Clinical trial NCT03270644
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2017-08-31; Completion date: 2017-11-22
Enrollment: 44 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will assess the effects on heart rate and blood pressure when a single dose of lasmiditan is administered with a daily dose of propranolol. This study will also measure how much lasmiditan gets into the bloodstream after taking lasmiditan alone and after taking it together with propranolol. The study will also look at how well both drugs are tolerated. Information about any side effects that may occur will be collected.

This study will last approximately 45 days including screening. This study will require 13 days/12 nights in a Clinical Research Unit (CRU) followed by 1 follow-up appointment approximately 7 days after the last dose. Screening is required within 28 days prior to the start of the study.

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

Detailed description:

Arms: arm 1: Single oral dose of lasmiditan 200 mg on Day 1 as reference treatment. arm 2: Twice-daily oral doses of propranolol 80 mg on Days 4-10 as reference treatment. arm 3: Single oral dose of lasmiditan 200 mg + two oral doses of propranolol 80 mg on Day 9 as test treatment.
Interventions: intervention 1: Lasmiditan intervention 2: Propranolol
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally

Protocol documents:
Prot_000.pdf: 
Protocol H8H-MC-LAHD(a) 
 
Effect of Lasmiditan on Heart Rate and Blood Pressure in Healthy Subjects Receiving Oral 
Doses of Propranolol 
 
 
NCT03270644 
 
 
Approval Date: 20-OCT-2017 


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Protocol H8H-MC-LAHD(a)
Effect of Lasmiditan on Heart Rate and Blood Pressure in 
Healthy Subjects Receiving Oral Doses of Propranolol
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
lasmiditan (LY573144), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act 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 June 
2017.
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 20-Oct-2017 GMT


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Table of Contents
Effect of Lasmiditan on Heart Rate and Blood Pressure in 
Healthy Subjects Receiving Oral Doses of Propranolol
Section
Page
Protocol H8H-MC-LAHD(a) Effect of Lasmiditan on Heart Rate and 
Blood Pressure in Healthy Subjects Receiving Oral Doses of 
Propranolol .........................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................17
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................20
5.
Study Design.....................................................................................................................21
5.1.
Overall Design .............................................................................................................21
5.2.
Number of Participants.................................................................................................22
5.3.
End of Study Definition ...............................................................................................22
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................26
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................26
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................26
6.3.3.
Activity................................................................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28
7.1.
Treatment Administered...............................................................................................28
7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................28
7.2.1.
Timing of Doses...................................................................................................29
7.3.
Blinding .......................................................................................................................29


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7.4.
Dose Modification........................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability...............................................................29
7.6.
Treatment Compliance .................................................................................................29
7.7.
Concomitant Therapy...................................................................................................29
7.8.
Treatment After the End of the Study...........................................................................29
8.
Discontinuation Criteria ....................................................................................................30
8.1.
Discontinuation from Study Treatment.........................................................................30
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................30
8.2.
Discontinuation from the Study....................................................................................30
8.3.
Subjects Lost to Follow-up...........................................................................................31
9.
Study Assessments and Procedures ...................................................................................32
9.1.
Efficacy Assessments...................................................................................................32
9.2.
Adverse Events ............................................................................................................32
9.2.1.
Serious Adverse Events........................................................................................33
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................33
9.2.2.
Complaint Handling.............................................................................................33
9.3.
Treatment of Overdose.................................................................................................34
9.4.
Safety...........................................................................................................................34
9.4.1.
Laboratory Tests ..................................................................................................34
9.4.2.
Vital Signs ...........................................................................................................34
9.4.3.
Electrocardiograms ..............................................................................................34
9.4.3.1.
12-Lead Electrocardiograms...........................................................................34
9.4.3.2.
Holter Ambulatory Monitoring .......................................................................35
9.4.4.
Safety Monitoring ................................................................................................36
9.4.4.1.
Hepatic Safety................................................................................................36
9.5.
Pharmacokinetics .........................................................................................................37
9.5.1.
Bioanalysis...........................................................................................................37
9.6.
Pharmacodynamics ......................................................................................................37
9.7.
Genetics .......................................................................................................................37
9.8.
Biomarkers...................................................................................................................38
9.9.
Health Economics ........................................................................................................38
10.
Statistical Considerations and Data Analysis.....................................................................39
10.1. Sample Size Determination ..........................................................................................39
10.2. Populations for Analyses..............................................................................................39
10.2.1.
Study Participant Disposition ...............................................................................39
10.2.2.
Study Participant Characteristics ..........................................................................39
10.3. Statistical Analyses ......................................................................................................39
10.3.1.
Safety Analyses....................................................................................................39


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10.3.1.1.
Clinical Evaluation of Safety..........................................................................39
10.3.1.2.
Statistical Evaluation of Safety.......................................................................40
10.3.2.
Pharmacokinetic Analyses....................................................................................40
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................40
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................40
10.3.3.
Cardiovascular Analyses ......................................................................................40
10.3.3.1.
Cardiovascular Parameter Estimation .............................................................40
10.3.3.2.
Statistical Inference of Cardiovascular Parameters..........................................41
10.3.4.
Interim Analyses..................................................................................................41
11.
References ........................................................................................................................42


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List of Tables
Table
Page
Table LAHD.1.
Objectives and Endpoints .......................................................................20
Table LAHD.2.
Treatments Administered........................................................................28


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List of Figures
Figure
Page
Figure LAHD.1.
Illustration of study design for Protocol H8H-MC-LAHD. .....................22


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................43
Appendix 2.
Clinical Laboratory Tests........................................................................47
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................48
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............51
Appendix 5.
Blood Sampling Summary......................................................................52
Appendix 6.
Protocol Amendment H8H-MC-LAHD(a) Summary:  Effect of 
Lasmiditan on Heart Rate and Blood Pressure in Healthy Subjects 
Receiving Oral Doses of Propranolol......................................................53


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1. Protocol Synopsis
Title of Study:
Effect of Lasmiditan on Heart Rate and Blood Pressure in Healthy Subjects Receiving Oral Doses of Propranolol
Rationale: 
In clinical practice, lasmiditan is likely to be coadministered with propranolol, and it is therefore pertinent to 
determine the potential for cardiovascular effects or pharmacokinetic (PK) drug interactions.  Propranolol is known 
to decrease heart rate. Study H8H-MC-LAHD is being conducted to evaluate the cardiovascular effects and PK 
impact of coadministration of lasmiditan with propranolol in healthy subjects.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To evaluate the effects of propranolol alone and in 
combination with lasmiditan on heart rate.
Heart rate by Holter ambulatory monitoring.
Secondary
To evaluate the effects of propranolol alone and in 
combination with lasmiditan on blood pressure and PR 
interval.
To explore the tolerability of a single dose of 
lasmiditan alone or in combination with propranolol.
To evaluate the PK of lasmiditan alone and in 
combination with propranolol.
To evaluate the PK of propranolol alone and in 
combination with lasmiditan.
PR interval by Holter ambulatory monitoring, systolic 
blood pressure, and diastolic blood pressure.
A summary of the number of treatment-emergent 
adverse events (TEAEs) and serious adverse events 
(SAEs).
Maximum observed drug concentration (Cmax), time of 
maximum observed drug concentration (tmax) and area 
under the concentration versus time curve (AUC) from 
time 0 extrapolated to infinity (AUC[0-∞]).
Cmax, tmax, and area under the concentration versus 
time curve during 1 dosing interval (AUCτ).
Summary of Study Design:  
This is an open-label, fixed-sequence study in healthy subjects to assess the cardiovascular effects of the 
coadministration of lasmiditan with propranolol.  Subjects will receive a single dose of 200 mg lasmiditan on Day 1, 
then receive a single dose of 200 mg lasmiditan coadministered with steady-state propranolol on Day 9.
Blood samples will be collected predose and up to 48 hours postdose on Days 1 and 9 for the measurement of 
plasma concentrations of lasmiditan and its metabolites, and predose and up to 12 hours postdose on Days 8 and 9 
for the measurement of plasma concentrations of propranolol.


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Safety will be assessed through reporting of adverse events (AEs), clinical laboratory evaluations, vital signs 
measurements, 12-lead electrocardiograms (ECGs), and physical examinations.
Cardiovascular effects will be assessed by Holter ambulatory monitoring and replicate measurements of blood 
pressure at predose, and for 12 hours postdose on Days -1, 1, 8, and 9.
Treatment Arms and Planned Duration for an Individual Subject:  
All subjects will be assigned to the same treatment sequence.  The planned duration for each individual subject will 
be approximately 45 days, including screening.
Number of Subjects:
Approximately 44 subjects may be enrolled so that at least 36 subjects complete the study.
Statistical Analysis:
The primary parameters for the cardiovascular analyses will be systolic blood pressure, diastolic blood pressure, 
mean hourly heart rate, mean hourly heart rate nadirs, heart rate, and PR interval. Mean hourly heart rates from 
1 hour predose to 12 hours postdose will be calculated on Days -1, 1, 8, and 9 from the Holter monitoring data.  
Negative chronotropic effects will be evaluated using nadir (1-6 h), nadir (>6 h–12 h), and nadir (1-12 h), which are 
defined as the lowest mean hourly heart rate during each postdose time period on each day.  Heart rate and PR 
interval will also be determined on Days -1, 1, 8, and 9 from the 10-second Holter traces extracted at the time points 
listed in the Schedule of Activities.
Cardiovascular parameters will be evaluated to determine the impact of coadministration of propranolol with 
lasmiditan on blood pressure, heart rate, and PR interval compared to propranolol alone.  Primary cardiovascular
parameters will be evaluated in a linear mixed-effects model with a fixed effect for treatment (lasmiditan 
coadministered with propranolol [Day 9; test treatment] versus propranolol alone [Day 8; reference treatment]), and 
a random effect for subject.  Least squares (LS) means will be calculated for the test and reference treatments.  Mean
treatment differences will be presented along with the corresponding 90% confidence interval (CI).  Primary PD 
parameters may be log-transformed prior to the statistical analysis if a review of the data indicates that the 
assumption of normality is violated.  A similar analysis will be performed to determine the impact of 
coadministration of lasmiditan with propranolol on blood pressure, heart rate, and PR interval compared to 
lasmiditan alone.  The model will include the following treatments:  propranolol coadministered with lasmiditan 
(Day 9; test treatment) versus lasmiditan alone (Day 1; reference treatment).
The impact of coadministration of propranolol with lasmiditan on orthostatic blood pressure and pulse rate will be 
evaluated using descriptive statistics as appropriate.  No formal statistical analysis is planned.
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and propranolol will be calculated by standard 
noncompartmental methods of analysis.
Pharmacokinetic parameters will be evaluated to determine the impact of propranolol coadministration on the PK of 
a single dose of lasmiditan and its metabolites.  Log-transformed Cmax and AUC parameters will be evaluated in a 
linear mixed-effects model with a fixed effect for treatment (lasmiditan coadministered with propranolol [Day 9; test 
treatment] versus lasmiditan alone [Day 1; reference treatment]), and a random effect for subject.  The treatment 
differences will be back-transformed to present the ratios of geometric means and the corresponding 90% CI.  


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The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference based on the 
observed medians, 90% CIs and p-values from the Wilcoxon test will be calculated.
A similar analysis will be performed to determine the impact of coadministration of a single dose of lasmiditan on 
the steady-state PK of propranolol.  The model will include the following treatments:  propranolol coadministered 
with lasmiditan (Day 9; test treatment) versus propranolol alone (Day 8; reference treatment). 
Safety parameters will be summarized using descriptive statistics, where appropriate.


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2. Schedule of Activities


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Study Schedule Protocol H8H-MC-LAHD
Screening
Study Days
Follow-
up/ED
Comments
Procedure
-28 to -3
days prior 
to Day 1
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~7 days 
post last 
dose
Informed 
Consent
X
Subject 
Admission to 
CRU
X
Subject 
Discharge 
from CRU
X
Lasmiditan 
Administration
X, 
indicates 
time = 0
X
Propranolol 
Administration
X
X
X
X
X
X
X
Medical 
History
X
Height
X
Weight
X
Temperature
X
Physical Exam
X
X
X
X
X
X
X
Full physical examination 
(to include neurological 
examination) at screening, 
Day -1 and follow-up visit 
only.  Symptom driven 
physical examination for 
all other time points.


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Screening
Study Days
Follow-
up/ED
Comments
Procedure
-28 to -3
days prior 
to Day 1
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~7 days 
post last 
dose
Supine Blood 
Pressure and 
Pulse Rate 
(hours)
X
X
Predose, 
1, 1.5, 2, 
2.5, 3, 4, 
6, 8, 12
X
X
X
X
Predose, 
1, 1.5, 2, 
2.5, 3, 4, 
6, 8, 12
Predose, 
1, 1.5, 2, 
2.5, 3, 4, 
6, 8, 12
X
Blood pressure and pulse 
rate should be assessed at 
predose on Days 4 to 7 and 
on Day 10.
Time points may be added
if warranted and agreed 
upon between Lilly and the 
investigator. All 
assessments should be 
performed in triplicate, 
with the exception of 
screening. See 
Section 9.4.2 for details.
If multiple procedures take 
place at the same time 
point, the following order 
of the procedures should be 
used: ECG, vital signs, and 
venipuncture.


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Screening
Study Days
Follow-
up/ED
Comments
Procedure
-28 to -3
days prior 
to Day 1
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~7 days 
post last 
dose
Orthostatic 
Vital Signs 
(hours)
X
X
Predose,
1, 2
Predose, 
1, 2
Predose, 
1, 2
Last triplicate vital sign can 
be used as the supine vital 
sign for calculation of 
orthostatic changes. If 
multiple procedures take 
place at the same time 
point, the following order 
of the procedures should be 
used: ECG, vital signs, and 
venipuncture.  Time points 
may be added if warranted 
and agreed upon between 
Lilly and the investigator.
Clinical Lab 
Tests
(including 
serum 
pregnancy 
test)
X
X
X
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for 
details.  If multiple 
procedures take place at the 
same time point, the 
following order of the 
procedures should be used: 
ECG, vital signs, and 
venipuncture.  
12-lead ECG
(hours)
X
X
Predose, 
1, 2, 4
24
Predose, 
1, 2, 4
Predose, 
1, 2, 4
24
Single ECGs to be taken at 
each time point.  If multiple 
procedures take place at the 
same time point, the 
following order of the 
procedures should be used: 
ECG, vital signs, and 
venipuncture.


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Screening
Study Days
Follow-
up/ED
Comments
Procedure
-28 to -3
days prior 
to Day 1
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~7 days 
post last 
dose
Holter 
Ambulatory 
Monitoring
X
X
X
X
Ambulatory monitoring 
through the 12-hour time 
point on Days -1, 1, 8, 
and 9.  Monitoring on 
Day -1 should be started 
approximately 1 hour prior 
to the anticipated dosing 
time.  Extractions should 
be made at -1, 0.5, 1, 2, 
2.5, 3, 4, 6, 8, and 12 hours 
postdose.  Triplicate ECG 
extractions to be taken at 
each time point.  
Genetic 
Sample
X
Single sample for 
pharmacogenetic analysis 
taken prior to/on Day 1
Lasmiditan 
and Metabolite 
PK Samples 
(hours)
Predose, 
0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 12
24, 
36
48
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).
If multiple procedures take 
place at the same time 
point, the following order 
of the procedures should be 
used: ECG, vital signs,
and venipuncture.


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Screening
Study Days
Follow-
up/ED
Comments
Procedure
-28 to -3
days prior 
to Day 1
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~7 days 
post last 
dose
Propranolol 
PK Samples 
(hours)
Predose, 
0.5, 1, 
1.5, 2, 3, 
4, 6, 8, 
12
Predose, 
0.5, 1, 
1.5, 2, 3, 
4, 6, 8, 
12
Sampling times are relative 
to the time of propranolol
administration (0 min).
If multiple procedures take 
place at the same time 
point, the following order 
of the procedures should be 
used: ECG, vital signs, 
and venipuncture.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; min = minutes; PK = pharmacokinetics. 


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3. Introduction
3.1.
Study Rationale
Lasmiditan is a small molecule serotonin (5-hydroxytryptamine; 5-HT)1F receptor agonist being 
developed for the acute treatment of migraine.  When administered intravenously (IV) at the 
highest dose of 180 mg (H8H-BD-LACA), lasmiditan produced a small but statistically 
significant 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.
Propranolol is a non-selective β-adrenergic receptor antagonist that is given for migraine 
prophylaxis.  In clinical practice, lasmiditan is likely to be coadministered with propranolol; it is 
therefore pertinent to determine the potential for cardiovascular effects or pharmacokinetic (PK) 
drug interactions.  β-adrenergic receptor antagonists (such as propranolol) are known to decrease 
heart rate by approximately 17 to 18% (LeWinter et al 1975).
Propranolol metabolism involves multiple cytochrome P450 (CYP) pathways, specifically via 
CYP2D6, CYP1A2, and CYP2C19, while it is a weak inhibitor of CYP2D6.  Propranolol may 
also be a moderate inhibitor of CYP1A2 based on its interaction with theophylline, a sensitive 
CYP1A2 substrate (Miners et al. 1985).  Although the major route of lasmiditan metabolism in 
humans is non-CYP mediated ketone reduction, minor CYP-mediated metabolism via CYP1A2 
and CYP3A4 was noted in vitro. In vitro, lasmiditan has been shown to be a weak CYP2D6 
inhibitor which is not expected to be clinically significant. Taken together, there is a low 
likelihood of a pharmacokinetic interaction between lasmiditan and propranolol.
Study LAHD is being conducted to evaluate the cardiovascular effects and PK impact of 
coadministration of a single dose of lasmiditan 200 mg with propranolol 80 mg twice daily (bid) 
in healthy subjects.
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 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 relief of most 
bothersome migraine symptoms (nausea, phonophobia, and photophobia) compared to placebo.
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.  Lasmiditan has been administered 
to 213 healthy subjects in five Phase 1 studies:  as IV doses ranging from 0.1 to 180 mg 
(H8H-MC-LACA; 40 subjects); as an oral or sublingual solution with doses ranging from 25 to 


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400 mg and 1 to 32 mg, respectively (COL MIG-102; 60 subjects); as an oral solution at a dose 
of 200 mg or as oral tablets at doses of 50 or 400 mg (COL MIG-103; 44 subjects); as oral 
tablets at a dose of 200 mg (COL MIG-104; 30 subjects); and as oral tablets at doses of 100 or 
400 mg (COL MIG-105; 56 subjects).  Two Phase 2 studies have been completed, evaluating IV 
doses ranging from 2.5 to 45 mg (COL MIG-201) and oral tablets ranging from 50 to 400 mg 
(COL MIG-202).  In the Phase 3 SAMURAI study (COL MIG-301), 1856 patients aged 18 to 
79 years received at least 1 dose of lasmiditan or placebo, with 1239 patients receiving oral 
tablets of 100 or 200 mg lasmiditan.  The most frequently reported lasmiditan treatment-
emergent adverse events (TEAEs) included dizziness (12.5 to 16.3%), paresthesia (5.7 to 7.9%), 
somnolence (5.4 to 5.7%), fatigue (3.1 to 4.1%), , and, compared to placebo where 3.4%, 2.1%, 
2.3%, and 0.3% of subjects reported each event, respectively.  The majority of these TEAEs 
were mild or moderate in severity and none led to subject withdrawal.  
Oral tablet doses of lasmiditan up to 400 mg did not result in any clinically relevant changes in 
ECGs (including QT interval/corrected QT interval [QTc]) or vital signs following 
administration to healthy subjects.  There was a consistent small decrease in heart rate at oral 
doses of 100 to 400 mg lasmiditan though this was not considered to be clinically significant 
(COL MIG-102, COL MIG-103, COL MIG-105).  A single SAE of dizziness with sinus 
bradycardia after an oral dose of 200 mg lasmiditan was reported; this event was moderate in 
severity, occurred approximately 30 minutes after dosing with lasmiditan 200 mg, and was 
considered to be probably related to lasmiditan.  The subject was admitted to hospital for 
overnight observation following review by the hospital emergency room physician.
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 doses ranging from 25 to 400 mg, and the geometric mean terminal 
half-life was approximately 4 to 6 hours.  Lasmiditan exhibited dose-linear PK; low to moderate 
inter-subject variability in exposure was observed across doses (coefficient of variation [%CV]
up to 61% and 45% for maximum observed drug concentration [Cmax] and area under the curve 
[AUC], respectively (COL MIG-102).  Renal clearance of lasmiditan was low, with 
approximately 2% of the parent dose recovered by 24 hours postdose.  Co-administration of 
lasmiditan with a high fat diet led to a delay in median time of maximum observed drug 
concentration (tmax) value by approximately 1 hour and a modest (~20%) increase in lasmiditan 
maximum observed drug concentration (Cmax) and AUC values, relative to that under fasted 
conditions.
Human metabolism has been investigated using liquid chromatography with tandem mass 
spectrometric detection (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 


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studied and their PK was approximately linear.  The half-life of the metabolites ranged from 
~4.5 hours to >12 hours.
3.3.
Benefit/Risk Assessment
In this study, the effects of propranolol alone, lasmiditan alone, and propranolol in combination 
with lasmiditan on blood pressure, heart rate, and PR interval will be evaluated in healthy 
subjects. There is no anticipated therapeutic benefit for the subjects.
Lasmiditan has been tolerated by healthy subjects as single oral doses up to 400 mg.  No 
clinically significant safety or tolerability concerns have been identified in subjects to date for 
lasmiditan up to the highest single oral dose given (400 mg).  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.
Propranolol is a marketed drug and will be administered within the recommended dose regimen 
for clinical use (80 mg bid); this dose regimen has been tolerated in previous PK/PD studies in 
healthy subjects (for example, Fleishaker et al. 2001; Marathe et al. 1998; Peck et al. 1997; Scott 
et al. 1991).  Dosing of propranolol in this study will be conducted in an inpatient setting, and 
subjects will be monitored in house for at least 24 hours after completing dosing.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated adverse events (AEs) of lasmiditan are to be found in the Investigator’s Brochure 
(IB).  
More detailed information about the known and expected benefits and risks of propranolol may 
be found in the following:  Patient Information Leaflet or Summary of Product Characteristics.


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4.Objectivesand Endpoints
TableLAHD.1shows the objectives and endpoints of the study.
TableLAHD.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the effects of propranololalone and in 
combination with lasmiditanon heart rate.
Heart rate by Holter ambulatory monitoring.
Secondary
To evaluate the effects of propranolol alone and in 
combination with lasmiditan on blood pressure and PR 
interval.
To explore the tolerability of a single dose of lasmiditan 
alone or in combination with propranolol.
To evaluate the PKof lasmiditan alone and in 
combination with propranolol.
To evaluate the PKof propranolol alone and in 
combination with lasmiditan.
PR interval by Holter ambulatory monitoring, systolic 
blood pressure, and diastolic blood pressure.
A summary of the number of TEAEs and SAEs.
Cmax, t
max, and AUC(0-∞).
Cmax, t
max, and AUCduring 1 dosing interval (AUCτ).
ExploratoryObjectives
To evaluate the effects of lasmiditan alone and in 
combination with propranolol on orthostatic changes in 
blood pressure and pulse rate.
To evaluate the PK of the metabolites M8, M7, and M18 
in healthy subjects following a single 200-mg oral dose 
of lasmiditan alone and in combination with propranolol.
Orthostatic changes in systolic blood pressure, diastolic 
blood pressure, and pulse rate.
PK parameters:  Cmax, t
max, and AUC(0-∞)


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5. Study Design
5.1.
Overall Design
This is an open-label, fixed-sequence study in healthy subjects to assess the cardiovascular 
effects of coadministration of lasmiditan with propranolol. 
Screening Period: 
All subjects will participate in a screening visit up to 28 days prior to the first lasmiditan dose.  
Dosing Period:
Subjects will be admitted to the clinical research unit (CRU) on Day -2.  On Day 1, subjects will 
receive a single dose of 200 mg lasmiditan, then receive propranolol (immediate release 
formulation; half-life approximately 3 to 6 hours) 80 mg bid on Days 4 through 10 and a single 
dose of 200 mg lasmiditan coadministered with propranolol on Day 9.  Subjects will reside in the 
CRU from Day -2 until Day 11 when they may be discharged from the CRU following 
completion of all study procedures, at the investigator’s discretion.
Study governance considerations are described in detail in Appendix 3.
Blood samples will be collected predose and up to 48 hours postdose on Days 1 and 9 for the 
measurement of plasma concentrations of lasmiditan and its metabolites. Blood samples will 
also be collected predose and up to 12 hours postdose on Days 8 and 9 for the measurement of 
plasma concentrations of propranolol.
Safety assessments performed during the study will include AEs, clinical laboratory evaluations, 
vital signs measurements, 12-lead ECGs, and physical examinations.
Cardiovascular effects will be assessed by Holter ambulatory monitoring and replicate 
measurements of blood pressure at predose, and for 12 hours postdose on Days -1, 1, 8, and 9.
Follow-up Period
Subjects will attend a follow-up visit approximately 7 days after the last dose.  
Figure LAHD.1 illustrates the study design.


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Figure LAHD.1.
Illustration of study design for Protocol H8H-MC-LAHD.
5.2.
Number of Participants
Approximately 44 subjects may be enrolled so that at least 36 subjects complete the study.  
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
The study has an open-label, fixed-sequence design in which each subject receives lasmiditan 
alone, propranolol alone, and lasmiditan coadministered with propranolol, allowing each subject 
to act as his/her own control for safety and PK comparisons.  A single 200 mg dose of lasmiditan 
was selected as it is the highest potential recommended dose for lasmiditan. The washout period 
between lasmiditan doses of 8 days is considered sufficient based on the half-life of lasmiditan of 
approximately 4 to 6 hours. Propranolol takes approximately 1 to 4 hours to reach maximum 
concentrations in the blood and has a plasma half-life of approximately 3 to 6 hours, although its 
biological effects may last longer (Propranolol SPC, 2016); therefore, it will be administered 
according to a twice daily (bid) dosing regimen.  Propranolol will be administered twice daily for 
7 days, with a single dose of lasmiditan coadministered on the 6th day, to ensure that propranolol 
concentrations are at steady-state at the time of lasmiditan dosing and throughout the lasmiditan 
PK sampling period (48 hours postdose).  
5.5.
Justification for Dose
The dose level of 200 mg lasmiditan has been well tolerated in previous studies of healthy 
subjects.  This dose level is expected to be the highest potential recommended single dose for 
lasmiditan.
The dose of propranolol (80 mg bid) is within the range used in clinical practice, and this dose 
regimen has been tolerated by healthy subjects in previous PK/PD studies (for example, 
Fleishaker et al. 2001; Marathe et al. 1998; Peck et al. 1997; Scott et al. 1991).
Study day
Follow-up 
7 days after 
last dose
2
3
4
9
-28
Propranolol
Lasmiditan
Lasmiditan
Screening
1
10


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


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[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.
[5]
have venous access sufficient to allow for blood sampling as per the protocol.
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[7]
have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[9] are Lilly or Covance employees.
[10] are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  
[11]
have known allergies to lasmiditan, propranolol, related compounds or any 
components of the formulation of lasmiditan or propranolol.
[12]
are persons who have previously received the investigational product in this 
study, withdrawn from this study or received lasmiditan in any other study 
investigating lasmiditan.
[13]
have participated (dosed with investigational product), within the last 30 days, 
in a clinical study involving an investigational product.  If the previous 
investigational product has a long half-life, 5 half-lives or 30 days (whichever 
is longer) should have passed.
[14]
have as history of, or ECG findings of, clinically significant bradycardia, heart
block, tachy or brady arrhythmias, sick sinus syndrome/sinoatrial block, or 
second or third-degree heart block, or have any other abnormality in the 
12-lead ECG that, in the opinion of the investigator, increases the risks 
associated with participating in the study. 
[15]
have an abnormal supine blood pressure, defined as systolic blood pressure 
<95 or >140 mmHg or diastolic blood pressure <65 or >90 mmHg at 
screening.  After screening, vital sign eligibility will be done at the discretion 
of the investigator.  Additional assessments may be performed to confirm 
eligibility.


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[16]
have a history of syncope, presyncope, uncontrolled vertigo, postural 
dizziness, or at risk for falls, as judged to be clinically significant by the 
investigator, or have orthostatic decreases in systolic blood pressure of 
>20 mmHg, or have orthostatic decreases in diastolic blood pressure of 
>10 mmHg at screening.  May be repeated if asymptomatic.
[17]
have a supine pulse rate of <50 or >90 bpm at screening.  Up to 2 additional 
assessments may be performed to confirm eligibility.  
[18]
have an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2.
[19]
have significant history of or current cardiovascular, respiratory (including 
bronchospasm or bronchial asthma, or chronic obstructive airways disease), 
hepatic, renal, gastrointestinal, endocrine, hematological, or neurological 
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.
[20]
have a history of or current pheochromocytoma.
[21]
show evidence of significant active neuropsychiatric disease (for example, 
manic depressive illness, schizophrenia, depression).
[22]
show a history of central nervous system (CNS) conditions such as strokes, 
transient ischaemic attacks, significant head trauma, CNS infections, 
migraines, brain surgery or any other neurological conditions that, in the 
opinion of the investigator, increases the risk of participating in the study.
[23]
currently use, or within the past 1 year used recreational drugs, or showed 
evidence of substance dependence within the past 6 months based on history 
at screening visit.
[24]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[25]
show evidence of hepatitis C and/or positive hepatitis C antibody.
[26]
show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[27]
are women with a positive pregnancy test or women who are lactating.
[28]
intend to use over-the-counter or prescription medication, dietary supplements
within 14 days prior to dosing and until study discharge (apart from 
occasional acetaminophen or HRT).
[29]
have donated blood of more than 500 mL within 1 month prior to the
screening visit.


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[30]
have an average weekly alcohol intake that exceeds 21 units per week (males 
aged up to 65 years) and 14 units per week (females and males over 65 years), 
or are unwilling to stop alcohol consumption 48 hours prior to dosing and 
whilst resident at the CRU.  At all other times, subjects must consume no 
more than 2 units per day (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL 
of wine; 1.5 oz or 45 mL of distilled spirits).
[31]
have a clinically significant abnormality in the neurological examination.
[32]
are unwilling to refrain from tobacco- or nicotine-containing products from 
3 months prior to screening until discharge from the study.
[33]
Have any history or hypersensitivity to food or medications.
[34]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
6.2.1. Rationale for Exclusion of Certain Study Candidates
Criteria [1] through [7] define a healthy population suitable for evaluation in a Phase 1 study.  
Criteria [8] and [9] prevent conflict of interest in study participants.  Criteria [10] through [33] 
predominantly exclude medical conditions, medication intolerance, and concomitant medication 
use that may confound the assessment of study endpoints.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Lasmiditan and propranolol will be administered after an overnight fast of at least 8 hours.  On 
intensive PK sampling days (Days 1, 8 and 9), subjects will abstain from water 1 hour before and 
after dosing (except for water given with the dose).  Subjects will remain fasting for 3 hours 
postdose, at which time a meal will be served.
Subjects may be permitted to consume a light breakfast at 1 hour postdose at the discretion of the 
investigator on all other days.
6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine – Subjects will refrain from consuming xanthine- or caffeine-containing food and 
drinks from 48 hours prior to admission, and while resident at the CRU.
Alcohol – Subjects will not consume alcohol for 48 hours prior to admission, and while resident 
at the CRU.  At all other times, subjects must consume no more than 2 units per day 
(1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits).
Tobacco – Subjects will refrain from smoking from 3 months prior to screening until discharge 
from the study.  


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Grapefruit – Subjects will refrain from consuming grapefruit and grapefruit-containing products 
from 7 days prior to Day 1 and until study discharge.
6.3.3. Activity
No strenuous exercise will be allowed for 48 hours prior to admission until after the follow-up 
visit.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened. 


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7. Treatment
7.1.
Treatment Administered
Investigational products used in this study are shown in Table LAHD.2.
Tablets of lasmiditan and propranolol will be administered orally with approximately 240 mL of 
room temperature water, in a sitting position.  Tablets of lasmiditan will be administered in the 
morning of each dosing day, and tablets of propranolol will be administered in the morning and 
evening, approximately 12 hours apart, of each dosing day.  Subjects will not be allowed to lie 
supine for 2 hours after dosing, unless clinically indicated or for study procedures.  
Table LAHD.2.
Treatments Administered
Treatment Name
Lasmiditan
Propranolol
Dosage Formulation
film-coated tablet
film-coated tablet
Unit Dose Strength/Dosage 
Level
(1 200-mg) tablets/
200 mg lasmiditan
(1 80-mg) tablets/
80 mg propranolol
Route of Administration
Oral
Oral
Dosing Instructions
1 tablet taken in the morning of 
Days 1 and 9
1 tablet taken in the morning and evening of 
Days 4-10
The investigator or designee is responsible for:

explaining the correct use of the investigational product(s) to the site personnel;

verifying that instructions are followed properly;

maintaining accurate records of investigational product dispensing and collection;

and returning all unused medication to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.
7.1.1. Packaging and Labeling
Each tablet of lasmiditan contains 200 mg of active ingredient and is provided as bulk supplies in 
bottles.  Propranolol will be sourced by the investigative site.
The investigational product will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
All subjects will receive the same treatments in the same sequence.


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7.2.1. Timing of Doses
Doses of propranolol will be administered at approximately the same time on each dosing day
(every 12 hours).  On study days where lasmiditan and propranolol are coadministered (Day 9), 
propranolol should be administered immediately prior to the lasmiditan dose.  Both lasmiditan 
doses should be administered at approximately the same time of day. The actual time of all dose 
administrations will be recorded in the subject’s electronic case report form (eCRF).
7.3.
Blinding
This is an open-label study.
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 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
In general, concomitant medication should be avoided; however, acetaminophen (maximum 
2 g/24 hours) may be administered at the discretion of the investigator for treatment of headaches 
etc.  Contraceptive medication is permitted as per the inclusion criteria.  Hormone replacement 
therapy is also allowed.  
If the need for concomitant medication (other than acetaminophen or HRT) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator after consultation with a 
Lilly clinical pharmacologist, clinical research physician (CRP), or designee.  Any medication 
used during the course of the study must be documented.
7.8.
Treatment After the End of the Study
Not applicable.


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8. Discontinuation Criteria
Subjects discontinuing from the study prematurely for any reason must complete adverse event 
and follow-up procedures per Section 9.2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

alanine aminotransferase (ALT), aspartate aminotransferase (AST) >5× ULN (upper limit 
of normal)

ALT or AST >3× ULN sustained for more than 2 weeks

ALT or AST >3× ULN and total bilirubin level (TBL) >2× ULN or INR >1.5

ALT or AST >3× ULN the appearance of fatigue, nausea, vomiting, right upper-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3× ULN

ALP>2.5× ULN and TBL >2× ULN

ALP>2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist/CRP or 
designee and the investigator to determine if the subject may continue in the study.  If both agree 
it is medically appropriate to continue, the investigator must obtain documented approval from 
the Lilly clinical pharmacologist/CRP or designee to allow the inadvertently enrolled subject to 
continue in the study with or without continued treatment with investigational product.
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study

Subject Decision
o
the subject requests to be withdrawn from the study.


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


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9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/clinical pharmacologist, or its designee, of any 
SAE as soon as practically possible.
Additionally, study site personnel must alert Lilly Global Subject Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to investigational product or procedure.  Lilly 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.


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Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product 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, clinical laboratory tests detailed in Appendix 2 should be conducted according 
to the Schedule of Activities (Section 2).
9.4.2. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  Vital signs measurements should be conducted within approximately 
20 minutes of the nominal timepoint.
Blood pressure and pulse rate should be measured after at least 5 minutes supine.  All supine 
blood pressure and pulse rate measurements except for screening will be done in triplicates at 
approximately 1-minute intervals.  Where possible, the last triplicate vital sign can be used as the 
supine vital sign for the calculation of orthostatic changes.  Vital signs measurements should be 
taken from the non-dominant and opposite arm as used for PK sampling whenever possible, and 
for each individual subject the same cuff size should be used throughout the study for 
measurements of blood pressure.
Where orthostatic measurements are required, subjects should be supine for at least 5 minutes, 
and then subjects should stand, and standing blood pressure will be measured after 2 minutes; no 
longer than 3 minutes.
In the event of a positive asymptomatic orthostatic response, repeats are at the investigator’s 
discretion.
If the subject feels unable to stand, supine vital signs only will be recorded. 
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured if warranted.
9.4.3. Electrocardiograms
9.4.3.1.
12-Lead Electrocardiograms
For each subject, single 12-lead digital safety ECGs will be collected according to the Schedule 
of Activities (Section 2).  Electrocardiograms should be collected within approximately 


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20 minutes of the nominal timepoint.  Electrocardiograms may be obtained at additional times, 
when deemed clinically necessary.
Electrocardiograms must be recorded before collecting any blood samples.  Subjects must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection.  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 quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the subject can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in subject management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point.
It is recognized that the ECG interpretations by the investigator (or qualified designee) and the 
cardiologist at the central ECG laboratory may be different.  Interpretation of the ECG by the 
investigator (or qualified designee) will be used for study entry and immediate subject 
management. 
9.4.3.2.
Holter Ambulatory Monitoring
Continuous 12-lead Holter recordings over 12 hours will be performed according to the Schedule 
of Activities (Section 2).  Extractions should be performed within approximately 30 minutes of 
the nominal timepoint.
Subjects must be in a quiet atmosphere without significant external stimulation (TV, internet, 
etc.), in a supine position for at least 5 to 10 minutes before the specified ECG collection times 
indicated in the Schedule of Activities, and remain supine but awake during ECG collection and 
for at least 10 minutes afterward.  Subjects should be encouraged to remain still, if possible, 
during this time.
Digital recordings of all periods of continuous ECG recordings in individual subjects will be 
transferred to a central ECG laboratory designated by Lilly.  The ECG laboratory will perform 
quality control checks for the time points of interest (for example, acquisition quality for ability 
to measure/interpret, demographics, and study details) and extract 3 unique 10-second ECGs at 
the times listed in the Schedule of Activities (Section 2).  
The ECG laboratory will then store the 12-hour recording as well as the extracted 10-second 
ECGs, and a cardiologist at the central ECG laboratory will conduct a full overread (including 
the measurement of all intervals) on one of the replicates that were extracted.  For each set of 
replicates, the cardiologist will determine the RR and QT intervals and heart rate on the ECGs 


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that were not fully overread.  No reports will be issued from the central ECG laboratory back to 
the sites for any ECGs.
All data from the overreads will be placed in a Lilly or Contract Research Organization database 
for analytical and study report purposes.
Interpretations of the ECG at the central laboratory will be used for data analysis and 
report-writing purposes.
9.4.4. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or CRP will periodically review the following data:

trends in safety data

laboratory analytes 

AEs
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Subject Safety therapeutic area physician or clinical research scientist.
9.4.4.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3× ULN, ALP ≥2× ULN, or elevated total bilirubin 
≥2× ULN, hepatic monitoring tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, conjugated bilirubin, gamma-glutamyl transferase (GGT), and creatinine 
phosphokinase (CPK) to confirm the abnormality and to determine if it is increasing or 
decreasing.  If the abnormality persists or worsens, clinical and laboratory monitoring should be 
initiated by the investigator based on consultation with the Lilly clinical pharmacologist or CRP.  
Monitoring should continue until levels normalize and/or are returning to approximate baseline 
levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥ 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.


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9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 2 mL each will be collected to determine the plasma concentrations of 
lasmiditan and its metabolites, and venous blood samples of approximately 2 mL each will be 
collected to determine the plasma concentrations of propranolol.  A maximum of 3 samples each 
may be collected for analysis of lasmiditan or propranolol at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling will be recorded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of lasmiditan and 3 major metabolites will be assayed using a validated LC-
MS/MS method. 
Concentrations of propranolol will be assayed using a validated LC-MS/MS method. 
Bioanalytical samples collected to measure investigational product and metabolite concentrations 
will be retained for a maximum of 2 years following last subject visit for the study.  During this 
time, samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
lasmiditan and to investigate genetic variants thought to play a role in migraine.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of lasmiditan or after lasmiditan is commercially available.  


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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 44 subjects may be enrolled to ensure 36 subjects complete the study.  Assuming a 
standard deviation for the change in heart rate of 10.9 (based on previous studies
[H8H-MC-CD-LAHO and H8H-CD-LAHJ]), this will result in a 90% probability that the 
half-width of the 90% CI about the mean within-subject change is no larger than 5 bpm.
Subjects who are randomized but do not complete the study may be replaced to ensure that 
enough subjects complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The subjects’ age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized 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 at least one 
dose of lasmiditan or propranolol and have evaluable PK.  
Cardiovascular analyses will be conducted on data from all subjects who have the relevant test 
and reference treatment measurements.
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product 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 investigational product 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 


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study.  Each symptom will be classified by the most suitable term from the medical regulatory 
dictionary.
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Clinical laboratory parameters, vital signs, and 12-lead ECG parameters will be listed, and 
summarized using standard descriptive statistics.  Additional analysis will be performed if 
warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and propranolol will be 
calculated by standard noncompartmental methods of analysis.
The primary parameters for analysis will be: Cmax, tmax, and AUC(0-∞) of lasmiditan and its 
metabolites on Days 1 and 9; and Cmax, tmax, and AUCτ of propranolol on Days 8 and 9.  Other 
noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of 
distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to determine the impact of propranolol 
coadministration on the PK of a single dose of lasmiditan and its metabolites.  Log-transformed 
Cmax and AUC parameters will be evaluated in a linear mixed-effects model with a fixed effect 
for treatment (lasmiditan coadministered with propranolol [Day 9; test treatment] versus 
lasmiditan alone [Day 1; reference treatment]), and a random effect for subject.  The treatment 
differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% CI.  
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CIs and p-values from the Wilcoxon test will be calculated.
A similar analysis will be performed to determine the impact of coadministration of a single dose 
of lasmiditan on the steady-state PK of propranolol.  The model will include the following 
treatments: propranolol coadministered with lasmiditan (Day 9; test treatment) versus 
propranolol alone (Day 8; reference treatment).
Additional analyses may be performed, as warranted.
10.3.3. Cardiovascular Analyses
10.3.3.1. Cardiovascular Parameter Estimation
The primary parameters for the cardiovascular analyses will be systolic blood pressure, diastolic 
blood pressure, mean hourly heart rate, mean hourly heart rate nadirs, heart rate, and PR interval.  
Mean hourly heart rates from 1 hour predose to 12 hours postdose will be calculated on Days -1,
1, 8, and 9 from the Holter monitoring data.  Negative chronotropic effects will be evaluated 


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using nadir (1–6 h), nadir (>6 h–12 h), and nadir (1–12 h), which are defined as the lowest mean 
hourly heart rate during each postdose time period on each day.  Heart rate and PR interval will 
also be determined on Days -1, 1, 8, and 9 from the 10-second Holter traces extracted at the time 
points listed in the Schedule of Activities (Section 2).
Orthostatic changes in blood pressure and pulse rate will be determined at the time points listed 
in the Schedule of Activities (Section 2)  
10.3.3.2. Statistical Inference of Cardiovascular Parameters
Cardiovascular parameters will be evaluated to determine the impact of coadministration of 
propranolol with lasmiditan on blood pressure, heart rate, and PR interval compared to 
propranolol alone.  Primary cardiovascular parameters will be evaluated in a linear mixed-effects 
model with a fixed effect for treatment (lasmiditan coadministered with propranolol [Day 9; test 
treatment] versus propranolol alone [Day 8; reference treatment]), and a random effect for 
subject.  Least squares means will be calculated for the test and reference treatments.  Mean
treatment differences will be presented, along with the corresponding 90% CI.  Primary PD 
parameters may be log-transformed prior to the statistical analysis if a review of the data 
indicates that the assumption of normality is violated.
A similar analysis will be performed to determine the impact of coadministration of lasmiditan 
with propranolol on blood pressure, heart rate, and PR interval compared to lasmiditan alone.  
The model will include the following treatments:  propranolol coadministered with lasmiditan 
(Day 9; test treatment) versus lasmiditan alone (Day 1; reference treatment).
The impact of coadministration of propranolol with lasmiditan on orthostatic blood pressure and 
pulse rate will be evaluated using descriptive statistics as appropriate.  No formal statistical 
analysis is planned.
10.3.4. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.


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11.
References
Fleishaker JC, Sisson TA, Carel BJ, Azie NE. Lack of pharmacokinetic interaction between the 
antimigraine compound, almotriptan, and propranolol in healthy volunteers. Cephalalgia. 
2001;21(1):61-65.
LeWinter MM, Crawford MH, Karliner JS, ORourke RA. Effects of oral propranolol in normal 
subjects. Clin Pharmacol Ther. 1975;17(6):709-12.
Marathe PH, Greene DS, Kollia GD, Barbhaiya RH. A pharmacokinetic interaction study of 
avitriptan and propranolol. Clin Pharmacol Ther. 1998;63(3):367-378.
Miners JO, Wing LMH, Lillywhite KJ, Robson RA. Selectivity and dose-dependency of the 
inhibitory effect of propranolol on theophylline metabolism in man. Br J Clin Pharmacol. 
1985;20:219-223.
Peck RW, Seaber EJ, Dixon R, Gillotin CG, Weatherley BC, Layton G, Posner J. The interaction 
between propranolol and the novel antimigraine agent zolmitriptan (311C90). Br J Clin 
Pharmacol. 1997;44(6):595-599.
Scott AK, Walley T, Breckenridge AM, Lacey LF, Fowler PA. Lack of an interaction between 
propranolol and sumatriptan. Br J Clin Pharmacol. 1991;32(5):581-584.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
5-HT
5-hydroxytryptamine (serotonin)
AE
adverse event:  Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotranferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve from zero to infinity
AUCτ
area under the concentration versus time curve during 1 dosing interval
bid
twice daily
BMI
body mass index
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed drug concentration
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CPK
creatine phosphokinase
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.


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CRU
clinical research unit
CV%
coefficient of variation
CYP
cytochrome P450
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
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
FSH
follicle-stimulating hormone
GCP
good clinical practice
GGT
gamma-glutamyl transferase
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
Investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
intravenous
LC-MS/MS
liquid chromatography with tandem mass spectrometric detection


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LS
least squares
Non-
investigational 
product (non-IP)
A product that is not being tested or used as a reference in the clinical study, but is provided 
to subjects and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PK
pharmacokinetic
QTc
corrected QT interval
randomize
the process of assigning subjects 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 
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
Tmax
time of maximum observed drug concentration


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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
Ethanol testingb
Ketones
Urine drug screenb
Bilirubin
Hepatitis B surface antigena
Urobilinogen
Hepatitis C antibodya
Blood
HIVa
Nitrite
Serum pregnancy test (females only)d
Urine microscopic (if positive result for blood)
FSH (females only, if applicable)c
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Performed at screening only.
b
Urine drug screen and ethanol level will be performed locally at screening and may be repeated prior to 
admission to the clinical research unit and at other times indicated in the Schedule of Activities (Section 2).  
c
Performed at screening only, for confirmation of postmenopausal status.
d
Performed at screening only, Day -1, and follow-up only.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject or legal representative.  This
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Ethical Review
The investigator or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB 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 (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 


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


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


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
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, clinical laboratory tests, and bioanalytical assays) during the study.  
Protocol H8H-MC-LAHD Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
19.5
1
19.5
Clinical laboratory testsa
12.5
6
75
Lasmiditan and metabolite PKb
2
31
62
Propranolol PKb
4
23
92
Pharmacogenetics
10
1
10
Total
258.5
Total for clinical purposes (rounded up to the nearest 10 mL)
260
a
Additional samples may be drawn if needed for safety purposes.
b
Includes a potential 3 additional samples.


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Appendix 6.
Protocol Amendment H8H-MC-LAHD(a) 
Summary: Effect of Lasmiditan on Heart Rate and Blood 
Pressure in Healthy Subjects Receiving Oral Doses of 
Propranolol
Overview
Protocol H8H-MC-LAHD, Effect of Lasmiditan on Heart Rate and Blood Pressure in Healthy 
Subjects Receiving Oral Doses of Propranolol, 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.
The overall changes and rationale for the changes made to this protocol are as follows:

Following feedback from the FDA from the Type C meeting on 12 October 2017, the 
protocol was amended to include an assessment of lasmiditan metabolites. 

Subjects should be admitted to the CRU on Day -2. The language in Section 5.1 has been 
updated to remove contradictory information that preceded “Day -2”. 

Clinical laboratory assessments and genetic sampling in the Schedule of Activities should 
be performed on Day -2 to allow determination of a dosing order prior to Holter 
monitoring on Day -1. 

Pregnancy tests are required only at screening, Day -1, and the follow up visit; the safety 
laboratory test appendix was updated accordingly.

Subjects should be excluded from the study if they have orthostatic decreases in systolic 
blood pressure of >20 mmHg, not supine blood pressure as is stated in the original 
protocol.

The alcohol restriction in this study should be observed from 48 hours prior to CRU 
admission and until discharge from the CRU, as described in Section 6.3.2. The 
exclusion criterion was updated to be consistent with this language.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Protocol Synopsis
Summary of Study Design:  
This is an open-label, fixed-sequence study in healthy subjects to assess the cardiovascular effects of the 
coadministration of lasmiditan with propranolol.  Subjects will receive a single dose of 200 mg lasmiditan on Day 1, 
then receive a single dose of 200 mg lasmiditan coadministered with steady-state propranolol on Day 9.
Blood samples will be collected predose and up to 48 hours postdose on Days 1 and 9 for the measurement of 
plasma concentrations of lasmiditan and its metabolites, and predose and up to 12 hours postdose on Days 8 and 9 
for the measurement of plasma concentrations of propranolol.
Statistical Analysis:
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and propranolol will be calculated by standard 
noncompartmental methods of analysis.
Pharmacokinetic parameters will be evaluated to determine the impact of propranolol coadministration on the PK of 
a single dose of lasmiditan and its metabolites.  Log-transformed Cmax and AUC parameters will be evaluated in a 
linear mixed-effects model with a fixed effect for treatment (lasmiditan coadministered with propranolol [Day 9; test 
treatment] versus lasmiditan alone [Day 1; reference treatment]), and a random effect for subject.  The treatment 
differences will be back-transformed to present the ratios of geometric means and the corresponding 90% CI.  


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2. Schedule of Activities
Study Schedule Protocol H8H-MC-LAHD
Screening
Study Days
Follow-
up/ED
Comments
Procedure
-28 to -3
days prior 
to Day 1
-2
-1
1
2
3
4
5
6
7
8
9
10
11
~7 days 
post last 
dose
Clinical Lab 
Tests
(including 
serum 
pregnancy 
test)
X
X
X
X
X
X
X
See Appendix 2, 
Clinical Laboratory 
Tests, for details.  If 
multiple procedures 
take place at the same 
time point, the 
following order of the 
procedures should be 
used: ECG, vital signs, 
and venipuncture. 
Genetic 
Sample
X
X
Single sample for 
pharmacogenetic 
analysis taken prior 
to/on Day 1
Lasmiditan 
and Metabolite 
PK Samples 
(hours)
Predose, 
0.5, 1, 
1.5, 2, 
2.5, 3, 4, 
6, 8, 12
24, 
36
48
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).
If multiple procedures 
take place at the same 
time point, the 
following order of the 
procedures should be 
used: ECG, vital signs, 
and venipuncture.


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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 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 relief of most 
bothersome migraine symptoms (nausea, phonophobia, and photophobia) compared to placebo.
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.  Lasmiditan has been administered 
to 213 healthy subjects in five Phase 1 studies:  as IV doses ranging from 0.1 to 180 mg 
(H8H-MC-LACA; 40 subjects); as an oral or sublingual solution with doses ranging from 25 to 
400 mg and 1 to 32 mg, respectively (COL MIG-102; 60 subjects); as an oral solution at a dose 
of 200 mg or as oral tablets at doses of 50 or 400 mg (COL MIG-103; 44 subjects); as oral 
tablets at a dose of 200 mg (COL MIG-104; 30 subjects); and as oral tablets at doses of 100 or 
400 mg (COL MIG-105; 56 subjects).  Two Phase 2 studies have been completed, evaluating IV 
doses ranging from 2.5 to 45 mg (COL MIG-201) and oral tablets ranging from 50 to 400 mg 
(COL MIG-202).  In the Phase 3 SAMURAI study (COL MIG-301), 1856 patients aged 18 to 
79 years received at least 1 dose of lasmiditan or placebo, with 1239 patients receiving oral 
tablets of 100 or 200 mg lasmiditan.  The most frequently reported lasmiditan treatment-
emergent adverse events (TEAEs) included dizziness (12.5 to 16.3%), paresthesia (5.7 to 7.9%), 
somnolence (5.4 to 5.7%), fatigue (3.1 to 4.1%), , and, compared to placebo where 3.4%, 2.1%, 
2.3%, and 0.3% of subjects reported each event, respectively.  The majority of these TEAEs 
were mild or moderate in severity and none led to subject withdrawal.  
Oral tablet doses of lasmiditan up to 400 mg did not result in any clinically relevant changes in 
ECGs (including QT interval/corrected QT interval [QTc]) or vital signs following 
administration to healthy subjects.  There was a consistent small decrease in heart rate at oral 
doses of 100 to 400 mg lasmiditan though this was not considered to be clinically significant 
(COL MIG-102, COL MIG-103, COL MIG-105).  A single SAE of dizziness with sinus 
bradycardia after an oral dose of 200 mg lasmiditan was reported; this event was moderate in 
severity, occurred approximately 30 minutes after dosing with lasmiditan 200 mg, and was 
considered to be probably related to lasmiditan.  The subject was admitted to hospital for 
overnight observation following review by the hospital emergency room physician.
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 doses ranging from 25 to 400 mg, and the geometric mean terminal 
half-life was approximately 4 to 6 hours.  Lasmiditan exhibited dose-linear PK; low to moderate 


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inter-subject variability in exposure was observed across doses (coefficient of variation [%CV]
up to 61% and 45% for maximum observed drug concentration [Cmax] and area under the curve 
[AUC], respectively (COL MIG-102).  Renal clearance of lasmiditan was low, with 
approximately 2% of the parent dose recovered by 24 hours postdose.  Co-administration of 
lasmiditan with a high fat diet led to a delay in median time of maximum observed drug 
concentration (tmax) value by approximately 1 hour and a modest (~20%) increase in lasmiditan 
maximum observed drug concentration (Cmax) and AUC values, relative to that under fasted 
conditions.    
Human metabolism has been investigated using liquid chromatography with tandem mass 
spectrometric detection (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 was approximately linear.  The half-life of the metabolites ranged from 
~4.5 hours to >12 hours.
4. Objectives and Endpoints
Table LAHD.1 shows the objectives and endpoints of the study.
Table LAHD.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the effects of propranolol alone and in 
combination with lasmiditan on heart rate.
Heart rate by Holter ambulatory monitoring.
Secondary
To evaluate the effects of propranolol alone and in 
combination with lasmiditan on blood pressure and PR 
interval.
To explore the tolerability of a single dose of lasmiditan 
alone or in combination with propranolol.
To evaluate the PK of lasmiditan alone and in 
combination with propranolol.
To evaluate the PK of propranolol alone and in 
combination with lasmiditan.
PR interval by Holter ambulatory monitoring, systolic 
blood pressure, and diastolic blood pressure.
A summary of the number of TEAEs and SAEs.
Cmax, tmax, and AUC(0-∞).
Cmax, tmax, and AUC during 1 dosing interval (AUCτ).
Exploratory Objectives
To evaluate the effects of lasmiditan alone and in 
Orthostatic changes in systolic blood pressure, diastolic 


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combination with propranolol on orthostatic changes in 
blood pressure and pulse rate.
blood pressure, and pulse rate.
To evaluate the PK of the metabolites M8, M7, and M18 
in healthy subjects following a single 200-mg oral dose 
of lasmiditan alone and in combination with propranolol.
PK parameters:  Cmax, tmax, and AUC(0-∞)
5.1. Overall Design
This is an open-label, fixed-sequence study in healthy subjects to assess the cardiovascular 
effects of coadministration of lasmiditan with propranolol. 
Screening Period: 
All subjects will participate in a screening visit up to 28 days prior to the first lasmiditan dose.  
Dosing Period:
Subjects will be admitted to the clinical research unit (CRU) on the day prior to dosing (Day -2).  
On Day 1, subjects will receive a single dose of 200 mg lasmiditan, then receive propranolol 
(immediate release formulation; half-life approximately 3 to 6 hours) 80 mg bid on Days 4
through 10 and a single dose of 200 mg lasmiditan coadministered with propranolol on Day 9.  
Subjects will reside in the CRU from Day -2 until Day 11 when they may be discharged from the 
CRU following completion of all study procedures, at the investigator’s discretion.
Study governance considerations are described in detail in Appendix 3.
Blood samples will be collected predose and up to 48 hours postdose on Days 1 and 9 for the 
measurement of plasma concentrations of lasmiditan and its metabolites. Blood samples will 
also be collected predose and up to 12 hours postdose on Days 8 and 9 for the measurement of 
plasma concentrations of propranolol.
6.2. Exclusion Criteria
[16]
have a history of syncope, presyncope, uncontrolled vertigo, postural dizziness, or at risk 
for falls, as judged to be clinically significant by the investigator, or have orthostatic decreases in 
supine systolic blood pressure of >20 mmHg, or have orthostatic decreases in diastolic blood 
pressure of >10 mmHg at screening.  May be repeated if asymptomatic.
[30]
have an average weekly alcohol intake that exceeds 21 units per week (males aged up to
65 years) and 14 units per week (females and males over 65 years), or are unwilling to stop 
alcohol consumption 48 hours prior to dosing until the completion of the study and whilst 
resident at the CRU.  At all other times, subjects must consume no more than 2 units per day (1 
unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits).
9.5. Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 2 mL each will be collected to determine the plasma concentrations of 
lasmiditan and its metabolites, and venous blood samples of approximately 2 mL each will be 


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collected to determine the plasma concentrations of propranolol.  A maximum of 3 samples each 
may be collected for analysis of lasmiditan or propranolol at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling will be recorded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of lasmiditan and 3 major metabolites will be assayed using a validated liquid 
chromatography with tandem mass spectrometric detection (LC-MS/MS) method. 
Concentrations of propranolol will be assayed using a validated LC-MS/MS method. 
Bioanalytical samples collected to measure investigational product and metabolite concentrations 
will be retained for a maximum of 2 years following last subject visit for the study.  During this 
time, samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for lasmiditan, its metabolites, and propranolol will be 
calculated by standard noncompartmental methods of analysis.
The primary parameters for analysis will be:  Cmax, tmax, and AUC(0-∞) of lasmiditan and its 
metabolites on Days 1 and 9; and Cmax, tmax, and AUCτ of propranolol on Days 8 and 9.  Other 
noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of 
distribution may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to determine the impact of propranolol 
coadministration on the PK of a single dose of lasmiditan and its metabolites.  Log-transformed 
Cmax and AUC parameters will be evaluated in a linear mixed-effects model with a fixed effect 
for treatment (lasmiditan coadministered with propranolol [Day 9; test treatment] versus 
lasmiditan alone [Day 1; reference treatment]), and a random effect for subject.  The treatment 
differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% CI.  
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians, 90% CIs and p-values from the Wilcoxon test will be calculated.
A similar analysis will be performed to determine the impact of coadministration of a single dose 
of lasmiditan on the steady-state PK of propranolol.  The model will include the following 
treatments:  propranolol coadministered with lasmiditan (Day 9; test treatment) versus 
propranolol alone (Day 8; reference treatment).


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Additional analyses may be performed, as warranted.
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
Ethanol testingb
Ketones
Urine drug screenb
Bilirubin
Hepatitis B surface antigena
Urobilinogen
Hepatitis C antibodya
Blood
HIVa
Nitrite
Serum pregnancy test (females only)d
Urine microscopic (if positive result for blood)
FSH (females only, if applicable)c
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Performed at screening only.
b
Urine drug screen and ethanol level will be performed locally at screening and may be repeated prior to 
admission to the clinical research unit and at other times indicated in the Schedule of Activities (Section 2).  
c
Performed at screening only, for confirmation of postmenopausal status.
d
Performed at screening only, Day -1, and follow-up only.
Appendix 5. Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, clinical laboratory tests, and bioanalytical assays) during the study.  


H8H-MC-LAHD(a) Clinical Pharmacology Protocol
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Protocol H8H-MC-LAHD Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
19.5
1
19.5
Clinical laboratory testsa
12.5
6
75
Lasmiditan and metabolite PKb
2
31
62
Propranolol PKb
4
23
92
Pharmacogenetics
10
1
10
Total
258.5
Total for clinical purposes (rounded up to the nearest 10 mL)
260
a
Additional samples may be drawn if needed for safety purposes.
b
Includes a potential 3 additional samples.

SAP_001.pdf: 
Statistical Analysis Plan H8H-MC-LAHD 
 
 
Effect of Lasmiditan on Heart Rate and Blood Pressure in Healthy Subjects Receiving Oral 
Doses of Propranolol 
 
 
NCT03270644 
 
 
Approval Date: 22-NOV-2017 


Final v2, 07 Nov 2017
             Page 1 of 17
STATISTICAL ANALYSIS PLAN
Effect of Lasmiditan on Heart Rate and Blood Pressure in Healthy Subjects Receiving Oral 
Doses of Propranolol
Statistical Analysis Plan Status:  Final v2
Statistical Analysis Plan Date:  07-November-2017
Study Drug: LY573144 (Lasmiditan)
Sponsor Reference:  H8H-MC-LAHD
Covance CRU Study: 1000071-8366406
Clinical Phase I
Approval Date: 22-Nov-2017 GMT


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             Page 2 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366406
Sponsor Reference H8H-MC-LAHD
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Primary Objective.................................................................................................... 6
4.2
Secondary Objectives .............................................................................................. 6
4.3
Exploratory Objectives ............................................................................................ 7
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 8
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 8
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 8
9.
STATISTICAL METHODOLOGY ............................................................................... 9
9.1
General.................................................................................................................... 9
9.2
Demographics and Subject Disposition.................................................................... 9
9.3
Pharmacokinetic Assessment................................................................................... 9
9.3.1
Pharmacokinetic Analysis............................................................................... 9
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 13
9.4
Cardiovascular Assessment ................................................................................... 14
9.4.1
Cardiovascular Analysis ............................................................................... 14
9.4.2
Cardiovascular Statistical Methodology........................................................ 14
9.5
Safety and Tolerability Assessments...................................................................... 15
9.5.1
Adverse events ............................................................................................. 15
9.5.2
Concomitant medication............................................................................... 15
9.5.3
Clinical laboratory parameters...................................................................... 15
9.5.4
Hepatic Monitoring ...................................................................................... 16
9.5.5
Vital signs .................................................................................................... 16
9.5.6
Electrocardiogram (ECG)............................................................................. 16
9.5.7
Holter Ambulatory Monitoring..................................................................... 16
9.5.8
Other assessments......................................................................................... 17
9.5.9
Safety and Tolerability Statistical Methodology............................................ 17


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366406
Sponsor Reference H8H-MC-LAHD
10. INTERIM ANALYSES ............................................................................................... 17
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 17
12. REFERENCES ............................................................................................................ 17
13. DATA PRESENTATION ............................................................................................ 17
13.1 Derived Parameters ............................................................................................... 17
13.2 Missing Data ......................................................................................................... 17
13.3 Insufficient Data for Presentation .......................................................................... 17


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366406
Sponsor Reference H8H-MC-LAHD
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
%AUC(tlast-)
Percentage of AUC(0-∞) extrapolated
AUC
Area under the concentration versus time curve during one dosing
interval
bid
Twice daily
bpm
Beats per minute
BQL
Below the quantifiable lower limit of the assay
CI
Confidence interval
Cmax
Maximum observed drug concentration
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
HR
Heart rate
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366406
Sponsor Reference H8H-MC-LAHD
MRE
Magnetic resonance elastography
NA
Not applicable
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SD
Standard deviation 
SOP
Standard Operating Procedure
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normla
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366406
Sponsor Reference H8H-MC-LAHD
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated
27 June 2017) and Protocol Amendment (a) (final version dated 20 October 2017) .
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as 
the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective
The primary objective of this study is to evaluate the effects of propranolol alone and in 
combination with lasmiditan on heart rate (HR).
4.2
Secondary Objectives
The secondary objectives of this study are:

To evaluate the effects of propranolol alone and in combination with lasmiditan on blood 
pressure and PR interval.

To explore the tolerability of a single dose of lasmiditan alone or in combination with 
propranolol.

To evaluate the PK of lasmiditan alone and in combination with propranolol.

To evaluate the PK of propranolol alone and in combination with lasmiditan.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366406
Sponsor Reference H8H-MC-LAHD
4.3
Exploratory Objectives
The exploratory objectives of this study are:

To evaluate the effects of lasmiditan alone and in combination with propranolol on 
orthostatic changes in blood pressure and pulse rate.

To evaluate the PK of the metabolites M8, M7, and M18 in healthy subjects following a 
single 200-mg oral dose of lasmiditan alone and in combination with propranolol.
5. STUDY DESIGN
This is an open-label, fixed-sequence study in healthy subjects to assess the cardiovascular
effects of coadministration of lasmiditan with propranolol.
Screening Period:
All subjects will participate in a screening visit up to 28 days prior to the first lasmiditan dose.
Dosing Period:
Subjects will be admitted to the clinical research unit (CRU) on Day -2. On Day 1, subjects will 
receive a single dose of 200 mg lasmiditan, then receive propranolol (immediate release 
formulation; half-life approximately 3 to 6 hours) 80 mg twice daily (bid) on Days 4 through 10 
and a single dose of 200 mg lasmiditan coadministered with propranolol on Day 9. Subjects will 
reside in the CRU from Day -2 until Day 11 when they may be discharged from the CRU 
following completion of all study procedures, at the investigator’s discretion.
Study governance considerations are described in detail in Appendix 3 of the protocol.
Blood samples will be collected predose and up to 48 hours postdose on Days 1 and 9 for the
measurement of plasma concentrations of lasmiditan and its metabolites. Blood samples will also 
be collected predose and up to 12 hours postdose on Days 8 and 9 for the measurement of plasma
concentrations of propranolol.
Safety assessments performed during the study will include adverse events (AEs), clinical 
laboratory evaluations, vital signs measurements, 12-lead ECGs, and physical examinations.
Cardiovascular effects will be assessed by Holter ambulatory monitoring and replicate
measurements of blood pressure at predose, and for 12 hours postdose on Days -1, 1, 8, and 9.
Follow-up Period
Subjects will attend a follow-up visit approximately 7 days after the last dose.
Figure 1 illustrates the study design.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8366406
Sponsor Reference H8H-MC-LAHD
Figure 1. Illustration of study design for Protocol H8H-MC-LAHD
6. TREATMENTS
The treatment sequence to be administered to all subjects is: 200 mg lasmiditan (Day 1); 80 mg 
propranolol bid (Day 4 to Day 10); 200 mg lasmiditan + 80 mg propranolol (Day 9).
The following is a list of the study treatments that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
200 mg lasmiditan
1
80 mg propranolol bid
2
80 mg propranolol bid + 200 mg lasmiditan 
3
7. SAMPLE SIZE JUSTIFICATION
Up to 44 subjects may be enrolled to ensure 36 subjects complete the study. Assuming a standard 
deviation for the change in HR of 10.9 (based on previous studies [H8H-MC-CD-LAHO and 
H8H-CD-LAHJ]), this will result in a 90% probability that the half-width of the 90% confidence 
interval (CI) about the mean within-subject change is no larger than 5 beats per minute (bpm). 
Subjects who are randomized but do not complete the study may be replaced to ensure that 
enough subjects complete the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
lasmiditan or propranolol and have evaluable PK data. 


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The “Cardiovascular” population will consist of all subjects who had the relevant test and 
reference treatment measurements.
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 are databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration 
versus time curve [AUCs] and maximum observed drug concentration [Cmax]) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
subjects included in the relevant analysis population. For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 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
Pharmacokinetic parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 6.4 or later).
Plasma concentrations of lasmiditan (LY573144) and its metabolites will be used to determine 
the following PK parameters, when possible:  


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Covance Clinical Study No. 8366406
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Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time 
zero to infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time 
zero to time t, where t is the last time point with a 
measurable concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
t½
H
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration (LY573144 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.
Plasma concentrations of propranolol will be used to determine the following PK parameters, 
when possible:  
Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUCτ
ng.h/mL
area under the concentration versus time curve during one 
dosing interval
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the 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. 8366406
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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 predose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the predose 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 predicted Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.


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
All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles
o
Individual concentrations will be plotted utilizing actual sampling times.
o
The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles
o
The average concentration profiles will be graphed using scheduled (nominal) 
sampling times. 
o
The average concentration profiles will be graphed using arithmetic average 
concentrations.
o
The predose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will
be used to calculate average concentrations.
o
Concentrations at a sampling time exceeding the sampling time window specified 
in the protocol, or ± 10%, will be excluded from the average concentration 
profiles.
o
Concentrations excluded from the mean calculation will be documented in the 
final study report.
o
A concentration average will be plotted for a given sampling time only if 2/3 of 
the individual data at the time point have quantifiable measurements that are 
within the sampling time window specified in the protocol or ± X%. An average 
concentration estimated with less than 2/3 but more than 3 data points may be 
displayed on the mean concentration plot if determined to be appropriate and will 
be documented within the final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all 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:


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Covance Clinical Study No. 8366406
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
For pharmacokinetic profiles during multiple dosing, the concentration of the pre-dose 
sample exceeds all measured concentrations for that individual in the subsequent 
post-dose samples.

For pharmacokinetic profiles during single dosing of non-endogenous compounds, the 
concentration in a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.
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
Pharmacokinetic parameters will be evaluated to determine the impact of propranolol
coadministration on the PK of a single dose of lasmiditan and its metabolites. Log-transformed 
Cmax, AUC(0-), and AUC(0-tlast) parameters will be evaluated in a linear mixed-effects model 
with a fixed effect for treatment (lasmiditan coadministered with propranolol [Day 9; test 
treatment] versus lasmiditan alone [Day 1; reference treatment]), and a random effect for subject. 
The treatment differences will be back-transformed to present the ratios of geometric means and 
the corresponding 90% CI.


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Covance Clinical Study No. 8366406
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An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
    class trtmnt subject;
    model l_pk = trtmnt / alpha=0.1;
    random subject;
    lsmeans trtmnt / pdiff;
run;
where l_pk is the log-transformed (base e) PK parameter.
The tmax will be analyzed using a Wilcoxon signed rank test. Estimates of the median difference
based on the observed medians, 90% CIs and p-values from the Wilcoxon test will be calculated.
A similar analysis will be performed to determine the impact of coadministration of a single dose
of lasmiditan on the steady-state PK of propranolol. The model will include the following
treatments: propranolol coadministered with lasmiditan (Day 9; test treatment) versus
propranolol alone (Day 8; reference treatment).
Additional analyses may be performed, as warranted.
9.4
Cardiovascular Assessment
9.4.1
Cardiovascular Analysis
The primary parameters for the cardiovascular analyses will be mean hourly HR, mean hourly 
HR nadirs, and HR. Mean hourly HR from 1 hour predose to 12 hours postdose will be 
calculated on Days -1, 1, 8, and 9 from the Holter monitoring data. Negative chronotropic effects 
will be evaluated using nadir (1–6 h), nadir (>6 h–12 h), and nadir (1–12 h), which are defined as 
the lowest mean hourly HR during each postdose time period on each day. The parameters HR 
and PR interval will also be determined on Days -1, 1, 8, and 9 from the 10-second Holter traces 
extracted at the time points listed in Section 2 of the protocol. Orthostatic changes in blood 
pressure and pulse rate will be determined at the time points listed in Section 2 of the protocol.
9.4.2
Cardiovascular Statistical Methodology
Cardiovascular parameters will be evaluated to determine the impact of coadministration of 
propranolol with lasmiditan on HR, PR interval, and blood pressure compared to propranolol 
alone. Primary cardiovascular parameters (mean hourly HR, mean hourly HR nadirs, and HR) 
will be evaluated in a linear mixed-effects model with a fixed effect for treatment (lasmiditan 
coadministered with propranolol [Day 9; test treatment] versus propranolol alone [Day 8; 
reference treatment]), and a random effect for subject. Least squares means will be calculated for 
the test and reference treatments. Mean treatment differences will be presented, along with the 
corresponding 90% CI. 


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An example of the SAS code that will be used is as follows:
proc mixed data=xxx;
    class trtmnt subject;
    model cardio = trtmnt / alpha=0.1;
    random subject;
    lsmeans trtmnt / pdiff;
run;
where cardio is the cardiovascular primary parameter.
Primary cardiovascular parameters may be log-transformed prior to the statistical analysis if a 
review of the data indicates that the assumption of normality is violated. 
A similar analysis will be performed to  determine the impact of coadministration of lasmiditan 
with propranolol on HR, PR interval, and blood pressure compared to lasmiditan alone. The 
model will include the following treatments: propranolol coadministered with lasmiditan (Day 9; 
test treatment) versus lasmiditan alone (Day 1; reference treatment). The impact of 
coadministration of propranolol with lasmiditan on orthostatic blood pressure and pulse rate will 
be evaluated using descriptive statistics as appropriate.
9.5
Safety and Tolerability Assessments
9.5.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose. Adverse events by day of onset will be presented.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of adverse events, the number of 
subjects experiencing an adverse event and the percentage of subjects experiencing an adverse 
event) of treatment-emergent adverse events will be summarized by treatment, Medical 
Dictionary for Regulatory Activities (MedDRA) version 20.0 system organ class and preferred 
term. The summary and frequency adverse event tables will be presented for all causalities and 
those considered related to the study drug. Any serious adverse events will be tabulated.
9.5.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017
Enhanced Dictionary B2 Format). Concomitant medication will be listed.
9.5.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be listed, as well as summarized together with 
changes from baseline, where baseline is defined as the last assessment prior to Day 1 dosing.


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Urinalysis data will be listed. Additionally clinical chemistry, hematology and urinalysis data 
outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.5.4
Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥ 3 × upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥ 2 × ULN, or elevated total bilirubin (TBL) ≥ 2 × ULN, 
liver tests will be performed to confirm the abnormality.  
The subjects’ liver disease history and associated person liver disease history data will be listed.  
Any concomitant medication of acetaminophen/paracetamol will be listed.  Results from a 
magnetic resonance elastography (MRE) scan and biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed.  Liver related signs and symptoms data will be 
summarized by treatment, and listed, if available. 
All hepatic chemistry, hematology, coagulation, and serology data will be summarized by 
parameter and treatment, and listed.  Values outside the reference ranges will be flagged on the 
individual subject data listings.
9.5.5
Vital signs
The means of the triplicate supine blood pressure and pulse rates values will be calculated and 
used in all subsequent calculations. When triplicate blood pressure or pulse rate measurements 
precede a standing measurement, the last supine blood pressure or pulse rate measurement will 
be used for orthostatic calculations. Orthostatic changes will be calculated as the standing value, 
minus the last supine value taken prior to the standing value.
Vital signs data will be summarized 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 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 will be presented over time. Furthermore, values for individual subjects will be listed.
9.5.6
Electrocardiogram (ECG)
For each subject, ECGs will be performed for safety purposes only, and will not be reported. 
9.5.7
Holter Ambulatory Monitoring
Continuous 12-lead Holter recordings over 12 hours will be performed. Mean hourly HR and 
mean hourly HR nadirs will be calculated. Data will be summarized by treatment together with 
changes from baseline, and listed. For ECG extractions baseline is defined as the mean of the last 
triplicate extractions taken predose.  For the mean hourly HR, baseline is defined as the hourly 
mean of the one hour predose time point. 


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9.5.8
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
9.5.9
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”