast.
Abuse potential will be assessed using Drug Effects VAS Battery. Adverse events (AEs), vital 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366187
Sponsor Reference H8H-MC-LAHB
signs, and electrocardiograms (ECGs) will be monitored, and PK samples will be collected 
according to the Study Schedule (Section 2 of the protocol).
Follow-up Phase: Subjects will have a follow-up visit approximately 1 week after their last dose
of study drug, and will present to the CRU for discharge from the study as deemed appropriate
by the investigator. Subjects who discontinued from the study before its completion will be
asked to attend an Early Discontinuation visit (according to the Study Schedule [Section 2 of the 
protocol]) approximately 1 week after the last dose of study drug dosing. Figure 1 illustrates the 
study design.
Figure 1. Illustration of study design
Abbreviations: High = high (400 mg) dose; Las = lasmiditan; Low = low (100 mg) dose; 
Med = medium (200 mg) dose.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366187
Sponsor Reference H8H-MC-LAHB
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Phase
Study Treatment Name
Treatment order in TFL
Qualification Phase
Placebo
1
1 mg alprazolam
2
Treatment Phase
Placebo
3
2 mg alprazolam
4
100 mg lasmiditan
5
200 mg lasmiditan
6
400 mg lasmiditan
7
7. SAMPLE SIZE JUSTIFICATION
The study design and analysis methods are as prescribed in “Assessment of Abuse Potential of
Drugs: Guidance for Industry” published by the US Food and Drug Administration (FDA), 
January 2017 (FDA 2017)3. Three different hypothesis tests are of primary interest:
1. Validation test of the sensitivity and integrity of the study: Does the positive control (C)
produce mean responses that show greater abuse potential compared to placebo (P)?
H10: μC – μP ≤ δ1 versus H1a: μC – μP > δ1 where δ1 > 0
2. Does the test drug (T) produce mean responses that show less abuse potential compared
to positive control?
H20: μC – μT ≤δ2 versus H2a: μC – μT > δ2 where δ2 ≥ 0
3. Does the test drug produce mean responses that show similar abuse potential, compared
to placebo?
H30: μT – μP ≥ δ3 versus H3a: μT – μP < δ3 where δ3 > 0
Approximately 60 subjects will be randomly assigned to 1 of 10 treatment sequences, in order to
get approximately 50 completers. Subjects who are randomized but who do not complete all 5 
periods during the Treatment Phase may be replaced. Replacement subjects will enter the same 
treatment sequence as the original subject to complete all 5 periods.  Treatment sequence 
assignment will be determined by the repeated Williams square design, as shown in Figure 1. 


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This will lead to 90% or more power for testing each of the hypotheses of primary interest listed 
above, with the following assumptions:

standard deviation of differences of 16 for the Drug Liking VAS (estimate based on
within-subject standard deviation estimate of 11.4 from previous studies [Blanchard et al.
2010]4)

actual mean difference between alprazolam and placebo of 22 or more for the Drug
Liking VAS,

actual mean difference between alprazolam and lasmiditan of 12 or more for the Drug
Liking VAS,

actual mean difference between lasmiditan and placebo of 7 or less for the Drug Liking
VAS,

δ1 = 15, δ2 = 5, and δ3 = 14; and

one-sided significance level of 0.05.
The margin for comparing alprazolam with placebo (δ1) is defined as 15 mm, based on the 2017
FDA guidance, stating that there should be a difference of at least 15 points between placebo and 
positive control response. The margin for comparing alprazolam with lasmiditan (δ2) is defined 
as 5 mm, based on the need to show that lasmiditan shows some non-negligible lower abuse 
potential compared to positive control. The margin for comparing lasmiditan with placebo (δ3) is 
defined as 14 mm. Consistent with FDA advice, the margin for comparing lasmiditan with 
placebo (δ3) is less than the margin for comparing the positive control (alprazolam) to placebo 
(δ1).
8. DEFINITION OF ANALYSIS POPULATIONS
8.1
Populations
The “Safety” population will consist of all subjects who received at least one dose of study drug 
(lasmiditan, alprazolam, or placebo).  This will be the population used for all analyses except the 
Drug Effects VAS battery analyses and PK/PD analyses.
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
lasmiditan, alprazolam or placebo and have evaluable PD data.  This will be evaluated for the 
Qualification Phase and Treatment Phase separately. Subjects may be excluded from the PD 
summary statistics and statistical analysis if a subject has an AE of vomiting that occurs at or 
before 2 times median time of maximum observed drug concentration (tmax).
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
lasmiditan or alprazolam and have evaluable PK data in the Treatment Phase.  The PK 
population is applicable to the Treatment Phase only.  Subjects may be excluded from the PK 
summary statistics and statistical analysis if a subject has an AE of vomiting that occurs at or 
before 2 times median tmax.
For the statistical analysis of the Drug Effects VAS Battery in the Treatment Phase, the analysis 
will be performed only subjects who complete all 5 periods.  


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Statistical Analysis Plan 
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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), standard 
error (SE), first quartile, median, third quartile, min, max and N; for log-normal data (e.g. the PK 
parameters: area under the concentration versus time curve [AUCs] and maximum observed 
drug concentration [Cmax]) the geometric mean and geometric coefficient of variation (CV%) 
will also be presented. For categorical data, frequency count and percentages will be presented. 
Data listings will be provided for all subjects up to the point of withdrawal, with any subjects 
excluded from the relevant population highlighted. Summary statistics and statistical analyses 
will generally only be performed for subjects included in the relevant analysis population. For 
the calculation of summary statistics and statistical analysis, unrounded data will be used. 
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 for 
the Qualification Phase and Treatment Phase separately using the Safety population. For 
subjects that don’t qualify for the Treatment Phase, the reason for not proceeding to the next 
phase will be listed.  Recreational drug use history will be listed and will include details of the 
specific substances taken.  A summary table and listings of the summary of number of lifetime 
non-therapeutic experiences with central nervous system (CNS) depressants, number of non-
therapeutic experiences with CNS depressants in 12 weeks prior to screening, and lifetime non-
therapeutic experiences with other classes of drugs of abuse (with the latter split out by drug 
class) will be produced.
9.3 Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
PK assessments and analysis will only be applicable to the Treatment Phase of this study.
PK parameter estimates will be determined using non-compartmental procedures in validated 
software program (Phoenix WinNonlin Version 6.4 or later).


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Statistical Analysis Plan 
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Plasma concentrations of lasmiditan (LY573144) and alprazolam will be used to determine the 
following PK parameters, when possible:  
Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration 
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration 
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the CSR. Any exceptions or special handling of data will 
be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for predose sampling times which will be set to zero. 

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. AUC(0-) values where the 
percentage of the total area extrapolated is more than 20% will be flagged. Any 


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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.


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


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Statistical Analysis Plan 
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Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
9.3.2 Pharmacokinetic Statistical Methodology
Plasma concentrations of lasmiditan and alprazolam will be summarized by nominal time point 
and treatment in a graphical and tabular format.  
The primary parameters for analysis will be Cmax and AUC of lasmiditan and alprazolam.  All 
PK parameters will be listed and summarized by treatment using standard descriptive statistics.
After inspection of the data, additional analyses may be performed to evaluate whether 
subjective measures, such as VAS and/or AEs, can be correlated with drug levels over time, if 
warranted.


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Statistical Analysis Plan 
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9.4
Pharmacodynamic Assessment
9.4.1 Pharmacodynamic Analysis
Drug Effects VAS Battery lists a series of Drug Effects VAS measures that evaluate different 
subjective effects of the abuse potential of the study drug as shown in the table below.
Scale Name
Scale Text
Response Anchors
Drug Liking
At this moment, my liking for this drug is
0:  Strong disliking
100:  Strong liking
Overall Drug Liking
Overall, my liking for this drug is
Take Drug Again
I would take this drug again
0:  Definitely not
100:  Definitely so 
Good Effects
I can feel good drug effects
Bad Effects
I can feel bad drug effects
Alertness/Drowsiness
I am feeling
0:  Very drowsy
100:  Very alert 
Agitation/Relaxation
My mood is
0:  Very relaxed
100:  Very agitated
High
I am feeling
0:  Not at all high
100: Extremely high
Hallucination
I am experiencing hallucinations
0:  Not at all
100:  Extremely  
The primary objective of the study is to assess the abuse potential of lasmiditan compared to the 
positive control alprazolam and to placebo using the maximal effect score (Emax) of the 
at-the-moment 100 mm bipolar Drug Liking VAS.  The bipolar Drug Liking VAS is consistent 
with FDA Guidance (January 2017)3 such that placebo should produce a score between 40 and 
60 representing neutral drug-liking (ie, neither like nor dislike); a score of 0 indicates strong 
disliking, and a score of 100 indicates strong liking.
The remaining questions in the Drug Effects VAS Battery and the Drug Similarity VAS Battery 
will be assessed as secondary endpoints.
The Drug Similarity VAS Battery is composed of two sets of VAS measures, the baseline set of 
VAS measures is to determine how familiar the subjects are with various drugs and how similar 
their most recently received drug is to those.  The second set of VAS measures is confined to 
checking how similar the most recent drug received was to a list of various drugs.  The Baseline 
set of VAS battery questions will be administered in the Qualification Phase and the second set 
of measures will be administered during the Treatment Phase.  In the tables below are the 
proposed Drug Similarity VAS measures of interest.


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Statistical Analysis Plan 
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Drug Similarity Visual Analog Scale Battery – Baseline
1
How familiar are you with cocaine (including crack) use? (not applicable)
2
How similar is the drug you most recently received to cocaine (including crack)? (not 
applicable)
3
How familiar are you with caffeine use? (not applicable)
4
How similar is the drug you most recently received to caffeine? (not applicable)
5
How familiar are you with ecstasy (MDMA) use? (not applicable)
6
How similar is the drug you most recently received to ecstasy (MDMA)? (not 
applicable)
7
How familiar are you with D-amphetamine or methamphetamine use? (not applicable)
8
How similar is the drug you most recently received to D-amphetamine or 
methamphetamine? (not applicable)
9
How familiar are you with phencyclidine (PCP) use? (not applicable)
10
How similar is the drug you most recently received to phencyclidine (PCP)? (not 
applicable)
11
How familiar are you with codeine or morphine use? (not applicable)
12
How similar is the drug you most recently received to codeine or morphine? (not 
applicable)
13
How familiar are you with herorin use? (not applicable)
14
How similar is the drug you most recently received to herorin? (not applicable)
15
How familiar are you with LDS use? (not applicable)
16
How similar is the drug you most recently received to LDS? (not applicable)
17
How familiar are you with nicotine use? (not applicable)
18
How similar is the drug you most recently received to nicotine? (not applicable)
19
How familiar are you with pseudoephredrine use? (not applicable)
20
How similar is the drug you most recently received to pseudoephredrine? (not 
applicable)
21
How familiar are you with cannabis use? (not applicable)
22
How similar is the drug you most recently received to cannabis? (not applicable)
23
How familiar are you with benzodiazepine use? (not applicable)
24
How similar is the drug you most recently received to benzodiazepine? (not applicable)
25
How familiar are you with ketamine use? (not applicable)
26
How similar is the drug you most recently received to ketamine? (not applicable)
27
How familiar are you with mushrooms use? (not applicable)
28
How similar is the drug you most recently received to mushrooms? (not applicable)
29
How familiar are you with barbiturates use? (not applicable)
30
How similar is the drug you most recently received to barbiturates? (not applicable)


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Statistical Analysis Plan 
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Covance Clinical Study No. 8366187
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Drug Similarity Visual Analog Scale Battery
1
How similar is the drug you most recently received to cocaine (including crack)? (not 
applicable)
2
How similar is the drug you most recently received to caffeine? (not applicable)
3
How similar is the drug you most recently received to ecstasy (MDMA)? (not 
applicable)
4
How similar is the drug you most recently received to D-amphetamine or 
methamphetamine? (not applicable)
5
How similar is the drug you most recently received to phencyclidine (PCP)? (not 
applicable)
6
How similar is the drug you most recently received to codeine or morphine? (not 
applicable)
7
How similar is the drug you most recently received to herorin? (not applicable)
8
How similar is the drug you most recently received to LSD? (not applicable)
9
How similar is the drug you most recently received to nicotine? (not applicable)
10
How similar is the drug you most recently received to pseudoephredrine? (not 
applicable)
11
How similar is the drug you most recently received to cannabis? (not applicable)
12
How similar is the drug you most recently received to benzodiazepine? (not applicable)
13
How similar is the drug you most recently received to ketamine? (not applicable)
14
How similar is the drug you most recently received to mushrooms? (not applicable)
15
How similar is the drug you most recently received to barbiturates? (not applicable)
In the “How similar” questions, a score of 0 indicates definitely not similar, and a score of 100 
indicates definitely similar.
In the “How familiar” questions, a score of 0 indicates definitely not familiar to, and a score of 
100 indicates definitely familiar.
9.4.2 Pharmacodynamic Statistical Methodology
Descriptive statistics for the Drug Liking VAS will be reported for each treatment and for each 
paired difference among treatments.
The Emax will be derived as the maximum at-the-moment Drug Liking VAS score among all the 
individual values that are collected at the scheduled assessment timepoints.  The time to Emax is 
the corresponding timepoint at which the maximum score occurs.  These will be derived for both 
the Qualification Phase and Treatment Phase separately for each treatment.
A linear mixed-effects model, which includes period, sequence, and treatment as fixed effects, 
and subject as a random effect will be used to evaluate the hypothesis tests of primary interest at 
the Emax at a significance level of 0.05 (1-sided).  The following pairwise comparisons will be 
made:

Alprazolam minus placebo, with null hypothesis that the difference is ≤ 15 mm;


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Statistical Analysis Plan 
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
Alprazolam minus each dose of lasmiditan, with the null hypothesis that the difference is 
≤ 5 mm; and

each dose of lasmiditan minus placebo, with the null hypothesis that the difference is 
≥14 mm.
Least square mean estimates and 90% confidence intervals (CI) will be reported for each 
treatment and for each paired difference among treatments.
An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
class trtmnt period sequence subject;
model emax = trtmnt period sequence / ddfm=kr alpha=0.1 residual outp=pred;
random subject;
lsmeans trtmnt / pdiff=control alpha=0.1;  /*Produce 90% CI*/
lsmeans trtmnt / pdiff=controll alpha=0.05; /*Test at 0.05 significance 1-sided*/
ods output lsmeans=lsm1;
ods output diffs=diff1;
run;
/* Wilcoxon signed rank test */
proc univariate data=tmax;
    var result;
    ods output Quantiles=quant; 
    ods output TestsforLocation=pvalues(where=(test='Signed Rank'));
run;
/* Paired sample t-test */
proc ttest data=all;
    title "Paired sample t-test";
    paired Control * Treatment;
run;
In the example SAS code, this is currently presenting a lower-tailed test, however this may need 
adjusting for some of the comparisons.
The residuals from the mixed-effect model will be investigated for normality using the Q-Q plot.  
If this normality assumption is not met, paired sample t-test or nonparametric test will be 
considered based on actual data distributions. For nonparametric analyses, pairwise treatment 
comparisons will be assessed using the Wilcoxon signed-rank test on the within-subject 
differences, and median and interquartile range will be reported.
Descriptive statistics for each other element of the Drug Effects VAS Battery, aside from the 
Drug Liking VAS, and for time to peak effect will be reported for each study phase and 
treatment.  If the normality assumptions of mixed effects model on the residuals are met, a linear 
mixed-effects model similar to that employed for the Emax of Drug Liking VAS will be employed 
for each other element of the Drug Effects VAS Battery. 


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Statistical Analysis Plan 
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Descriptive statistics for each element of the Drug Similarity Visual Analog Scale Battery –
Baseline and Drug Similarity Visual Analog Scale Battery will be reported for each study phase 
and treatment.
The pattern of missing data will be assessed in the population of patients who entered into the 
treatment phase and took at least 1 dose of study drug in the treatment phase by looking at the 
trend of dropout rates among the first 4 periods, as well as comparing the dropout rates among 
the 5 treatments.
A sensitivity analysis will be performed on all patients who entered into the treatment phase and 
received at least 1 dose of study drug in the treatment phase, regardless of completion of all the 5 
periods. The same mixed model and model diagnosis procedure as the primary analysis will be 
implemented.
9.5
Safety and Tolerability Assessments
9.5.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to first dosing of the Qualification Phase. A 
treatment-emergent AE is defined as an AE which occurs postdose or which is present prior to 
dosing and becomes more severe postdose.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA)
version 20.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated. All AE outputs will be presented by Qualification Phase and Treatment Phase 
separately.  An AE that starts during the Qualification Phase or before the Treatment Phase start 
will be presented under the Qualification Phase summaries only.  In the Treatment Phase outputs, 
any AEs that are ongoing from the Qualification Phase will be flagged in listings, and excluded 
from tables.
9.5.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017
Enhanced Dictionary B2 Format. Concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
Clinical chemistry, hematology and urinalysis data outside the reference ranges will be listed.


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Statistical Analysis Plan 
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Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.5.4 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥ 3 × upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥ 2 × ULN, or elevated total bilirubin (TBL) ≥ 2 × ULN, 
liver tests will be performed to confirm the abnormality.  
The subjects’ liver disease history and associated person liver disease history data will be listed.  
Any concomitant medication of acetaminophen/paracetamol will be listed.  Results from a 
magnetic resonance elastography (MRE) scan and biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed by study phase.  Liver related signs and 
symptoms data will be summarized by study phase and treatment, and listed, if available. 
All hepatic chemistry, hematology, coagulation, and serology data will be summarized by study 
phase, parameter, and treatment, and listed.  Values outside the reference ranges will be flagged 
on the individual subject data listings.
9.5.5 Vital signs
Vital signs data will be summarized by study phase and treatment together with changes from 
baseline, where baseline is defined as Day 1 predose for each study phase separately. Figures of 
mean vital signs and mean changes from baseline profiles by treatment will be presented by 
study phase and treatment. Furthermore, values for individual subjects will be listed by study 
phase.
Changes from baseline (predose) will be calculated for vitals signs. 
9.5.6 Electrocardiogram (ECG)
For each subject, ECGs will be performed for safety purposes only, and will not be reported.
9.5.7 Columbia-Suicide Severity rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale will be listed for individual subjects.
9.5.8 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.5.9 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8366187
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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. [FDA] Food and Drug Administration. Guidance for Industry:  Assessment of Abuse 
Potential of Drugs. January 2017. Available at:
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
ucm198650.pdf.
4. Blanchard RL, Sun H, McCrea JB, Schoedel K, Ngo P, Li X, Panebianco DL, Rosen LB, 
Sellers E, Murphy MG. A clinical study demonstrates no potential for recreational abuse of 
telcagepant. Headache. 2010;50(Suppl 1):S54
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Approver: 
Approval Date & Time: 07-Sep-2017 16:57:17 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 07-Sep-2017 17:03:39 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 07-Sep-2017 18:39:58 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Sep-2017 12:35:08 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD
PPD