Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 35
Healthy volunteers: yes

Brief summary:
The purpose of this study is to look at the amount of study drug that gets into the blood stream and how long it takes the body to get rid of it by comparing the results of healthy elderly participants to those of healthy young participants. The tolerability of the study drug will be evaluated. Information about any side effects that may occur will also be collected.

This study will last up to approximately 19 days, not including screening. This study requires either one (Group 2) or two (Group 1) stays at the clinic each of at least four days/three nights. Participants will return for a follow-up seven days after last dose of study drug. Screening is required within 28 days prior to Day 1.

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

Detailed description:

Arms:
arm 1: 200 milligrams (mg) lasmiditan on Day 1 of 1 of 2 dosing periods. arm 2: Placebo on Day 1 of 1 of 2 dosing periods. arm 3: 200 mg lasmiditan on Day 1.

Interventions: intervention 1: Lasmiditan intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration intervention 2: Oral administration

Protocol document:
Prot_002.pdf: 
Protocol H8H-MC-LAHA (a) 
 
Effect of Age on the Pharmacokinetics, Safety, and Tolerability of Lasmiditan in Healthy 
Subjects 
 
NCT03182920 
Approval Date: 05-Jul-2017 


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.
Protocol H8H-MC-LAHA (a)
Effect of Age on the Pharmacokinetics, Safety, and 
Tolerability of Lasmiditan in Healthy Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
lasmiditan, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act Exemption 4 and 
may not be reproduced or otherwise disseminated without the written approval of Eli Lilly 
and Company or its subsidiaries.
Lasmiditan (LY573144)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:  27 April 
2017.
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 05-Jul-2017 GMT


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Table of Contents
Effect of Age on the Pharmacokinetics, Safety, and 
Tolerability of Lasmiditan in Healthy Subjects
Section
Page
Protocol H8H-MC-LAHA (a) Effect of Age on the Pharmacokinetics, 
Safety, and Tolerability of Lasmiditan in Healthy Subjects .................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................13
3.1.
Study Rationale............................................................................................................13
3.2.
Background..................................................................................................................13
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................16
5.
Study Design.....................................................................................................................17
5.1.
Overall Design .............................................................................................................17
5.2.
Number of Participants.................................................................................................17
5.3.
End of Study Definition ...............................................................................................17
5.4.
Scientific Rationale for Study Design...........................................................................17
5.5.
Justification for Dose ...................................................................................................18
6.
Study Population...............................................................................................................19
6.1.
Inclusion Criteria..........................................................................................................19
6.2.
Exclusion Criteria ........................................................................................................20
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................22
6.3.
Lifestyle and/or Dietary Requirements .........................................................................22
6.3.1.
Meals and Dietary Restrictions.............................................................................22
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................22
6.3.3.
Activity................................................................................................................23
6.4.
Screen Failures.............................................................................................................23
7.
Treatment..........................................................................................................................24
7.1.
Treatment Administered...............................................................................................24
7.1.1.
Packaging and Labeling .......................................................................................24
7.2.
Method of Treatment Assignment ................................................................................25
7.2.1.
Selection and Timing of Doses.............................................................................25
7.3.
Blinding .......................................................................................................................25


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7.4.
Dose Modification........................................................................................................25
7.5.
Preparation/Handling/Storage/Accountability...............................................................25
7.6.
Treatment Compliance .................................................................................................26
7.7.
Concomitant Therapy...................................................................................................26
7.8.
Treatment After the End of the Study...........................................................................26
8.
Discontinuation Criteria ....................................................................................................27
8.1.
Discontinuation from Study Treatment.........................................................................27
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................27
8.2.
Discontinuation from the Study....................................................................................27
8.3.
Subjects Lost to Follow-up...........................................................................................27
9.
Study Assessments and Procedures ...................................................................................28
9.1.
Efficacy Assessments...................................................................................................28
9.2.
Adverse Events ............................................................................................................28
9.2.1.
Serious Adverse Events........................................................................................29
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................29
9.2.2.
Complaint Handling.............................................................................................30
9.3.
Treatment of Overdose.................................................................................................30
9.4.
Safety...........................................................................................................................30
9.4.1.
Laboratory Tests ..................................................................................................30
9.4.2.
Vital Signs ...........................................................................................................30
9.4.3.
Electrocardiograms ..............................................................................................30
9.4.4.
Safety Monitoring ................................................................................................31
9.4.4.1.
Hepatic Safety................................................................................................31
9.5.
Pharmacokinetics .........................................................................................................32
9.5.1.
Bioanalysis...........................................................................................................32
9.6.
Pharmacodynamics ......................................................................................................32
9.7.
Genetics .......................................................................................................................32
9.8.
Biomarkers...................................................................................................................33
9.9.
Health Economics ........................................................................................................33
10.
Statistical Considerations and Data Analysis.....................................................................34
10.1. Sample Size Determination ..........................................................................................34
10.2. Populations for Analyses..............................................................................................34
10.2.1.
Study Participant Disposition ...............................................................................34
10.2.2.
Study Participant Characteristics ..........................................................................34
10.3. Statistical Analyses ......................................................................................................34
10.3.1.
Safety Analyses....................................................................................................34
10.3.1.1.
Clinical Evaluation of Safety..........................................................................34
10.3.1.2.
Statistical Evaluation of Safety.......................................................................34


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10.3.2.
Pharmacokinetic Analyses....................................................................................35
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................35
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................35
10.3.3.
Interim Analyses..................................................................................................35
11.
References ........................................................................................................................36


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List of Tables
Table
Page
Table LAHA.1.
Objectives and Endpoints .......................................................................16
Table LAHA.2.
Treatments Administered........................................................................24


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................37
Appendix 2.
Clinical Laboratory Tests........................................................................40
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................41
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............44
Appendix 5.
Blood Sampling Summary......................................................................45
Appendix 6.
Protocol Amendment H8H-MC-LAHA (a) Summary:  Effect of 
Age on the Pharmacokinetics, Safety, and Tolerability of 
Lasmiditan in Healthy Subjects ..............................................................46


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1. Protocol Synopsis
Title of Study:
Effect of Age on the Pharmacokinetics, Safety, and Tolerability of Lasmiditan in Healthy Subjects
Objectives/Endpoints:  
Objectives
Endpoints
Primary
To determine the pharmacokinetics (PK) of lasmiditan 
in healthy elderly subjects (≥65 years of age) following 
a single 200 mg oral dose of lasmiditan.

PK parameters:  maximum observed 
concentration (Cmax), time of Cmax (tmax), and 
the area under the concentration versus time 
curve from zero to infinity (AUC[0-∞])
Secondary
To compare the PK of lasmiditan in healthy elderly 
subjects (≥65 years of age) against the PK of 
lasmiditan in healthy young subjects (18 to 45 years of 
age) following a single 200 mg oral dose of lasmiditan.
To assess the safety and tolerability of a single 200 mg 
oral dose of lasmiditan in elderly and young healthy 
subjects.

PK parameters:  Cmax, tmax, and AUC(0-∞)

A summary of the number of 
treatment-emergent adverse events (TEAEs) 
and serious adverse events (SAEs)
Exploratory
To determine the PK of the metabolites M8, M7, and 
M18 in healthy elderly and young subjects following a 
single 200 mg oral dose of lasmiditan.

PK parameters:  Cmax, tmax, and AUC(0-∞)
Summary of Study Design:  
This is a single dose study to determine the PK of lasmiditan following a single 200 mg oral dose in healthy elderly 
and young subjects.  Two groups of subjects will be studied as follows:
Group 1 (healthy elderly subjects):  200 mg lasmiditan and matching placebo in a randomized double-blind 
cross-over design
Group 2 (healthy young subjects):  200 mg lasmiditan in an open label design
Subjects in Group 2 will be matched by race, sex, and body mass index (BMI) (±20%) to subjects in Group 1.  Both 
groups may be evaluated concurrently.  
Treatment Arms and Duration:  
Screening Period: 


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All subjects will participate in a screening visit up to 28 days prior to study drug dosing.  
Dosing Period:
Subjects in Group 1 will participate in 2 dosing periods. Subjects will be randomized to receive lasmiditan in one 
dosing period, and placebo in the other.  They will be admitted to the CRU the day prior to dosing (Day -1), and 
receive study drug on Day 1 for each dosing period. Subjects may be discharged from the CRU on Day 3 based on 
investigator discretion. There will be a washout period of 3 to 10 days between each dosing day. Subjects may stay 
as inpatient during the entire dosing period. 
Subjects in Group 2 will participate in 1 dosing period. They will be admitted to the CRU on Day -1 and receive 
study drug on Day 1. Subjects may be discharged from the CRU on Day 3 based on investigator discretion.
All subjects will be discharged from the study approximately 7 days post their final dose of lasmiditan.
Number of Subjects:
Up to 36 subjects may be enrolled to ensure 30 subjects (2 groups of 15) complete the study.  Group 1 will be 
subjects aged ≥65 years of age.  Attempts will be made to enroll at least 4 subjects who are ≥75 years of age. 
Group 2 will be subjects aged 18 to 45 years, inclusive.
Statistical Analysis:
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 12-lead 
electrocardiogram (ECG) parameters.  The parameters will be listed, and summarized using standard descriptive 
statistics, as appropriate.  
Pharmacokinetic parameter estimates for lasmiditan and its metabolites will be calculated by standard 
noncompartmental methods of analysis.  Pharmacokinetic parameter estimates will be evaluated to determine the 
impact of age on the PK of lasmiditan and its metabolites.  Log-transformed Cmax and AUC(0-∞) will be evaluated 
in a linear fixed-effects model with a fixed effect of age group.  The 90% confidence intervals (CIs) of the ratios of 
geometric means of the elderly group versus the young group will be presented.  
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference based on the 
observed medians, 90% CIs and the p-value from the Wilcoxon test will be calculated.


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2. Schedule of Activities


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Study Schedule Protocol H8H-MC-LAHA (a)
Screening
Periods 1 and 2a
Discharge from 
Study/ Early 
Discontinuation
Comments
Procedure
-28 to -2 
days prior to 
Day 1
Day -1b
Day 1
Day 2
Day 3
approximately 7 days 
post final dose
Informed 
Consent
X
Subject 
Admission to 
CRU
X
Subject 
Discharge from 
CRU
Xc
Randomization
Predosed
Investigational 
Product 
Administration
Day 1, 
indicates 
Time = 0
Medical History
X
AEs and 
Medication 
review
X
X
X
X
X
Height
X
Weight
X
Temperature
X
Vital Signs 
(supine)
X
Predose, 
0.5, 1, 1.5, 
2, 2.5, 3, 
4, 6, 8, 12
24
48
X
Time points may be added for each study 
period, if warranted and agreed upon 
between Lilly and the investigator.
All assessments except for screening should 
be performed in triplicate. See Section 9.4.2
for further details.


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Study Schedule Protocol H8H-MC-LAHA
Screening
Periods 1 and 2a
Discharge from 
Study/ Early 
Discontinuation
Comments
Procedure
-28 to -2 
days prior to 
Day 1
Day -1b
Day 1
Day 2
Day 3
approximately 7 days 
post final dose
Orthostatic
Vital Signs 
X
X
Predose, 
0.5, 1, 2
24
Last triplicate vital sign can be used as the 
supine vital sign for calculation of orthostatic 
changes, where applicable. Time points may 
be added for each study period, if warranted 
and agreed upon between Lilly and the 
investigator.
Screening 
laboratory 
Tests
X
Clinical Lab 
Tests
X
X
Predose
X
X
See Appendix 2, Clinical Laboratory Tests, 
for details.
Urine Drug 
Screen and 
alcohol screen
X
Xe
Pregnancy 
Test 
X
X
X
Serum pregnancy test will be performed at 
all time points.
Physical Exam
X
X
X
X
X
Full physical examination at Day -1 of each 
study period (as applicable for Group 1) and 
discharge from the study only. Symptom 
driven physical examination for all other 
timepoints.
12-lead ECG
X
X
Predose, 1, 
2, 4 hours 
postdose
24 hours 
postdose
X
Single ECG readings will be taken.
PK Samples
Predose, 
0.5, 1, 1.5, 
2, 2.5, 3, 4, 
24, 36
48
Sampling times are relative to the time of 
study treatment administration (0 min).


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6, 8, 12
Genetic 
Sample
X
Single sample for pharmacogenetic analysis 
taken prior to/on Day 1
Abbreviations:  AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; min = minutes; PK = pharmacokinetics. 
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used: ECG, supine vital signs, and orthostatic vital 
signs, venipuncture.  Where venipuncture and other procedures take place at the same time point, the following time windows for obtaining blood samples 
should be maintained:  >0 to 2 hours postdose: ±5 minutes; 2.5 to 6 hours postdose: ±10 minutes; >6 to 12 hours postdose: ±20 minutes; >12 hours postdose: 
±30 minutes.  Where repeats of vital signs measurements are required, repeats should be performed after venipuncture.
a Only subjects in Group 1 (elderly subjects) will participate in Period 2.
b To be repeated for all subjects in Group 1 ahead of participation in Period 2.
c For Group 1 patients who complete Period 1 and will remain inpatient through Period 2, CRU discharge will occur after completion of Period 2.
d Group 1 (elderly subjects) only.
e Not required at Period 2 for subjects in Group 1 who are not discharged between treatment periods.


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3. Introduction
3.1.
Study Rationale
Lasmiditan is a small molecule 5-HT1F receptor agonist being developed for the acute treatment 
of migraine. Triptans, which are 5-HT1B/1D receptor agonists, are well established as an acute 
therapy for migraine, though they are not effective in all patients or attacks. Triptans were 
developed as cerebral vasoconstrictors, mediated via their affinity for 5-HT1B receptors located 
on vascular smooth muscle. Inherent in this mechanism of action is a liability for coronary 
vasoconstriction, and therefore, triptans are contraindicated in patients with cardiovascular 
disease. Unlike triptans, lasmiditan is a highly selective and potent agonist at the 5-HT1F 
receptor with >470-fold higher affinity for the 5-HT1F receptor than for 5-HT1B/1D receptors. 
Lasmiditan is under development as a neurally acting treatment for migraine without the 
vasoconstrictor liability of triptans. 
While the prevalence of migraine declines in population older than 50 years of age, between 5-
10% of population older than 65 still suffer from migraine (Victor et al. 2010).  Elderly patients 
are among those in the target population for lasmiditan.  
The present clinical study is being conducted to determine the PK of lasmiditan in elderly and 
young healthy subjects following a single oral administration of lasmiditan.
3.2.
Background
Two Phase 2 studies have been completed with lasmiditan in the acute treatment of migraine, 
using doses of up to 45 mg over 20 minutes of the intravenous (IV) formulation, and up to 
400 mg of the oral tablet formulation.  One Phase 3 randomized, double-blind, placebo 
controlled trial has been completed in the United States (COL MIG-301 [SAMURAI]), where 
1856 patients were randomized to 100 mg lasmiditan (630 subjects), 200 mg (609 subjects), or 
placebo (617 subjects), respectively. In the SAMURAI study, both 100 mg and 200 mg doses of 
orally administered lasmiditan achieved superior 2-hour pain free rate and the most relief of 
bothersome migraine symptoms (nausea, phonophobia, and photophobia) compared to placebo.
Five Phase 1 studies of lasmiditan have been completed and methods of administration included 
IV, oral, and sublingual. Single doses of lasmiditan were tolerated by healthy subjects when 
administered IV up to 180 mg over 60 minutes (H8H-MC-LAHA; 40 subjects), as solution 
formulations administered orally or sublingually up to doses of 400 and 32 mg, respectively 
(COL MIG-102; 60 subjects), as oral tablets or a solution formulation up to doses of 400 and 
200 mg, respectively (COL MIG-103; 44 subjects), and as oral tablets up to 200 mg (COL 
MIG-104; 30 subjects) and 400 mg (COL MIG-105; 55 subjects).
Across the completed Phase 1, 2, and 3 clinical studies, doses of 0.1 mg to 400 mg of lasmiditan 
were evaluated in healthy subjects or patients with migraine.  To date, lasmiditan has been 
administered to 213 healthy subjects, and to 1632 patients with migraine.  In the SAMURAI 
study, 1239 patients aged 18 to 79 years received at least 1 dose of lasmiditan. No PK data were 
obtained in this study, and by-age analyses of safety data have not been completed.  Compared 
with placebo, the most frequently reported lasmiditan treatment emergent adverse events 


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(TEAEs) included somnolence, fatigue, dizziness, paresthesia, and hot flashes.  The majority of 
these TEAEs were mild or moderate in severity and none led to subject withdrawal.  One subject 
experienced an SAE of dizziness that was moderate in severity (lasmiditan 200 mg).
When administered intravenously at the highest dose of 180 mg (H8H-MC-LAHA), lasmiditan 
produced a statistically significant but small dose-related decrease in heart rate and increase in 
blood pressure, although the magnitude of these effects was considered unlikely to be of clinical 
significance.  Following oral administration at doses of up to 400 mg, heart rate again was 
slightly reduced, but there were no consistent effects on blood pressure.  The effects on vital 
signs were transient, not dose-related, and unlikely to be clinically significant given the intended 
intermittent use of lasmiditan.
Oral tablet doses of lasmiditan up to 400 mg (COL MIG-103) did not result in any clinically 
relevant changes in ECGs (including QT/QTc duration) following administration to healthy 
subjects.  In the thorough QT study (COL MIG-105) in healthy subjects, no clinically significant
changes in blood pressure, heart rate, or 12-lead ECG were observed at the 100 or 400 mg dose 
levels.  Lasmiditan caused no significant QT prolongation at either dose.
In healthy subjects, peak plasma concentrations of lasmiditan were observed approximately 1 to 
2.5 hours after a single oral dose, and the geometric mean terminal half-life was approximately 
4 to 6 hours. Lasmiditan exhibited dose-linear pharmacokinetics with low to moderate inter-
subject variability in exposure (AUC %CV ranged from 14 to 45%; COL MIG-102) after oral
dose administration.  Renal clearance of lasmiditan was low with approximately 2% of the dose 
recovered by 24 hours postdose.  Co-administration of lasmiditan with a high fat diet led to a 
delay in median tmax value by approximately 1 hour and a modest (~20%) increase in lasmiditan 
Cmax and AUC values, relative to that under fasted conditions. Based on the short terminal 
half-life observed following a single oral dose, accumulation of lasmiditan is not expected.  
There are currently no PK data from elderly subjects available from the completed or ongoing 
trials.
Human metabolism has been investigated using LC-MS/MS following oral dosing with 
lasmiditan, where up to 11 metabolites were detected in plasma and urine, including 3 major 
metabolites (M7, M8, and M18).  These metabolites lacked significant pharmacological activity 
at the 5-HT1F receptor and were generally considered to be pharmacologically inactive.  The 
relative proportions of metabolites to intact lasmiditan remained reasonably constant throughout 
the oral dose range studied and their PK were approximately linear.  The half-life of the 
metabolites ranged from ~4.5 hours to >12 hours.
3.3.
Benefit/Risk Assessment
The primary objective for this study is to evaluate the PK profile of lasmiditan after a single oral 
dose in healthy elderly and young subjects. There is no anticipated therapeutic benefit for the 
subjects.
Lasmiditan has been well tolerated by healthy subjects as single oral doses up to 400 mg.  
Elderly patients were enrolled in the completed Phase 3 program (SAMURAI) for acute 


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migraine treatment that tested single doses up to 200 mg, where a second dose was permitted 
within the same day if migraine relief had not been achieved.. No clinically significant safety or 
tolerability concerns have been identified in subjects to date for lasmiditan up to the highest 
single oral dose given (400 mg). Dosing of lasmiditan in this study will be conducted in an 
inpatient setting, and subjects will be monitored in house for at least 48 hours after dosing.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of lasmiditan are to be found in the IB.


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4. Objectives and Endpoints
Table LAHA.1 shows the objectives and endpoints of the study.
Table LAHA.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine the pharmacokinetics (PK) of lasmiditan in 
healthy elderly subjects (≥65 years of age) following a 
single 200 mg oral dose of lasmiditan.

PK parameters:  Cmax, tmax, and AUC(0-∞)
Secondary
To compare the PK of lasmiditan in healthy elderly 
subjects (≥65 years of age) against the PK of lasmiditan 
in healthy young subjects (18 to 45 years of age) 
following a single 200 mg oral dose of lasmiditan.
To assess the safety and tolerability of a single 200 mg 
oral dose of lasmiditan in elderly and young healthy 
subjects.

PK parameters:  Cmax, tmax, and AUC(0-∞)

A summary of the number of 
treatment-emergent AEs (TEAEs) and SAEs
Exploratory
To determine the PK of the metabolites M8, M7, and 
M18 in healthy elderly and young subjects following a 
single 200 mg oral dose of lasmiditan.

PK parameters:  Cmax, tmax, and AUC(0-∞)


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5. Study Design
5.1.
Overall Design
This is a single dose study to determine the PK of lasmiditan following a single 200 mg oral dose
in healthy elderly and young subjects.  Two groups of subjects will be evaluated as follows:

Group 1 (healthy elderly subjects; ≥65 years):  200 mg lasmiditan and placebo in a 
randomized, double-blind, 2-period crossover design

Group 2 (healthy young subjects; 18 to 45 years, inclusive):  200 mg lasmiditan in an 
open label design
Subjects in Group 2 will be matched by primary race, sex, and BMI (±20%) to subjects in 
Group 1 where feasible.  Both groups may be studied concurrently.  
Screening Period:
All subjects will participate in a screening visit up to 28 days prior to study drug dosing.
Dosing Period:
Subjects in Group 1 will participate in 2 dosing periods.  They will be admitted to the CRU on 
the day prior to dosing (Day -1), and receive study drug on Day 1 for each dosing period.  
Subjects may be discharged from the CRU on Day 3 based on investigator discretion.  There will 
be a washout period of 3 to 10 days between each dose.  Subjects may stay in the CRU as 
inpatient during the entire dosing period.
Subjects in Group 2 will participate in 1 dosing period.  They will be admitted to the CRU on 
Day -1 and receive study drug on Day 1.  Subjects may be discharged from the CRU on Day 3 
based on investigator discretion.
All subjects will be discharged from the study approximately 7 days post their final dose of 
lasmiditan.
5.2.
Number of Participants
Up to 36 subjects may be enrolled to ensure 30 subjects (2 groups of 15) complete the study.  
Group 1 will be subjects aged ≥65 years of age.  Attempts will be made to enroll at least 
4 subjects who are ≥75 years of age. Group 2 will be young subjects aged 18 to 45 years, 
inclusive. Subjects who discontinue from the study prior to completion may be replaced. 
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
A subject- and investigator-blinded, randomized and placebo controlled design is being used for 
Group 1, to minimize bias on the safety and tolerability objective for this group. A crossover 


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design improves the sensitivity for detecting any safety / tolerability signals in the elderly 
subjects, particularly in relation to vital signs (as described in Section 3.2). Lasmiditan 
administered by IV infusion has been generally well tolerated by healthy subjects, with most 
AEs being mild in intensity at all dose levels, but there was a dose-related increase in the number 
of moderate AEs.  The most frequently reported AEs following IV administration in healthy 
subjects were nervous system related (tiredness, drowsiness, dizziness, somnolence, fatigue, and 
paresthesia).  The AE profile of orally administered lasmiditan in healthy subjects was 
qualitatively similar to that observed in the IV study.  At the highest dose of 400 mg, most AEs 
were mild in severity and none were severe.
A minimal duration for the washout period is 3 days, which is adequate based on the half-life of 
lasmiditan.
An open label design is being used for Group 2, as the key objective for this group is based on 
PK, which is not subject to bias.  
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications.
The nonclinical and clinical data enable conducting clinical pharmacology studies in young and 
elderly healthy subjects.  The single dose design of this study limits exposure of subjects to 
lasmiditan and is appropriate to address the study objectives.
5.5.
Justification for Dose
The dose level of 200 mg lasmiditan has been well tolerated in previous studies of healthy 
subjects and in elderly patients enrolled in the SAMURAI study. This dose level is in the 
therapeutic dose range and is expected to be the highest potential recommended single dose for 
lasmiditan.


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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 electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to Day 1.  Subjects who are not enrolled within 28 days 
of screening may be subjected to an additional medical assessment and/or clinical measurements 
to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and enrollment (Day 1):
[1] are overtly healthy males or females, as determined by medical history and 
physical examination  
[1a] male subjects:
are not required to adhere to contraceptive requirements.
[1b] female subjects:
of childbearing potential, must test negative for pregnancy at 
screening, and agree to use a reliable method of birth control 
during the study and for 3 months following the dose of lasmiditan.  
Reliable methods of contraception for female subjects of 
childbearing potential include the use of stable oral, implanted, or 
injected contraceptive hormones, bilateral tubal ligation, 
intrauterine device, or diaphragm with spermicide along with male 
partner’s use of male condom with spermicide.
of non-child-bearing potential, i.e. postmenopausal or permanently 
sterile following hysterectomy, bilateral salpingectomy or 
confirmed tubal occlusion (not tubal ligation), as determined by 
medical history.  Postmenopausal is defined as spontaneous 
amenorrhea for at least 12 months, and a plasma 
follicle-stimulating hormone (FSH) level greater than 40 mIU/mL, 
unless the subject is taking hormone replacement therapy.
[2]
For Group 1, subjects must be aged ≥65 years, and Group 2, subjects must be 
aged between 18 and 45 years, inclusive.
[3]
have a BMI of 19 to 35 kg/m2, inclusive, at the time of screening.


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[4]
have clinical laboratory test results within normal reference range for the 
population or investigator site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.
[5]
have venous access sufficient to allow for blood sampling as per the protocol.
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[7]
have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment (Day 1):
[8] are investigator site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, parent, child or 
sibling, whether biological or legally adopted.
[9]
are Lilly or Covance employees.
[10] are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  
[11] have known allergies to lasmiditan, related compounds or any components of 
the formulation.
[12]
are persons who have previously received the investigational product in this 
study, withdrawn from this study or any other study investigating lasmiditan.
[13]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study.
[14]
have significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, hematological, or neurological disorders 
capable of significantly altering the absorption, metabolism, or elimination of 
drugs; of constituting a risk when taking the study medication; or of 
interfering with the interpretation of data.  Appendectomy, splenectomy, and 
cholecystectomy are considered as acceptable.
[15]
show evidence of significant active neuropsychiatric disease (for example, 
manic depressive illness, schizophrenia, depression).
[16] have an increased risk of seizures based on a history of:

one or more seizures;

head trauma with loss of consciousness or a post-concussive syndrome or 
lifetime history of head trauma with persistent neurological deficit (focal 
or diffuse);


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
active CNS infection, uncontrolled migraine or transient ischemic attack 
(TIA); stroke with persistent neurological deficit (focal or diffuse).  
Uncontrolled migraine is defined as migraine attacks that produce 
headache lasting up to 72 hours and are often accompanied by associated 
symptoms (nausea, photophobia, and phonophobia) that impair well-being 
and disrupt social functioning.  TIA is defined as "mini-stroke" caused by 
temporary disturbance of blood supply to an area of the brain, which 
results in a sudden, brief decrease in brain function;

CNS infection with persistent neurological deficit (focal or diffuse); 

brain surgery; 

electroencephalogram (EEG) with paroxysmal (epileptiform) activity 
(isolated spikes waves, repetitive bursts of sharp waves, paroxysmal 
activity, frank seizures, spike-wave complexes, or sharp-slow wave 
complexes, or as locally defined);

brain structural lesion, including developmental abnormalities, as 
determined by examination or imaging studies (except hydrocephalus 
treated by shunt and without neurological deficit).
[17]
show evidence of active renal disease (for example, diabetic renal disease, 
polycystic kidney disease) or estimated glomerular filtration rate (eGFR) 
<60 mL/min/1.73 m2.  
[18]
currently use, or within the past 1 year used recreational drug use, or showed 
evidence of substance dependence within the past 6 months based on history 
at screening visit
[19]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies/antigens.
[20]
show evidence of hepatitis C and/or positive hepatitis C antibody.
[21]
show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[22]
are women with a positive pregnancy test or women who are lactating.
[23]
intend to use over-the-counter or prescription medication, dietary supplements 
or strong inhibitors or inducers of CYP1A and CYP3A activities within 
14 days prior to dosing of lasmiditan (except for those described in 
criterion 1b and Section 7.7).  For group 1 (elderly), exceptions allowable for 
subjects on a stable dose of hormone replacement therapy, thyroid 
replacement therapy, prophylactic anti-platelet drugs, 
angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor 
blockers (ARBs), thiazides, statins, or protein pump inhibitors (PPIs) for at 
least 3 months; medications falling into the exceptions listed above, and/or 
others that may be considered not to impact study integrity may be allowed 
following discussion with the Lilly CRP/CP or designee.


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[24]
subjects on any anti-arrhythmic medications, or medications that could 
significantly affect QTc intervals.  
[25]
have donated blood of more than 500 mL within 3 months prior to the 
screening visit.
[26]
have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (males over 65 and females), or are 
unwilling to stop alcohol consumption 48 hours prior to admission and whilst 
resident at the CRU (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of 
wine; 1.5 oz or 45 mL of distilled spirits).
[27]
have a clinically significant abnormality in the neurological examination.
[28]
have a history of syncope, presyncopy, uncontrolled vertigo, postural 
dizziness, or at risk for falls, as judged to be clinically significant by the 
investigator.
[29]
have ECG findings or clinically significant bradycardia, cardiac block, tachy 
or brady arrhythmias.
[30]
are unwilling to refrain from tobacco- or nicotine-containing products while in 
the CRU or are unable to abide by CRU restrictions.
[31]
have orthostatic hypotension with or without dizziness and/or syncope at 
screening or Day -1 upon repeat testing, or a history of it.
6.2.1. Rationale for Exclusion of Certain Study Candidates
The use of lasmiditan in elderly patients is anticipated, thus this study will specifically examine 
the PK, safety, and tolerability in an elderly population (Group 1).  Criteria 2 and 17 define the 
elderly population for the purposes of this study.  Therefore, subjects meeting the elderly criteria 
are excluded from Group 2. 
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Lasmiditan or placebo will be administered after an overnight fast of at least 8 hours.  Subjects 
will be given a snack prior to bedtime.  Subjects will abstain from water 1 hour before and after 
dosing (except for water given with the dose).  Subjects may be permitted to consume a light 
breakfast (e.g. cereal, toast) at 1 hour postdose at the discretion of the investigator; with the 
exception of this light breakfast, subjects will remain fasting for 3 hours postdose at which time a 
meal will be served.
6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine – Subjects will refrain from consuming xanthine- or caffeine-containing food and 
drinks from 48 hours prior to admission, and while resident at the CRU.


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Alcohol – Subjects will not consume alcohol for 48 hours prior to admission, and while resident 
at the CRU.
Tobacco – Subjects will refrain from smoking while resident at the CRU.  
6.3.3. Activity
No strenuous exercise will be allowed for 48 hours prior to admission until after discharge from 
the study.
6.4.
Screen Failures
Individuals being recruited into Group 1 may be re-screened once.  The interval between 
re-screenings should be at least 1 week.  When re-screening is performed, the individual must 
sign a new informed consent form (ICF) and will be assigned a new identification number.
Individuals being recruited into Group 2 who do not meet the criteria for participation in this 
study (screen failure) may not be re-screened.  


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7. Treatment
7.1.
Treatment Administered
Investigational products used in this study are shown in Table LAHA.2.
Tablets of lasmiditan or placebo will be administered orally in the fasted state with 
approximately 240 mL of room temperature water in the morning of Day 1 of each period (where 
applicable), in a sitting position.  Subjects will not be allowed to lie supine for 2 hours after 
dosing, unless clinically indicated or for study procedures.
Table LAHA.2.
Treatments Administered
Treatment Name
lasmiditan
Placebo
Dosage Formulation
film-coated tablet
film-coated tablet 
(matching to lasmiditan)
Unit Dose Strengtha
(1 200-mg) tablet
or (2 100-mg) tablets/
200 mg lasmiditan
--
Route of Administration
Oral
Oral
Dosing Instructionsa
1 or 2 x tablet taken in the morning 
of Day 1
      1 or 2 x tablet taken in the morning of 
Day 1
a All subjects will receive the same number of tablets at each dosing occasion, i.e. 1 200-mg OR 2 100-mg 
tablets or 1 or 2 matching placebos.  Whether subjects will receive 1 OR 2 tablets will be determined prior to study 
start.
The investigator or designee is responsible for:

explaining the correct use of the investigational product to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.
7.1.1. Packaging and Labeling
Each tablet of lasmiditan contains 100 or 200 mg of active ingredient and is provided as bulk 
supply in bottles.  Placebo tablets look identical but contain no active ingredient and will be 
provided in similar bulk bottles.
The investigational product will be labeled according to the country’s regulatory requirements.


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7.2.
Method of Treatment Assignment
Subjects in Group 1 will be randomized to 1 of 2 treatment sequences (lasmiditan in Period 1 and 
placebo in Period 2; or placebo in Period 1 and lasmiditan in Period 2) using a 
computer-generated allocation schedule.
All subjects in Group 2 will receive the same treatment and will not be subject to randomization.
7.2.1. Selection and Timing of Doses
On Day 1, subjects will receive a single oral dose of 200 mg lasmiditan (Group 1 and 2) or 
placebo (Group 1 only).
The actual time of all dose administrations will be recorded in the subject’s case report form 
(CRF).
7.3.
Blinding
Group 1 will be subject- and investigator-blind.  For this group, the investigator, site staff (except 
unblinded pharmacy staff), and subjects will be blinded to study treatment.
Group 2 will be open-label.
Emergency codes for Group 1 will be available to the investigator.  A code, which reveals the 
treatment for a specific study subject, may be opened during the study only if the subject’s 
well-being requires knowledge of the subject’s treatment assignment.
If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist or 
clinical research physician for the study participant to continue in the study.  During the study, 
emergency unblinding should occur only by accessing the study subject’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
Dose modification will not be allowed during the study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm all investigational product was received in good 
condition, and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product. All 
investigational product should be stored in an environmentally controlled and monitored (manual 


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or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
Concomitant medications are to be avoided during the study unless required to treat an AE or for 
the treatment of an ongoing medical problem.
Contraceptive medication is permitted as outlined in Inclusion Criterion 1b.  For subjects in 
group 1 (elderly), hormone replacement therapy, thyroid replacement therapy, prophylactic 
anti-platelet drugs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor 
blockers (ARBs), thiazides, statins, and proton pump inhibitors (PPIs) may be permitted 
following discussion with the Lilly CRP/CP, or designee.
Acetaminophen may be allowed at the investigator’s discretion, up to 2 grams in a 24-hour
period, without prior consultation.
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, CRP, or designee.  Any medication used during the course of the 
study must be documented.
7.8.
Treatment After the End of the Study
This section is not applicable to this study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Subjects discontinuing from the investigational product prematurely for any reason must 
complete adverse event and discharge procedures per Section 2 of this protocol.
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist/CRP or 
designee and the investigator to determine if the patient may continue in the study.  If both agree 
it is medically appropriate to continue, the investigator must obtain documented approval from 
the Lilly clinical pharmacologist/CRP or designee to allow the inadvertently enrolled patient to 
continue in the study with or without continued treatment with investigational product.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she fails to return for a scheduled visit and 
is unable to be contacted by the study site.  Site personnel are expected to make diligent attempts 
to contact subjects who fail to return for a scheduled visit or were otherwise unable to be 
followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record, via CRF, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the concomitant 
treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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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 patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
All AEs occurring after signing the ICF are recorded in the case report forms and assessed for 
serious criteria.  The SAE reporting to the sponsor begins after the subject has signed the ICF 
and has received investigational product.  However, if an SAE occurs after signing the ICF, but 
prior to receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to Investigational product [IP]) does not meet the 
definition of an adverse event.  However, to fulfill regulatory requirements any pregnancy should 
be reported following the SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to IP 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 IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of lasmiditan is considered any dose higher than the 
planned study dose.  There is no specific antidote for lasmiditan.  In the event of overdose, the 
subject should receive appropriate supportive care and AEs should be documented.
No drug interaction studies in humans have yet been performed with lasmiditan.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the subject receives the first dose of IP should be reported to Lilly or its designee as an AE
via eCRF.
9.4.2. Vital Signs
For each subject, vital signs 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.  Elderly 
subjects may be permitted to lie in a semi-recumbent position, if required.  All 
supine/semi-recumbent blood pressure and pulse rate except for screening will be done in 
triplicates at approximately 1-minute intervals.  Where applicable, the last triplicate vital sign 
can be used as the supine/semi-recumbent vital sign for the calculation of orthostatic changes.
Where orthostatic measurements are required, subjects should be supine/semi-recumbent for at 
least 5 minutes and stand for at least 2 minutes.
If the subject feels unable to stand, supine/semi-recumbent vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.4.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).  


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Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP, should be reported to Lilly, or its designee, as an AE via 
eCRF. 
For each subject, a single 12-lead digital electrocardiogram (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.  All ECGs recorded should be stored at the 
investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed, and must document his/her review of the ECG 
printed at the time of collection.  Any new clinically relevant finding should be reported as an 
adverse event.
9.4.4. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes 

AEs
9.4.4.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, 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. 


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Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥ 5 × ULN on two or more consecutive blood tests

elevated serum TBL to ≥ 2 × ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥ 2 × 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, venous blood samples of 
approximately 2 mL each will be collected to determine the plasma concentrations of lasmiditan
and metabolites.
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  The actual date and 
time (24-hour clock time) of each sampling will be recorded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Plasma concentrations of lasmiditan and three major metabolites will be assayed using a 
validated LC/MS/MS method.  
Plasma remaining after the analyses may be used for exploratory work to further understand the 
disposition and metabolism of lasmiditan.
Bioanalytical samples collected to measure lasmiditan and metabolite concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.  
9.6.
Pharmacodynamics
This section is not applicable for this study.
9.7.
Genetics
A mandatory blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities, where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to lasmiditan and to 
investigate genetic variants thought to play a role in migraine.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.  


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All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of lasmiditan or after lasmiditan is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.8.
Biomarkers
This section is not applicable for this study.
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 36 subjects may be enrolled in order that 30 subjects (2 groups of 15) complete the study.
For AUC or Cmax, assuming inter-subject CV of 40% and a sample size of 15 per group, the 
90% confidence interval around the ratio of the geometric means (elderly group : non-elderly 
group) will have half-width of 24.3% on the log scale with 90% coverage probability.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The subjects’ age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized using descriptive statistics.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on data from all subjects who receive one dose of 
the IP and have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to enrollment will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.
The number of IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, and 
ECG parameters.  The parameters will be listed and summarized using standard descriptive 


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statistics, as appropriate.  Additional analysis will be performed if warranted upon review of the 
data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for lasmiditan and its metabolites will be calculated by 
standard noncompartmental methods of analysis and will be listed and summarized for each 
group of subjects using descriptive statistics.  
The primary parameters for analysis will be maximum drug concentration (Cmax) and area under 
the concentration versus time curve (AUC) from zero to infinity (AUC[0-∞]), and the time of 
maximum drug concentration (tmax) of lasmiditan and its metabolites.  Other noncompartmental 
parameters, such as half-life, apparent clearance, and apparent volume of distribution may be 
reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameter estimates will be evaluated to determine the impact of age on the PK
of lasmiditan and its metabolites. Log-transformed Cmax and AUC(0-∞) will be evaluated in a 
linear fixed-effects model with a fixed effect of age group.  The 90% CIs of the ratios of 
geometric means of the elderly group versus the young group will be presented.  
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CIs and the p-value from the Wilcoxon test will be 
calculated.
Additional analysis will be performed if warranted upon review of the data.
10.3.3. 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
Victor TW, Hu X, Campbell JC, Buse DC, Lipton RB. Migraine prevalence by age and sex in 
the United States: a life-span study. Ceph alalgia. 2010;30(9):1065-1072.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ACE
angiotensin-converting-enzyme
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ARB
angiotensin receptor blocker
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
Clinical Pharmacologist
CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form


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ICH
International Council for Harmonization
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate. Informed consent is documented by means of a 
written, signed and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.
Non-
investigational 
product 
A product that is not being tested or used as a reference in the clinical study, but is provided 
to subjects and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
open label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PPI
protein pump inhibitor
randomize
the process of assigning subjects/patients to an experimental group on a random basis
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
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 


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Total CO2
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC)
Glucose (random)
Platelets
Blood urea nitrogen (BUN)
Differential WBC absolute counts and % of:
  Total protein
Neutrophils
  Albumin
Lymphocytes
  Total bilirubin
Monocytes
  Alkaline phosphatase (ALP)
Eosinophils
  Aspartate aminotransferase (AST)
Basophils
  Alanine aminotransferase (ALT)
Creatinine
Urinalysis
   Specific gravity
   pH
   Protein
   Glucose
Urine drug and alcohol screen
   Ketones
Hepatitis B surface antigena
   Bilirubin
Hepatitis C antibodya
   Urobilinogen
HIVa
   Blood
Serum Pregnancy test
   Nitrite
   Urine microscopicc
FSHb
Thyroid stimulating hormoned
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a Screening only
b Screening only for confirmation of post-menopausal status.
c Test only if dipstick result is abnormal and per investigator’s discretion.
d Per investigator’s discretion.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of IP.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Ethical Review
The investigator or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Council for Harmonization
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 sites.  Lilly or its representatives must approve the ICF 
before it is used at the investigative sites.  All ICFs must be compliant with the ICH guideline on 
GCP.
The study sites’ ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines 


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


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Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject 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 patients in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol H8H-MC-LAHA Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
45
1
45
Clinical laboratory tests
8
8b/5c
64b/40c
Serum pregnancy test
5
4b/3c
20b/15c
Pharmacokinetics
2
28b/ 14c
56b/28c
Pharmacogenetics
10
1
10
Total
195b/138c
Total for clinical purposes rounded up to nearest 10 mL
200b/140c
a
Additional samples may be drawn if needed for safety purposes.
b Group 1.
c
Group 2.


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Appendix 6.
Protocol Amendment H8H-MC-LAHA (a) 
Summary: Effect of Age on the Pharmacokinetics, 
Safety, and Tolerability of Lasmiditan in Healthy 
Subjects
Overview
Protocol H8H-MC-LAHA, Effect of Age on the Pharmacokinetics, Safety, and Tolerability of 
Lasmiditan in Healthy Subjects, has been amended.  The new protocol is indicated by 
Amendment (a) and will be used to conduct the study in place of any preceding version of the 
protocol.
Changes were made to the protocol based on feedback from the investigative staff.  Specifically, 
edits were made to clarify the schedule of assessments, the exclusion criteria, concomitant 
medication specifications, data protection, and the clinical laboratory test parameters.


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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.


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2. 
Schedule of Activities
Study Schedule Protocol H8H-MC-LAHA
Screening
Periods 1 and 2a
Discharge from 
Study/ Early 
Discontinuation
Comments
Procedure
-28 to -2 
days prior to 
Day 1
Day -1b
Day 1
Day 2
Day 3
approximately 7 days 
post final dose
Informed 
Consent
X
Subject 
Admission to 
CRU
X
Subject 
Discharge from 
CRU
Xc
Randomization
Predosed
Investigational 
Product 
Administration
Day 1, 
indicates 
Time = 0
Medical History
X
AEs and 
Medication 
review
X
X
X
X
X
Height
X
Weight
X
Temperature
X
Vital Signs 
(supine)
X
Predose, 
0.5, 1, 1.5, 
2, 2.5, 3, 
4, 6, 8, 12
24
48
X
Time points may be added for each study 
period, if warranted and agreed upon 
between Lilly and the investigator.
All assessments except for screening should 
be performed in triplicate. See Section 0 for 
further details.


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Study Schedule Protocol H8H-MC-LAHA
Screening
Periods 1 and 2a
Discharge from 
Study/ Early 
Discontinuation
Comments
Procedure
-28 to -2 
days prior to 
Day 1
Day -1b
Day 1
Day 2
Day 3
approximately 7 days 
post final dose
Orthostatic
Vital Signs 
X
X
Predose, 
0.5, 1, 2
24
Last triplicate vital sign can be used as the 
supine vital sign for calculation of orthostatic 
changes, where applicable. Time points may 
be added for each study period, if warranted 
and agreed upon between Lilly and the 
investigator.
Screening 
laboratory
Tests
X
Clinical Lab 
Tests
X
X
Predose
X
X
See Appendix 2, Clinical Laboratory Tests, 
for details.
Urine Drug 
Screen and 
alcohol screen
X
Xe
Pregnancy 
Test 
X
X
X
Serum pregnancy test will be performed at 
all time points.
Physical Exam
X
X
X
X
X
Full physical examination at Day -1 of each 
study period (as applicable for Group 1) and 
discharge from the study visit only.  
Symptom driven physical examination for all 
other timepoints.
12-lead ECG
X
X
Predose, 1, 
2, 4 hours 
postdose
24 hours 
postdose
X
Single ECG readings will be taken.
PK Samples
Predose, 
0.5, 1, 1.5, 
2, 2.5, 3, 4, 
6, 8, 12
24, 36
48
Sampling times are relative to the time of 
study treatment administration (0 min).


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Genetic 
Sample
X
Single sample for pharmacogenetic analysis 
taken prior to/on Day 1
Abbreviations:  AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; min = minutes; PK = pharmacokinetics. 
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be used: ECG, supine vital signs, and orthostatic vital 
signs, venipuncture.  Where venipuncture and other procedures take place at the same time point, the following time windows for obtaining blood samples 
should be maintained:  >0 to 2 hours postdose: ±5 minutes; 3 2.5 to 6 hours postdose: ±10 minutes; 7>6 to 12 hours postdose: ±20 minutes; >12 hours 
postdose: ±30 minutes.  Where repeats of vital signs measurements are required, repeats should be performed after venipuncture.
a Only subjects in Group 1 (elderly subjects) will participate in Period 2.
b To be repeated for all subjects in Group 1 ahead of participation in Period 2.
c For Group 1 patients who complete Period 1 and will remain inpatient through Period 2, CRU discharge will occur after completion of Period 2.
d Group 1 (elderly subjects) only.
e Not required at Period 2 for subjects in Group 1 who are not discharged between treatment periods.


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6.2.
Exclusion Criteria
[23]
intend to use over-the-counter or prescription medication, dietary supplements 
or strong inhibitors or inducers of CYP1A and CYP3A activities within 
14 days prior to dosing of lasmiditan (except for those described in
criterion 1b and Section 7.7).  For group 1 (elderly), exceptions allowable for 
subjects on a stable dose of hormone replacement therapy, thyroid 
replacement therapy, prophylactic anti-platelet drugs, 
angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor 
blockers (ARBs), thiazides, statins, or protein pump inhibitors (PPIs) for at 
least 3 months; medications falling into the exceptions listed above, and/or 
others that may be considered not to impact study integrity may be allowed 
following discussion with the Lilly CRP/CP or designee.
[26]
have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (males over 65 and females), or are 
unwilling to stop alcohol consumption 48 hours prior to admission and whilst 
resident at the CRUdosing until the completion of the study (1 unit = 12 oz or 
360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits).
7.7.
Concomitant Therapy
Concomitant medications are to be avoided during the study unless required to treat an AE or for 
the treatment of an ongoing medical problem.
Contraceptive medication is permitted as outlined in Inclusion Criterion 1b.  For subjects in 
group 1 (elderly), hormone replacement therapy, thyroid replacement therapy, prophylactic 
anti-platelet drugs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor 
blockers (ARBs), thiazides, statins, and proton pump inhibitors (PPIs) may be permitted 
following discussion with the Lilly CRP/CP, or designee.
Acetaminophen may be allowed at the investigator’s discretion, up to 2 grams in a 24 hour 
period, without prior consultation.
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, CRP, or designee.  Any medication used during the course of the 
study must be documented.


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Appendix 2
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Total CO2
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC)
Glucose (random) 
Platelets
Blood urea nitrogen (BUN)
Differential WBC absolute counts and % of:
  Total protein
Neutrophils
  Albumin
Lymphocytes
  Total bilirubin
Monocytes
  Alkaline phosphatase (ALP)
Eosinophils
  Aspartate aminotransferase (AST)
Basophils
  Alanine aminotransferase (ALT)
Creatinine
Urinalysis
   Specific gravity
   pH
   Protein
   Glucose
Urine drug and alcohol screen
   Ketones
Hepatitis B surface antigena
   Bilirubin
Hepatitis C antibodya
   Urobilinogen
HIVa
   Blood
Serum Pregnancy test
   Nitrite
   Urine microscopicc
FSHb
Thyroid stimulating hormoned
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a Screening only
b Screening only for confirmation of post-menopausal status.
c Test only if dipstick result is abnormal and per investigator’s discretion.
d Per investigator’s discretion.


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Appendix 3
Study Governance, Regulatory and Ethical 
Considerations
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.

SAP_000.pdf: 
Statistical Analysis Plan H8H-MC-LAHA 
 
Effect of Age on the Pharmacokinetics, Safety, and Tolerability of Lasmiditan in Healthy 
Subjects 
 
NCT03182920 
 
Approval Date: 05-Jul-2017 
 


Final, 03 July 2017
             Page 1 of 14
STATISTICAL ANALYSIS PLAN
Effect of Age on the Pharmacokinetics, Safety, and Tolerability of Lasmiditan in Healthy 
Subjects
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  03-July-2017
Study Drug: LY573144 (Lasmiditan)
Sponsor Reference:  H8H-MC-LAHA
Covance CRU Study: 1000071-8364953
Clinical Phase I
Approval Date: 05-Jul-2017 GMT


Final, 03 July 2017
             Page 2 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8364953
Sponsor Reference H8H-MC-LAHA
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary objective .................................................................................................... 5
4.2
Secondary objectives ............................................................................................... 5
4.3
Exploratory objective .............................................................................................. 6
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENT ............................................................................................................... 6
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 7
9.1
General.................................................................................................................... 7
9.2
Demographics and Subject Disposition.................................................................... 8
9.3
Pharmacokinetic Assessment................................................................................... 8
9.3.1
Pharmacokinetic Analysis............................................................................... 8
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 11
9.4
Safety and Tolerability Assessments...................................................................... 12
9.4.1
Adverse events ............................................................................................. 12
9.4.2
Concomitant medication............................................................................... 12
9.4.3
Clinical laboratory parameters...................................................................... 12
9.4.4
Hepatic Monitoring ...................................................................................... 12
9.4.5
Vital signs .................................................................................................... 13
9.4.6
Electrocardiogram (ECG)............................................................................. 13
9.4.7
Other assessments......................................................................................... 13
9.4.8
Safety and Tolerability Statistical Methodology............................................ 13
10. INTERIM ANALYSES ............................................................................................... 14
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 14
12. REFERENCES ............................................................................................................ 14
13. DATA PRESENTATION ............................................................................................ 14
13.1 Derived Parameters ............................................................................................... 14
13.2 Missing Data ......................................................................................................... 14
13.3 Insufficient Data for Presentation .......................................................................... 14


Final, 03 July 2017
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Covance Clinical Study No. 8364953
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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
AST
Aspartate aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from 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
BMI
Body mass index
BQL
Below the level of quantitation
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
GGT
Gamma-glutamyl transferase
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MR
Metabolic ratio
MRE
Magnetic resonance elastography


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Covance Clinical Study No. 8364953
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MW
Molecular weight
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SD
Standard deviation 
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
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Covance Clinical Study No. 8364953
Sponsor Reference H8H-MC-LAHA
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 27 
April 2017).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as 
the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary objective

To determine the PK of lasmiditan in healthy elderly subjects (≥65 years of age) 
following a single 200 mg oral dose of lasmiditan.
4.2
Secondary objectives

To compare the PK of lasmiditan in healthy elderly subjects (≥65 years of age) against 
the PK of lasmiditan in healthy young subjects (18 to 45 years of age) following a single 
200 mg oral dose of lasmiditan.

To assess the safety and tolerability of a single 200 mg oral dose of lasmiditan in elderly 
and young healthy subjects.


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Covance Clinical Study No. 8364953
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4.3
Exploratory objective

To determine the PK of the metabolites M8, M7, and M18 in healthy elderly and young 
subjects following a single 200 mg oral dose of lasmiditan.
5. STUDY DESIGN
This is a single dose study to determine the PK of lasmiditan following a single 200 mg oral dose 
in healthy elderly and young subjects. Two groups of subjects will be evaluated as follows:

Group 1 (healthy elderly subjects; ≥65 years): 200 mg lasmiditan and placebo in a 
randomized, double-blind, 2-period crossover design.

Group 2 (healthy young subjects; 18 to 45 years, inclusive): 200 mg lasmiditan in an 
open label design.
Subjects in Group 2 will be matched by primary race, sex, and body mass index (BMI) (±20%) 
to subjects in Group 1 where feasible. Both groups may be studied concurrently. 
Screening Period:
All subjects will participate in a screening visit up to 28 days prior to study drug dosing.
Dosing Period:
Subjects in Group 1 will participate in 2 dosing periods. They will be admitted to the clinical 
research unit (CRU) on the day prior to dosing (Day -1), and receive study drug on Day 1 for 
each dosing period. Subjects may be discharged from the CRU on Day 3 based on investigator 
discretion. There will be a washout period of 3 to 10 days between each dose. Subjects may stay 
in the CRU as inpatient during the entire dosing period.
Subjects in Group 2 will participate in 1 dosing period. They will be admitted to the CRU on 
Day -1 and receive study drug on Day 1. Subjects may be discharged from the CRU on Day 3 
based on investigator discretion.
All subjects will be discharged from the study approximately 7 days post their final dose of
lasmiditan.
6. TREATMENT
The following is a list of the study treatments and age group names that will be used in the TFLs.
Treatment Name
Order in TFL
Placebo
1
200 mg lasmiditan 
2


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Covance Clinical Study No. 8364953
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Age Group Name
Order in TFL
Elderly
1
Young
2
7. SAMPLE SIZE JUSTIFICATION
Up to 36 subjects may be enrolled in order that 30 subjects (2 groups of 15) complete the study. 
For area under the curve (AUC) or maximum observed drug concentration (Cmax), assuming 
inter-subject coefficient of variation (CV) of 40% and a sample size of 15 per group, the 90% 
confidence interval around the ratio of the geometric means (elderly group : non-elderly group) 
will have half-width of 24.3% on the log scale with 90% coverage probability.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug 
or placebo, and have at least one postdose safety assessment.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data.  Subjects may be excluded from the PK summary 
statistics and statistical analysis if a subject has an adverse event of vomiting that occurs at or 
before 2 times median time of maximum observed drug concentration (tmax). 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median,
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric CV% will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.


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Covance Clinical Study No. 8364953
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Data analysis will be performed using SAS® Version 9.3 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized and listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
Plasma concentrations of lasmiditan (LY573144) and its metabolites M8, M7 and M18 will be 
used to determine the following PK parameters, when possible:  
Parameter
Units
Definition
AUC(0-)
ng.h/mL
area under the concentration versus time curve from 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
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration (LY573144 only)
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration (LY573144 only)
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration (LY573144 only)
MR
metabolic ratioa
a = no molar correction will be applied since the metabolites are very similar in molecular weight  and within 5% of 
the molecular weight for lasmiditan.
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the clinical study report. Any exceptions or special 
handling of data will be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.


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Covance Clinical Study No. 8364953
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General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. AUC(0-) values where the percentage 
of the total area extrapolated is more than 20% will be flagged. Any AUC(0-) value 
excluded from summary statistics will be noted in the footnote of the summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
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 observed concentration at last quantifiable timepoint (Clast) will 
be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 


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Covance Clinical Study No. 8364953
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
Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all pharmacokinetic analyses is not a requirement. Rather, this 
procedure provides justification for exclusion of data when scientifically appropriate. This 
procedure describes the methodology for identifying an individual value as an outlier for 
potential exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data Within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For pharmacokinetic profiles during multiple dosing, the concentration of the pre-dose 
sample exceeds all measured concentrations for that individual in the subsequent post-
dose samples.


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Covance Clinical Study No. 8364953
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
For pharmacokinetic profiles during single dosing of non-endogenous compounds, the 
concentration in a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data Between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a. Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.
c. Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e. If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
9.3.2 Pharmacokinetic Statistical Methodology
The PK parameter estimates will be evaluated to determine the impact of age on the PK of 
lasmiditan and its metabolites. Log-transformed Cmax and AUC(0-∞) will be evaluated in a linear 
fixed-effects model with a fixed effect of age group (elderly, young). The 90% confidence 
intervals (CIs) of the ratios of geometric means of the elderly group versus the young group will 
be presented. An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
class agegroup;
model l_pk = agegroup / alpha=0.1;
lsmeans agegroup / pdiff;
run;
where l_pk is the log-transformed (base e) PK parameter. 


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The tmax will be analyzed using a Wilcoxon rank sum test. Estimates of the median difference 
between elderly and young subjects based on the observed medians, 90% CIs and the p-value 
from the Wilcoxon test will be calculated.
Additional analysis will be performed if warranted upon review of the data.
9.4
Safety and Tolerability Assessments
9.4.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose. 
All AEs will be listed.  Treatment-emergent AEs will be summarized by age group, treatment, 
severity and relationship to the study drug. The frequency (the number of adverse events, the 
number of subjects experiencing an adverse event and the percentage of subjects experiencing an 
adverse event) of treatment-emergent adverse events will be summarized by age group, 
treatment, Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 system organ 
class and preferred term. The summary and frequency adverse event tables will be presented for 
all causalities and those considered related to the study drug. Any serious adverse events will be 
tabulated.
9.4.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version September 2016 
Enhanced Dictionary B2 Format). Concomitant medication will be listed.
9.4.3 Clinical laboratory parameters
All clinical chemistry, hematology and urinalysis data will be listed. Additionally clinical 
chemistry, hematology and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.4.4 Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥ 3 × upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥ 2 × ULN, or elevated total bilirubin (TBL) ≥ 2 × ULN, 
liver tests will be performed to confirm the abnormality.  
The subjects’ liver disease history and associated person liver disease history data will be listed.  
Any concomitant medication of acetaminophen/paracetamol will be listed.  Results from any 


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Covance Clinical Study No. 8364953
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hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan and a 
biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed.  Liver related signs and symptoms data will be 
summarized by age group and treatment, and listed, if available. 
All hepatic chemistry, hematology, coagulation, and serology data will be summarized by 
parameter, age group, and treatment, and listed.  Values outside the reference ranges will be 
flagged on the individual subject data listings.
9.4.5 Vital signs
Where supine (or semi-recumbent for elderly subjects) blood pressure and pulse rate are 
measured in triplicate, the mean value will be calculated and used in all subsequent calculations. 
When triplicate blood pressure or pulse rate measurements precede a standing measurement, the 
last supine (or semi-recumbent for elderly subjects) blood pressure or pulse rate measurement 
will be used for orthostatic calculations. Orthostatic changes will be calculated as the standing 
value, minus the last supine (or semi-recumbent for elderly subjects) value taken prior to the 
standing value.
Vital signs data will be summarized by age group and treatment together with changes from 
baseline, where baseline is defined as the mean of the triplicate measurement on Day 1 predose 
of each treatment period for supine (or semi-recumbent for elderly subjects) vital signs, and the 
last measurement on Day 1 predose of each treatment period for standing and orthostatic vital 
signs. Figures of mean vital signs and mean changes from baseline profiles by treatment will be 
presented by age group and treatment over time. Furthermore, values for individual subjects will 
be listed.
Changes from baseline will be calculated for vitals signs. Changes from baseline of >30 mmHg 
for systolic blood pressure and of >20 mmHg for diastolic blood pressure are considered to be of 
potential clinical concern and will be highlighted on the individual changes from baseline data 
listings. Orthostatic decreases of >20 mmHg for systolic and diastolic blood pressure or an 
increase in heart rate of >20 bpm are considered to be of potential clinical concern, and will also 
be highlighted on the individual data listings. 
9.4.6 Electrocardiogram (ECG)
For each subject, ECGs will be performed for safety purposes only, and will not be reported.
9.4.7 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.4.8 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.


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10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
Since the data will not be paired due to the study design, Wilcoxon rank sum test will be used for 
the analysis of tmax instead of the Wilcoxon signed rank test that was stated in the protocol.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 2263d53e-f038-48e7-ae74-397afc94edbe
Approver: 
Approval Date & Time: 05-Jul-2017 12:17:40 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Jul-2017 12:59:09 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Jul-2017 13:02:55 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Jul-2017 13:15:00 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD