Conditions: Migraine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
The purpose of the study is the measure the levels of lasmiditan in the body of children aged 6 to 17 with migraine. The study also will also examine the safety and tolerability of lasmiditan in children aged 6 to 17 with migraine.

The study will last about 6 weeks, and includes 4 visits.

Detailed description:

Arms:
arm 1: Participants with lower body weight (15 to ≤40 kilograms (kg)) received single oral dose of 100 milligrams (mg) Lasmiditan in Cohort 1 and higher body weight (\>40 to ≤55 kg) participants received single oral dose of 200 mg Lasmiditan in Cohort 2.

Interventions: intervention 1: Lasmiditan
Intervention descriptions: intervention 1: Administered orally.

Protocol document:
Prot_002.pdf: 
Protocol Addendum H8H-MC-LAHX(1.1)
A Phase 1, Open-Label, Single-Dose Pharmacokinetic Study of Lasmiditan in Pediatric Patients 
with Migraine
NCT03988088   
Approval Date: 11-Jun-2019 


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1. Protocol Addendum H8H-MC-LAHX(1.1)
An Open-Label Study of Lasmiditan in Pediatric Patients
with Migraine
Confidential Information
The information contained in this protocol addendum 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.  This document and 
its associated attachments are subject to United States Freedom of Information Act (FOIA) 
Exemption 4.
Lasmiditan (LY573144)
This addendum is to be performed in addition to all procedures required by protocol 
H8H-MC-LAHX or any subsequent amendments to that protocol.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Addendum (1) Electronically Signed and Approved by Lilly: 29 March 2019
Revised Protocol Addendum (1.1) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 11-Jun-2019 GMT


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2. Table of Contents
Protocol Addendum H8H-MC-LAHX(1)
An Open-Label Study of Lasmiditan in Pediatric Patients with 
Migraine
Section
Page
1.
Protocol Addendum H8H-MC-LAHX(1.1) An Open-Label Study of 
Lasmiditan in Pediatric Patients with Migraine....................................................................1
2.
Table of Contents................................................................................................................2
3.
Rationale for Addendum .....................................................................................................7
4.
Protocol Additions or Changes............................................................................................8
4.1.
Objectives and Endpoints...............................................................................................8
4.2.
Study Design..................................................................................................................9
4.3.
Justification for Dose ...................................................................................................10
4.4.
Inclusion and Exclusion Criteria...................................................................................10
4.5.
Lifestyle and Dietary Considerations............................................................................10
4.6.
Method of Treatment Assignment ................................................................................10
4.7.
Dose Modification........................................................................................................11
4.8.
Preparation/Handling/Storage/Accountability...............................................................12
4.9.
Study Treatment Compliance .......................................................................................12
4.10. Concomitant Therapy...................................................................................................12
4.10.1.
Rescue .................................................................................................................13
4.11. Discontinuation of Study Treatment .............................................................................13
4.12. Discontinuation from the Study Addendum..................................................................14
4.13. Study Assessments and Procedures ..............................................................................14
4.13.1.
Efficacy Assessment ............................................................................................14
4.13.2.
Safety...................................................................................................................14
4.13.2.1.
Safety Assessments ........................................................................................14
4.13.2.2.
Clinical Safety Laboratory Assessments .........................................................14
4.13.2.3.
Puberty and Menstrual Status..........................................................................14
4.13.3.
Adverse Events and Serious Adverse Events........................................................14
4.13.3.1.
Method of Detecting AEs and SAEs...............................................................15
4.14. Treatment of Overdose.................................................................................................15
4.15. Pharmacokinetics .........................................................................................................15
4.16. Statistical Considerations and Data Analysis ................................................................15
4.16.1.
Sample Size Determination ..................................................................................15
4.16.2.
Statistical Analyses ..............................................................................................15


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4.16.2.1.
Efficacy Analyses...........................................................................................16
4.16.2.2.
Clinical Evaluation of Safety..........................................................................16
4.16.2.3.
Statistical Evaluation of Safety.......................................................................16
4.16.3.
Pharmacokinetic Analyses....................................................................................16
4.16.4.
Data Review during the Study..............................................................................16
4.16.5.
Interim Analyses..................................................................................................16
5.
References ........................................................................................................................17


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List of Tables
Table
Page
Table LAHX(1).1.
Planned Treatment Regimen .....................................................................11


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List of Figures
Figure
Page
Figure LAHX(1)1.
Study design visit schedule. ..................................................................9


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List of Attachments
Attachment
Page
Attachment 1.
Schedule of Activities....................................................................................18
Attachment 2.
Clinical Laboratory Tests...............................................................................20
Attachment 3.
Abbreviations and Definitions........................................................................22
Attachment 4.
Protocol Addendum LAHX(1.1) Revisions....................................................25


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3. Rationale for Addendum
Country and Sites
This addendum applies only to participants in Study H8H-MC-LAHX (LAHX) at clinical sites in 
the United States (US).
Rationale
This addendum provides participants the opportunity to treat up to 4 migraine attacks per month 
with lasmiditan for a period of 3 months after completing pharmacokinetic (PK) assessments in 
the single-dose PK study LAHX.


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4. Protocol Additions or Changes
This protocol addendum provides the requirements applicable to the open-label extension of 
Study LAHX.
4.1.
Objectives and Endpoints
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the safety and tolerability of 3-month 
intermittent use of lasmiditan in the acute treatment of 
migraine in pediatric patients

TEAEs

SAEs

AEs of interest

Change from baseline in laboratory, ECG, and 
vital sign parameters
Secondary
To characterize the reasons for discontinuation

Discontinuation rates
Exploratory
To describe patient-reported global impression of 
change after treatment with lasmiditan
The proportion of migraine attacks with PGI-C scores of 
better or a lot better
Abbreviations:  AE = adverse event; ECG = electrocardiogram; PGI-C = Patient Global Impression of Change; 
SAE = serious adverse event; TEAE = treatment-emergent adverse event.


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4.2.
Study Design
This is an open-label, 3-month extension of Study LAHX in pediatric patients with migraine
(Figure LAHX(1)1).
Abbreviations:  PK = pharmacokinetic.
Figure LAHX(1)1.
Study design visit schedule.
Visit 4
All potential study participants will complete assessments noted in the Schedule of Activities in 
Attachment 1 to determine if they are eligible to participate in this addendum.
Enrolled study participants and their parent or guardian will receive instructions regarding study 
procedures.  The participant’s parent or guardian is responsible for assisting children, if 
necessary, with completion of the diary assessments and other study procedures.
Lasmiditan will be dispensed to enrolled participants.  The amount of lasmiditan dispensed will 
be determined by weight measured at Visit 4, and will be sufficient to treat up to 4 migraine 
attacks per month with 1 dose of lasmiditan per 24 hours.
Visits 5 and 6
Study participant assessments will be completed as noted in the Schedule of Activities.
Participant diaries will be reviewed and recorded in the appropriate electronic case report form 
(eCRF).
Lasmiditan will be dispensed at each visit.  The amount of lasmiditan dispensed will be sufficient 
to treat up to 4 migraine attacks per month with 1 dose of lasmiditan per 24 hours.
Visit 7
This is the end of study visit.  Study participant assessments will be completed as noted in the 
Schedule of Activities.
Visit 1
Screening
Visit 2
PK and Safety
Assessments
Visit 3
24 hour 
Assessments
Visit 801
Follow-up
Visit 4
Visit 5
Month 1
Visit 6
Month 2
Visit 7
Month 3
End of Study
Participants in 
Japan or those 
who will not 
proceed to 
addendum
Participants 
proceeding to 
addendum
Addendum visits


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4.3.
Justification for Dose
This addendum will include doses corresponding to the 100-mg adult equivalent exposure. 
Because the main PK study will still be ongoing at the start of this open-label addendum, a 
conservative approach was taken to target a lower exposure than that used in the main protocol.  
This will provide additional safety information for treatment of multiple migraine attacks in the 
pediatric population.
4.4.
Inclusion and Exclusion Criteria
The inclusion and exclusion criteria for Study LAHX apply to this addendum with the exception 
of the following changes.
Inclusion Criterion [3] and Exclusion Criterion [24] are not applicable for this addendum.
[3]
Are migraine free on day of lasmiditan administration at the time of predose 
assessments.
[24] Are on a central nervous system active drug, which is known to affect levels 
of attention or sedation, such as a benzodiazepine for sleep or anxiety, or 
stimulants for Attention Deficit Hyperactivity Disorder.
Exclusion criterion 23 is changed to
[23] Have a positive urine drug screen for any substances of abuse.
One retest is allowed if the urine drug screen is positive, at the investigators 
discretion.  Positive results are acceptable if due to regular and medically 
acceptable use of a prescribed medication, such as a benzodiazepine for sleep 
or anxiety, or stimulants for Attention Deficit Hyperactivity Disorder.
4.5.
Lifestyle and Dietary Considerations
Diary
Participants will record information about the migraine attacks, use of medication, global 
impression of change, and any adverse events (AEs) in a paper diary between study visits.
Both study participants and their parent or guardian will receive instructions for completion of 
the diary in case participants need help completing the assessments.
Activity Restrictions
During the treatment of a migraine attack, patients may have some transient restrictions on their 
usual activities due to the experience of pain and symptoms of a migraine attack, study 
procedures, and effects of study treatment.
4.6.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will receive blisters that contain doses of lasmiditan 
50 mg or lasmiditan 100 mg, according to their body weight determined at Visit 4.


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The lasmiditan dose will be determined by the participant’s weight, with the target to achieve an 
adult exposure equivalent of 100 mg (Table LAHX(1).1).
Participants can take a single dose of lasmiditan to treat up to 4 migraine attacks per month.
Only 1 lasmiditan dose is allowed per 24 hours.
Lasmiditan will be supplied to the clinical sites in blisters.
Table LAHX(1).1.
Planned Treatment Regimen
Participant Body Weight 
15 kg to ≤40 kg 
>40 kg to ≤55 kg
Treatment Name
Lasmiditan
Lasmiditan
Dosage Formulation
Tablet
Tablet
Unit Dose Strength(s)/Dosage 
Level(s)
50 mg x1 
100 mg x1
Route of Administration
Oral
Oral
Dosing Instructions
With approximately 240 mL of room temperature water in a sitting position
The investigator or his or her designee is responsible for

explaining the correct use of lasmiditan to the patient and parent or guardian and site 
personnel

ensuring that patients are able to swallow whole tablets

verifying that instructions are followed properly

maintaining accurate records of lasmiditan dispensing and collection at each visit, and

returning all unused medication to Eli Lilly and Company (Lilly), or its designee, unless 
the sponsor and sites have agreed that all unused medication is to be destroyed by the 
site, as allowed by local law.
The participant’s parent or guardian is responsible for

maintaining control and inventory of lasmiditan, and

ensuring that lasmiditan is taken properly.
4.7.
Dose Modification
No dose modification is allowed in this study.


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4.8.
Preparation/Handling/Storage/Accountability
Lasmiditan will be labeled in accordance with regulatory requirements.
All study treatment must be stored in a secure, 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 or his or her designee is responsible for

confirming that appropriate temperature conditions have been maintained during transit 
for all study treatment received and any discrepancies are reported and resolved before 
use of the study treatment

ensuring that only participants enrolled in the study receive study treatment and only 
authorized site staff supply study treatment, and

study treatment accountability, reconciliation, and record maintenance (that is, receipt, 
reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy manual.
4.9.
Study Treatment Compliance
Participant compliance with study treatment will be assessed at each visit by counting returned 
tablets. Deviation(s) from the prescribed dosage regimen will be recorded in the eCRF.
4.10. Concomitant Therapy
What Is Allowed
Patients may use their usual treatment for migraine attacks when they do not choose to treat with 
lasmiditan.
For patients taking medication for a chronic condition, including preventive medications for
migraine, treatment regimen must be stable for at least 3 months prior to Visit 4.
What Is Not Allowed
Any investigational treatment other than lasmiditan is prohibited for the duration of a patient’s 
participation in the study from Visit 4 through end of study.
If a patient requires the initiation of concomitant medication to reduce the frequency of migraine 
episodes, or a change in ongoing migraine medication after Visit 4, they should be withdrawn 
from the study.
Patient Diary
Patients will be asked to record all medication use, including changes in dosing of previous 
medications, in a paper diary.  Information needed includes

name of medication

reason for use


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
start and end dates of medication, and

dosage strength and frequency.
Parents or guardians can assist the patient in completing the diary.  This information will be 
reviewed with the clinic site staff during each clinic visit.
4.10.1. Rescue
Rescue medication is permitted as needed 2 hours after taking lasmiditan.
The patient may use their usual headache therapy.
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication must be recorded in the paper diary.
Exceptions
Ergots, opioids, and barbiturates may not be used until 24 hours after lasmiditan administration.
4.11. Discontinuation of Study Treatment
Possible reasons leading to discontinuation of lasmiditan:

Pregnancy

The participant or the participant’s parents or legal guardian requests to discontinue 
lasmiditan

A hepatic event or liver test abnormality
Discontinuation of the investigational product for abnormal liver tests should be 
considered by the investigator when a patient meets 1 of the following conditions after 
consultation with the Lilly-designated medical monitor:
o
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8x upper 
limit of normal (ULN)
o
ALT or AST >5x ULN sustained for more than 2 weeks
o
ALT or AST >3x ULN and total bilirubin level (TBL) >2x ULN or international 
normalized ratio >1.5
o
ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
o
alkaline phosphatase (ALP) >3x ULN
o
ALP >2.5x ULN and TBL >2x ULN
o
ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, right quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%).
Participants who are discontinued from investigational product due to a hepatic event or 
liver test abnormality should have additional hepatic safety data collected via eCRF.

Participants experiencing signs of suicidal ideation or behavior
Discontinuation of investigational product should be considered, following a risk 
assessment, for participants who
o
answered “yes” to Question 4 or Question 5 on the “Suicidal Ideation” portion of 
the Columbia-Suicide Severity Rating Scale (C-SSRS), or


H8H-MC-LAHX(1.1) Clinical Protocol Addendum
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o
answered “yes” to any of the suicide-related behaviors on the Suicidal Behavior 
portion of the C-SSRS.
A psychiatrist or appropriately trained professional may assist in the decision to 
discontinue the participant.
Participants discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Attachment 1 (Schedule of Activities) of the 
addendum, and Section 8.2 (Safety Assessments) and Section 8.3 (Adverse Events and Serious 
Adverse Events) of the protocol.
4.12. Discontinuation from the Study Addendum
The investigator will confirm eligibility of the patient for this addendum during Visit 4 as 
defined in the Schedule of Activities.  Patients who do not meet eligibility will be discontinued 
from the study addendum.
4.13. Study Assessments and Procedures
Attachment 1 lists the Schedule of Activities, detailing the study procedures and their timing.
Attachment 2 lists the Clinical Laboratory Tests.
4.13.1. Efficacy Assessment
A Patient Global Impression of Change (PGI-C) is a patient-rated global measure of change 
(Guy 1976) and represents a global assessment of effects of the study medication on multiple 
outcomes, including migraine pain, associated symptoms, side effects, and function (Geisser et 
al. 2010; Scott and McCracken 2015).
Patients will be asked to record their PGI-C at approximately 2 hours after dosing with 
lasmiditan in the patient diary. Results will be reviewed at each patient visit and entered in the 
eCRF.
4.13.2. Safety
4.13.2.1. Safety Assessments
Unscheduled or repeat safety assessments may be performed at the discretion of the investigator 
as needed.
4.13.2.2. Clinical Safety Laboratory Assessments
For each patient, laboratory tests detailed in Attachment 2 should be conducted according to the 
Schedule of Activities (Attachment 1).
4.13.2.3. Puberty and Menstrual Status
During the open-label extension addendum, only menstrual status will be collected at each visit.
4.13.3. Adverse Events and Serious Adverse Events
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.


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If a participant’s lasmiditan is discontinued as a result of an AE, study site personnel must report 
this to Lilly or its designee via eCRF, clarifying if possible the circumstances leading to 
discontinuations of treatment.
4.13.3.1. Method of Detecting AEs and SAEs
Patients will record AEs that occur during the treatment period in a paper diary.  Information will 
include start and end dates of AEs and severity.
At every postscreening visit, site personnel will review the patient paper diary with the 
patient/guardian and record any change in the preexisting condition(s) and any new conditions as 
AEs.
Investigators should record the following via eCRF for each AE:  date of onset, date of 
termination, severity, and their assessment of the potential relatedness of each AE to 
investigational product.
4.14. Treatment of Overdose
There is limited clinical trial experience with lasmiditan overdose.  There were no instances of 
overdose in the clinical pharmacology program.  In the Phase 2 and Phase 3 clinical studies, the 
maximum dose received by any adult patient in a 24-hour period was 600 mg.  No 
treatment-emergent AEs (TEAEs) were reported following any instance of dosing >400 mg (in a 
24-hour period).  Doses exceeding the maximum therapeutic dose may be associated with 
increased incidence and/or severity of AEs. Therefore, the patient should be monitored for signs 
and symptoms of adverse reactions. Patients who develop adverse reactions should receive 
appropriate treatment.
4.15. Pharmacokinetics
Pharmacokinetics is not applicable for this addendum.
4.16. Statistical Considerations and Data Analysis
4.16.1. Sample Size Determination
Only previously enrolled participants of Study LAHX at clinics in the US are eligible for this 
addendum.  Therefore, the sample size is determined by the number of these participants who 
decide to continue in this addendum.
4.16.2. Statistical Analyses
Statistical analysis of this addendum will be the responsibility of Lilly or its designee.
Efficacy and safety analyses will be conducted for all enrolled patients who receive a dose of 
lasmiditan in this addendum.
Data analyses will be presented by body weight category.
Additional exploratory analyses of the data will be conducted as deemed appropriate.


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4.16.2.1. Efficacy Analyses
The proportion and exact 95% confidence interval of patients reporting a PGI-C score better or a 
lot better for each migraine attack after baseline will be reported.
Additional analyses of the PGI-C will be included in the statistical analysis plan.
4.16.2.2. Clinical Evaluation of Safety
All investigational product and protocol procedure-related AEs will be listed, and if the 
frequency of events allows, safety data will be summarized using descriptive methodology.
Adverse events will be classified by the most suitable term from the most current Medical 
Dictionary for Regulatory Activities (MedDRA) version.
The incidence of TEAEs will be presented by severity and by association with investigational 
product as perceived by the investigator.  Adverse events reported to occur prior to enrollment 
will be distinguished from those reported as new or increased in severity during the study.
All serious adverse events (SAEs) will be reported and classified by the most suitable term from 
the most current MedDRA version.
4.16.2.3. Statistical Evaluation of Safety
Safety parameters for analysis will be

AEs (including clinically significant ECGs [electrocardiograms])

clinical laboratory parameters

vital signs

C-SSRS assessments
The parameters will be listed, and summarized using standard descriptive statistics.
Additional analysis will be performed if warranted upon review of the data.
4.16.3. Pharmacokinetic Analyses
Pharmacokinetic analyses are not applicable for this addendum.
4.16.4. Data Review during the Study
Safety data will be reviewed on an ongoing basis.  Additional reviews may be performed, as 
deemed appropriate.
4.16.5. Interim Analyses
There will be no interim analyses in this addendum.


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5. References
Geisser ME, Clauw DJ, Strand V, Gendreau RM, Palmer R, Williams DA. Contributions of 
change in clinical status parameters to Patient Global Impression of Change (PGIC) scores 
among persons with fibromyalgia treated with milnacipran. Pain. 2010;149(2):373-378.
Guy W. Clinical Global Impressions (028-CGI), ECDEU Assessment Manual for 
Psychopharmacology, US Department of Health, Education, and Welfare, ADAMHA, NIMH 
Psychopharmacology Research Branch. Rockville (MD); 1976; p 217-222.
Scott W, McCracken LM. Patients’ impression of change following treatment for chronic pain: 
global, specific, a single dimension, or many? J Pain. 2015;16(6):518-526.


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Attachment 1.Schedule of Activities
Schedule of Activities for Patients Participating in H8H-MC-LAHX(1) Addendum
Visit
Month 
1
Month 
2
Month 
3
EOS
ED
Notes
4a
5
6
7
(Target) interval (days) 
since previous visit
30±3
30±3
30±3
Procedure/Assessments
Informed consent/assent
X
Consent and assent form signed by patient and parent 
or guardian.
Physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
Blood pressure, pulse, and temperature.
Triplicate measurements at all visits, in the sitting 
position.  Measure blood pressure by an automated 
calibrated machine, if calibration is required
Weight
X
Menstrual status
X
X
X
X
12-lead ECG (single)
X 
X
X
Patients must be supine for at least 5 minutes before 
collection and remain supine, but awake during the 
procedure
Concomitant medications
X
X
X
X
X
Adverse events
X
X
X
X
X
Study drug dispensed
X
X
X
Provide detailed instructions to participant for study 
drug
Review study diary
X
X
X
X
X
Study drug accountability
X
X
X
X
Collect empty dosing card(s) and unused study drug.  
Review dosing compliance
Clinical Laboratory 
Tests
Hematology
X
X
X
Clinical chemistry
X
X
X
Urinalysis
X
X
X
Urine drug screen 
X
X
X
X
X
For patients aged > 10 years
Pregnancy test 
for females of 
childbearing potential
X
X
X
X
X
A positive urine pregnancy test must be followed by a 
serum pregnancy test for confirmation
Scales and
Questionnaires
C-SSRS/SHSF/SHFU
X
X
X
X
X
Suicidal ideation and behavior subscales are adapted 
for the assessment of 11 preferred ideation and 
behavior categories.  The C-SSRS will be collected 
only in patients ≥7 years old.  The SHFU Form is 
required only if triggered by the SHSF
PGI-C
X
X
X
X
The PGI-C is contained within the patient diary


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Abbreviations:  C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early 
discontinuation; EOS = end of study visit; PGI-C = Patient Global Impression of Change; SHFU = Self-Harm 
Follow-Up form; SHSF = Self-Harm Supplement Form.
a
The confirmation of eligibility visit for the addendum will occur at the same time as Study LAHX Day 14, 
Follow-up visit.


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Attachment 2.Clinical Laboratory Tests
Hematologya
Clinical Chemistrya,
Hemoglobin  
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC) 
Platelets
Magnesium 
Absolute counts of:
Neutrophils
Total bilirubin
Lymphocytes
Direct bilirubin
Monocytes
Alkaline phosphatase (ALP)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Alanine aminotransferase (ALT)
     
Blood urea nitrogen (BUN)
Creatinine
Urinalysisa,
Uric acid
Specific gravity
pH
Glucose (random)
Protein
Albumin 
Glucose
Total protein
Ketones
Bilirubin
Urobilinogen
Other Tests
Leukocyte esteraseb
Serum pregnancy testa
Blood
Nitrite
Urine pregnancy test (local)
Urine cultureb
Urine drug screena
Microsopic analysisb
Abbreviations:  RBC = red blood cell; WBC = white blood cell.
a
Assayed by sponsor-designated laboratory.
b
A positive leukocyte esterase result will require a follow-up sample with microscopic analysis and possibly a 
urine culture.
Note:  Additional tests may be performed at the discretion of the investigator as needed.


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Protocol H8H-MC-LAHX Addendum Sampling Summary
Purpose
Blood Volume per Sample 
(mL)
Maximum Number of 
Blood Samples
Total Volume (mL)
Hematologya
2
2
4
Chemistrya
2.5
2
5
Serum pregnancy testa,b
0
1
0
Total
9
Total for clinical purposes rounded up to the nearest 10 mL
10
Hepatic monitoringc
3-30
Abbreviations:  CRP = Clinical Research Physician; CRS = Clinical Research Scientist.
a
Additional samples may be drawn if needed for safety purposes.
b
Sample volume included with chemistry test volume.
c
Unscheduled hepatic monitoring testing may be performed as part of patient follow-up, based on laboratory 
safety values and in consultation with Lilly CRP/CRS.


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Attachment 3.Abbreviations and Definitions


H8H-MC-LAHX(1.1) Clinical Protocol Addendum
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Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
assent
Agreement from a child or other individual who is not legally capable of providing consent, 
but who can understand the circumstances and potential risks involved in participating in a 
study (required by some institutional review boards [IRBs]/ethical review boards [ERBs]).
AST
aspartate aminotransferase
C-SSRS
Columbia-Suicide Severity Rating Scale
eCRF
electronic case report form
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
informed consent
A process by which a patient 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 patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
Investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
MedDRA
Medical Dictionary for Regulatory Activities
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.
PGI-C
Patient Global Impression of Change
PK
pharmacokinetic


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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.
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.
ULN
upper limit of normal
US
the United States


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Attachment 4.Protocol Addendum LAHX(1.1) Revisions
Overview
Protocol Addendum I6T-MC-LAHX(1) has been revised.  The revised protocol addendum is 
indicated by revision (1.1) and will be used to conduct the study in place of any preceding 
version of the protocol addendum.
This table describes the changes to this addendum. 
Section
Additions 
Deletions
Rationale
Attachment 2 
Clinical Laboratory Tests
Urinalysis:  

Blood

Nitrite
Clinical Chemistry: 

Bicarbonate

Chloride

Calcium

Phosphorus

Magnesium 
Alkaline phosphatase

Triglycerides

Total cholesterol

Bone specific 
alkaline 
phosphatase
Tests were added/deleted
to harmonize with what is 
collected in the main 
protocol.


Leo Document ID = 394f1c0b-90de-4857-a0c7-b9338974df19
Approver: 
Approval Date & Time: 11-Jun-2019 14:09:27 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Jun-2019 15:45:29 GMT
Signature meaning: Approved
PPD
PPD

Prot_000.pdf: 
Protocol: H8H-MC-LAHX
A Phase 1, Open-Label, Single-Dose Pharmacokinetic Study of Lasmiditan in Pediatric Patients 
with Migraine
NCT03988088   
Approval Date: 29-Mar-2019 


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A Phase 1, Open-Label, Single-Dose Pharmacokinetic 
Study of Lasmiditan in Pediatric Patients with Migraine
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 patient to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Lasmiditan (LY573144)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 29-Mar-2019 GMT


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Table of Contents
A Phase 1, Open-Label, Single-Dose Pharmacokinetic Study 
of Lasmiditan in Pediatric Patients with Migraine
Section
Page
A Phase 1, Open-Label, Single-Dose Pharmacokinetic Study of 
Lasmiditan in Pediatric Patients with Migraine....................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Summary ..............................................................................................................8
1.1.
Protocol Synopsis...........................................................................................................8
1.2.
Schema ........................................................................................................................10
1.3.
Schedule of Activities ..................................................................................................10
2.
Introduction ......................................................................................................................15
2.1.
Study Rationale............................................................................................................15
2.2.
Background..................................................................................................................15
2.3.
Benefit/Risk Assessment..............................................................................................16
3.
Objectives and Endpoints..................................................................................................17
4.
Study Design.....................................................................................................................18
4.1.
Overall Design .............................................................................................................18
4.2.
Scientific Rationale for Study Design...........................................................................19
4.3.
Justification for Dose ...................................................................................................19
4.4.
End of Study Definition ...............................................................................................21
5.
Study Population...............................................................................................................22
5.1.
Inclusion Criteria..........................................................................................................22
5.2.
Exclusion Criteria ........................................................................................................23
5.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................26
5.3.
Lifestyle and/or Dietary Considerations........................................................................26
5.3.1.
Meals and Dietary Restrictions.............................................................................26
5.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................26
5.4.
Screen Failures.............................................................................................................26
6.
Treatment..........................................................................................................................28
6.1.
Treatment Administered...............................................................................................28
6.1.1.
Packaging and Labeling .......................................................................................28
6.2.
Preparation/Handling/Storage/Accountability...............................................................29
6.3.
Measures to Minimize Bias:  Randomization and Blinding...........................................29
6.4.
Treatment Compliance .................................................................................................29
6.5.
Concomitant Therapy...................................................................................................29


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6.6.
Dose Modification........................................................................................................29
6.7.
Treatment after the End of the Study............................................................................30
7.
Discontinuation of Study Treatment and Participant Discontinuation 
and Withdrawal.................................................................................................................31
7.1.
Discontinuation from Study Treatment.........................................................................31
7.2.
Participant Discontinuation and Withdrawal from the Study.........................................31
7.2.1.
Discontinuation of Inadvertently Enrolled Patients...............................................31
7.3.
Patients Lost to Follow-Up...........................................................................................32
8.
Study Assessments and Procedures ...................................................................................33
8.1.
Efficacy Assessments...................................................................................................33
8.2.
Safety Assessments ......................................................................................................33
8.2.1.
Physical Examination...........................................................................................33
8.2.2.
Vital Signs ...........................................................................................................33
8.2.3.
Electrocardiograms ..............................................................................................34
8.2.4.
Clinical Safety Laboratory Assessments...............................................................34
8.2.4.1.
Hepatic Safety Monitoring..............................................................................35
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring ..................................................35
8.2.5.1.
C-SSRS..........................................................................................................35
8.2.5.2.
Columbia-Suicide Severity Rating Scale – Child Version ...............................36
8.2.5.3.
Self-Harm and Follow-up Supplement Forms .................................................36
8.2.6.
Cognition.............................................................................................................36
8.2.7.
Height and Weight ...............................................................................................37
8.2.8.
Puberty and Menstrual Status...............................................................................37
8.2.9.
Targeted Neurological Examination .....................................................................37
8.3.
Adverse Events and Serious Adverse Events................................................................38
8.3.1.
Serious Adverse Events........................................................................................38
8.3.2.
Suspected Unexpected Serious Adverse Reactions ...............................................39
8.3.3.
Time Period and Frequency for Collecting AE and SAE 
Information..........................................................................................................39
8.3.4.
Method of Detecting AEs and SAEs.....................................................................40
8.3.5.
Follow-Up of AEs and SAEs................................................................................40
8.3.6.
Regulatory Reporting Requirements for SAEs......................................................40
8.3.7.
Pregnancy ............................................................................................................40
8.3.8.
Safety Topics of Interest.......................................................................................41
8.3.9.
Complaint Handling.............................................................................................41
8.4.
Treatment of Overdose.................................................................................................41
8.5.
Pharmacokinetics .........................................................................................................41
8.5.1.
Bioanalysis...........................................................................................................42


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8.6.
Pharmacodynamics ......................................................................................................42
8.7.
Genetics .......................................................................................................................42
8.8.
Biomarkers...................................................................................................................42
8.9.
Health Economics ........................................................................................................42
9.
Statistical Considerations and Data Analysis.....................................................................43
9.1.
Statistical Hypotheses ..................................................................................................43
9.2.
Sample Size Determination ..........................................................................................43
9.3.
Populations for Analyses..............................................................................................43
9.3.1.
Patient Disposition...............................................................................................43
9.3.2.
Patient Characteristics..........................................................................................43
9.4.
Statistical Analyses ......................................................................................................43
9.4.1.
Safety Analyses....................................................................................................44
9.4.1.1.
Clinical Evaluation of Safety..........................................................................44
9.4.1.2.
Statistical Evaluation of Safety.......................................................................44
9.4.2.
Pharmacokinetic Analyses....................................................................................44
9.4.2.1.
Pharmacokinetic Parameter Estimation...........................................................44
9.4.3.
Data Review during the Study..............................................................................45
9.5.
Interim Analyses ..........................................................................................................45
9.6.
Data Monitoring Committee.........................................................................................45
10.
Supporting Documentation and Operational Considerations..............................................46
10.1. Regulatory, Ethical, and Study Oversight Considerations .............................................46
10.1.1.
Regulatory and Ethical Considerations.................................................................46
10.1.2.
Informed Consent.................................................................................................46
10.1.3.
Data Protection ....................................................................................................47
10.1.4.
Protocol Signatures ..............................................................................................47
10.1.5.
Final Report Signature .........................................................................................47
10.1.6.
Data Quality Assurance........................................................................................47
10.1.7.
Study and Site Closure .........................................................................................49
10.1.7.1.
Discontinuation of Study Sites........................................................................49
10.1.7.2.
Discontinuation of the Study...........................................................................49
11.
References ........................................................................................................................50
12.
Appendices .......................................................................................................................51


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List of Tables
Table
Page
Table LAHX.1.
Schedule of Activities for Patients Participating in the Open-Label 
PK Study................................................................................................11
Table LAHX.2.
Objectives and Endpoints .......................................................................17
Table LAHX.3.
Planned Treatment Regimen...................................................................28


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List of Figures
Figure
Page
Figure LAHX.1.
Predicted lasmiditan Cmax and AUC values for pediatric subjects............21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................52
Appendix 2.
Clinical Laboratory Tests........................................................................55
Appendix 3.
Liver Safety:  Suggested Actions and Follow-Up Assessments...............57


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1. Protocol Summary
1.1.
Protocol Synopsis
Title of Study:
A Phase 1, Open-Label, Single-Dose Pharmacokinetic Study of Lasmiditan in Pediatric Patients with Migraine.
Rationale: 
This study is being conducted to determine the pharmacokinetics (PK), safety, and tolerability of lasmiditan in
pediatric patients with migraine following a single oral dose.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To assess the single-dose pharmacokinetics of 
lasmiditan in pediatric migraine patients
Pharmacokinetic parameters including:

Maximum observed drug concentration (Cmax)

Time to reach Cmax (tmax)

Area under the concentration-versus-time curve (AUC) 
from time zero to infinity (AUC[0-])

AUC from time zero to the time t, where t is the last 
time point with measurable concentration (AUC[0-tlast])
Secondary
To assess the safety and tolerability of a single dose 
of lasmiditan in pediatric migraine patients
Summary of: 

SAEs

AEs

ECG

vital signs
Exploratory
To assess the safety, tolerability, and 
pharmacokinetics of lasmiditan in Japanese 
pediatric migraine patients
Pharmacokinetic parameters including:

Cmax

tmax

AUC[0-]

AUC[0-tlast]
Summary of adverse events, SAEs, ECG, and vital signs.
Abbreviations: AE = adverse event; ECG = electrocardiogram; SAE = serious adverse event.
Summary of Study Design
This is a Phase 1, multicenter, open-label, single-dose study to determine the PK, safety, and tolerability of 
lasmiditan in pediatric patients with a diagnosis of migraine.
Treatment Arms and Planned Duration
Two cohorts will be evaluated concurrently:

Primary Cohort 1: 15 kg to ≤40 kg

Secondary Cohort 2: >40 kg to ≤55 kg
The planned doses for Cohorts 1 and 2 are 100 mg and 200 mg, respectively.
Visit 1: Screening


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All patients are screened to determine if they are eligible to participate in the study.
Screening will occur up to 28 days to 3 days prior to lasmiditan dosing.
Visits 2–3: Dosing and PK Assessments
Day 1 (Visit 2)

Patients arrive at the Clinical Research Unit (CRU) for assessments prior to dosing.

Patients receive the single lasmiditan dose.

Patients can go home after the 12-hour assessments.  Patients may be offered the opportunity to spend the 
night depending on CRU capabilities.
Day 2 (Visit 3)

Patient assessments are done at the CRU approximately 24 hours after dosing.
Visit 4/801
Visit 4/801 will occur approximately 14 days after dosing.
Visit 801 – Patients in Japan and those who will not proceed to the 3-month addendum will complete assessments 
according to Visit 801 in the Schedule of Activities.
Visit 4 – Patients continuing to the addendum will complete assessments according to the Schedule of Activities in 
the addendum.
Number of Patients
Cohort 1
Approximately 13 patients may be enrolled to obtain 11 patients with evaluable PK data.
Cohort 2
Approximately 8 patients may be enrolled to obtain 6 patients with evaluable PK data.
Statistical Analysis:
Safety parameters that will be assessed include:

adverse events including clinically significant electrocardiograms

serious adverse events

vital signs

Columbia-Suicide Severity Rating Scale (C-SSRS) assessments

Cognition, as assessed by Cogstate Pediatric Brief Battery
Pharmacokinetic parameter estimates for lasmiditan will be calculated by standard noncompartmental methods of 
analysis from plasma lasmiditan concentrations, and listed and summarized using descriptive statistics.


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1.2.
Schema
Abbreviation:  PK = pharmacokinetic.
1.3.
Schedule of Activities
Visit 1
Screening
Visit 2
PK and Safety
Assessments
Visit 3
24 hour 
Assessments
Visit 801
Follow-up
Addendum 
Visits
Participants in 
Japan or those 
who will not 
proceed to 
addendum
Participants 
proceeding to 
addendum


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Table LAHX.1.
Schedule of Activities for Patients Participating in the Open-Label PK Study
Study Period (SP)
SP I
Screening
SP II
PK Assessment/Safety
EDa
SP III
Notes
Visit
1
2
3
4/801b
Time from 
Lasmiditan Dose 
(hr)
Predose
Dose
0.5
1
1.5
2
3
4
8
12
24
Study Day
-28 to -3 
Day 1
Day 
2
Day 
14±3
Assessments and Procedures
Informed 
consent/Assent
X
Inclusion/exclusion 
criteria review
X
X
Demographics
X
Medical history
X
X
Substance use 
history
X
X
Alcohol and tobacco use for patients aged 
>10 years
Concomitant 
medications
X
X
X
X
X
X
At screening, previous and ongoing 
migraine treatments will be collected.
Physical 
examination
X
X
X
X
Targeted neurologic 
examination
X
X
X
X
Height
X
Height will be measured using a 
stadiometer and measured in triplicate.
Weight
X
X
X
Weight will be measured once.
Menstrual status
X
12-lead ECG
(single)
X
X
X
ECG procedure occurs prior to blood 
draws and dosing. Patients must be supine 
for at least 5 minutes before collection and 
remain supine but awake during the 


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Study Period (SP)
SP I
Screening
SP II
PK Assessment/Safety
EDa
SP III
Notes
Visit
1
2
3
4/801b
Time from 
Lasmiditan Dose 
(hr)
Predose
Dose
0.5
1
1.5
2
3
4
8
12
24
Study Day
-28 to -3 
Day 1
Day 
2
Day 
14±3
procedure.
Vital signs
  Blood pressure and
pulse
X
X
X
X
X
X
X
X
X
At screening – single measurement.
All other time points – triplicate
measurements, and prior to blood draws 
and lasmiditan administration.  Blood 
pressure measurements will be taken by an
automated calibrated (if calibration is 
required) machine.
Orthostatic Vital 
Signs
X
X
X
X
X
Temperature
X
X
Adverse events
X
X
X
X
X
Lasmiditan dosing
X
Clinical Laboratory Tests and Sampling
Hematology
X
X
X
Clinical chemistry
X
X
X
Gonadal hormones
X
Estradiol (for females) or testosterone (for 
males) will be collected in patients aged 8 
to <18 years, to assess pubertal status.
Urinalysis
X
Urine drug screen
X
X
For patients aged > 10 years.


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Study Period (SP)
SP I
Screening
SP II
PK Assessment/Safety
EDa
SP III
Notes
Visit
1
2
3
4/801b
Time from 
Lasmiditan Dose 
(hr)
Predose
Dose
0.5
1
1.5
2
3
4
8
12
24
Study Day
-28 to -3 
Day 1
Day 
2
Day 
14±3
Pregnancy test
for females of 
childbearing 
potential
X
X
X
X
Serum pregnancy test at screening.  Urine 
pregnancy test at all other visits.  A 
positive urine test must be followed by a 
serum pregnancy test for confirmation.
If a patient discontinues within 24 hours of 
the lasmiditan dose, an early 
discontinuation urine test is not needed.
PK blood sample
X
X
X
X
X
X
X
X
X
An indwelling catheter is required for 
blood collection on Day 1.  See Notes for 
time windows and order of procedures.
Scales and Questionnaires
C-SSRS
Children’s version
SHSF, SHFU
X
X
X
X
X
Suicidal ideation and behavior subscales 
excerpt – Adapted for the assessment of 11 
preferred ideation and behavior categories. 
The C-SSRS will be scored only in patients 
≥7 years old. The Self-Harm Follow-Up 
Form is required only if triggered by the 
Self-Harm Supplement Form.
Cogstate Pediatric 
Brief Battery
X
X
X
X
X
X
Participants will be instructed on use at 
screening.


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Abbreviations:  C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; PK = pharmacokinetic; SHFU = 
Self-Harm Follow-Up form; SHSF = Self-Harm Supplement form.
a
Early discontinuation procedures should be conducted if a patient discontinues from the study before follow-up visit.
b
Visit 801 – For patients in Japan and those who will not proceed to the 3-month addendum.  Visit 4 – Patients continuing to the addendum will complete 
assessments according to the Schedule of Activities in the addendum.
Note:  If multiple procedures take place at the same time point, the following order of the procedure should be used: 
ECG, vital signs and orthostatic vital signs, and venipuncture.
Where venipuncture and other procedures take place at the same time point, the following time windows for obtaining blood samples should be maintained:  
>0 to 2 hours postdose: ±5 minutes 
2.5 to 6 hours postdose: ±10 minutes 
>6 to 12 hours postdose: ±20 minutes 
12 hours postdose: ±30 minutes
24 hours postdose: ±60 minutes.
Where repeats of vital signs measurements are required, repeats should be performed after venipuncture.


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2. Introduction
2.1.
Study Rationale
This study is being conducted to determine the pharmacokinetics (PK), safety, and tolerability of 
lasmiditan in pediatric migraine patients following a single oral dose of lasmiditan.
This study is part of a pediatric (6 to 18 years) clinical program for lasmiditan. The data from 
this study will be used to inform dose selection in subsequent clinical studies intended to provide 
pivotal efficacy and safety data to support use of lasmiditan for acute treatment of migraine in 
children and adolescents.
This study will also include Japanese pediatric patients to facilitate lasmiditan pediatric clinical 
development in Japan.
2.2.
Background
Lasmiditan is being developed as a novel therapy for the acute treatment of migraine.  
Lasmiditan is a high-affinity, centrally penetrant, selective human serotonin 1F (5-HT1F) receptor 
agonist that exerts its therapeutic effects in the treatment of migraine by decreasing neuropeptide 
release and inhibiting pain pathways, including the trigeminal nerve.  Lasmiditan is structurally 
and mechanistically distinct from other approaches for the acute treatment of migraine, such as 
triptans, and lacks the vasoconstrictive effects of triptans that result from 5-HT1B activity.
Across clinical trials in adults, lasmiditan was generally well tolerated and the majority of 
adverse events (AEs) were mild to moderate, with a duration of 1 to 5 hours for the common 
treatment-emergent adverse events (TEAEs).  Lasmiditan use is associated with neurologic 
TEAEs, with the most common being dizziness, paresthesia, somnolence, fatigue, nausea, 
hypoesthesia, and muscle weakness.  In a variety of analyses of Phase 3 data, proportions of 
adult patients reporting TEAEs generally decreased over time.
In the pivotal efficacy trials in adults, doses of 50 mg, 100 mg, and 200 mg were studied. All 
doses were superior to placebo in the primary and key secondary endpoints of pain freedom and 
freedom from most bothersome symptoms.  A consistent dose–response relationship was 
observed, with patients in higher dose groups having a greater likelihood of response across 
multiple efficacy endpoints. Based on these data in adults with migraine, lasmiditan may 
provide therapeutic benefit to children and adolescents from 6 to <18 years of age with migraine.
A population pharmacokinetic (popPK) analysis of adult PK data following oral administration
indicates that lasmiditan is rapidly absorbed with a median time to reach maximum observed 
drug concentration (tmax) of 1.8 hours and is eliminated with a geometric mean value of 5.7 hours 
for terminal half-life.  Over the clinical dose range of 50 to 200 mg, lasmiditan exposure 
generally increases linearly with dose.  The interindividual variability of lasmiditan maximum 
observed drug concentration (Cmax) and area under the concentration-versus-time curve (AUC)
are 43% and 39%, respectively, based on the popPK analysis.  The covariates of body weight, age 
[elderly vs. nonelderly], and population [healthy vs. patient] were statistically significant in the 


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LY573144
popPK model, but the magnitude of these effects was within the PK variability and therefore not 
considered to be clinically relevant over the range of covariate values in the population.
2.3.
Benefit/Risk Assessment
This is an open-label study in which all pediatric patients will receive a single dose of lasmiditan. 
Participants in the United States (US) will have the opportunity to participate in an open-label, 3-
month addendum to this study.
Participants will also have the opportunity to participate in an open-label, 12-month long-term 
safety study (Study H8H-MC-LAHW) when it is available.
As a centrally penetrant and neurally active drug, lasmiditan use is associated with neurologic 
TEAEs, with the most common being dizziness, paresthesia, somnolence, fatigue, nausea, 
hypoesthesia, and muscle weakness.  It is generally well tolerated, and the vast majority of 
events are mild to moderate and self-limiting.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated AEs of lasmiditan may be found in the Investigator’s Brochure (IB).


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3. Objectives and Endpoints
Table LAHX.2 shows the objectives and endpoints of the study.
Table LAHX.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the single-dose pharmacokinetics of 
lasmiditan in pediatric migraine patients
Pharmacokinetic parameters including:

Maximum observed drug concentration (Cmax)

Time to reach Cmax (tmax)

Area under the concentration-versus-time curve 
(AUC) from time zero to infinity (AUC[0-])

AUC from time zero to the time t, where t is the 
last time point with measurable concentration 
(AUC[0-tlast]).
Secondary
To assess the safety and tolerability of a single dose of 
lasmiditan in pediatric migraine patients
Summary of:

SAEs

AEs

ECG

vital signs
Exploratory
To assess the safety, tolerability, and pharmacokinetics 
of lasmiditan in Japanese pediatric migraine patients
Pharmacokinetic parameters including:

Cmax

tmax

AUC[0-]

AUC[0-tlast]
Summary of adverse events, SAEs, and vital signs.
Abbreviations:  AE = adverse event; ECG = electrocardiogram; SAE = serious adverse event.


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4. Study Design
4.1.
Overall Design
This is a Phase 1, multicenter, open-label, single-dose study to determine the PK, safety, and 
tolerability of lasmiditan in pediatric patients with a diagnosis of migraine.
Two cohorts will be evaluated concurrently:

Primary Cohort 1: 15 kg to ≤40 kg

Secondary Cohort 2: >40 kg to ≤55 kg
The planned doses for Cohorts 1 and 2 are 100 mg and 200 mg, respectively.
Visit 1: Screening
All patients are screened to determine if they are eligible to participate in the study.
The study and potential risks are explained to the patient and their parent or guardian.
The informed consent form (ICF) and patient assent form must be signed before any study 
procedures are performed.
Screening will occur 28 days to 3 days prior to lasmiditan dosing.
Visits 2–3: Dosing and PK Assessments
Enrolled patients and patient’s parent or guardian will receive instructions regarding study 
procedures prior to dosing.
Day 1 (Visit2)

Patients arrive at the Clinical Research Unit (CRU) for assessments prior to dosing.

Patients receive the single lasmiditan dose.

Patients can go home after the 12-hour assessments.  Patients may be offered the 
opportunity to spend the night depending on CRU capabilities.
Day 2 (Visit 3)

Patient assessments are done at the CRU approximately 24 hours after dosing.
Visit 4/801
Visit 4/801 will occur approximately 14 days after dosing.
Visit 801 – Patients in Japan and those who will not proceed to the 3-month addendum will 
complete assessments according to Visit 801 in the Schedule of Activities.
Visit 4 – Patients continuing to the addendum will complete assessments according to the 
Schedule of Activities in the addendum.


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4.2.
Scientific Rationale for Study Design
This is an open-label, single-dose study to determine the PK, safety, and tolerability of 
lasmiditan in pediatric migraine patients.  This study is part of a pediatric migraine clinical 
development program, and the data from this study will be used to inform dose selection in 
subsequent clinical studies intended to provide pivotal efficacy and safety data to support use of 
lasmiditan for acute treatment of migraine in children and adolescents.
The single-dose administration:

limits exposure of patients to lasmiditan, compared with repeat dosing

is consistent with the intended use of lasmiditan as a medication that is taken on an “as 
needed” basis for abortive treatment of migraines

is appropriate to assess PK, safety, and tolerability of lasmiditan.
Body Weight Selection
The lower end of the weight range for this study is 15 kg, as only 1% of pediatric subjects who 
are 6 years of age weigh < 15 kg, based on US pediatric growth charts.  Additionally, in Japan, 
<3% of pediatric subjects who are 6 years of age weigh < 15.6 kg (Kato et. al. 2014).
The higher end of the weight range for this study is 55 kg. The body weight evaluated in adults 
ranged from 48 to 115 kg, with limited exposure data in subjects ≤55 kg (lower 5th percentile).  
Therefore, the body weight range of 15 to 55 kg is considered suitable for evaluation in this 
study.  For body weights above 55 kg, the pediatric exposure of lasmiditan is anticipated to be 
similar to that of adults of the same body weight for a given dose.
Pharmacokinetics
This study is designed to characterize the PK of lasmiditan after a single dose of lasmiditan.  
Blood samples will be collected for 24 hours after dosing, which is considered adequate to 
characterize the PK profile in pediatric patients.  The plasma concentration of lasmiditan is an 
objective measurement; therefore, the open-label design is appropriate for this evaluation.
Japanese Patients
Data from Japanese pediatric patients will be used to inform subsequent clinical studies in 
Japanese patients.
4.3.
Justification for Dose
The planned doses for this study are 100 mg for patients who are 15 to ≤40 kg and 200 mg for 
patients who are >40 to ≤55 kg.
Efficacy and Safety Data
Efficacy and safety data in adults support the use of 50 mg, 100 mg, and 200 mg of lasmiditan 
for the acute treatment of migraine.  Although lower doses were statistically superior to placebo 
on pain freedom at 2 hours, the proportion of patients achieving pain freedom at 2 hours after a 


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migraine attack in adult Phase 3 studies was numerically highest for the 200-mg dose.  It is 
important to assess pediatric dose(s) predicted to achieve exposures comparable to adult 200-mg 
exposure, because demonstrating efficacy in pediatric migraine studies has been challenging, in 
part because of the high placebo rates reported in these studies (Evers 2006; Fernandes 2008).
Although 200 mg was the highest dose tested in the Phase 3 migraine program, lasmiditan was 
generally well tolerated in adults, including Japanese adults, up to 400 mg in Phase 1 and 2 
studies.  Also, the margin of safety for the 200-mg dose is estimated to be approximately 3 times, 
based on the ratio of the observed no-observed-adverse-effect-level exposure from the juvenile 
toxicology study to the estimated human exposure at 200 mg.
Dose Levels and Weight Ranges
The planned dose levels and weight ranges are supported by model-based simulations of 
pediatric exposures.  A popPK model was developed using PK data following oral dosing in 
adult patients pooled from multiple Phase 1 studies.  In the model, the effect of body weight on 
apparent total body clearance and volume of distribution resulted in lower lasmiditan exposure in 
heavier patients relative to lighter patients.  Model-based simulations were subsequently 
performed to predict lasmiditan exposures in pediatric patients at 5-kg body weight increments 
(Figure LAHX.1).
The maximum observed drug concentration (Cmax) was considered the primary exposure 
measure used to guide dose selection, as it is expected to be a more relevant response for acute 
treatment.  For pediatric patients (15 to ≤40 kg) receiving 100 mg, the predicted ratio of mean 
Cmax ranged from 0.68 for 40 kg to 1.19 for 15 kg, relative to that of adults receiving 200 mg.  
For pediatric patients (>40 kg to ≤55 kg) receiving 200 mg, the predicted ratio of mean peak 
exposure Cmax ranged from 1.22 for 55 kg to 1.37 for 45 kg, relative to that of adults receiving 
200 mg.
Therefore, the proposed dosing regimen should provide exposures in pediatric patients, 
comparable to the predicted range of adult 200-mg exposures.  PK exposure data will be 
reviewed during the study.  The dose may be adjusted, if lasmiditan exposure is substantially 
different from PK predictions.


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Abbreviations: AUC = area under the concentration-versus-time curve; Cmax =
maximum observed drug concentration; PI = prediction interval.
The boxes depict geometric mean and the interquartile range; whiskers depict 90% 
prediction interval (PI) in pediatric subjects.  The black solid and dashed lines depict 
the geometric mean exposure value and 90% PI for 200 mg dose in adults, respectively. 
Figure LAHX.1.
Predicted lasmiditan Cmax and AUC values for pediatric subjects.
4.4.
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 for the last patient.


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5. Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
5.1.
Inclusion Criteria
Study investigator(s) will review patient history and screening test results at Visit 1 and Visit 2 to 
determine if the patient meets all inclusion and none of the exclusion criteria to qualify for 
enrollment in the study. All screening activities must be completed and reviewed before the 
patient is enrolled and receives the investigational product.
A patient is eligible for inclusion in the study only if all the criteria apply at screening.
Type of Patient and Disease Characteristics
[1]
Patient is between 6 and <18 years of age.
[2]
have a history of migraine with or without aura, as defined by International 
Headache Society International Classification of Headache Disorders, 3rd edition 
guidelines (ICHD-3 2018) migraine definitions and meets the following criteria:

history of migraine attacks for more than 6 months

reports ≥2 and ≤15 migraine attacks per month in the 2 months prior to screening
[3] are migraine free on day of lasmiditan administration at the time of predose 
assessments.
[4] have a minimum body weight of 15 kg and a maximum of 55 kg.
[5] are able to swallow a tablet.
[6] have received age-appropriate immunizations according to their country-specific 
public health policy as confirmed by patient’s immunization record.
Informed Consent and Patient Agreements
[7] the patient and the patient’s parent or guardian must understand the nature of the 
study.  The patient’s parent or guardian must sign an ICF and the patient must 
sign an informed assent document as required by local regulations.
[8] are reliable and willing to make themselves available for the duration of the study 
and are willing to follow study procedures.
[9] Agree not to post any personal medical data related to the study or information 
related to the study on any website or social media site, such as Facebook, 
Twitter, Snapchat, Instagram, Google+, until notification that the study has 
completed.
[10] Are male or female
If female, must agree to abide by the following guidance:


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
Adolescent females who have started menses (even 1 cycle and any amount 
of spotting) are considered to be of childbearing potential.

Females of childbearing potential must agree to use a highly effective 
method of contraception (that is, one with less than 1% failure rate) such as 
combination oral contraceptives, implanted/injected contraceptives, 
intrauterine devices, or a sterile partner until 30 days after the last dose of 
study medication.

Females of childbearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same-sex 
relationship (as part of their preferred and usual lifestyle) must agree to 
either remain abstinent or stay in a same-sex relationship without sexual 
relationships with males.

Periodic abstinence (for example, calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence just for the duration of a 
trial, and withdrawal are not acceptable methods of contraception.

Females not of childbearing potential may participate and include those
who are infertile because of surgical sterilization by hysterectomy, bilateral 
oophorectomy, or tubal ligation, or who have a congenital anomaly such as 
mullerian agenesis.
5.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
Medical Conditions
[11] Have a history or clinical evidence of congenital heart disease, suspected or
confirmed; or a history of stroke.
[12] Have electrocardiogram (ECG) showing abnormalities compatible with acute 
cardiovascular events and/or serious cardiovascular disease risk.
[13] Have had myocardial infarction, unstable angina, percutaneous coronary 
intervention, or coronary artery bypass graft within 6 months of screening.
[14] Have planned cardiovascular surgery or percutaneous coronary angioplasty.
[15] Have liver tests outside the normal range that are clinically significant

alanine aminotransferase (ALT) >2x upper limit of normal (ULN), or 

total bilirubin level (TBL) >1.5x ULN, or 

alkaline phosphatase (ALP) >2x ULN. 
Exceptions


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o
if test results outside the normal range are discussed and judged not 
clinically significant by Eli Lilly and Company (Lilly) Medical
o
Patients with TBL ≥1.5x ULN and the following criteria for Gilbert 
syndrome:

Bilirubin is predominantly indirect (unconjugated) at screening 
(direct bilirubin within normal limits)

Absence of liver disease

ALT, aspartate aminotransferase (AST), and ALP ≤1x ULN at 
screening

Hemoglobin not significantly decreased at screening.
[16] Have, in the judgment of the investigator, a psychiatric disorder as defined by 
the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition that 
would interfere with adherence to study requirements or safe participation in the 
trial.
[17] Are, in the judgment of the investigator, actively suicidal and therefore deemed 
to be at significant risk for suicide.
[18] At baseline:

have answered “yes” to either Question 4 or Question 5 on the “Suicidal 
Ideation” portion of the Columbia-Suicide Severity Rating Scale (C-SSRS), or 

have answered “yes” to any of the suicide-related behaviors on the “suicidal 
behavior” portion of the C-SSRS, and the ideation or behavior occurred within 
the past month.
[19] Are pregnant or nursing.
[20] Have, in the judgment of the investigator, an acute, serious, or unstable medical 
condition, or a history or presence of any other medical illness that would 
preclude study participation.
Prior and Concomitant Therapy/Substances of Abuse
[21] Have used opioids or barbiturate-containing analgesics >3x per month for the 
treatment of pain in more than 2 of the past 6 months (opioid administration in 
an emergency setting [either urgent or emergent] may be an exception.).
[22] Have a history of drug or alcohol abuse/dependence within 1 year prior to Visit 
1 (excessive or compulsive use as judged by the investigator), or are currently 
using drugs of abuse (including opioids, barbiturates, and marijuana), or any
prescribed or over-the-counter medication in a manner that the investigator
considers indicative of abuse/dependence.
[23] Have a positive urine drug screen for any substances of abuse. One retest is 
allowed if the urine drug screen is positive, at the investigator’s discretion.


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[24] Are on a CNS active drug, which is known to affect levels of attention or 
sedation, such as a benzodiazepine for sleep or anxiety, or stimulants for 
Attention Deficit Hyperactivity Disorder.
[25] Have known allergies to lasmiditan, related compounds, or any components of 
the formulation.
Diagnostics Assessments
[26] Have a history of any type of headache except for migraine with or without aura, 
tension type headache or medication overuse headache, as defined by ICHD 3. 
Migraine subtypes including sporadic or familial hemiplegic migraine and 
migraine with brainstem aura, previously known as basilar type migraine, should 
be excluded.
[27] Have a history of traumatic head injury associated with significant change in the
quality or frequency of their headaches, including a new onset of migraine
following traumatic head injury or a history of post-traumatic headache.
[28] Have a known history of intracranial tumors or developmental malformations 
including Chiari malformations.
Prior/Concurrent Clinical Trial Experience
[29] 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.
[30] Have participated, 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.
[31] Have previously completed or withdrawn from this study or any other study 
investigating lasmiditan, and have previously received the investigational 
product.
Other Exclusions
[32] Are legally incapacitated.
[33] Are children of investigator site personnel directly affiliated with this study 
and/or their immediate families.  Immediate family is defined as a spouse, 
biological or guardian, child, or sibling.
[34] Are children of Lilly employees.
[35] Have donated more than a single unit of blood within 4 weeks prior to screening 
or intend to donate blood during the course of the study.
[36] In the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.


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5.2.1. Rationale for Exclusion of Certain Study Candidates
Criteria [11] through [20] exclude medical conditions, [21] through [28] exclude concomitant 
medication, substances of abuse, and medical history that may confound the assessment of study 
endpoints, [29] through [31] exclude concurrent clinical trial experience, and [33] and [34] 
prevent conflict of interest in study participants.
5.3.
Lifestyle and/or Dietary Considerations
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
5.3.1. Meals and Dietary Restrictions
Patients will:

fast overnight prior to the day of dosing with the exception of a light breakfast, such as
cereal with fat-free milk or toast or white rice, 2 hours prior to the time of dosing

abstain from water 1 hour before and after dosing, except for up to 240 mL of water 
given with the dose

fast until approximately 2 hours after dosing, at which time a meal will be served.
5.3.2. Caffeine, Alcohol, and Tobacco
From approximately 48 hours prior to dosing, and up to 24 hours after dosing, patients are not 
allowed to:

consume xanthine- or caffeine-containing food and drink
Examples - cola, chocolate drinks, tea, coffee, and energy drinks containing 
methylxanthine (caffeine, theophylline, or theobromine)

consume alcoholic beverages

use tobacco products.
Limits may be adjusted to meet local requirements if local requirements are more stringent.
5.4.
Screen Failures
At Visit 2, inclusion and exclusion criteria will be reviewed prior to the first dose of 
investigational product.
Screen failures are defined as patients who consent to participate in the study but do not meet the 
enrollment criteria and do not receive any dose of investigational product.
Based on the clinical judgment of the investigator, patients who fail to qualify at enrollment may 
be rescreened at a later date.  Only 1 rescreening visit is permitted.
If rescreening is performed, the parent or guardian and the patient must sign a new assent and 
ICF, and the patient will be assigned a new identification number.


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If changes in circumstances have allowed a patient to be rescreened, a complete screening visit 
must be repeated. However, if the rescreen visit is within 30 days from the original screening 
visit and it was a result of only specific out-of-range value/findings, then only those assessments 
should be repeated and not the entire laboratory panel.
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities.  Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.


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6. Treatment
6.1.
Treatment Administered
Lasmiditan 50-mg and 100-mg tablets will be used in this study, to achieve a single total dose of 
either 100 mg or 200 mg (Table LAHX.3).  The investigator will decide which tablet strength to 
administer to achieve the appropriate dose based on the patient’s ability to swallow and patient’s 
preference.
Lasmiditan will be administered orally, on Day 1, in a sitting position.  The actual time of the 
dose administered will be recorded in the patient’s case report form (CRF).
Patients should not lie supine for 2 hours after dosing, unless clinically indicated or for study 
procedures.
Table LAHX.3.
Planned Treatment Regimen
Cohort
1
2
Patient Body Weight 
15 kg to ≤ 40 kg
>40 kg to ≤ 55 kg
Treatment Name
Lasmiditan
Lasmiditan
Dosage Formulation
Tablet
Tablet
Unit Dose Strength(s)/
Dosage Level(s)
50 mg x2 or
100 mg x1
50 mg x4 or
100 mg x2
Route of 
Administration
Oral
Oral
Dosing Instructions
With approximately 240 mL of room temperature water 
in a sitting position
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
6.1.1. Packaging and Labeling
Lasmiditan will be supplied to the clinics with bulk bottles of 50-mg and 100-mg tablets.  The 
investigational product will be labeled according to the country’s regulatory requirements.


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6.2.
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 drug.
Only patients 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 a secure, 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).
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study. Patients who meet all criteria for enrollment at Visit 2 will receive a
dose of lasmiditan 100 mg or 200 mg, according to their body weight, as shown in 
Table LAHX.3.
6.4.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
6.5.
Concomitant Therapy
For patients taking preventive medication for migraine, treatment regimen must be stable for at 
least 3 months prior to Visit 1.
This study will be conducted during a migraine-free period; therefore concomitant acute 
medications for migraine or migraine symptoms on the day of Visit 1 are not allowed, with the 
exception of acetaminophen, which may be administered at the discretion of the investigator, 
according to label recommendations.
A topical anesthetic cream may be used by the investigator to reduce discomfort associated with 
cannula/needle insertion.
If the need for concomitant medication other than acetaminophen or topical anesthetic arises, 
inclusion or continuation of the patient may be at the discretion of the investigator after 
consultation with Lilly medical. All concomitant medications, whether prescription or over the 
counter, used at baseline and/or during the course of the study, must be recorded on the 
appropriate Concomitant Medication CRF.
6.6.
Dose Modification
The planned dose is 100 mg and 200 mg in pediatric patients with body weight ≥15 kg to ≤40 kg 
and >40 kg to ≤55 kg, respectively.  Safety and PK data will be reviewed on an ongoing basis.


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Doses may be adjusted when data are available from at least 3 patients with evaluable PK data in 
the primary cohort (Section 9.4.3).
6.7.
Treatment after the End of the Study
This section is not applicable to this study.


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7. Discontinuation of Study Treatment and Participant 
Discontinuation and Withdrawal
7.1.
Discontinuation from Study Treatment
This is a single-dose study.  If a patient discontinues after receiving the single dose of lasmiditan, 
early discontinuation procedures will be completed per the Schedule of Activities of this 
protocol.
7.2.
Participant Discontinuation and Withdrawal from the Study
Patients 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 patient should be discontinued from the study.
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent.

Patient Decision
o
the patient requests to be withdrawn from the study, or
o
the parent or patient’s guardian requests that the patient be withdrawn from the 
study.
Participants discontinuing from the study prematurely for any reason should complete AE and 
other safety follow-up per Section 1.3 (Schedule of Activities), Section 8.3 (Adverse Events 
and Serious Adverse Events), and Section 8.2 (Safety Assessments) of this protocol.
7.2.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between Lilly Medical and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from Lilly Medical to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product.
Safety follow-up is as outlined in Section 1.3 (Schedule of Activities), Section 8.3 (Adverse 
Events and Serious Adverse Events), and Section 8.2 (Safety Assessments) of this protocol.


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7.3.
Patients Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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8. Study Assessments and Procedures
The Schedule of Activities details the study procedures and their timing (including tolerance 
limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.  A separate table in 
this section 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.
8.1.
Efficacy Assessments
This section is not applicable to this study.
8.2.
Safety Assessments
The Lilly clinical pharmacologist or Clinical Research Physician (CRP)/scientist will monitor 
safety data throughout the course of the study.
8.2.1. Physical Examination
For each patient, a complete physical examination (excluding pelvic and rectal examinations) 
will be performed according to the Schedule of Activities.  A complete physical examination 
may be repeated at the investigator’s discretion at any time a patient presents with physical 
complaints.  A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.
8.2.2. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities.
Vital signs will consist of 1 pulse rate, 1 temperature, and 3 blood pressure (BP) measurements. 
Three consecutive BP readings will be recorded at intervals of at least 1 minute.  Where 
applicable, the last triplicate vital sign can be used as the supine/semi-recumbent vital sign for 
the calculation of orthostatic changes.
Blood pressure and pulse rate measurements:

will be taken when the patient is in a supine position

should be preceded by at least 5 minutes of rest for the patient in a quiet setting without 
distractions (for example, television, cell phones)

will be collected using the appropriate size pediatric BP cuffs

will be assessed with a completely automated device
o
Manual techniques will be used only if an automated device is not available.


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When orthostatic measurements are required, patients should be supine for at least 5 minutes and 
stand for at least 2 minutes. If the patient feels unable to stand, supine vital signs only will be 
recorded. Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of 
dizziness or posture-induced symptoms.  Additional vital signs may be measured during each 
study period if warranted.
Any clinically significant findings from vital sign measurements that result in a diagnosis should 
be reported to Lilly or its designee as an AE via electronic case report form (eCRF).
Any abnormal finding for vital signs at 24 hours postdose will need to be repeated at follow-up 
to check if it has returned to baseline.
8.2.3. Electrocardiograms
For each patient, a single12-lead digital ECG will be collected according to the Schedule of 
Activities.  Electrocardiograms may be obtained at additional times, when deemed clinically 
necessary.  Electrocardiograms must be recorded before collecting any blood samples.
Patients must be in supine position for at least 5 minutes before ECG collection and remain 
supine, but awake during ECG collection.
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 
patient is still present for immediate patient management, should any clinically relevant findings 
be identified.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
At a future time, the stored ECG data may be overread at the central ECG laboratory for further 
evaluation of machine-read measurements or to meet regulatory requirements.
Any clinically significant findings from ECGs that result in a diagnosis should be reported to 
Lilly or its designee as an AE via eCRF.
Any abnormal finding for ECGs at 24 hours postdose will need to be repeated at follow-up to 
check if it has returned to baseline.
8.2.4. Clinical Safety Laboratory Assessments
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities.  Use of local anesthetics (for example, EMLA cream) consistent with 
local prescribing information is permitted during the study visit to ease discomfort associated 
with venipunctures.
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor, if a central vendor is used for the clinical trial.
Alkaline phosphatase laboratory results may be out of the normal range in pediatric patients 
because of normal bone growth processes, and collection of a blood sample for bone ALP may 
be requested by the sponsor as a reflex test if the ALP result is high.


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Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via CRF.
Investigators must document their review of each laboratory safety report.
8.2.4.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3x ULN, ALP ≥2x ULN, or elevated TBL ≥2x
ULN, liver tests (Appendix 3) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator based on 
consultation with the CRP/CRS.  Monitoring should continue until levels normalize and/or are 
returning to approximate baseline levels.
Additional safety data should be collected if 1 or more of the following conditions occur:

elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2x ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests

patient discontinued from treatment because of a hepatic event or abnormality of 
liver tests

hepatic event considered to be an SAE.
8.2.5. Suicidal Ideation and Behavior Risk Monitoring
8.2.5.1.
C-SSRS
Columbia-Suicide Severity Rating Scale (C-SSRS) is a scale that captures the occurrence, 
severity, and frequency of suicidal ideation and behavior during the assessment period via a 
questionnaire.  The scale was developed by the National Institute of Mental Health (NIMH) trial 
group (TASA) for the purpose of being counterpart to the Columbia Classification Algorithm of 
Suicide Assessment (C-CASA) categorization of suicidal events.
Suicidality will be assessed by the children’s version of the C-SSRS (Posner et al. 2011).  The 
C-SSRS scale includes suggested questions to solicit information needed to determine if a 
suicide-related thought or behavior occurred during the assessment period.
The Self-Harm Supplement should be completed every time the patient is assessed by C-SSRS.  
If there are positive findings on the Self-Harm Supplement, then the Lilly Self-Harm Follow-Up 
form will be used to collect additional information to allow for a more complete assessment of 
these behaviors.
The C-SSRS and a corresponding Self-Harm Supplement Form will be used for assessment of 
the patient according to the Schedule of Activities by appropriately trained site personnel.


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Before using the C-SSRS, study site personnel will question the patient about any change in the 
preexisting condition(s) and the occurrence and nature of any AEs.
Nonserious AEs obtained through the questionnaire are recorded and analyzed separately.
Only SAEs and AEs leading to discontinuation elicited through the C-SSRS are to be recorded as 
AEs via the CRF.  Serious adverse events must be reported to Lilly or its designee within 24 
hours as SAEs.
8.2.5.2.
Columbia-Suicide Severity Rating Scale – Child Version
The C-SSRS captures the occurrence, severity, and frequency of suicidal ideation and/or 
behavior during the assessment period.  A children’s version of the C-SSRS will be completed 
for all patients.  The scale includes suggested questions to solicit the type of information needed 
to determine if suicidal ideation and/or behavior occurred.  The C-SSRS is administered by 
qualified site personnel.  The tool was developed by the National Institute of Mental Health trial 
group for the purpose of being a counterpart to the Columbia Classification Algorithm of Suicide 
Assessment categorization of suicidal events.  For this study, the scale has been adapted (with 
permission from the scale authors) to include only the portion of the scale that captures the 
occurrence of the 11 preferred ideation and behavior categories.
The nonleading AE collection should occur prior to the collection of the C-SSRS.  If a 
suicide-related event is discovered during the C-SSRS, but was not captured during the 
nonleading AE collection, sites should not change the AE form.  If an event is serious or leads to 
discontinuation, this is an exception where the SAE and/or AE leading to discontinuation should 
be included on the AE form and the process for reporting SAEs should be followed.
8.2.5.3.
Self-Harm and Follow-up Supplement Forms
The Self-Harm Supplement Form is an administrative form to denote the presence of any 
reported self-harm events and is used to trigger a Self-Harm Follow-Up form in the data capture 
system.  The Self-Harm Follow-Up form is a series of questions that provides a more detailed 
description of the behavior.
As part of the C-SSRS, the Self-Harm Follow-Up form will be completed for each event if the 
patient reports 1 or more self-harm events.
8.2.6. Cognition
Cognition will be assessed by the Cogstate Pediatric Brief Battery (2018 Cogstate Ltd).  This 
is a brief 15- to 18-minute computerized cognitive assessment that measures processing speed, 
attention, visual learning, and working memory.
This battery of cognitive assessments was selected because the assessments are brief, resistant to 
practice effects, culture and language neutral, and have well-established reliability and validity 
for the repeated assessment of cognitive function in children (Mollica et al. 2005).  Evidence 
supports its use in children with chronic pain (Bredlau et al. 2015) and in other indications such 
as mild traumatic brain injury, schizophrenia, and acquired immunodeficiency syndrome–
dementia complex (Maruff et al. 2009).


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8.2.7. Height and Weight
Height and weight will be assessed according to the Schedule of Activities.

Height will be measured using a stadiometer and measured in triplicate.

Weight must be measured once, and recorded to 1 decimal place without rounding.

Instruments used for measuring height and weight should be appropriately and regularly 
calibrated.

All measurements of height and weight should be taken without shoes and after the 
removal of any heavy personal items (that is, large jewelry, wallets, coats, etc.).
8.2.8. Puberty and Menstrual Status
Pubertal status, including menstrual history, will be determined by the investigator at the 
screening visit based on an interview with the patient and the patient’s guardian, and results of 
blood hormone levels.   
8.2.9. Targeted Neurological Examination
A targeted neurological examination will be performed at the visits and times specified in the 
Schedule of Activities.
Examination
Components
Considerations
General
Speech
Monitor for dysarthria or other speech changes 
during neurological examination and interactions
Motor
Upper and lower extremity 
strength
Tone
Assess for motor weakness
Assess for decrease or increase in tone
Cerebellar
Arms extended
Finger–nose–finger
Heel to shin (supine)
Rapid alternating movement 
(pronation/supination of one hand 
on opposite palm)
Assess for tremor and coordination;
ataxia of lower extremities; 
dysdiadochokinesia
Gait
Casual
Toe
Heel
Tandem
Assess for strength and coordination
Reflexes
Biceps
Brachioradialis
Patellar 
Ankle jerk
Assess for upper and lower limb reflexes


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8.3.
Adverse Events and Serious Adverse Events
Investigators are responsible for monitoring the safety of patients 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 patient.
The investigator is responsible for the appropriate medical care of patients 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 patient to discontinue before completing the study.  The 
patient should be followed up 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 ICF and patient assent form are signed, study site personnel will record, via CRF, the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a potential cause-and-effect relationship between 
the investigational product, study device, 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.
8.3.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.


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All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious criteria.  
The SAE reporting to the sponsor begins after the participant has signed the ICF and has 
received the investigational product.  However, if an SAE occurs after signing the ICF, but prior 
to receiving the investigational product, the SAE should be reported to the sponsor according to 
SAE reporting requirements and timelines (see Section 8.3.3) if it is considered reasonably 
possibly related to study procedure.
Study site personnel must alert Lilly 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.  Participants with a serious hepatic AE should have additional data collected using 
the CRF.
Pregnancy (during 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.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the participant disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.
8.3.2. 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 identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the 
identification, recording, and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
8.3.3.
Time Period and Frequency for Collecting AE and SAE 
Information
All AEs and SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the Schedule of Activities (Section 1.3).
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the CRF 
and not on the AE section.
All SAEs will be recorded and reported to the sponsor or designee immediately, and under no 
circumstance should this exceed 24 hours. The investigator will submit any updated SAE data to 
the sponsor within 24 hours of data being available.


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Investigators are not obligated to actively seek AE or SAE data after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.4. Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
8.3.5.
Follow-Up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow up each patient 
at subsequent visits/contacts. All SAEs, and nonserious AEs of special interest (Section 8.3.8),
will be followed up until resolution, stabilization, the event is otherwise explained, or the patient 
is lost to follow-up as defined in Section 7.3.
8.3.6.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator of an SAE to the sponsor is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and investigators.

Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (for example, summary or listing of SAEs) from the sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.7.
Pregnancy
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of lasmiditan dosing and until at least 1 month 
following the last dose of lasmiditan.
To fulfill regulatory requirements, any pregnancy should be reported following the SAE process 
to collect data on the outcome for both mother and fetus.
Abnormal pregnancy outcomes, such as the following, are also considered SAEs:

spontaneous abortion


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
fetal death

stillbirth

congenital anomalies

ectopic pregnancy.
8.3.8.
Safety Topics of Interest
In addition to those identified above, the following safety topics of interest will be monitored:

Cardiovascular safety

Hepatic safety

Neurologic effects, including injuries and accidents secondary to neurologic AEs 

Road traffic accidents

Abuse potential.
8.3.9. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Participants will 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.
8.4.
Treatment of Overdose
This is a single-dose study.  This section is not applicable for this study.
8.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of a 
maximum of 2 mL each will be collected to determine the plasma concentrations of lasmiditan. 
An indwelling catheter is recommended for blood collection on Day 1.  Patients who choose to 
go home after the 12-hour assessments will have the catheter removed prior to leaving the site.
Timing of PK samples collected after lasmiditan dosing was determined by applying a 
D-optimality algorithm to the adult popPK model, which was scaled for pediatric population.  
Patient burden and other factors were also taken into consideration.
One additional sample may be collected at an additional time point 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.


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8.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of lasmiditan will be assayed using a validated liquid chromatography with 
tandem mass spectrometry method.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following the last patient visit for the study.
8.6.
Pharmacodynamics
This section is not applicable for this study.
8.7.
Genetics
This section is not applicable for this study.
8.8.
Biomarkers
This section is not applicable for this study.
8.9.
Health Economics
This section is not applicable for this study.


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9. Statistical Considerations and Data Analysis
9.1.
Statistical Hypotheses
No inferential statistical analyses are planned for this study.
9.2.
Sample Size Determination
Cohort 1
Approximately 13 patients may be enrolled to obtain at least 11 patients with evaluable PK data
for the primary cohort (body weight between 15 kg and 40 kg, inclusive).  Patients who do not 
have evaluable PK data may be replaced.
From the popPK analysis in adults, the interpatient coefficient of variation (CV) was estimated to 
be 43% for Cmax and 39% for AUC.  Assuming the CV of total variability is not larger than 45%, 
11 pediatric patients will provide at least 80% coverage probability that the 95% confidence 
intervals (CIs) for the geometric mean of these key PK parameters will be within 70% and 140%.  
The CV for apparent total body clearance and apparent central volume of distribution are similar
to those of Cmax and AUC and, therefore, the precision of estimates for these parameters are 
expected to be sufficient (Wang et al. 2012).
Cohort 2
Approximately 8 patients may be enrolled to obtain at least 6 patients with evaluable PK data for 
the secondary cohort (body weight >40 kg and ≤55 kg). This sample size is customary for Phase 
1 studies evaluating PK, safety, and tolerability, and is not powered on the basis of statistical 
hypothesis testing.
Efforts will be made to enroll male and female patients of varying body weights across the 
weight range defined for the primary and secondary cohorts.
9.3.
Populations for Analyses
9.3.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study.
9.3.2. Patient Characteristics
For each cohort, age, sex, weight, height, body mass index, race, and other patient demographic 
characteristics will be summarized using descriptive statistics.
Patient characteristics may be summarized by region (Japanese vs. non-Japanese), if appropriate.
9.4.
Statistical Analyses
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Pharmacokinetic analyses will be conducted on data from all patients who receive a dose of the 
investigational product and have evaluable PK data.


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Safety analyses will be conducted for all enrolled patients who receive a dose of the 
investigational product, whether or not they completed all protocol requirements.
Data analyses will be presented by body weight category, age, body surface area, and glomerular 
filtration rate.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
9.4.1. Safety Analyses
Safety analyses will be conducted based on safety data obtained from the screening, PK/safety 
assessment, and follow-up/early discontinuation phases of the study.
9.4.1.1.
Clinical Evaluation of Safety
All investigational product and protocol procedure-related AEs will be listed, and if the 
frequency of events allows, safety data will be summarized using descriptive methodology.
Adverse events will be classified by the most suitable term from the most current Medical 
Dictionary for Regulatory Activities (MedDRA) version.
The incidence of TEAEs will be presented by severity and by association with investigational 
product as perceived by the investigator.  AEs reported to occur prior to enrollment will be 
distinguished from those reported as new or increased in severity during the study.
All SAEs will be reported and classified by the most suitable term from the most current 
MedDRA version.
9.4.1.2.
Statistical Evaluation of Safety
Safety parameters for analysis will be:

AEs (including clinically significant ECGs)

clinical laboratory parameters

vital signs

C-SSRS assessments

Cogstate Pediatric Brief Battery parameters.
The parameters will be listed, and summarized using standard descriptive statistics.  Additional 
analysis will be performed if warranted upon review of the data.
Safety parameters may be summarized by region (Japanese vs. non-Japanese), if appropriate.
9.4.2. Pharmacokinetic Analyses
9.4.2.1.
Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for lasmiditan will be calculated by standard 
noncompartmental methods of analysis from plasma lasmiditan concentrations, and listed and 
summarized using descriptive statistics.


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The primary parameters for analysis will be Cmax, tmax, and AUC of lasmiditan.
Other noncompartmental parameters, such as half-life, apparent clearance, and apparent volume 
of distribution may be reported.
In addition to estimates of geometric means, the corresponding 95% CIs will also be determined.
Pharmacokinetic parameters may be summarized by region (Japanese vs. non-Japanese) if 
appropriate.
Additional analysis will be performed if warranted upon review of the data.
9.4.3. Data Review during the Study
Safety and PK data will be reviewed on an ongoing basis.  Doses may be adjusted when data are 
available from at least 3 patients with evaluable PK data in the primary cohort.  The purpose of 
the review is to assess safety/tolerability, evaluate PK data, and inform the dosing of subsequent 
patients.  The investigator and the Lilly sponsor team will make the determination regarding 
dosing, based on their review of the safety and PK data.  If lasmiditan plasma concentrations are 
unexpected relative to PK predictions, then the dose may be adjusted.  Additional reviews may 
be performed, as deemed appropriate.
9.5.
Interim Analyses
Because all patients in a cohort receive the same treatment, review of nonfinal data is not 
considered an interim analysis.  Therefore, there will be no interim analyses in this study.
9.6.
Data Monitoring Committee
An external data monitoring committee (DMC) will be used for this study. The DMC will 
review safety data on an ongoing basis concurrent with team and investigator reviews.


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10.
Supporting Documentation and Operational 
Considerations
10.1. Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical 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 International Council for Harmonisation (ICH) GCP Guidelines
3. applicable laws and regulations.
Some of the obligations of the sponsor will be assigned to a third party organization.
Ethical Review
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by ICH guidelines and other 
applicable laws and regulations.
Documentation of ERB approval of the protocol, the ICF, and Assent Form must be provided to 
Lilly before the study may begin at the investigative sites.  Lilly or its representatives must 
approve the ICF before it is used at the investigative sites.  All ICFs must be compliant with the 
ICH guideline on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF and Assent Form

relevant curricula vitae.
10.1.2. Informed Consent
The investigator is responsible for:

ensuring that the patient or patient’s legal representative 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 patient 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.


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
answering any questions the patient or patient’s legal representative may have 
throughout the study and sharing in a timely manner any new information that may be 
relevant to the patient’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.
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
10.1.3. Data Protection

Participants will be assigned a unique identifier by the investigator. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information that would make the participant identifiable will 
not be transferred.

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, appropriate IRB/IEC members, and inspectors from regulatory authorities.
10.1.4. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
10.1.5. Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the final report coordinating investigator.
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.
10.1.6. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:


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
provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, or fax

review and verify data reported to detect potential errors.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives 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 Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, electronic Clinical Outcome Assessment (eCOA) data, such as the cognition 
assessment, will be directly recorded by the patient into a computer.  The eCOA data will serve 
as the source documentation and the investigator does not maintain a separate, written, or 
electronic record of these data.
Data collected via the sponsor-provided data capture system(s) will be stored at third parties.  
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.


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Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.
The purpose and use of patient personal information collected will be provided in a written 
document to the patient by the sponsor.
10.1.7. Study and Site Closure
10.1.7.1. 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.
10.1.7.2. 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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11.
References
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition DSM-5®. CBS Publishers and Distributors, 2017.
Bredlau AL, Harel BT, McDermott MP, Dworkin RH, Korones DN, Dolan JG, Adams HR. 
Neurocognitive changes after sustained ketamine administration in children with chronic pain. 
J Palliat Care Med. 2015;5(2): doi:10.4172/2165-7386.1000215.
Evers S, Rahmann A, Kraemer C, Kurlemann G, Debus O, Husstedt IW, Frese A. Treatment of 
childhood migraine attacks with oral zolmitriptan and ibuprofen. Neurology. 
2006;67(3):497-499.
Fernandes R, Ferreira JJ, Sampaio C. The placebo response in studies of acute migraine. J 
Pediatr. 2008;152(4):527-533.
International Headache Society. The International Classification of Headache Disorders, 3rd 
edition. Cephalalgia. 2018;38(1):1-211. Available at: https://www.ichd-3.org/wp-
content/uploads/2018/01/The-International-Classification-of-Headache-Disorders-3rd-Edition-
2018.pdf.
Kato N, Takimoto H, Yokoyama T, Yokoya S, Tanaka T, Tada H. Updated Japanese growth 
references for infants and preschool children, based on historical, ethnic and environmental 
characteristics. Acta Paediatr. 2014;103(6):e251–e261.
Maruff P, Thomas E, Cysique L, Brew B, Collie A, Snyder P, Pietrzak RH. Validity of CogState 
Brief Battery: relationship to standardized tests and sensitivity to cognitive impairment in mild 
traumatic brain injury, schizophrenia, and AIDS dementia complex. Arch Clin Neuropsychol. 
2009;24(2):165-178.
Mollica CM, Maruff P, Collie A, Vance A. Repeated assessment of cognition in children and the 
measurement of performance change. Child Neuropsychol. 2005;11(3):303-310.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277.
Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample 
size when designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2012;52(10):1601-
1606.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
assent
Agreement from a child or other individual who is not legally capable of providing consent, 
but who can understand the circumstances and potential risks involved in participating in a 
study (required by some institutional review boards [IRBs]/ethical review boards [ERBs]).
AST
aspartate aminotransferase
AUC
area under the concentration-versus-time curve
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
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.
CRF
case report form
CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist 
(CRS), global safety physician, or other medical officer.
CRU
Clinical Research Unit
C-SSRS
Columbia-Suicide Severity Rating Scale


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CV
coefficient of variation
eCOA
electronic Clinical Outcome Assessment
eCRF
electronic case report form
EDC
electronic data capture
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
informed consent
A process by which a patient 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 patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IRB
institutional review board
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
MedDRA
Medical Dictionary for Regulatory Activities
open label
A study in which there are no restrictions on knowledge of treatment allocation; therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PK
pharmacokinetic(s)


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popPK
population pharmacokinetic
randomize
the process of assigning patients to an experimental group on a random basis
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.
SUSAR
suspected unexpected serious adverse reaction
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 to reach maximum observed drug concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC) 
Magnesium
Platelets
Glucose (random)
Absolute counts of:
Blood urea nitrogen (BUN)
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Direct bilirubin
Basophils
Total protein
Alkaline phosphatase (ALP)
Urinalysisa
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Uric acid
Protein
Estimated glomerular filtration rate (eGFR)b
Glucose
Creatinine
Ketones
Bilirubin
Urobilinogen
Blood
Other Tests
Nitrite
Urine drug screena
Leukocyte esterasec
Urine pregnancy testd
Urine culturec
Serum pregnancy testa
Microsopic analysisc
Gonadal hormonea (estradiol for females, and 
testosterone for males)
Abbreviations:  RBC = red blood cell; WBC = white blood cell.
a
Assayed by sponsor-designated laboratory.
b
GFR calculated by Bedside Schwartz 2009 formula or the Japanese Society for Pediatric Nephrology formula for 
patients in Japan.
c
A positive urine leukocyte esterase result will require a follow-up sample with microscopic analysis and possibly
a urine culture.
d
Performed locally.
Note:  Additional tests may be performed at the discretion of the investigator as needed.


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This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.
Protocol H8H-MC-LAHX Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Maximum Number of Blood 
Samples
Total Volume 
(mL)
Hematologya
2
3
6
Chemistrya
2.5
3
7.5
Gonadal hormones
3.5
1
3.5
Serum pregnancy testa,b
0
1
0
Pharmacokinetics
2
9
18
Blood discard for cannula 
patency
1
9
9
Total
44
Total for clinical purposes rounded up to nearest 10 mL
50
Hepatic monitoringc
3-30 
a
Additional samples may be drawn if needed for safety purposes.
b
Sample volume included with chemistry or gonadal hormones test volume.
c
Unscheduled hepatic monitoring testing may be performed as part of patient follow-up, based on laboratory 
safety values and in consultation with Lilly CRP/CRS.


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Appendix 3.
Liver Safety:  Suggested Actions and 
Follow-Up Assessments
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly Medical or its designee.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or central laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


Leo Document ID = d443c63b-d4f7-4e9e-841a-ea05c0a724fe
Approver: 
Approval Date & Time: 28-Mar-2019 18:18:07 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 29-Mar-2019 02:36:10 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan: H8H-MC-LAHX(V2)
A Phase 1, Open-Label, Single-Dose Pharmacokinetic Study of Lasmiditan in Pediatric Patients 
with Migraine
NCT03988088   
Approval Date: 15-Jul-2019


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1.
Statistical Analysis Plan:  
H8H-MC-LAHX:  A Phase 1, Open-Label, Single-dose 
Pharmacokinetic Study of Lasmiditan in Pediatric 
Patients with Migraine
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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 patient to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Lasmiditan (LY573144)
Indication:  Acute treatment of migraine in pediatric patients
Study H8H-MC-LAHX is a Phase 1, open-label, single-dose, pharmacokinetic (PK) and 
tolerability study of lasmiditan in pediatric patients with a diagnosis of migraine.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol H8H-MC-LAHX
Phase 1
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 15-Jul-2019 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   H8H-MC-LAHX:  A Phase 1, Open-
Label, Single-dose Pharmacokinetic Study of Lasmiditan in Pediatric 
Patients with Migraine ........................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
5.
Study Design.......................................................................................................................8
5.1.
Summary of Study Design..............................................................................................8
5.2.
Determination of Sample Size ........................................................................................8
5.3.
Method of Assignment to Treatment ..............................................................................9
6.
A Priori Statistical Methods ..............................................................................................10
6.1.
General Considerations ................................................................................................10
6.2.
Handling of Dropouts or Missing Data.........................................................................11
6.3.
Extent of Exposure.......................................................................................................11
6.4.
Patient Disposition .......................................................................................................11
6.5.
Patient Characteristics ..................................................................................................11
6.5.1.
Demographics......................................................................................................11
6.6.
Pharmacokinetic Assessment........................................................................................12
6.6.1.
Pharmacokinetic Analysis ....................................................................................12
6.6.2.
Pharmacokinetic Statistical Methodology.............................................................16
6.7.
Safety and Tolerability Assessments ............................................................................16
6.7.1.
Adverse Events ....................................................................................................16
6.7.2.
Concomitant Therapy...........................................................................................17
6.7.3.
Prior Migraine Therapy........................................................................................17
6.7.4.
Clinical Laboratory Evaluation.............................................................................17
6.7.4.1.
Clinical Laboratory Parameters.......................................................................17
6.7.4.2.
Hepatic Monitoring ........................................................................................17
6.7.5.
Vital Signs ...........................................................................................................19
6.7.6.
Electrocardiograms ..............................................................................................21
6.7.7.
Cognition.............................................................................................................21
6.7.8.
Safety Topics of Interest.......................................................................................22
6.7.8.1.
Evaluation of Cardiovascular Safety...............................................................22
6.7.8.2.
Evaluation of Hepatic Safety ..........................................................................23
6.7.8.3.
Evaluation of Injuries and Accidents Secondary to 
Neurologic Adverse Events ............................................................................23


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6.7.8.4.
Road Traffic Accidents...................................................................................23
6.7.8.5.
Drug Abuse Liability Evaluation ....................................................................23
6.7.8.6.
Suicide-Related Thoughts and Behaviors........................................................24
6.7.8.7.
Potential Hypersensitivity Reactions...............................................................25
6.7.9.
Other Assessments...............................................................................................25
6.7.10.
Safety and Tolerability Statistical Methodology ...................................................25
6.8.
Interim Analyses and Data Monitoring.........................................................................25
6.9.
Changes from the Protocol Specified Statistical Analyses.............................................25
6.10. Reports to be Generated ...............................................................................................25
6.11. Clinical Trial Registry Analyses...................................................................................25
7.
References ........................................................................................................................27
8.
Appendices .......................................................................................................................29


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Table of Contents
Table
Page
Table LAHX.4.1.Objectives and Endpoints ................................................................................7
Table LAHX.5.1.Planned Treatment Regimen............................................................................9
Table LAHX.6.1.Criteria for Categorical Shifts in Vital Signs..................................................20


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Table of Contents
Appendix
Page
Appendix 1.
Cogstate Normative Population Standard Deviation and Test-Retest 
Reliability Values ..........................................................................................30
Appendix 2.
Lilly Search Category of Additional Potential Abuse Liability Terms............32
Appendix 3.
Onset/Duration of Plots (Mock Plots) ............................................................38


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3.
Revision History
SAP Version 1 was approved prior to the first visit when a patient receives study drug.  
SAP Version 2 was approved prior to the first visit when a patient receives study drug.
Changes in Version 2 include: 

Removal of analyses for orthostatic pulse (Section 6.7.5).

Addition of normative population standard deviation and test-reliability values for 
Cogstate reliable change index, and corresponding references (Section 6.7.7, Appendix 1, 
References).

Addition of potential hypersensitivity reactions as a safety topic of interest 
(Section 6.7.8.7).


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4.
Study Objectives
Table LAHX.4.1 shows the objectives and endpoints of the study.  
Table LAHX.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the single-dose pharmacokinetics of 
lasmiditan in pediatric migraine patients
Pharmacokinetic parameters including:

Maximum observed drug concentration (Cmax)

Time to reach Cmax (tmax)

Area under the concentration-versus-time curve (AUC) 
from time zero to infinity (AUC[0-])

AUC from time zero to the time t, where t is the last 
time point with measurable concentration (AUC[0-tlast])
Secondary
To assess the safety and tolerability of a single dose 
of lasmiditan in pediatric migraine patients
Summary of: 

SAEs

AEs

ECG

Vital signs
Exploratory
To assess the safety, tolerability, and 
pharmacokinetics of lasmiditan in Japanese 
pediatric migraine patients
Pharmacokinetic parameters including:

Cmax

tmax

AUC[0-]

AUC[0-tlast]
Summary of adverse events, SAEs, ECG, and vital signs.
Abbreviations:  AE = adverse event; ECG = electrocardiogram; SAE = serious adverse event.


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5.
Study Design 
5.1.
Summary of Study Design
This is a Phase 1, multi-center, open-label, single dose study to determine the pharmacokinetic 
(PK), safety, and tolerability of lasmiditan in pediatric patients with a diagnosis of migraine.  
Two cohorts will be evaluated:  

Primary Cohort 1:  15 kg to ≤40 kg

Secondary Cohort 2:  >40 kg to ≤55 kg
The planned doses for Cohorts 1 and 2 are 100 mg and 200 mg, respectively.
Study Period I (Screening)
All patients are screened to determine if they are eligible to participate in the study.
Screening will occur 28 days to 3 days prior to lasmiditan dosing.  
Study Period II (PK Assessment/Safety)
Enrolled patients and the patient’s parent or guardian will receive instructions regarding study 
procedures prior to dosing, including fasting requirements. 
Day 1:

Patients arrive at the Clinical Research Unit (CRU) for assessments prior to dosing.  

Patients receive the single lasmiditan dose.

Patients can go home after the 12-hour assessments.  Patients may be offered the 
opportunity to spend the night depending on CRU capabilities.
Day 2:

Patient assessments are done at the CRU approximately 24 hours after dosing.
Study Period III (Follow-Up Period)
Patients return to the CRU for a follow-up visit approximately 14 days after dosing.
5.2.
Determination of Sample Size
For the primary cohort (body weight between 15 and ≤40 kg, inclusive), approximately 
13 patients may be enrolled to obtain at least 11 patients with evaluable PK data.  Patients who 
do not have evaluable PK data may be replaced.
From the population PK analysis in adults, the inter-patient coefficient of variation was estimated 
to be 43% for Cmax and 39% for AUC.  Assuming the coefficient of variation of total variability 
is not larger than 45%, 11 pediatric patients will provide at least 80% coverage probability that 
the 95% confidence interval (CI) for the geometric mean of these key PK parameters will be 
within 70% and 140%.  The coefficient of variation for apparent total body clearance and 


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apparent central volume of distribution are similar and, therefore, the precision of estimates for 
these parameters are expected to be sufficient.
Moreover, approximately 8 patients (body weight >40 kg and ≤55 kg) in the secondary cohort 
may be enrolled to obtain at least 6 patients with evaluable PK data.  This sample size is
customary for Phase 1 studies evaluating PK, safety, and tolerability, and is not powered on the 
basis of statistical hypothesis testing.
Efforts will be made to enroll female and male patients of varying body weights across the 
weight range defined for the primary and secondary cohorts.
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment at Visit 2 will receive an open label dose of lasmiditan 
200 mg or lasmiditan 100 mg, according to their body weight, as shown in Table LAHX.5.1
below.
Table LAHX.5.1.
Planned Treatment Regimen
Cohort
1
2
Participant Body Weight 
15 kg to ≤40 kg 
>40 kg to ≤55kg
Treatment Name
Lasmiditan
lasmiditan
Dosage Formulation
Tablet
Tablet
Unit dose strength(s)/Dosage 
Level(s)
50 mg x2 or
100 mg x1
50 mg x4 or
100 mg x2
Route of Administration
Oral
Oral
Dosing instructions
With approximately 240 mL of room temperature water in a sitting position


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6.
A Priori Statistical Methods
6.1.
General Considerations
Data listings will be provided for all data that is databased, and will be presented by cohort.  
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, minimum, maximum and number of patients that provided data 
(N).  For log-normal data (eg, the PK parameters:  AUCs and Cmax), the geometric mean and the 
corresponding 95% CI, and geometric CV% will also be presented.  For categorical data, 
frequency count and percentages will be presented.  Data listings will be provided for all patients 
up to their last collected measurement, and will highlight patients who discontinue from the 
study before follow-up. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Change from baseline values will be calculated for laboratory data, vital signs data, and Cogstate 
Pediatric Brief Battery data.  Each individual change from baseline will be calculated by 
subtracting the individual patient’s baseline value from the value at the timepoint. Mean change 
from baseline is the mean of all individual patients’ change from baseline values.  The individual 
patients’ change from baseline values will be used to calculate the mean change from baseline 
using a SAS procedure such as Proc Univariate.  
Individual derived parameters (eg, PK parameters) and appropriate summary statistics will be 
reported to 3 significant figures.  Observed concentration data, eg, Cmax, should be reported as 
received.  Observed time data, eg, tmax, should be reported as received.  Observed safety data 
should be reported as received.  Counts should be reported as whole numbers and percentage 
values should be reported to 1 decimal place.  Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
Pharmacokinetic analyses will be conducted on data from all patients who receive a dose of the 
investigational product and have evaluable PK data.  Patients may be excluded from the PK 
summary statistics and statistical analysis if a patient has an adverse event (AE) of vomiting that 
occurs at or before 2 times median time of maximum observed drug concentration (tmax).
Safety analyses will be conducted for all enrolled patients who receive a dose of the 
investigational product, whether or not they completed all protocol requirements.
Pharmacokinetic data analyses will be presented by:

body weight category (15 kg to ≤40 kg, >40 kg to ≤55 kg)

age category (6 to <12 years of age, 12 to <18 years of age)

body surface area (0.65 m2 to ≤1.3 m2, >1.3 m2 to ≤1.6 m2)

glomerular filtration rate (<75 mL/min/1.73 m2, ≥75 mL/min/1.73 m2)

region (Japan, US), if appropriate


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Safety data analyses will be presented by body weight category or age category, as appropriate.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when PK and safety analyses are conducted.
Data analysis will be performed using SAS® Version 9.4 or greater.
6.2.
Handling of Dropouts or Missing Data
Missing data will not be displayed in listings.
Some of the tables, figures, and listings (TFLs) may not have sufficient numbers of patients or 
data for presentation.  If this occurs, the blank TFL shell will be presented with a message 
printed in the center of the table, such as, “No serious adverse events occurred for this study”.
6.3.
Extent of Exposure
Dosing details for each patient will be displayed in a listing.
6.4.
Patient Disposition
Patient disposition will be displayed in a listing.  
6.5.
Patient Characteristics
6.5.1. Demographics
The following patient characteristics at screening will be summarized for all enrolled patients 
who receive a dose of the investigational product, and presented by body weight category and
age category:

Age (continuous variable)

Sex (Male, Female)

Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, Caucasian, Multiple, Other)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Height (cm) (continuous variable)

Weight (kg) (continuous variable)

Average number of attacks per month in the last 2 months (continuous variable)

Body mass index (BMI) (weight (kg) / [height (m)]
2) (continuous variable)

Body surface area (0.65 m2 to ≤1.2 m2, >1.2 m2 to ≤1.6 m2) (Sharkey et al. 2001)

Glomerular filtration rate (<75 mL/min/1.73 m2, ≥75 mL/min/1.73 m2) (Pottel et al. 
2015)

Menstrual status for female patients (Pre-menarchal, Menarchal)

Pubertal status (Prepubertal, Pubertal)
Age will be calculated using the difference in days between the date of birth and the date of 
informed consent.


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Body surface area (m2) will be calculated as:  0.03330 ∗ܹ൫଴.଺ଵହ଻ି଴.଴ଵ଼଼௟௢௚భబሺௐሻ൯∗ܪ଴.ଷ, where 
ܹ is weight (kg) and ܪ is height (cm) (Boyd 1935). 
Height will be measured in triplicate and the mean value will be recorded. 
Glomerular filtration rate will be calculated using the Bedside Schwartz formula:  0.413 x 
(height [cm] /serum creatinine [mg/dL]) (Schwartz et al. 2009).   
All demographic data will be presented in a listing.  For Japanese patients, glomerular filtration 
rates in this listing will be calculated using both the Bedside Schwartz formula and the Japanese 
Society for Pediatric Nephrology formula:  110.2*(reference serum creatinine [mg/dL]/patient 
serum creatinine [mg/dL]) + 2.93 (Uemura 2015). 
6.6. Pharmacokinetic Assessment 
6.6.1. Pharmacokinetic Analysis 
Pharmacokinetic parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 6.4 or later).  Pharmacokinetic analysis 
using a compartmental modeling approach will be described in a separate PK/pharmacodynamic 
analysis plan document. 
Plasma concentrations of lasmiditan will be used to determine the following PK parameters, 
when possible:   


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Parameter
Units
Definition
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the clinical study report. Any exceptions or special 
handling of data will be clearly documented within the final study report.
Formatting of tables, figures, and abbreviations will follow the Eli Lilly and Company (Lilly) 
Global PK/PD/TS Tool:  NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE.  
The version of the tool effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.  For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than 1 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 
3 consecutive plasma concentrations above the lower limit of quantification, with at least 
1 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.


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
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 patient 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 concentration at last quantifiable timepoint 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 patient or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

In addition, where 2 or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.


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


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times as necessary, excluding only 1 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.
6.6.2. Pharmacokinetic Statistical Methodology
Pharmacokinetic parameter estimates will be listed and summarized using descriptive statistics, 
which will be presented separately by body weight category, age category, body surface area, 
glomerular filtration rate, and region (if applicable).
For log-normal data (eg, the PK parameters:  AUCs and Cmax), the geometric mean and the 
corresponding 95% CI, and geometric CV% will also be presented.
Additional analysis may be performed if warranted upon review of the data.
6.7.
Safety and Tolerability Assessments
6.7.1. 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 patient has provided 
written informed consent and is ongoing at consent.  A treatment-emergent AE (TEAE) is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose. A non-treatment emergent AE (non-TEAE) is defined as an AE which starts 
after informed consent but prior to dosing.  
All AEs occurring on or after the date of informed consent form signing, discontinuations due to 
AEs, pre-existing conditions and medical history, serious AEs, and serious TEAEs will be listed.  
The number and percentage of patients who report TEAEs will be summarized using preferred 
terms (PTs) from the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA), where PTs will be nested within system organ class (SOC).  System organ classes 
will be listed alphabetically and PTs within each SOC will be listed by decreasing frequency in 
the total population.  The number and percentage of patients who report TEAEs will also be 
summarized using MedDRA PTs listed by decreasing frequency in the total population.
The number and percentage of patients with TEAEs by maximum severity will be summarized 
using MedDRA PTs listed by decreasing frequency in the total population.  For each patient and 
TEAE, the maximum severity for the MedDRA PT is the maximum post-baseline severity 
observed from all associated lower level terms mapping to the MedDRA PT.  The maximum 
severity will be determined based on the non-missing severities.  If all severities are missing for 
the defined postbaseline period of interest, it will show as missing in the table.


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The number and percentage of patients with TEAEs that are related to study drug will be 
summarized using MedDRA PTs listed by decreasing frequency in the total population.  Related 
TEAEs are those that are recorded on the AE CRF page as related to study treatment or those 
with a missing relationship.  
For events that are gender-specific, the denominator and computation of the percentage will 
include only patients from the specific gender.
Descriptive statistics will be presented separately by body weight category and age category.
6.7.2. Concomitant Therapy
Concomitant medications taken during the study will be coded using the most current version of 
the World Health Organization drug dictionary.  All concomitant medications will be listed.
6.7.3. Prior Migraine Therapy
All migraine therapies that patients have stopped taking prior to the date of informed consent 
signing will be provided in a listing.
6.7.4. Clinical Laboratory Evaluation
6.7.4.1.
Clinical Laboratory Parameters
All clinical chemistry, hematology, and urinalysis data will be summarized by parameter, and 
listed.  Values for any clinical chemistry, hematology, and urinalysis that are outside the 
reference ranges will be flagged as high or low on the individual patient data listings.
Change from baseline will be summarized for all lab parameters measured at 24 hours postdose, 
where baseline is defined as the predose measurement for all laboratory parameters.
6.7.4.2.
Hepatic Monitoring
Patients with the following elevations in hepatic laboratory tests at 24 hours postdose will be
listed:

Patients with an alanine aminotransferase (ALT) measurement greater than or 
equal to 3X, 5X, and 10X the performing laboratory upper limit of normal (ULN)
at 24 hours postdose will be listed by the following subsets based on various 
levels of baseline value.  
o
The analysis of 3X ULN will contain 4 subsets:  

patients whose non-missing baseline ALT value is less than or 
equal to 1X ULN 

patients whose baseline ALT value is greater than 1X ULN but 
less than 3X ULN 

patients whose baseline ALT value is greater than or equal 3X 
ULN 

patients whose baseline ALT values are missing  


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o
The analysis of 5X ULN will contain 5 subsets:  

patients whose non-missing baseline ALT value is less than or 
equal to 1X ULN 

patients whose baseline ALT value is greater than 1X ULN but 
less than 3X ULN 

patients whose baseline ALT value is greater than or equal to 3X 
ULN but less than 5X ULN 

patients whose baseline ALT value is greater than or equal to 5X 
ULN 

patients whose baseline ALT values are missing
o
The analysis of 10X ULN will contain 6 subsets:  

patients whose non-missing baseline ALT value is less than or 
equal to 1X ULN

patients whose baseline ALT value is greater than 1X ULN but 
less than 3X ULN

patients whose baseline ALT value is greater than or equal to 3X 
ULN but less than 5X ULN

patients whose baseline ALT value is greater than or equal to 5X 
ULN but less than 10X ULN

patients whose baseline ALT value is greater than or equal to 10X 
ULN

patients whose baseline ALT values are missing

Patients with an aspartate aminotransferase (AST) measurement greater than or 
equal to 3X, 5X, and 10X the performing lab ULN at 24 hours post-dose will be 
listed by subsets based on various levels of baseline value, as described above for 
ALT.

Patients with an alkaline phosphatase (ALP) measurement greater than or equal to 
2X the performing lab ULN at 24 hours post-dose will be listed by the following 
subsets based on various levels of baseline.
o
The analysis of 2X ULN will contain 4 subsets:  

patients whose non-missing baseline ALP value is less than or 
equal to 1X ULN 

patients whose baseline ALP value is greater than 1X ULN but less 
than 1.5X ULN 

patients whose baseline ALP value is greater than or equal to 1.5X 
ULN 


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
patients whose baseline ALP values are missing  

Patients with a total bilirubin (TBIL) measurement greater than or equal to 2X the 
performing lab ULN at 24 hours postdose will be listed by the following subsets 
based on various levels of baseline:  
o
patients whose non-missing baseline TBIL value is less than or equal to 
1X ULN
o
patients whose baseline TBIL value is greater than 1X ULN but less than 
2X ULN
o
patients whose baseline TBIL value is greater than or equal to 2X ULN
o
patients whose baseline TBIL values are missing
Baseline is defined as the predose measurement for all hepatic laboratory parameters.
6.7.5. Vital Signs
Where supine blood pressure is measured in triplicate, the mean value will be calculated and 
used in all subsequent calculations.  When triplicate blood pressure measurements precede a 
standing measurement, the last supine blood pressure measurement will be used for orthostatic 
calculations.  Orthostatic values will be calculated as the standing value minus the last supine 
value taken prior to the standing value.
Vital signs data for individual patients will be listed by time point.  Vital signs data will also be 
summarized at each time point by body weight category and age category, together with changes 
from baseline for supine vital signs.  For supine vital signs, baseline is defined as the mean of the 
triplicate measurement taken at predose.  Figures of mean vital signs and mean changes from 
baseline profiles will be presented by cohort and region over time.  
Counts and percentages of patients displaying categorical shifts (as given by the criteria in
Table LAHX.6.1) will be summarized by body weight category.  Table LAHX.6.1. displays the 
Lilly-defined criteria for categorical shifts for supine blood pressure, pulse, and orthostatic blood 
pressure.  The last column of the table displays the patient populations defined by baseline 
categories.


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Table LAHX.6.1.
Criteria for Categorical Shifts in Vital Signs
Parameter
Age 
Group
Direction
Criteria
Patient Population 
defined by Baseline 
Categories
Systolic BP (mm 
Hg) (supine)
6-9
Low
≤80 and decrease ≥15
>80
High
≥122 and increase ≥15
<122
10-11
Low
High
≤85 and decrease ≥20
≥126 and increase ≥20
>85
<126
12-14
Low
High
≤90 and decrease ≥20
≥136 and increase ≥20
>90
<136
15-17
Low
High
≤90 and decrease ≥20
≥140 and increase ≥20
>90
<140
Diastolic BP (mm 
Hg) (supine)
6-9
Low
≤45 and decrease ≥10
>45
High
≥78 and increase ≥10
<78
10-11
Low
High
≤50 and decrease ≥10
≥82 and increase ≥10
>50
<82
12-14
Low
High
≤50 and decrease ≥10
≥86 and increase ≥10
>50
<86
15-17
Low
High
≤50 and decrease ≥10
≥90 and increase ≥10
>50
<90
Pulse (bpm)
(supine)
6-9
Low
<60 and decrease ≥25
60
High
>150 and increase ≥25
150
10-11
Low
High
<60 and decrease ≥25
>140 and increase ≥25
60
140
12-14
Low
High
<50 and decrease ≥15
>120 and increase ≥15
50
120
15-17
Low
High
<50 and decrease ≥15
>100 and increase ≥15
50
100
Systolic BP (mm 
Hg)
(orthostatic)
All
Decrease
Decrease ≥20
All patients
Diastolic BP (mm 
Hg) (orthostatic)
All
Decrease
Decrease ≥10
All patients
Abbreviations:  BP = blood pressure; bpm = beats per minute; mm Hg = millimeters of mercury.  
Note:  “all patients” include all safety analysis patients with both a non-missing baseline (predose) measure and at 
least 1 non-missing postbaseline measure.
Beasley and Moscarelli 2015. 
The criteria consist of 2 parts, an absolute threshold and a change from baseline (predose)
amount. 

The absolute threshold in the criteria is based on: 1) minimum postbaseline when 
the direction is low; 2) maximum postbaseline when the direction is high. 

The change from baseline amount in the criteria is: 1) decrease from non-missing 
baseline to minimum postbaseline when the direction is low; 2) increase from 
non-missing baseline to maximum post baseline when the direction is high. 


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6.7.6. Electrocardiograms 
Any clinically significant electrocardiogram (ECG) finding that results in a diagnosis and that 
occurs after the patient receives lasmiditan will be reported as an AE.  
Counts and percentages displaying shifts from normal, abnormal (not clinically significant), or 
abnormal (clinically significant) at baseline (predose) to normal, abnormal (not clinically 
significant), or abnormal (clinically significant) at 24 hours postdose will be summarized.  
Baseline is defined as ECG findings taken at predose. 
Descriptive statistics will be presented separately by body weight category and age category.  
6.7.7. Cognition 
Data for the following Cogstate Pediatric Brief Battery parameters will be listed by time point: 
 Detection Test score:  mean of the log10 transformed reaction times for correct responses 
 Identification Test score:  mean of the log10 transformed reaction times for correct 
responses 
 One Back Test score:  mean of the log10 transformed reaction times for correct responses 
 One Card Learning Test score:  arcsine transformation of the square root of the 
proportion of correct responses 
For each test score, listings will also include change from baseline (predose) and the reliable 
change index (RCI) score at each post-dose time point, which will be computed as follows: 
ܴܥܫൌ ݏܿ݋ݎ݁௣௢௦௧െ ݏܿ݋ݎ݁௕௔௦௘௟௜௡௘
ݏ௡௢௥௠ඥ2ሺ1 െݎሻ
ൈܯݑ݈ݐ݅݌݈݅ܿܽ݊݀  
where: 
o ݏܿ݋ݎ݁௣௢௦௧ = patient’s score at the given post-dose time point 
o ݏܿ݋ݎ݁௣௢௦௧ = patient’s score at baseline 
o ݏ௡௢௥௠ = population standard deviation from age-matched normative data 
o ݎ = normative test-retest reliability 
 
o ܯݑ݈ݐ݅݌݈݅ܿܽ݊݀ = -1 for the Detection, Identification, and One Back tests 
= +1 for the One Card Learning test 
 
The number and percent of patients with at least 2 RCI scores less than or equal to -1.65 will be 
reported and summarized by age category at each postdose time point (Ingraham and Aiken 
1996; Louey et al. 2014).  Age-specific normative ݏ௡௢௥௠ and ݎ values for each test are provided 
in Appendix 1 (Cromer et al. 2015; Hammers et al. 2012; Mollica et al. 2005; Rosenfeld et al. 
2018; Yoshida et al. 2011). 
 
Descriptive statistics for the Detection, Identification, One Back, and One Card Learning test 
scores, together with changes from baseline, will be presented by age category at each time 
point.  For each test score, the Cohen’s d effect size measure (Cohen 1988) will also be 
computed at each postdose time point as follows: 


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݀ൌ݉݁ܽ݊௖௛௔௡௚௘,௖௔௧,ଵെ ݉݁ܽ݊௖௛௔௡௚௘,௖௔௧,ଶ
ݏ௖௛௔௡௚௘
 
where: 
 ݉݁ܽ݊௖௛௔௡௚௘,௖௔௧,௜ = mean change from baseline for the ݅௧௛ age category (i = 1 → 6 to <12 
years of age; i = 2 → 12 to <18 years of age) 
 ݏ௖௛௔௡௚௘ൌ standard deviation of change from baseline values, pooled across the 2 age 
categories 
6.7.8. Safety Topics of Interest 
This section includes areas of interest whether due to observed safety findings, potential findings 
based on drug class, or requested by a regulatory agency for any reason.   
Standardized MedDRA Queries (SMQs) are groupings of terms from 1 or more MedDRA SOCs 
that relate to a defined medical condition or area of interest.  When an SMQ is specified, the 
resulting tabular display will include counts and percentages by treatment group at the SMQ 
level and at the PT level within the SMQ.  When an SMQ involves both narrow and broad terms, 
the summaries will occur at the SMQ level, then the narrow/broad level, and subsequently the PT 
level within the SMQ. 
6.7.8.1. Evaluation of Cardiovascular Safety 
Definitions of Lilly Search Categories (LSCs) for cardiovascular (CV) events: 
1. Potential CV AEs:  all PTs (for TEAEs and AEs) in the SMQs listed below plus 
PTs of abdominal pain, abdominal pain upper, and abdominal pain lower.   
2. Likely CV AEs:  a subset of the potential CV AEs.  All clinical information from 
patients who reported the PT events identified from the search described above 
for potential CV AEs will undergo medical review and medical judgment will be 
applied to determine if the AE (for each patient) was likely CV in nature.  If so, it 
will be defined as a likely CV AE.   
SMQs: 
 broad and narrow terms in cardiac arrhythmias (includes sub SMQs) (SMQ 
20000049) 
 broad and narrow terms in cardiac failure (SMQ 20000004) 
 broad and narrow terms in cardiomyopathy (SMQ 20000150) 
 broad and narrow terms in central nervous system vascular disorders (includes 
sub SMQs) (SMQ 20000060) 
 broad and narrow terms in embolic and thrombotic events (includes sub SMQs) 
(SMQ 20000081) 
 broad and narrow terms in hypertension (SMQ 20000147) 


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
broad and narrow terms in ischemic heart disease (includes sub SMQs) (SMQ 
20000043)

broad and narrow terms in pulmonary hypertension (SMQ 20000130)

broad and narrow terms in Torsade de pointes/QT prolongation (SMQ 20000001)
Patient narratives will be provided for patients with potential and likely CVs, likely CV SAEs, 
and likely CV AEs leading to discontinuations.
6.7.8.2.
Evaluation of Hepatic Safety
Refer to Section 6.7.4.2 for a description of hepatic analyses.
6.7.8.3.
Evaluation of Injuries and Accidents Secondary to Neurologic Adverse 
Events
The number and percentage of patients with at least 1 TEAE in the ‘Nervous System Disorders’ 
SOC and/or at least 1 AE in the ‘Injury, Poisoning, and Procedural Complications’ SOC will be
summarized.
Among patients with at least 1 AE in the ‘Injury, Poisoning, and Procedural Complications’ 
SOC, the number and percentage of patients who reported AEs in this SOC will be summarized, 
using MedDRA PTs listed by decreasing frequency in the total population.  For each AE in this 
summary, the number and percentage of patients who reported at least 1 TEAE in the ‘Nervous 
System Disorders’ SOC will also be summarized.  Descriptive statistics will be presented
separately by body weight category and age category.
Outcomes will be evaluated by medical review of any other AEs (for example, falls, fractures, 
sprains, head injury) reported when the patients experienced neurologic-related events.  Patient 
narratives for patients with adverse functional outcomes associated with neurologic-related 
events will be provided based on medical review that includes the neurologic-related events and 
any other AEs indicative of an adverse outcome that could be potentially related to the 
neurological TEAE.
6.7.8.4.
Road Traffic Accidents
Patient narratives for patients who reported AEs with PTs of road traffic accident, impaired 
ability to use machinery, or accident, will be provided.
6.7.8.5.
Drug Abuse Liability Evaluation
With 2 exceptions described below (SMQ of Drug abuse and dependence, listing of patients with 
reported overdose AEs), all analyses to evaluate abuse potential will only be performed in 
patients 12 to <18 years of age.
The following event clusters will be used to evaluate potential abuse liability:  

The SMQ of Drug abuse and dependence [20000101], including individual PTs, 
all narrow terms, and all (narrow and broad) terms.  This will also be done 
separately in patients 6 to <12 years of age.


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
The LSC of “Additional potential abuse liability” terms.  This LSC contains 
additional terms based on Food and Drug Administration guidance (FDA 2017 
[WWW]) that are not included in the Drug abuse and dependence SMQ, including 
terms for Dissociation/psychotic, Euphoria, Impaired attention, Cognition and 
mood, and Other abuse-related terms.  Summaries will be provided at the PT level
and the overall level.  
The term list is based on the most current MedDRA version and is provided in Appendix 2.
The analyses in this section will include a total count of patients experiencing TEAEs from the 
above search and will be listed by SMQ or LSC Additional potential abuse liability terms, and 
then sorted by decreasing frequency in the total population within each SMQ or LSC Additional 
Terms group.  For the SMQ, a summary will also be provided at the narrow and broad level.  For 
both the SMQ and LSC Additional potential abuse liability terms list, each PT will be
summarized.  Additionally, the overall number (the number and percent of patients who 
experienced any TEAE from the above search) will be analyzed.  
Patient narratives of possible abuse related events (time of onset and duration of event, dose of 
drug, severity and outcome) will be provided.
The following additional analyses will be performed:

Times to onset and durations of TEAEs which may represent a sign of abuse liability 
(AL) will be summarized for individual abuse potential terms and any AL term.  

Onset times relative to first dose and durations of AEs for patients with at least 2 AL 
TEAEs will be plotted for any abuse potential AEs for these patients.

Onset/duration plots (see Appendix 3) by cohort for each AL TEAE.  In the event that 
1 or more AL TEAEs occur in a disproportionate percentage of the population, this 
analysis will exclude those terms.  
All the time to onset analysis will exclude events that are missing event start times/dates or 
missing dosing times/dates, and all duration analysis will exclude events that are missing event 
start or stop times/dates or missing dosing times/dates.
Descriptive statistics will be presented separately by body weight category and age category.
6.7.8.6.
Suicide-Related Thoughts and Behaviors
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent, based on 
the Columbia-Suicide Severity Rating Scale (C-SSRS)-Children’s Version (Posner et al. 2011), 
will be listed for individual patients by time point.  Only patients that show suicidal 
ideation/behavior or self-injurious behavior without suicidal intent will be displayed (ie, if a 
patient answers are all ‘no’ for the C-SSRS, then that patient will not be displayed).  However, if 
a patient reported any suicidal ideation/behavior or self-injurious behavior without suicidal intent 
at any time point then all their ideation and behavior will be displayed, even if not positive.


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6.7.8.7.
Potential Hypersensitivity Reactions
Potential hypersensitivity reactions are AEs whose MedDRA PTs are contained in the following 
SMQs:

broad and narrow terms in anaphylactic reaction (SMQ 20000021)

broad and narrow terms in hypersensitivity (SMQ 20000214)

broad and narrow terms in angioedema (SMQ 20000024)
Patient narratives will be provided for patients with potential immediate hypersensitivity 
reactions (TEAEs that are potential hypersensitivity reactions) and for those with potential 
non-immediate hypersensitivity reactions (non-TEAEs that are potential hypersensitivity 
reactions).
6.7.9. Other Assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
6.7.10. Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
6.8.
Interim Analyses and Data Monitoring
No interim statistical analyses are planned.
6.9.
Changes from the Protocol Specified Statistical Analyses
There were no changes from the protocol specified statistical analyses.
6.10. Reports to be Generated
All reports will be generated at final database lock.
6.11. Clinical Trial Registry Analyses
Additional analyses will be performed for fulfilling the Clinical Trial Registry (CTR) 
requirements.  
Analyses provided for the CTR requirements include the following:
Summary of AEs, provided as a dataset, which will be converted to an XML file.  Both SAEs
and ‘Other’ AEs are summarized by treatment group and MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each ‘Serious’ AE and ‘Other’ AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term


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o
the number of events experienced

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/patients in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the clinical 
study report, manuscripts, and so forth. 


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7.
References 
Beasley C, Moscarelli E. Selected Reference Limits for Pulse/Heart Rate, Arterial Blood 
Pressure (Including Orthostasis), and Electrocardiogram Numerical Parameters for Use in 
Analyses of Phase 2-4 Clinical Trials. Cardiovascular Safety Advisory Committee, Global 
Patient Safety, Eli Lilly and Company, 2015.
Boyd E. The Growth of the Surface Area of the Human Body. University of Minnesota. The 
Institute of Child Welfare, Monograph Series, No. x. London: Oxford University Press; 1935.
Cohen J. Statistical power for the behavioral sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988.
Cromer JA, Schembri AJ, Harel BT, Maruff P. The nature and rate of cognitive maturation from 
late childhood to adulthood. Front Psychol. 2015;6:704.
[FDA] Food and Drug Administration. Guidance for Industry: Assessment of Abuse Potential of 
Drugs. 2017. 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198
650. Accessed July 11, 2019.
Hammers DB, Jung M, Pressler SJ, Sullivan BJ, Koelling T, Giordani B. Clinical utility of
auditory memory testing in a heart failure population. J Cardiovasc Nurs. 2013;28(5):444-452.
Ingraham LJ, Aiken CB. An empirical approach to determining criteria for abnormality in test 
batteries with multiple measures. Neuropsychology. 1996;10(1):120-124.
Louey AG, Cromer JA, Schembri AJ, Darby DG, Maruff P, Makdissi M, Mccrory P. Detecting 
cognitive impairment after concussion: sensitivity of change from baseline and normative 
methods using the CogSport/Axon cognitive test battery. Archives of Clinical 
Neuropsychology. 2014;29(5):432-441.
Mollica CM, Maruff P, Collie A, Vance A. Repeated assessment of cognition in children and the 
measurement of performance change. Child Neuropsychol. 2005;11(3):303-310.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277.
Pottel H, Hoste L, Delanaye P. Abnormal glomerular filtration rate in children, adolescents, and 
young adults starts below 75 mL/min/1.73 m2. Pediatr Nephrol. 2015;30:821-828.
Rosenfeld A, Etzl M, Gieseking A, Goodman A, Peterson D, Daniels T, Schmebri A, Harel B. 
QOL-57. At home neurocognitive testing is possible in pediatric brain tumor patients. 
Neuro-Oncology. 2018;20(Suppl 2):i169.
Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J 
Am Soc Nephrol. 2009;4(11):1832-1843.
Sharkey I, Boddy AV, Wallace H, Mycroft J, Hollis R, Picton S, Chemotherapy Standardisation 
group of the United Kingdom Children's Cancer Study Group. Body surface area estimation in 
children using weight alone: application in paediatric oncology. Br J of Cancer.
2001;85(1):23-28.


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Uemura O, Nagai T, Ishikura K, Ito S, Hataya H, Gotoh Y, Fujita N, Akioka Y, Kaneko T, 
Honda M. Reference glomerular filtration rate levels in Japanese children: using the creatinine 
and cystatin C based estimated glomerular filtration rate. Clin Exp Nephrol.
2015;19(4):683-687.
Yoshida T, Suga M, Arima K, Muranaka Y, Tanaka T, Eguchi S, Lin C, Yoshida S, Ishikawa M, 
Higuchi Y, Seo T, Ueoka Y, Tomotake M, Kaneda Y, Darby D, Maruff P, Iyo M, Kasai K, 
Higuchi T, Sumiyoshi T, Ohmori T, Takahashi K, Hashimoto K. Criterion and construct 
validity of the CogState Schizophrenia Battery in Japanese patients with schizophrenia. PLoS 
One. 2011;6(5):e20469.


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8.
Appendices


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Appendix 1. 
Cogstate Normative Population Standard 
Deviation and Test-Retest Reliability Values 
For each Cogstate test, normative population standard deviation (ݏ௡௢௥௠) and test-retest reliability 
(ݎ) values are listed below for each age. 
Detection Test (Reaction Time) 
Age 
snorm 
r 
6 
0.09264 
0.79 
7 
0.09901 
0.79 
8 
0.13746 
0.79 
9 
0.13506 
0.79 
10 
0.08007 
0.79 
11 
0.07896 
0.79 
12 
0.07682 
0.79 
13 
0.07535 
0.79 
14 
0.08101 
0.79 
15 
0.07674 
0.79 
16 
0.07644 
0.79 
17 
0.07528 
0.79 
 
Identification Test (Reaction Time) 
Age 
snorm 
r 
6 
0.06801 
0.80 
7 
0.07695 
0.80 
8 
0.11548 
0.80 
9 
0.09222 
0.80 
10 
0.07096 
0.80 
11 
0.07068 
0.80 
12 
0.06719 
0.80 
13 
0.06782 
0.80 
14 
0.06954 
0.80 
15 
0.06687 
0.80 
16 
0.06561 
0.80 
17 
0.06456 
0.80 
   
 
 


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One Back Test (Reaction Time)
Age
snorm
r
6
0.06515
0.78
7
0.11496
0.78
8
0.11140
0.78
9
0.11960
0.78
10
0.09147
0.78
11
0.08742
0.78
12
0.08970
0.78
13
0.08832
0.78
14
0.08875
0.78
15
0.08837
0.78
16
0.08920
0.78
17
0.09017
0.78
One Card Learning Test (Accuracy)
Age
snorm
r
6
0.16830
0.70
7
0.17329
0.70
8
0.14007
0.70
9
0.16395
0.70
10
0.08819
0.70
11
0.08805
0.70
12
0.08754
0.70
13
0.08762
0.70
14
0.08567
0.70
15
0.08539
0.70
16
0.08588
0.70
17
0.08719
0.70


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Appendix 2.
Lilly Search Category of Additional Potential 
Abuse Liability Terms
Lilly Search Category of Additional Potential Abuse Liability Terms
The following are the MedDRA v21.1 terms and categories to comprise the Lilly Search 
Category that will be used for analysis of drug abuse potential. 
Cluster
Preferred Term (PT)
PT code
Dissociation/psychotic
ACUTE PSYCHOSIS
10001022
Dissociation/psychotic
AGGRESSION
10001488
Dissociation/psychotic
AGITATION
10001497
Dissociation/psychotic
ALICE IN WONDERLAND SYNDROME
10001666
Dissociation/psychotic
ANGER
10002368
Dissociation/psychotic
ANTISOCIAL BEHAVIOUR
10002820
Dissociation/psychotic
BELLIGERENCE
10004224
Dissociation/psychotic
CONFABULATION
10010297
Dissociation/psychotic
CONFUSIONAL STATE
10010305
Dissociation/psychotic
DEJA VU
10012177
Dissociation/psychotic
DELIRIUM
10012218
Dissociation/psychotic
DELUSION
10012239
Dissociation/psychotic
DELUSION OF GRANDEUR
10012241
Dissociation/psychotic
DELUSION OF REFERENCE
10012244
Dissociation/psychotic
DELUSION OF REPLACEMENT
10012245
Dissociation/psychotic
DELUSIONAL DISORDER, 
EROTOMANIC TYPE
10012249
Dissociation/psychotic
DELUSIONAL DISORDER, GRANDIOSE 
TYPE
10012250
Dissociation/psychotic
DELUSIONAL DISORDER, JEALOUS 
TYPE
10012251
Dissociation/psychotic
DELUSIONAL DISORDER, MIXED TYPE
10012252
Dissociation/psychotic
DELUSIONAL DISORDER, SOMATIC 
TYPE
10012254
Dissociation/psychotic
DELUSIONAL DISORDER, 
UNSPECIFIED TYPE
10012255
Dissociation/psychotic
DELUSIONAL PERCEPTION
10012258
Dissociation/psychotic
DERAILMENT
10012411
Dissociation/psychotic
DIENCEPHALIC SYNDROME OF 
INFANCY
10012774
Dissociation/psychotic
DISORIENTATION
10013395
Dissociation/psychotic
DISSOCIATION
10013457
Dissociation/psychotic
DISSOCIATIVE AMNESIA
10013461


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Dissociation/psychotic
DISSOCIATIVE IDENTITY DISORDER
10013468
Dissociation/psychotic
EROTOMANIC DELUSION
10015134
Dissociation/psychotic
FEAR
10016275
Dissociation/psychotic
FLASHBACK
10016754
Dissociation/psychotic
FORMICATION
10017062
Dissociation/psychotic
HALLUCINATION
10019063
Dissociation/psychotic
HALLUCINATION, AUDITORY
10019070
Dissociation/psychotic
HALLUCINATION, GUSTATORY
10019071
Dissociation/psychotic
HALLUCINATION, OLFACTORY
10019072
Dissociation/psychotic
HALLUCINATION, TACTILE
10019074
Dissociation/psychotic
HALLUCINATION, VISUAL
10019075
Dissociation/psychotic
HALLUCINATIONS, MIXED
10019079
Dissociation/psychotic
HOMICIDE
10020364
Dissociation/psychotic
HOSTILITY
10020400
Dissociation/psychotic
HYPNAGOGIC HALLUCINATION
10020927
Dissociation/psychotic
HYPNOPOMPIC HALLUCINATION
10020928
Dissociation/psychotic
IDEAS OF REFERENCE
10021212
Dissociation/psychotic
ILLOGICAL THINKING
10021402
Dissociation/psychotic
ILLUSION
10021403
Dissociation/psychotic
IRRITABILITY
10022998
Dissociation/psychotic
JAMAIS VU
10023118
Dissociation/psychotic
JEALOUS DELUSION
10023164
Dissociation/psychotic
MAGICAL THINKING
10025429
Dissociation/psychotic
PANIC ATTACK
10033664
Dissociation/psychotic
PANIC REACTION
10033670
Dissociation/psychotic
PARAMNESIA
10033848
Dissociation/psychotic
PARANOIA
10033864
Dissociation/psychotic
PERSECUTORY DELUSION
10034702
Dissociation/psychotic
PERSONALITY CHANGE
10034719
Dissociation/psychotic
PERSONALITY DISORDER
10034721
Dissociation/psychotic
PHYSICAL ASSAULT
10034983
Dissociation/psychotic
PSYCHOTIC BEHAVIOUR
10037249
Dissociation/psychotic
SENSORY DISTURBANCE
10040026
Dissociation/psychotic
SLEEP TERROR
10041010
Dissociation/psychotic
SOMATIC DELUSION
10041317
Dissociation/psychotic
STARING
10041953
Dissociation/psychotic
SUSPICIOUSNESS
10042635
Dissociation/psychotic
THOUGHT BLOCKING
10043495
Dissociation/psychotic
THOUGHT INSERTION
10043496
Dissociation/psychotic
THOUGHT WITHDRAWAL
10043497
Dissociation/psychotic
VIOLENCE-RELATED SYMPTOM
10047426
Dissociation/psychotic
HYPERVIGILANCE
10048533
Dissociation/psychotic
HOMICIDAL IDEATION
10049666
Dissociation/psychotic
IMPATIENCE
10049976
Dissociation/psychotic
THOUGHT BROADCASTING
10052214


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Dissociation/psychotic
DELUSIONAL DISORDER, 
PERSECUTORY TYPE
10053195
Dissociation/psychotic
REACTIVE PSYCHOSIS
10053632
Dissociation/psychotic
TRANSIENT PSYCHOSIS
10056326
Dissociation/psychotic
SENSORY LEVEL ABNORMAL
10061567
Dissociation/psychotic
PARASOMNIA
10061910
Dissociation/psychotic
PSYCHOTIC DISORDER
10061920
Dissociation/psychotic
HYSTERICAL PSYCHOSIS
10062645
Dissociation/psychotic
SOMATIC HALLUCINATION
10062684
Dissociation/psychotic
HALLUCINATION, SYNAESTHETIC
10062824
Dissociation/psychotic
DEPRESSIVE DELUSION
10063033
Dissociation/psychotic
PAROXYSMAL PERCEPTUAL 
ALTERATION
10063117
Dissociation/psychotic
SLEEP SEX
10067492
Dissociation/psychotic
CONFUSIONAL AROUSAL
10067494
Dissociation/psychotic
REBOUND PSYCHOSIS
10074833
Dissociation/psychotic
MIXED DELUSION
10076429
Dissociation/psychotic
FRUSTRATION TOLERANCE 
DECREASED
10077753
Dissociation/psychotic
DEPERSONALISATION/DEREALISATION 
DISORDER
10077805
Euphoria
ATTENTION-SEEKING BEHAVIOUR
10003739
Euphoria
DISINHIBITION
10013142
Euphoria
DIZZINESS
10013573
Euphoria
EUPHORIC MOOD
10015535
Euphoria
FEELING ABNORMAL
10016322
Euphoria
FEELING DRUNK
10016330
Euphoria
FEELING JITTERY
10016338
Euphoria
FEELING OF RELAXATION
10016352
Euphoria
FLIGHT OF IDEAS
10016777
Euphoria
IMPULSIVE BEHAVIOUR
10021567
Euphoria
INAPPROPRIATE AFFECT
10021588
Euphoria
INCOHERENT
10021630
Euphoria
JUDGEMENT IMPAIRED
10023236
Euphoria
LOGORRHOEA
10024796
Euphoria
LOOSE ASSOCIATIONS
10024825
Euphoria
MANIA
10026749
Euphoria
MOOD SWINGS
10027951
Euphoria
PSYCHOMOTOR HYPERACTIVITY
10037211
Euphoria
RESTLESSNESS
10038743
Euphoria
TANGENTIALITY
10043114
Euphoria
THINKING ABNORMAL
10043431
Euphoria
ENERGY INCREASED
10048779
Euphoria
HOT FLUSH
10060800
Euphoria
ABNORMAL BEHAVIOUR
10061422


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Euphoria
CENTRAL NERVOUS SYSTEM 
STIMULATION
10061444
Euphoria
GAMBLING DISORDER
10078070
Impaired attention, cognition and mood
ABNORMAL DREAMS
10000125
Impaired attention, cognition and mood
AFFECTIVE DISORDER
10001443
Impaired attention, cognition and mood
ALTERED STATE OF CONSCIOUSNESS
10001854
Impaired attention, cognition and mood
AMNESIA
10001949
Impaired attention, cognition and mood
ANHEDONIA
10002511
Impaired attention, cognition and mood
ANTEROGRADE AMNESIA
10002711
Impaired attention, cognition and mood
ANXIETY
10002855
Impaired attention, cognition and mood
APATHY
10002942
Impaired attention, cognition and mood
ASOCIAL BEHAVIOUR
10003472
Impaired attention, cognition and mood
ASTHENIA
10003549
Impaired attention, cognition and mood
BLUNTED AFFECT
10005885
Impaired attention, cognition and mood
COMPULSIONS
10010219
Impaired attention, cognition and mood
COORDINATION ABNORMAL
10010947
Impaired attention, cognition and mood
CRYING
10011469
Impaired attention, cognition and mood
DEPRESSED LEVEL OF 
CONSCIOUSNESS
10012373
Impaired attention, cognition and mood
DISTURBANCE IN ATTENTION
10013496
Impaired attention, cognition and mood
DYSARTHRIA
10013887
Impaired attention, cognition and mood
DYSPHORIA
10013954
Impaired attention, cognition and mood
EMOTIONAL DISORDER
10014551
Impaired attention, cognition and mood
EMOTIONAL POVERTY
10014557
Impaired attention, cognition and mood
FATIGUE
10016256
Impaired attention, cognition and mood
FEELING OF DESPAIR
10016344
Impaired attention, cognition and mood
FLAT AFFECT
10016759
Impaired attention, cognition and mood
MEMORY IMPAIRMENT
10027175
Impaired attention, cognition and mood
MENTAL DISABILITY
10027353
Impaired attention, cognition and mood
MENTAL IMPAIRMENT
10027374
Impaired attention, cognition and mood
MOANING
10027783
Impaired attention, cognition and mood
MOOD ALTERED
10027940
Impaired attention, cognition and mood
PREMENSTRUAL SYNDROME
10036618
Impaired attention, cognition and mood
PSYCHOMOTOR RETARDATION
10037213
Impaired attention, cognition and mood
RETROGRADE AMNESIA
10038965
Impaired attention, cognition and mood
SEDATION
10039897
Impaired attention, cognition and mood
SOMNOLENCE
10041349
Impaired attention, cognition and mood
STUPOR
10042264
Impaired attention, cognition and mood
TRANSIENT GLOBAL AMNESIA
10044380
Impaired attention, cognition and mood
MENTAL STATUS CHANGES
10048294
Impaired attention, cognition and mood
EMOTIONAL DISTRESS
10049119
Impaired attention, cognition and mood
PSYCHOMOTOR SKILLS IMPAIRED
10049215
Impaired attention, cognition and mood
IMPAIRED DRIVING ABILITY
10049564
Impaired attention, cognition and mood
BALANCE DISORDER
10049848
Impaired attention, cognition and mood
BRADYPHRENIA
10050012


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Impaired attention, cognition and mood
CONSCIOUSNESS FLUCTUATING
10050093
Impaired attention, cognition and mood
PREMENSTRUAL DYSPHORIC 
DISORDER
10051537
Impaired attention, cognition and mood
ALTERED VISUAL DEPTH PERCEPTION
10053549
Impaired attention, cognition and mood
AFFECT LABILITY
10054196
Impaired attention, cognition and mood
DYSLOGIA
10054940
Impaired attention, cognition and mood
COGNITIVE DISORDER
10057668
Impaired attention, cognition and mood
MENTAL DISORDER
10061284
Impaired attention, cognition and mood
AMNESTIC DISORDER
10061423
Impaired attention, cognition and mood
ABNORMAL SLEEP-RELATED EVENT
10061613
Impaired attention, cognition and mood
EXECUTIVE DYSFUNCTION
10070246
Impaired attention, cognition and mood
IMPAIRED REASONING
10071176
Impaired attention, cognition and mood
SLOW SPEECH
10071299
Impaired attention, cognition and mood
NEUROLEPTIC-INDUCED DEFICIT 
SYNDROME
10075295
Impaired attention, cognition and mood
ALEXITHYMIA
10077719
Other abuse-related terms
ACCIDENTAL POISONING
10000383
Other abuse-related terms
ALCOHOL ABUSE
10001584
Other abuse-related terms
ALCOHOL PROBLEM
10001606
Other abuse-related terms
ALCOHOLIC HANGOVER
10001623
Other abuse-related terms
ALCOHOLISM
10001639
Other abuse-related terms
ATAXIA
10003591
Other abuse-related terms
COMPLETED SUICIDE
10010144
Other abuse-related terms
HANGOVER
10019133
Other abuse-related terms
HEADACHE
10019211
Other abuse-related terms
INCREASED APPETITE
10021654
Other abuse-related terms
INTENTIONAL SELF-INJURY
10022524
Other abuse-related terms
MIOSIS
10027646
Other abuse-related terms
MUSCLE RIGIDITY
10028330
Other abuse-related terms
MYDRIASIS
10028521
Other abuse-related terms
NASAL NECROSIS
10028747
Other abuse-related terms
NASAL SEPTUM PERFORATION
10028765
Other abuse-related terms
NASAL SEPTUM ULCERATION
10028766
Other abuse-related terms
PARAESTHESIA
10033775
Other abuse-related terms
SUICIDAL IDEATION
10042458
Other abuse-related terms
SUICIDE ATTEMPT
10042464
Other abuse-related terms
TOBACCO ABUSE
10043903
Other abuse-related terms
TREATMENT NONCOMPLIANCE
10049414
Other abuse-related terms
PRESCRIBED OVERDOSE
10051076
Other abuse-related terms
SELF-INJURIOUS IDEATION
10051154
Other abuse-related terms
URINE AMPHETAMINE POSITIVE
10051400
Other abuse-related terms
ALCOHOL WITHDRAWAL SYNDROME
10053164
Other abuse-related terms
ANALGESIC THERAPY
10053469
Other abuse-related terms
ANTITUSSIVE THERAPY
10055120


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Other abuse-related terms
NICOTINE DEPENDENCE
10057852
Other abuse-related terms
MUSCLE RELAXANT THERAPY
10058909
Other abuse-related terms
TOBACCO WITHDRAWAL SYMPTOMS
10059612
Other abuse-related terms
URINE AMPHETAMINE
10059955
Other abuse-related terms
POISONING
10061355
Other abuse-related terms
DECREASED APPETITE
10061428
Other abuse-related terms
AMPHETAMINES
10063227
Other abuse-related terms
AMPHETAMINES POSITIVE
10063228
Other abuse-related terms
ACCIDENTAL DEATH
10063746
Other abuse-related terms
SUICIDAL BEHAVIOUR
10065604
Other abuse-related terms
ANXIOLYTIC THERAPY
10066478
Other abuse-related terms
PRODUCT TAMPERING
10069330
Other abuse-related terms
PRODUCT USED FOR UNKNOWN 
INDICATION
10070592
Other abuse-related terms
BINGE DRINKING
10071238
Other abuse-related terms
BENZODIAZEPINE DRUG LEVEL
10072337
Other abuse-related terms
DOPAMINERGIC DRUG THERAPY
10072385


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Appendix 3.
Onset/Duration of Plots (Mock Plots)
Onset/Duration of Plots (Mock Plots)