A Phase 1 Study to Investigate the Absorption, Metabolism, and Excretion of [14C]-Lasmiditan Following Single Oral Dose Administration in Healthy Male and Female Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol H8H-CD-LAHH  
 
 
A PHASE 1 STUDY TO INVESTIGATE THE ABSORPTION, METABOLISM, AND 
EXCRETION OF [14C]-LASMIDITAN FOLLOWING SINGLE ORAL DOSE 
ADMINISTRATION IN HEALTHY MALE AND FEMALE SUBJECTS 
 
NCT03040362 
 
Approval Date: 23-Jan-2017 
 
 
 

Clinical Study Report 
CoLucid Reference: COL MIG-110 
 
 
CONFIDENTIAL
16.1.1 
Protocol and Amendments 
Final
Page 1 of 49
Approval Date: 26-Mar-2018 GMT

CoLucid Pharmaceuticals, Inc. 
Clinical Protocol 
Covance Study 8331469 
CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0:23 January 2017 
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A PHASE 1 STUDY TO INVESTIGATE THE ABSORPTION, METABOLISM, 
AND EXCRETION OF [14C]-LASMIDITAN FOLLOWING SINGLE ORAL 
DOSE ADMINISTRATION IN HEALTHY MALE AND FEMALE SUBJECTS 
 
 
 
 
Protocol COL MIG-110 
 
Covance Study 8331469 
 
IND 103,420 
 
 
 
for 
 
CoLucid Pharmaceuticals, Inc. 
222 Third Street, Suite 1320 
Cambridge, Massachusetts 02142 
 
 
 
 
by 
 
Covance Early Clinical Services 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
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CoLucid Pharmaceuticals, Inc. 
Clinical Protocol 
Covance Study 8331469 
CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0:23 January 2017 
Page 2 of 48 
 
STUDY IDENTIFICATION 
Sponsor 
CoLucid Pharmaceuticals, Inc. 
 
222 Third Street, Suite 1320 
 
Cambridge Massachussets 02142 
 
 (Main Telephone No.) 
 
 (Main Facsimile No.) 
 
Sponsor’s Study Contact 
 
 
 
 
CoLucid Pharmaceuticals, Inc. 
 
222 Third Street, Suite 1320 
 
Cambridge Massachussets 02142 
 
 (Office Telephone No.) 
 
 (Office Facsimile No.) 
 
Medical Monitor 
To be determined 
 
 
Clinical Site 
Covance Clinical Research Unit Inc. 
 
3402 Kinsman Boulevard 
 
Madison, Wisconsin 53704 
 
 (Main Telephone No.) 
 
 (Main Facsimile No.) 
 
Principal Investigator/ 
 
Authorized User 
 
 
Covance Clinical Research Unit, Inc. 
 
 (Office Telephone No.) 
 
 
 
Main Clinical Laboratory 
Meriter Laboratories 
 
36 South Brooks Street 
 
Madison, Wisconsin 53715 
 
 (Main Telephone No.) 
 
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Clinical Protocol 
Covance Study 8331469 
CONFIDENTIAL 
Protocol COL MIG-110 
 
 
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Bioanalytical Laboratory 
Covance Laboratories, Inc. 
 
3301 Kinsman Boulevard 
 
Madison, Wisconsin 53704 
 
 (Main Telephone No.) 
 
Radioanalytical Laboratory Covance Laboratories, Inc. 
 
3301 Kinsman Boulevard 
 
Madison, Wisconsin 53704 
 
 (Main Telephone No.) 
 
Radiation Safety Officer 
 
 
Covance Inc. 
 
 (Office Telephone No.) 
 
 
 
Clinical Nuclear Pharmacist 
 
 
Covance Inc. 
 
 (Office Telephone No.) 
 
 
 
Protocol Biostatistician 
 
 
Covance Biometrics 
 
 (Office Telephone No.) 
 
 
 
Protocol Pharmacokineticist 
 
 
Covance Biometrics 
 
 (Office Telephone No.) 
 
 
 
Protocol Medical Writer 
 
 
Covance Global Medical and Regulatory Writing 
 
 (Office Telephone No.) 
 
 
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CoLucid Pharmaceuticals, Inc. 
Clinical Protocol 
Covance Study 8331469 
CONFIDENTIAL 
Protocol COL MIG-110 
Final 1.0:23 January 2017 
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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................1 
STUDY IDENTIFICATION ...............................................................................................2 
TABLE OF CONTENTS .....................................................................................................4 
ABBREVIATIONS .............................................................................................................8 
1 
SYNOPSIS .............................................................................................................10 
2 
INTRODUCTION .................................................................................................13 
2.1 
Background ................................................................................................13 
2.1.1 Nonclinical Background ................................................................13 
2.1.1.1 
Nonclinical Metabolism and Excretion .....14 
2.1.2 Clinical Background ......................................................................14 
2.1.2.1 
Clinical Pharmacokinetics .........................15 
2.2 
Dose Rationale ...........................................................................................15 
2.3 
Study Rationale ..........................................................................................15 
3 
STUDY OBJECTIVES ..........................................................................................16 
4 
INVESTIGATIONAL PLAN ................................................................................16 
4.1 
Study Design ..............................................................................................16 
4.2 
Discussion of Study Design .......................................................................18 
5 
SUBJECT SELECTION ........................................................................................18 
5.1 
Inclusion Criteria .......................................................................................18 
5.2 
Exclusion Criteria ......................................................................................19 
5.3 
Removal of Subjects from Study Participation ..........................................21 
6 
STUDY PROCEDURES .......................................................................................22 
6.1 
Schedule of Study Procedures ...................................................................22 
6.2 
Study Treatment .........................................................................................26 
6.2.1 Drug Supplies and Accountability .................................................26 
6.2.2 Subject Number and Identification ................................................27 
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6.2.3 Dose Preparation and Administration ............................................27 
6.2.4 Blinding..........................................................................................27 
6.3 
Study Restrictions ......................................................................................28 
6.3.1 Diet, Fluid, and Activity Control ...................................................28 
6.3.2 Concomitant Medications ..............................................................28 
6.3.3 Contraception .................................................................................29 
6.4 
Pharmacokinetic, [14C] Radioactivity, and Metabolism Procedures .........29 
6.4.1 Pharmacokinetic, [14C] Radioactivity, and Metabolism Blood 
Sample Collection ..............................................................29 
6.4.2 Pharmacokinetic, [14C] Radioactivity, and Metabolism Urine 
Sample Collection ..............................................................29 
6.4.3 [14C] Radioactivity and Metabolism Fecal Sample Collection ......30 
6.4.4 Emesis Sample Collection .............................................................30 
6.4.5 Collection of Feminine Hygiene Products .....................................30 
6.4.6 Analytical Methodology ................................................................30 
6.5 
Safety Procedures.......................................................................................30 
6.5.1 Adverse Events ..............................................................................31 
6.5.2 Clinical Laboratory Evaluations ....................................................31 
6.5.3 Vital Signs ......................................................................................32 
6.5.4 Orthostatic Vital Signs ...................................................................32 
6.5.5 Twelve-lead Electrocardiograms ...................................................32 
6.5.6 Physical Examinations ...................................................................32 
6.5.7 Columbia Suicide Severity Rating Scale .......................................33 
7 
DATA ANALYSES AND SAMPLE SIZE ...........................................................33 
7.1 
Sample Size ................................................................................................33 
7.2 
Study Populations ......................................................................................33 
7.3 
Pharmacokinetic Analysis ..........................................................................33 
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7.4 
Statistical Analysis of Pharmacokinetic Data ............................................35 
7.5 
Statistical Analyses of Safety Data ............................................................35 
7.6 
Data Handling and Record Keeping ..........................................................36 
7.7 
Quality Control and Quality Assurance .....................................................36 
8 
ADMINISTRATIVE ASPECTS ...........................................................................36 
8.1 
Change in Protocol .....................................................................................36 
8.2 
Site Initiation Visit/Investigator Meeting ..................................................37 
8.3 
Disclosure ..................................................................................................37 
8.4 
Monitoring .................................................................................................37 
8.5 
Institutional Review Board ........................................................................38 
8.6 
Informed Consent.......................................................................................38 
8.7 
Records ......................................................................................................38 
8.8 
Reference to Declaration of Helsinki/Basic Principles ..............................39 
8.9 
Financing and Insurance ............................................................................39 
INVESTIGATOR AGREEMENT.....................................................................................40 
SPONSOR AGREEMENT ................................................................................................41 
REFERENCES ..................................................................................................................42 
APPENDIX A - CLINICAL LABORATORY EVALUATIONS ....................................43 
APPENDIX B - BLOOD SAMPLING SUMMARY ........................................................44 
APPENDIX C - ADVERSE EVENTS ..............................................................................45 
1 
ADVERSE EVENTS .............................................................................................45 
1.1 
Definition of Adverse Events.....................................................................45 
1.2 
Categorization of Adverse Events .............................................................45 
1.3 
Pregnancy ...................................................................................................46 
1.4 
Definition of Serious Adverse Events........................................................47 
1.5 
Unexpected Adverse Drug Experience ......................................................47 
1.6 
Reporting....................................................................................................47 
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TABLE OF TABLES AND FIGURES 
Table 6-1  Study Flow Chart ............................................................................................. 23 
Table 6-2  Study Drugs ..................................................................................................... 26 
Figure 4-1 Study Design Schematic ................................................................................. 17 
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ABBREVIATIONS 
AUCextrap
percentage of AUC that is due to extrapolation from the last 
measurable concentration 
%FR 
percentage of lasmiditan recovered in feces 
%UR 
percentage of lasmiditan recovered in urine 
5-HT 
serotonin 
5-HT1B 
5-HT 1B receptor 
5-HT1F 
5-HT 1F receptor 
AE 
adverse event 
Aef 
amount excreted in feces over sampling interval 
Aeu 
amount excreted in urine over sampling interval 
AME 
absorption, metabolism, and excretion 
AUC 
area under the concentration-time curve 
AUC0-∞ 
area under the concentration-time curve extrapolated to 
infinity 
AUC0-∞ Blood/Plasma 
Ratio 
AUC0-∞ of total radioactivity in blood/AUC0-∞ of total 
radioactivity in plasma 
AUC0-∞ Plasma 
Lasmiditan/ Total 
Radioactivity Ratio 
AUC0-∞ of lasmiditan in plasma/AUC0-∞ of total radioactivity 
in plasma 
AUC0-t 
area under the concentration-time curve from Hour 0 to the 
last measurable concentration 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL/F 
apparent oral clearance (for lasmiditan only) 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV% 
coefficient of variation 
CYP 
cytochrome 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
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FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
HIV 
human immunodeficiency virus 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
IV 
intravenous 
λZ 
apparent terminal elimination rate constant 
No. 
number 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected for heart rate using Fridericia's formula 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
t1/2 
apparent terminal elimination half-life 
TFLs 
tables, figures, and listings 
tmax 
time to maximum concentration 
Total %FR 
cumulative % FR 
Total %UR 
cumulative % UR 
Total Aeu 
cumulative Aeu 
Total Aef 
cumulative Aef
UA 
urinalysis 
US 
United States 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
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1 SYNOPSIS 
Title of Study: 
A Phase 1 Study to Investigate the Absorption, Metabolism, and Excretion of 
[14C]-Lasmiditan Following Single Oral Dose Administration in Healthy Male and 
Female Subjects 
Objectives: 
Primary: 
• 
to assess the pharmacokinetics (PK), metabolism, and routes and extent of 
elimination of a single oral dose of 200 mg (approximately 100 µCi) 
[14C]-lasmiditan in healthy male and female subjects. 
Secondary: 
• 
to characterize and identify metabolites of lasmiditan in plasma, urine, and 
feces; 
• 
to assess the safety and tolerability of lasmiditan. 
Methodology/Study 
Design: 
This study will be an open-label, nonrandomized, absorption, metabolism, and 
excretion study of [14C]-lasmiditan administered as a 200-mg (approximately 
100 µCi) oral solution to 8 healthy male and female subjects, following at least a 
10-hour fast from food (not including water). 
 
 
PK = pharmacokinetic. 
Note: Single oral dose of [14C]-lasmiditan at 200 mg (approximately 100 µCi) administered 
orally to subjects in a fasted state. 
Subjects will be confined at the clinical site from the time of Check-in (Day -1) 
until Discharge (between Days 9 and 14, inclusive). After completing discharge 
procedures, subjects will be discharged from the clinical site on Day 14 or as early 
as Day 9, provided radioactivity has reached all of the following threshold values: 
• 
plasma radioactivity levels below the limit of quantitation; AND 
• 
≥90% of the dose is recovered; AND 
• 
urine total radioactivity ≤1% of the administered dose for 2 consecutive 
24-hour intervals; AND 
• 
fecal total radioactivity ≤1% of the administered dose for 2 consecutive 
24-hour intervals. 
Pharmacokinetic and radioanalytical samples will be obtained through at least 
192 hours (8 days) postdose and metabolism samples will be obtained through 
96 hours (4 days) postdose. 
Number of Subjects: 
Eight subjects will be enrolled in order that a minimum of 6 subjects complete the 
study. Every effort will be made to enroll 4 females and 4 males in this study. 
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Diagnosis and Main 
Criteria for 
Inclusion: 
Healthy male and female subjects between 18 and 60 years of age, inclusive, with a 
body mass index of 18.5 to 32.0 kg/m2, inclusive. 
Females must be nonpregnant, nonlactating, and either postmenopausal (defined as 
no menstrual period for at least 12 months and confirmed by a serum 
follicle-stimulating hormone level of ≥40 mIU/mL), surgically sterile (e.g., bilateral 
oophorectomy, salpingectomy, and/or hysterectomy) for at least 90 days prior to 
Screening, or must have undergone bilateral tubal ligation and agree to use effective 
contraception. For all females, the pregnancy test results must be negative at 
Screening and Check-in. 
Test Product(s), 
Dose, and Mode of 
Administration: 
Subjects will receive a single dose of 200 mg (approximately 100 µCi) lasmiditan 
as an oral solution after at least a 10-hour fast. 
Duration of 
Treatment: 
Planned Enrollment/Screening Duration: up to 28 days 
Length of Confinement: Day -1 through Day 9 or up to Day 14 
Follow-up Phone Call: 4 ± 2 days after Discharge 
Planned Study Conduct Duration (Screening to Follow-up Phone Call): 13 days 
(minimum) to 49 days (maximum) 
Criteria for 
Evaluation: Safety 
Safety endpoints for this study include: adverse events, clinical laboratory 
evaluations, vital sign measurements (including orthostatic vital sign 
measurements), 12-lead electrocardiograms, physical examination findings, and the 
Columbia Suicide Severity Rating Scale. 
Criteria for 
Evaluation: 
Pharmacokinetics 
The following PK parameters will be calculated, whenever possible, based on the 
plasma concentrations of lasmiditan and total radioactivity in plasma and blood: 
maximum observed concentration (Cmax), time to maximum concentration (tmax), 
area under the concentration-time curve (AUC) from Hour 0 to the last measurable 
concentration (AUC0-t), AUC extrapolated to infinity (AUC0-∞), percentage of AUC 
that is due to extrapolation from the last measurable concentration (%AUCextrap), 
apparent terminal elimination rate constant (λZ), apparent terminal elimination 
half-life (t1/2), apparent oral clearance (CL/F, for lasmiditan only), apparent volume 
of distribution (Vz/F, for lasmiditan only), AUC0-∞ of total radioactivity in 
blood/AUC0-∞ of total radioactivity in plasma (AUC0-∞ Blood/Plasma Ratio), and 
AUC0-∞ of lasmiditan in plasma/AUC0-∞ of total radioactivity in plasma (AUC0-∞ 
Plasma Lasmiditan/Total Radioactivity Ratio). 
The following PK parameters will be calculated, whenever possible, based on the 
urine concentrations of lasmiditan and total radioactivity: amount excreted in urine 
over sampling interval (Aeu), cumulative Aeu (Total Aeu), renal clearance (CLR; for 
lasmiditan only), percentage of lasmiditan recovered in urine (%UR), and 
cumulative %UR (Total %UR). 
The following PK parameters will be calculated, whenever possible, based on the 
fecal concentrations of total radioactivity: amount excreted in the feces over 
sampling interval (Aef), cumulative Aef (Total Aef), percentage of lasmiditan 
recovered in feces (%FR), and cumulative %FR (Total %FR). 
Other parameters may be added as appropriate. Final PK parameters reported will 
be detailed in the Statistical Analysis Plan. 
PK parameters for the metabolites of lasmiditan will be calculated, as deemed 
appropriate, based on plasma, urine, and fecal concentration levels. 
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Statistical Methods: 
Descriptive statistics (mean, standard deviation, coefficient of variation [CV%], 
geometric mean, geometric CV%, etc.) will be calculated for the PK parameters. No 
formal statistical analyses are planned. 
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2 INTRODUCTION 
2.1 Background 
Migraine is a common neurological disorder characterized by severe headaches, nausea, 
photophobia, phonophobia, and vomiting. In its 2010 Global Burden of Disease survey, 
the World Health Organizations ranked migraine as one of the 7 most debilitating 
conditions and as the third most common disease in the world in both males and females. 
Migraine was previously attributed to cycles of vasoconstriction with reactive 
vasodilation that activated the nociceptive terminals on the cerebral and extracerebral 
vasculature. It is now believed that this dilation of cerebral and extracerebral blood 
vessels is secondary to noxious sensory signals transmitted through the trigeminal 
system.1 
The current first-line treatment for migraine is triptans, selective serotonin (5-HT) 1B 
receptor (5-HT1B) agonists. Agonism at 5-HT1B results in vasoconstriction and subsequent 
migraine relief. Because of their vasoconstrictive mechanism, triptans are contraindicated 
in patients with coronary artery disease. In addition, triptans are associated with a 
relatively high incidence of neck, jaw, and chest symptoms of unknown etiology that 
limit tolerability. Concerns about cardiovascular safety are believed to limit the 
prescription of triptans to less than 50% of those suffering from migraine.2 There is a 
large, unmet need to provide migraine treatment for individuals for whom triptans are not 
an option. 
CoLucid Pharmaceuticals, Inc. (CoLucid) is developing lasmiditan (COL-144), a small 
molecule 5-HT 1F receptor (5-HT1F) agonist. Lasmiditan is intended for the acute 
treatment of migraine patients with and without aura. In preclinical models relevant to 
migraine, selective 5-HT1F agonists have been shown to inhibit trigeminal nociceptive 
processing without affecting blood vessel tone. The non-vasoconstrictive mechanism of 
selective 5-HT1F agonists may offer migraine relief to those unable to use triptans. 
2.1.1 
Nonclinical Background 
The primary adverse events (AEs) identified in single- and repeat-dose toxicology studies 
with intravenous (IV) or oral administration of lasmiditan were central nervous system 
(CNS)-related and were accompanied by emesis in dogs and reductions in body weight or 
body weight gain across species. The incidence and severity of CNS-related clinical signs 
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was dose dependent and onset tended to coincide with the time to maximum observed 
concentration (tmax). These signs were transient and spontaneously resolved within 1 and 
6 hours, respectively, of IV and oral dosing. Aside from the CNS-related clinical signs, 
there was no consistent evidence of a common, specific target organ of toxicity across 
species. 
The no-observed-adverse-effect levels calculated from a 26-week repeat-dose study in 
rats, a 39-week repeat-dose study in dogs, and a 13-week repeat-dose study in mice were 
2 to 5 times higher than the projected exposures at the 200-mg dose. 
2.1.1.1 Nonclinical Metabolism and Excretion 
Lasmiditan showed negligible in vitro metabolism by microsomes and human 
recombinant cytochromes (CYPs), but there was higher turnover in hepatocytes and 
S9 fractions, suggesting that metabolism may depend on other enzymes than CYPs. A 
total of 13 metabolites were detected in incubations with hepatocytes of animal species 
and 12 with human hepatocytes. No metabolites were unique to humans. 
The excretion of drug-related products from rats and dogs dosed with either oral or IV 
[14C]-lasmiditan was relatively rapid with the majority excreted within 48 hours of 
dosing. During the first 48 hours, urinary excretion was approximately 60% in rats and 
45% in dogs. 
2.1.2 
Clinical Background 
Five Phase 1 studies of lasmiditan have been completed using IV, sublingual, and oral 
formulations of lasmiditan in 213 healthy subjects, two Phase 2 studies have been 
completed with lasmiditan in the acute treatment of migraine in 393 patients, and one 
Phase 3 study (COL MIG-301) has been completed with 1239 patients treated with 
lasmiditan. A second Phase 3 study (COL MIG-302) evaluating 50, 100, and 200 mg 
lasmiditan compared to placebo in the acute treatment of migraine is ongoing as is a 
Phase 3, open-label, one-year dosing study to assess long-term safety (COL MIG-305). 
In healthy male and female subjects, oral doses of lasmiditan up to 400 mg were not 
associated with drug-related serious AEs (SAEs) or withdrawals due to AEs. The most 
frequently reported AEs in all lasmiditan groups were tiredness, drowsiness, dizziness, 
and paresthesia. At the highest dose of 400 mg lasmiditan, most AEs were mild in 
intensity and none were severe. 
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2.1.2.1 Clinical Pharmacokinetics 
The pharmacokinetics (PK) of lasmiditan were linear with respect to maximum observed 
concentration (Cmax) and area under the concentration-time curve (AUC) following 
administration of 25 to 400 mg lasmiditan as an oral solution. The tmax was approximately 
1.9 hours and the mean terminal elimination half-life (t1/2) ranged from 4.66 to 
6.38 hours.  
In subjects receiving oral lasmiditan, 3 major metabolites (M7, M8, and [S, R]-M18) 
were detected. These 3 metabolites were pharmacologically inactive against over 40 
G protein-coupled receptors, ion channels, and transporters. The non-reduced metabolites 
exhibited a t1/2 of ~4.5 hours, while the reduced metabolites had a t1/2 greater than 
12 hours. 
2.2 Dose Rationale 
A dose of 200 mg was chosen for this study. The 200-mg dose level, currently under 
investigation as a therapeutic dose in Phase 3 clinical trials, is safe and well tolerated. 
The radioactive dose will be approximately 100 µCi in 200 mg of [14C]-lasmiditan (i.e., 
0.5 µCi/mg). 
Based on data in male and female Lister Hooded rats (with supporting data from male 
Sprague Dawley rats), the overall whole body radiation dose following administration of 
a single 100 µCi dose of [14C]-lasmiditan is calculated to be 65.9 and 77.0 mrem in 
human male and female subjects, respectively.3 These values for whole body exposure 
are well below the FDA exposure limit of 3000 mrem after a single dose for human 
isotope studies. Based on these results, a single 100-µCi oral dose of [14C]-lasmiditan is 
not expected to represent a significant radiation exposure risk to human male or female 
subjects. 
2.3 Study Rationale 
The purpose of this study is to determine the absorption and excretion kinetics of 
lasmiditan, and to determine and characterize metabolites present in plasma, urine, and 
feces in healthy male and female subjects following a single dose of 200 mg 
(approximately 100 µCi) of [14C]-lasmiditan administered as an oral solution. 
The optimization of absorption, metabolism, and excretion (AME) parameters is a key 
part of the drug development process. The characteristics of AME modulate the efficacy 
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and toxicity of a drug and inform the researcher of the potential impacts of hepatic or 
renal impairment on drug disposition. It is therefore crucial to understand the clearance 
mechanism and characteristics of metabolism of a new drug. 
It has been established that migranes are more common in the female population, with 
onset typically occurring during peak child-bearing years. Because lasmiditan will be 
administered to more females than males, females will be included in this AME study. 
The inclusion of females in this study will ellucidate any relevant differences in 
lasmiditan AME between male and females. 
3 STUDY OBJECTIVES 
The primary objectives of this study are: 
• 
to assess the PK, metabolism, and routes and extent of elimination of a 
single oral dose of 200 mg (approximately 100 µCi) [14C]-lasmiditan in 
healthy male and female subjects. 
The secondary objectives of this study are: 
• 
to characterize and identify metabolites of lasmiditan in plasma, urine, and 
feces; 
• 
to assess the safety and tolerability of lasmiditan. 
4 INVESTIGATIONAL PLAN 
4.1 Study Design 
This study will be an open-label, nonrandomized, AME study of [14C]-lasmiditan 
administered as a 200-mg (approximately 100 µCi) oral solution to 8 healthy male and 
female subjects following at least a 10-hour fast from food (not including water). 
A schematic of the study design is presented in Figure 4-1. The start of the study is 
defined as the date the first subject enrolled in the study signs an Informed Consent Form 
(ICF). A subject who completes all PK, radioactivity, and metabolism sampling prior to 
Discharge is considered to have completed the study. The end of the study is defined as 
the date the last subject completes the Follow-up Phone Call. The planned duration of 
study conduct is up to approximately 49 days from Screening through the Follow-up 
Phone Call. 
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Figure 4-1 Study Design Schematic 
 
PK = pharmacokinetic. 
Note: Single oral dose of [14C]-lasmiditan at 200 mg (approximately 100 µCi) administered orally to subjects in a 
fasted state. 
Subjects will be confined at the clinical site from the time of Check-in (Day -1) until 
Discharge (between Days 9 and 14, inclusive). After completing discharge procedures, 
subjects will be discharged from the clinical site on Day 14 or as early as Day 9, provided 
radioactivity has reached all of the following threshold values: 
• 
plasma radioactivity levels below the limit of quantitation; AND 
• 
≥90% of the dose is recovered; AND 
• 
urine total radioactivity ≤1% of the administered dose for 
2 consecutive 24-hour intervals; AND 
• 
fecal total radioactivity ≤1% of the administered dose for 
2 consecutive 24-hour intervals. 
Sample collection and confinement will continue until discharge criteria are met or the 
maximum stay (Day 14) is reached, unless otherwise agreed upon by the Sponsor and 
Investigator. A Follow-up Phone Call will be conducted 4 ± 2 days after Discharge. 
Subjects experiencing emesis during the first 4 hours postdose may be discharged on the 
same day from the clinical site, provided there are no safety concerns, and after follow-up 
study procedures are performed. Subjects who are discharged from the study early will 
not be replaced. 
Safety will be monitored with AE inquiries, clinical laboratory evaluations (Appendix A), 
vital sign measurements (including orthostatic vital sign measurements), 12-lead 
electrocardiograms (ECGs), physical examination findings, and the Columbia Suicide 
Severity Rating Scale (C-SSRS) during the study.  
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Pharmacokinetic and radioanalytical samples will be obtained through at least 192 hours 
(8 days) postdose and metabolism samples will be obtained through 96 hours (4 days) 
postdose. A study flow chart is presented in Table 6-1. 
4.2 Discussion of Study Design 
This study is designed to characterize the AME of lasmiditan using radiolabeled drug in 
healthy adult male and female subjects to support its further development and 
registration. 
The study will be conducted as an open-label trial because the study measures are 
objective outcomes (e.g., total radioactivity in select biological matrices, metabolite 
profiling/characterization). Conducting the trial in healthy subjects will allow the 
evaluation of lasmiditan metabolism in the absence of concomitant medications. The 
dose, subject population, study duration, and sample collection timing are considered 
adequate to achieve the study objectives. 
5 SUBJECT SELECTION 
Subjects who meet all the inclusion criteria and for whom none of the exclusion criteria 
apply will be eligible to be enrolled into the study. Safety evaluations may be repeated at 
the Investigator’s (or designee’s) discretion. 
Eight subjects will be enrolled to have at least 6 subjects complete the study. Every effort 
will be made to enroll 4 females and 4 males in this study. 
5.1 Inclusion Criteria 
Subjects who meet the following criteria may be included in the study: 
1. 
males and females, between 18 and 60 years of age, inclusive, at 
Screening; 
2. 
have a body mass index range of 18.5 to 32.0 kg/m2, inclusive, at 
Screening; 
3. 
in good health, determined by no clinically significant findings from 
medical history, 12-lead ECG, and vital signs measurements at Screening 
or Check-in (Day -1) as determined by the Investigator (or designee); 
4. 
clinical laboratory evaluations (including clinical chemistry panel [fasted 
at least 10 hours], hematology/complete blood count [CBC], and 
urinalysis [UA]; Appendix A) within the reference range for the test 
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laboratory at Screening and Check-in, unless deemed not clinically 
significant by the Investigator (or designee); 
5. 
negative test for selected drugs of abuse at Screening (does not include 
alcohol) and at Check-in (does include alcohol; Appendix A); 
6. 
negative hepatitis panel (including hepatitis B surface antigen and 
hepatitis C virus antibody and negative human immunodeficiency virus 
(HIV) antibody screens (Appendix A) at Screening; 
7. 
females must be nonpregnant, nonlactating, and either postmenopausal 
(defined as no menstrual period for at least 12 months and confirmed by a 
serum follicle-stimulating hormone [FSH] level of ≥40 mIU/mL), 
surgically sterile (e.g., bilateral oophorectomy, salpingectomy, and/or 
hysterectomy) for at least 90 days prior to Screening, or must have 
undergone bilateral tubal ligation and agree to use effective contraception 
as detailed in Section 6.3.3. For all females, the pregnancy test results 
must be negative at Screening and Check-in; 
8. 
males will be surgically sterile for at least 90 days prior to Screening or 
when sexually-active with female partners of child-bearing potential will 
agree to use contraception as detailed in Section 6.3.3 from Check-in until 
90 days following Discharge. Male subjects must also be willing to refrain 
from donating sperm from Check-in until 90 days following Discharge; 
9. 
able to comprehend and willing to sign an ICF; 
10. 
a minimum of 1 to 2 bowel movements per day. 
5.2 Exclusion Criteria 
The following will exclude potential subjects from the study: 
1. 
significant history or clinical manifestation of any metabolic, allergic, 
infectious, dermatological, hepatic, renal, hematological, pulmonary, 
cardiovascular, gastrointestinal, neurological, or psychiatric disorder (as 
determined by the Investigator [or designee]) prior to Check-in; 
2. 
history of significant hypersensitivity, intolerance, or allergy to any drug 
compound, food, or other substance, unless approved by the Investigator 
(or designee) prior to Check-in; 
3. 
history of stomach or intestinal surgery or resection that could alter 
absorption or excretion of orally administered drugs prior to Check-in, 
except that cholecystectomy, appendectomy, and hernia repair will be 
allowed if it was not associated with complications; 
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4. 
history or presence of an abnormal ECG that, in the Investigator’s (or 
designee’s) opinion, is clinically significant at Screening or Check-in; 
5. 
history of orthostatic hypotension with or without syncope; 
6. 
a sustained seated systolic blood pressure >150 mmHg or <90 mmHg or a 
diastolic blood pressure >90 mmHg or <50 mmHg at Screening or 
Check-in. Blood pressure may be retested twice at intervals of 5 minutes. 
The out-of-range blood pressure values will be considered sustained if 
either the systolic or diastolic blood pressures are outside the stated limits 
after these 3 assessments; 
7. 
history of alcoholism or drug addiction within 1 year prior to Check-in; 
8. 
use of any tobacco- or nicotine-containing products (including but not 
limited to cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine 
patches, nicotine lozenges, or nicotine gum) within 6 months prior to 
Check-in, or positive cotinine screen at Screening or Check-in;  
9. 
participation in more than 1 other radiolabeled investigational study drug 
trial within 12 months prior to Check-in. The previous radiolabeled study 
drug must have been received more than 6 months prior to Check-in for 
this study and the total exposure from this study and the previous study 
will be within the recommended levels considered safe, per United States 
(US) Title 21 Code of Federal Regulations (CFR) 361.1 (e.g., less than 
5,000 mrem whole body annual exposure); 
10. 
exposure to significant radiation (e.g., serial x-ray or computed 
tomography scans, barium meal, current employment in a job requiring 
radiation exposure monitoring) within 12 months prior to Check-in; 
11. 
participation in any other investigational study drug trial in which receipt 
of an investigational study drug occurred within 5 half-lives (if known) or 
30 days prior to Check-in, whichever is longer; 
12. 
use of any prescription medications/products within 14 days prior to 
Check-in, unless deemed acceptable by the Investigator (or designee); 
13. 
use of any over-the-counter, nonprescription preparations (including 
vitamins, minerals, and phytotherapeutic/herbal/plant-derived 
preparations) within 7 days prior to Check-in, unless deemed acceptable 
by the Investigator (or designee); 
14. 
poor peripheral venous access prior to Check-in; 
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15. 
donation of whole blood from 56 days prior to Screening through 
Discharge, inclusive, or of plasma from 30 days prior to Screening 
through Discharge, inclusive; 
16. 
receipt of blood products within 2 months prior to Check-in; 
17. 
subject is at imminent risk of suicide (positive response to question 4 or 5 
on the baseline C-SSRS) or had a suicide attempt within 6 months prior to 
the Screening visit; 
18. 
any acute or chronic condition that, in the opinion of the Investigator (or 
designee), would limit the subject’s ability to complete or participate in 
this clinical study; 
19. 
any other unspecified reason that, in the opinion of the Investigator (or 
designee) or Sponsor, makes the subject unsuitable for enrollment. 
5.3 Removal of Subjects from Study Participation 
Subjects will be informed that they are free to withdraw from the study at any time and 
for any reason. The Investigator (or designee) may remove a subject from the study if, in 
the Investigator’s (or designee’s) opinion, it is not in the best interest of the subject to 
continue the study. Subjects may be withdrawn due to the following: change in 
compliance with inclusion/exclusion criterion that is clinically relevant and affects 
subject safety, occurrence of AEs, intake of nonpermitted concomitant medication that 
might affect subject safety or study assessments/objectives, etc. Notification of 
withdrawal will immediately be made to the Sponsor’s Study Monitor. In case of 
withdrawal of study participation, efforts will be made to perform all final study day 
assessments (Table 6-1). The date the subject is withdrawn from the study and the reason 
for withdrawal will be recorded on the subject’s Case Report Form (CRF). All withdrawn 
subjects will be followed until resolution of all their AEs or until the unresolved AEs are 
judged by the Investigator (or designee) to have stabilized. 
The entire study may be discontinued at the discretion of the Investigator (or designee), 
Sponsor, or Sponsor’s Medical Monitor based on the occurrence of the following: 
• 
AEs unknown to date with respect to their nature, severity, and/or 
duration; 
• 
increased frequency and/or severity and/or duration of known AEs; 
• 
medical or ethical reasons affecting the continued performance of 
the study; 
• 
difficulties in the recruitment of subjects; 
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• 
cancellation of drug development. 
6 STUDY PROCEDURES 
6.1 Schedule of Study Procedures 
A study flow chart is presented in Table 6-1. The total blood volume that will be taken 
during the study is outlined in Appendix B. 
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Table 6-1  Study Flow Chart 
 
Screening 
Check
-in 
 
 
 
 
 
 
 
 
Discharge 
Follow-up 
Phone Call 
Study Procedures 
Days (-29 
through -2) Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
(Day 9 or up 
to Day 14)a 
4 ± 2 days 
after 
Discharge 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
Height, Weight, and 
BMI 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and Drug 
Screend 
X 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
FSHf 
X 
 
 
 
 
 
 
 
 
 
 
 
Confined to the 
Clinical Site 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
Examination 
 
X 
 
 
 
 
 
 
 
 
Xg  
 
C-SSRSh 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Orthostatic Vital 
Signsj 
X 
X 
X 
 
 
 
 
 
 
 
 
 
12-lead ECGk 
X 
X 
 
 
 
 
 
 
 
 
X 
 
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Screening 
Check
-in 
 
 
 
 
 
 
 
 
Discharge 
Follow-up 
Phone Call 
Study Procedures 
Days (-29 
through -2) Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
(Day 9 or up 
to Day 14)a 
4 ± 2 days 
after 
Discharge 
Clinical Chemistry 
Panel, Complete 
Blood Count, 
Urinalysis 
X 
X 
 
X 
 
 
 
 
 
 
X 
 
SAE Monitoringl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Monitoringm 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant 
Medication 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
[14C]-Lasmiditan 
Administrationn 
 
 
X 
 
 
 
 
 
 
 
 
 
Pharmacokinetic/ 
Radioactivity Blood 
Sampleso 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Metabolism Blood 
Samplesp 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
Urine Samplesq 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fecal Samples r 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE = adverse event; BMI = body mass index; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HIV = human immunodeficiency virus; SAE = serious adverse event 
a Early termination procedures to be performed in close proximity to discontinuation of subject from the study. Other procedures may be performed at Investigator (or designee) or 
Sponsor discretion. 
b Interim medical history only. 
c Weight only. 
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d Drug screen does not include alcohol testing at Screening but does include an alcohol breath test at Check-in (Day -1). 
e Females only. A serum pregnancy test will be collected at Screening and Check-in. 
f To confirm postmenopausal status in females only. 
g Abbreviated physical examination only. 
h A baseline version of the C-SSRS survey will be given at Screening and the “since last visit” version of the C-SSRS will be given at Check-in, on Day 2, and at Discharge.  
i Vital sign measurements (oral temperature, respiratory rate, and seated blood pressure and pulse) will be obtained at single timepoints at Screening, Check-in, and at 1, 2, 4, 24, 
48, 72, 96, 120, 168, and 192 hours postdose. If the subject is not discharged on Day 9, additional vital sign measurements will be performed every 24 hours until Discharge. Vital 
sign measurements will be performed with the subject in a seated position after the subject has rested for at least 5 minutes. When the timepoints for blood draws and vital sign 
measurements coincide, the vital sign measurements will be collected prior to the blood draws and as close to the scheduled timepoint as possible. 
j Orthostatic blood pressure and pulse will be obtained at Screening, Check-in, at 0 Hour (predose), and at 1.25, 1.75, and 2.25 hours postdose. Blood pressure and pulse will first 
be collected with the subject in a seated position after the subject has rested for at least 5 minutes. Blood pressure and pulse will be taken again after the subject has been standing 
for 2 to 4 minutes. The same arm will be used during each assessment of blood pressure and pulse. When the timepoints for blood draws and orthostatic vital sign measurements 
coincide, the orthostatic vital sign measurements will be collected prior to the blood draws and as close to the scheduled timepoint as possible. 
k Single 12-lead ECGs obtained at Screening, Check-in, and Discharge. The 12-lead ECGs will be collected after the subject has been resting in a supine position for at least 
10 minutes. When the timepoints for blood draws and ECGs coincide, the ECGs will be collected prior to the blood draws and as close to the scheduled timepoint as possible. 
l Any SAEs occurring after the subject signs the Informed Consent Form will be recorded. 
m Subjects will be monitored for AEs beginning at initiation of study drug. An AE inquiry will be performed at each postdose vital sign measurement. 
n Single oral dose of [14C]-lasmiditan at 200 mg (approximately 100 µCi) administered orally to subjects in a fasted state. 
o Blood samples for pharmacokinetics and radioanalysis will be collected at 0 Hour (predose) and at 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours postdose. 
If the subject is not discharged on Day 9, additional blood samples will be collected every 24 hours until Discharge. If the plasma radioactivity levels fall below the limit of 
quantitation, then samples for radioanalysis will no longer be collected. 
p Blood samples for metabolite profiling and identification collected at 0 Hour (predose) and at 2, 4, 8, 24, 72, and 96 hours postdose. 
q Urine samples collected at -12 to 0 hours (predose, the last void within 1 hour prior to dosing) and at the following collection intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 48, 48 to 
72, 72 to 96, 96 to 120, 120 to 144, 144 to 168, and 168 to 192 hours postdose. If the subject is not discharged on Day 9 (after the 192 hour postdose timepoint), then urine will be 
collected at 24-hour intervals until Discharge. 
r If possible, a baseline fecal sample will be collected predose (within 24 hours of dosing). Fecal samples will also be collected daily (24-hour intervals) from Days 1 through 9. If a 
subject is not discharged on Day 9, then fecal samples will be collected at 24-hour intervals until Discharge.
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6.2 Study Treatment 
6.2.1 
Drug Supplies and Accountability 
The Sponsor (or designee) will provide the Investigator (or designee) with adequate 
quantities of the study drugs (Table 6-2). 
Table 6-2  Study Drugs 
Study Drug 
[14C]-Lasmiditan 
Lasmiditan 
Forma 
Powder 
Powder 
Specific Activity 
0.5µCi/mg 
Not applicable 
Supplier 
ARCINOVA Ltd. 
Aptuit (UK) Ltd. OR Produits 
Chimiques Auxillaires et de Synthèse 
(PCAS) 
Manufacturer 
ARCINOVA Ltd. 
Aptuit (UK) Ltd. OR Produits 
Chimiques Auxillaires et de Synthèse 
(PCAS) 
aSpecific ingredients/purity will be identified in the Certificate of Analysis (or equivalent) that is supplied with the 
study drug(s). 
The lot numbers for the study drug(s) will be provided to the clinical site by the 
supplier/manufacturer as soon as available. 
Nonradiolabeled study drugs will be stored at room temperature (between 15°C and 
30°C) under secure conditions and protected from light). Radiolabeled study drug will be 
stored in a freezer set to maintain -80°C (±10°C). 
The Investigator (or designee) will maintain an accurate record of the receipt of the 
clinical trial materials as shipped by the Sponsor (or designee), including the date 
received. One copy of this receipt will be returned to the Sponsor when the contents of 
the shipment have been verified. In addition, an accurate drug disposition record will be 
kept, specifying the amount dispensed to each subject and the date of dispensation. This 
drug accountability record will be available for inspection at any time. At the completion 
of the study, the original drug accountability record will be available for review by the 
Sponsor on request. 
At the completion of the study, all unused drug supplies will be returned to the Sponsor 
(or designee) or disposed of by the clinical site, per the Sponsor’s (or designee’s) written 
instructions. 
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6.2.2 
Subject Number and Identification 
Subjects will be assigned a number by clinical site staff. Assignment of numbers will be 
in ascending order and no numbers will be omitted. Subject numbers will be used on all 
study documentation. For subjects who are withdrawn by the Investigator (or designee) 
or who voluntarily withdraw prematurely from the study, replacement subjects will not 
be enrolled. 
6.2.3 
Dose Preparation and Administration 
Each unit dose will be prepared by qualified clinical staff. Each unit dose container will 
be appropriately labeled. 
Appropriate unit doses will be administered to consecutively-numbered subjects. 
Although the timing of events requires that each subject will be consistently administered 
the appropriate dose at specific times, the exact dose time of consecutive subjects may be 
staggered to obviate the need to have all subjects on precisely the same study schedule. 
For each dose, the subject’s actual dose time will be recorded in the source documents 
and transcribed into the CRFs. 
Each dose will be administered orally with room temperature water to attain a total 
volume of 240 mL (dose volume + bottle rinses + room temperature water). A hand and 
mouth check will be performed to verify that the dose administered was swallowed. 
Doses will be preceded by an overnight fast (i.e., at least 10 hours) from food (not 
including water) and will be followed by a fast from food (not including water) for at 
least 4 hours postdose. Except as part of dose administration, subjects will restrict their 
consumption of water for 1 hour predose and for 2 hours postdose; at all other times 
during the study, subjects may consume water ad libitum.  
Except when they are using the toilet, study subjects will be observed for approximately 
4 hours postdose to monitor potential AEs and/or nausea. Subjects will not lay supine for 
1 hour following each dose administered, except as necessitated by the occurrence of an 
AE(s) and/or study procedures. 
6.2.4 
Blinding 
This is an open-label study. 
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6.3 Study Restrictions 
6.3.1 
Diet, Fluid, and Activity Control 
Subjects are required to refrain from use of tobacco- or nicotine-containing products 
within 6 months prior to Check-in until Discharge. 
Subjects are required to abstain from consuming alcohol-, grapefruit-, or 
caffeine-containing foods and beverages for 72 hours prior to Check-in until Discharge, 
unless deemed acceptable by the Investigator (or designee). 
Subjects will refrain from strenuous exercise from 48 hours prior to Check-in until 
Discharge and will otherwise maintain their normal level of physical activity throughout 
the entire study (i.e., will not begin a new exercise program nor participate in any 
unusually strenuous physical exertion). 
While confined at the clinical site, subjects will receive a standardized high fiber diet at 
scheduled times that do not conflict with other study-related activities. Prune juice may 
be administered on an as-needed basis to aid in normal bowel function and will not be 
considered a concomitant medication. 
6.3.2 
Concomitant Medications 
Subjects will refrain from participation in any other investigational study drug trial in 
which receipt of any investigational drug occurred within 5 half-lives (if known) or 
30 days, whichever is longer, prior to Check-in until Discharge. 
Subjects will also refrain from the use of any prescription medications/products during 
the interval from 14 days prior to Check-in through Discharge, unless deemed acceptable 
by the Investigator (or designee). In addition, subjects will refrain from the use of any 
over-the-counter nonprescription medications (including vitamins, minerals, and 
phytotherapeutic/herbal/plant-derived preparations) from 7 days prior to Check-in 
through Discharge, unless deemed acceptable by the Investigator (or designee). 
A mild laxative (i.e., Milk of Magnesia®, Colace®) may be used to help with bowel 
movements if necessary. Up to 2 grams per day of acetaminophen may be administered if 
approved by the Investigator (or designee). Subjects on hormone replacement therapy 
will be allowed to continue their regimen throughout the study. The administration of any 
other concomitant medications during the study is prohibited without prior approval of 
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the Investigator (or designee), unless its use is deemed necessary in a medical emergency. 
Any medication taken by a subject during the study and the reason for its use will be 
documented in the source documents and the CRF.  
6.3.3 
Contraception 
Males will be surgically sterile for at least 90 days prior to Screening or must use a male 
condom with spermicide from Check-in (Day -1) until 90 days following Discharge when 
sexually-active with female partners of child-bearing potential. 
Males will refrain from sperm donation from Check-in until 90 days following 
Discharge. 
Females will be surgically sterile (e.g., bilateral oophorectomy, salpingectomy, and/or 
hysterectomy) for at least 90 days prior to Screening, postmenopausal, or will have 
undergone bilateral tubal ligation AND will agree to use 1 of the following methods of 
contraception from Check-in until 90 days following Discharge: 
• diaphragm with spermicide; 
• cervical cap with spermicide; 
• use by the male partner of a condom with spermicide. 
6.4 Pharmacokinetic, [14C] Radioactivity, and Metabolism Procedures 
6.4.1 Pharmacokinetic, [14C] Radioactivity, and Metabolism Blood Sample 
Collection 
Blood samples for PK analysis, total radioactivity, and metabolite profiling and 
identification will be collected via direct venipuncture. Blood samples will be collected at 
the timepoints specified in Table 6-1. The number of blood samples and total blood 
volume required for analysis of PK, radioactivity, and/or for metabolite characterization 
are presented in Appendix B. 
6.4.2 Pharmacokinetic, [14C] Radioactivity, and Metabolism Urine Sample 
Collection 
Urine samples for PK analysis, total radioactivity, and metabolite profiling and 
identification will be collected during the time intervals specified in Table 6-1. 
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6.4.3 
[14C] Radioactivity and Metabolism Fecal Sample Collection 
Fecal samples for total radioactivity and metabolite profiling and identification will be 
collected during the time intervals specified in Table 6-1. 
6.4.4 
Emesis Sample Collection 
For subjects experiencing emesis within 4 hours following dosing, vomitus will be 
collected. Attempts will be made to collect vomitus from subjects experiencing emesis 
after 4 hours postdose. All vomitus collected will be stored for possible analysis. The 
time and date of collection will be recorded on the subject’s source documents and CRF. 
Vomitus will be analyzed as deemed appropriate. 
6.4.5 
Collection of Feminine Hygiene Products 
For female subjects experiencing menses, all feminine hygiene products (e.g., tampons, 
pads, etc.) will be collected from dosing until Discharge and will be stored for possible 
future analysis, as determined by the Sponsor. The time and date of collection will be 
recorded on the subject’s source documents and CRF. Feminine hygiene products will be 
analyzed for radioactivity only as deemed appropriate by the Sponsor (based on the 
overall recovery data). 
6.4.6 
Analytical Methodology 
Plasma and urine concentrations of lasmiditan will be determined by Covance 
Laboratories, Inc. using a validated analytical procedure. Total radioactivity 
concentrations will be determined by Covance Laboratories, Inc. in whole blood, plasma, 
urine, and feces using liquid scintillation counting. Profiling and characterization of 
metabolites in plasma, urine, and feces will be conducted by Covance Laboratories, Inc. 
using standard laboratory procedures. Specifics of the analytical methods will be 
provided in a separate document.  
6.5 Safety Procedures 
Safety evaluations may be repeated at the Investigator’s (or designee’s) discretion. 
Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical 
restrictions, and the other procedures to be performed at the same timepoint. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
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• 
dosing 
• 
blood sampling for PK, radioanalysis, and metabolite identification 
• 
start and end of urine and feces collections (for drug assay) 
• 
vital sign measurements 
• 
ECGs 
• 
blood and urine samples for clinical laboratories 
• 
physical examinations 
• 
C-SSRS 
6.5.1 
Adverse Events 
Adverse event definitions (assignment of severity, causality, action taken, and outcome) 
and procedures for reporting serious AEs are detailed in Appendix C. 
Subjects will be asked a nonleading question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” at the timepoints specified 
in Table 6-1 to assess for the occurrence of AEs. Subjects will also be encouraged to 
voluntarily report AEs occurring at any other time during the study. 
All nonserious AEs, whether volunteered, reported during AE inquiries, or noted on 
physical examination, will be recorded from initiation of study drug until study 
completion. Nonserious AE information should also be collected from the start of a 
washout period or other observational period intended to establish a baseline status for 
the subjects. Serious AEs will be recorded from the time the subject signs the ICF until 
study completion. 
All AEs (nonserious and serious) should be followed until the event has resolved, 
returned to baseline, or is assessed as stable by the Investigator (or designee). 
6.5.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations (including clinical chemistry panel [fasted at least 
10 hours], CBC, and UA; Appendix A) will be collected at the timepoints specified in 
Table 6-1. 
Screens for a hepatitis panel and HIV antibody will be performed at Screening. A drug 
screen for selected drugs of abuse (not including alcohol) will be performed at Screening 
and repeated (including alcohol) at Check-in.  
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6.5.3 
Vital Signs 
Vital sign measurements (including oral temperature, respiratory rate, and seated blood 
pressure and pulse) will be obtained at the timepoints specified in Table 6-1. Seated 
blood pressure and pulse will be measured after the subject has been seated for at least 
5 minutes. 
6.5.4 
Orthostatic Vital Signs 
Orthostatic vital sign measurements (seated and standing blood pressure and pulse) will 
be obtained at the timepoints specified in Table 6-1. The seated blood pressure and pulse 
will be measured after the subject has been seated for at least 5 minutes. The subject will 
then stand for at least 2 minutes, but no more than 4 minutes, and the standing blood 
pressure and pulse will be measured. 
Postural hypotension will be defined as a drop in blood pressure of >10 mmHg for 
diastolic blood pressure, >20 mmHg for systolic blood pressure, or an increase of 
>30 beats per minute in heart rate. 
6.5.5 
Twelve-lead Electrocardiograms 
A 12-lead ECG will be obtained at the timepoints specified in Table 6-1. Subjects will be 
supine for at least 10 minutes prior to obtaining an ECG measurement. 
Electrocardiogram parameters (including heart rate; PR, QRS, and QT intervals; and QT 
interval corrected for heart rate using Fridericia’s formula [QTcF]) and the Investigator’s 
overall interpretation of the ECG will be recorded in the CRF. 
6.5.6 
Physical Examinations 
A routine physical examination will be performed at the timepoints specified in 
Table 6-1. An abbreviated exam (including exam of general appearance, skin, 
thorax/lungs, cardiovascular system, and abdomen) will be performed at the timepoints 
specified in Table 6-1.  
The time and date of the physical examination will be recorded in the CRF and any 
clinically significant findings will be recorded as AEs. 
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6.5.7 
Columbia Suicide Severity Rating Scale 
The C-SSRS rates an individual’s degree of suicidal ideation on a scale ranging from 
“wish to be dead” to “active suicidal ideation with specific plan and intent”. The scale 
intends to prospectively identify and classify suicidal ideation and behavior based on a 
semi-structured interview by the Investigator or designee trained in administering the 
questionnaire. Two versions of the C-SSRS will be used: 
• the baseline version will be administered at Screening; 
• the “since last visit” version will be administered on Days -1, 2, and at Discharge. 
If present, suicidal ideation will be classified in 5 classes (1-5), the intensity of suicidal 
ideation will be classified in 5 dimensions, and any suicidal behavior will be classified in 
6 classes (actual attempt, interrupted attempt, aborted attempt, preparatory acts towards 
an attempt, suicidal behavior, suicide). 
7 DATA ANALYSES AND SAMPLE SIZE 
7.1 Sample Size 
The sample size chosen for this study was based on precedent set by other PK studies of 
similar nature and was not based on power calculations. 
7.2 Study Populations 
The PK population will consist of all subjects who received at least 1 dose of study drug 
and have evaluable PK data. 
The safety population will consist of all subjects who received at least 1 dose of study 
drug and have at least 1 postdose safety assessment. 
7.3 Pharmacokinetic Analysis 
For each subject, the following PK parameters will be calculated, whenever possible, 
based on the plasma concentrations of lasmiditan and total radioactivity in plasma and 
blood, according to the model independent approach4: 
Cmax 
maximum observed concentration 
tmax 
time to maximum concentration 
AUC0-t 
area under the concentration-time curve (AUC) from 
Hour 0 to the last measurable concentration, calculated 
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using the linear trapezoidal rule for increasing 
concentrations and the logarithmic rule for decreasing 
concentrations 
AUC0-∞ 
AUC extrapolated to infinity, calculated using the formula: 
 
 
AUC0-∞ = AUC0-t + 
z
t
λ
C  
 
 
where Ct is the last measurable concentration and λZ is the 
apparent terminal elimination rate constant 
%AUCextrap 
percentage of AUC that is due to extrapolation from the last 
measurable concentration to infinity. 
λZ 
apparent terminal elimination rate constant, where λZ is the 
magnitude of the slope of the linear regression of the log 
concentration versus time profile during the terminal phase 
t1/2 
apparent terminal elimination half-life (whenever possible), 
where t1/2 = natural log (2)/λZ 
CL/F 
apparent oral clearance (for lasmiditan only) 
Vz/F 
apparent volume of distribution (for lasmiditan only) 
AUC0-∞ Blood/Plasma Ratio 
 
AUC0-∞ of total radioactivity in blood/AUC0-∞ of total 
radioactivity in plasma 
AUC0-∞ Plasma lasmiditan/Total Radioactivity Ratio 
 
AUC0-∞ of lasmiditan in plasma/AUC0-∞ of total 
radioactivity in plasma 
In addition, the following PK parameters will be calculated, whenever possible, for each 
subject based on the urine concentrations of lasmiditan and total radioactivity: 
Aeu 
amount excreted in urine over sampling interval 
Total Aeu 
Cumulative Aeu 
CLR 
renal clearance, where CLR = Aeu/AUC0-x (where x is the 
last interval collected; for lasmiditan only) 
%UR 
percentage of lasmiditan recovered in urine, where 
%UR = 100 (Aeu/dose) 
Total %UR 
Cumulative %UR 
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The following PK parameters will be calculated, whenever possible, for each subject 
based on the fecal concentration of total radioactivity: 
 
Aef 
amount excreted in the feces over sampling interval 
Total Aef 
Cumulative Aef 
 
% FR 
percentage of lasmiditan recovered in feces, where 
%FR = 100 (Aef/dose) 
Total %FR 
Cumulative %FR 
Pharmacokinetic calculations will be performed, if appropriate, using commercial 
software such as Phoenix™ WinNonlin® Version 6.4 or higher (Certara USA Inc.). 
Pharmacokinetic parameters for the metabolites of lasmiditan may be calculated, as 
deemed appropriate, based on plasma, urine, and fecal concentration levels. 
Other parameters may be added as appropriate. Final PK parameters reported will be 
detailed in the Statistical Analysis Plan (SAP). 
Pharmacokinetic analysis will use actual times as recorded on the CRF. Other data 
handling procedures will be detailed in the SAP. 
7.4 Statistical Analysis of Pharmacokinetic Data 
Descriptive statistics (mean, standard deviation, coefficient of variation [CV%], 
geometric mean, geometric CV%, etc.) will be calculated for the PK parameters. No 
formal statistical analyses are planned. 
Specification of PK parameters for analysis; statistical level of significance to be used; 
procedures for accounting for missing, unused, or spurious data; procedures for reporting 
deviations from the original statistical plan; and selection of subjects to be included in the 
analyses population(s), as applicable, will be presented in the Clinical Study Report 
and/or SAP as appropriate. 
7.5 Statistical Analyses of Safety Data 
Descriptive statistics will be calculated for the safety parameters. No formal statistical 
analyses are planned. 
For change from baseline calculations, baseline will be defined as the last non-missing 
safety assessment (including any unscheduled assessments) prior to dose. 
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7.6 Data Handling and Record Keeping 
Any changes to information in the trial progress notes and other source documents will be 
initialed and dated on the day the change is made by a clinical site staff member 
authorized to make the change. Changes will be made by striking a single line through 
erroneous data and clearly entering the correct data (e.g., wrong data right data). If the 
reason for the change is not apparent, a brief explanation for the change will be written 
adjacent to the change by the clinician. 
The Data Management Plan will be approved by the Sponsor. 
Data will be validated during data entry by the clinical site and verified by the study 
monitor. Data will then be reviewed by the data management group to resolve any 
outstanding issues. Listings will be generated after the database is cleaned by Data 
Management and will be reviewed by the Covance scientific team. The CRF/electronic 
Case Report Form (eCRF) and ancillary data will be converted into final SAS datasets 
following Study Data Tabulation Model or client-provided specifications. The final 
datasets structure will be verified using Pinnacle 21 OpenCDISC®, while the dataset 
content will be peer-reviewed by an independent programmer. 
The tables, figures, and listings (TFLs) will be programmed per the final SAP. All TFLs 
will be peer-reviewed by an independent programmer. In addition, draft TFLs will be 
reviewed by the Covance scientific team during the dry run and data review meetings. 
The peer-review will be performed by independent programmers following the quality 
control process and programming checklists. 
7.7 Quality Control and Quality Assurance 
Quality control and quality assurance will be performed according to Covance standard 
operating procedures or per client request and as applicable according to the contract 
between Covance and the Sponsor. 
8 ADMINISTRATIVE ASPECTS 
8.1 Change in Protocol 
There will be no alterations in the protocol without agreement between the Sponsor and 
the Investigator. 
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There will be no alterations in the protocol affecting subject safety without the express 
written approval of the Sponsor, Investigator, and the Institutional Review Board (IRB; 
see Form FDA 1572). 
8.2 Site Initiation Visit/Investigator Meeting 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with 
the Investigator(s) and appropriate clinical staff to familiarize the Investigator(s) and 
clinical staff with the materials necessary for conducting the clinical study. 
8.3 Disclosure 
All information provided regarding the study, as well as all information 
collected/documented during the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Any publication of the results, in part or in total (e.g., articles in journals or newspapers, 
oral presentations, abstracts) by the Investigator(s) or their representative(s), shall require 
prior notification and review, within a reasonable time frame, by the Sponsor, and cannot 
be made in violation of the Sponsor’s confidentiality restrictions or to the detriment of the 
Sponsor’s intellectual property rights. 
8.4 Monitoring 
The Sponsor will designate a Sponsor’s Study Monitor who will be responsible for 
monitoring this clinical trial. The Sponsor’s Study Monitor will monitor the study 
conduct, proper CRF and source documentation completion and retention, and accurate 
study drug accountability. To this end, the Sponsor’s Study Monitor will visit the clinical 
site at suitable intervals and be in frequent contact through verbal and written 
communication. It is essential that the Sponsor’s Study Monitor has access to all 
documents (related to the study and the individual participants) at any time these are 
requested. In turn, the Sponsor’s Study Monitor will adhere to all requirements for 
subject confidentiality as outlined in the ICF. The Investigator and Investigator’s staff 
will be expected to cooperate with the Sponsor’s Study Monitor, to be available during a 
portion of the monitoring visit to answer questions, and to provide any missing 
information. 
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8.5 Institutional Review Board 
In accordance with US Title 21 CFR 56, the protocol, advertisement, ICF, and other 
information provided to subjects will be reviewed and approved by the IRB. The Sponsor 
will supply relevant material for the Investigator (or designee) to submit to the IRB for 
the protocol’s review and approval. Verification of the IRB unconditional approval of the 
protocol and the written ICF statement will be transmitted to the Investigator (or 
designee). 
The IRB will be informed by the Investigator (or designee) of subsequent protocol 
amendments and of serious and unexpected AEs. Approval for protocol amendments will 
be transmitted in writing to the Investigator (or designee). If requested, the Investigator 
(or designee) will permit audits by the IRB and regulatory inspections by providing direct 
access to source data/documents. 
The Investigator (or designee) will provide the IRB with progress reports at appropriate 
intervals (not to exceed 1 year) and a Study Progress Report following the completion, 
termination, or discontinuation of the Investigator’s participation in the study. 
8.6 Informed Consent 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out. The ICF will be approved (along with the 
protocol) by the IRB and will be acceptable to the Sponsor. 
The Investigator (or designee) will explain the nature of the study and the action of the 
test product. The subjects will be informed that participation is voluntary and that they 
can withdraw from the study at any time. In accordance with 21 CFR 50, the informed 
consent process shall be documented by the use of a written ICF approved by the IRB 
and signed by the subject prior to protocol-specific procedures being performed. 
The subject will sign 2 copies of the ICF. One copy will be given to the subject, and the 
other will be maintained with the subject’s records. 
8.7 Records 
The results from data collected at Screening and during the study will be recorded in the 
subject’s CRF (paper or eCRF). To maintain confidentiality, the subjects will be 
identified only by numbers. 
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The completed CRFs will be transferred to the Sponsor (or designee). Copies of each 
CRF will be retained by the Investigator (or designee). All source documents, records, 
and reports will be retained by the clinical site in accordance with 21 CFR 312.62(c). 
All primary data, or copies thereof (e.g., laboratory records, CRFs, data sheets, 
correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report, will be retained in the clinical site archives. 
8.8 Reference to Declaration of Helsinki/Basic Principles 
The study procedures outlined in this protocol will be conducted in accordance with the 
US CFR governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by 
Clinical Investigators (21 CFR 54), IRBs (21 CFR 56), Investigational New Drug 
Application (21 CFR 312), Applications for FDA Approval to Market a New Drug 
(21 CFR 314), and Radioactive Drugs For Certain Research Uses (21 CFR 361.1), as 
appropriate. As such, these sections of US Title 21 CFR, along with the applicable 
International Conference on Harmonisation Guidelines, are commonly known as Good 
Clinical Practices, which are consistent with the Declaration of Helsinki. 
8.9 Financing and Insurance 
Financing and insurance will be addressed in a separate agreement. 
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CoLucid Pharmaceuticals, Inc. 
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INVESTIGATOR AGREEMENT 
CONFIDENTIAL 
Protocol COL MIG-II 0 
I have read the foregoing protocol and agree to conduct the study as described herein. 
 
Date 
 
Covance Clinical Research Unit, Inc. 
Finall.O: 23 January 2017 
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PPD
PPD
PPD
PPD

CoLucid Pharmaceuticals, Inc. 
Clinical Protocol 
Covance Study 8331469 
SPONSOR AGREEMENT 
CONFIDENTIAL 
Protocol COL :tv.IIG-110 
I have read the foregoing protocol and agree to conduct the study as described herein: 
 
Date 
 
CoLucid Pharmaceuticals, Inc. 
Final 1.0: 23 January 2017 
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Page 42 of 48 
 
REFERENCES 
1. Goadsby PJ, Lipton RB, Ferrari MD. Migraine-current understanding and 
treatment. N Engl J Med. 2002;346(4):257-270. 
2. Dodick DW, Lipton RB, Martin V, et al. Triptan Cardiovascular Safety Expert 
Panel. Consensus statement: cardiovascular safety profile of triptans (5-HT 
agonists) in the acute treatment of migraine. Headache. 2004;44:414-425. 
3. Potchoiba MJ and Oswald J. Covance 8332113. Dosimetry Calculations for 
[14C]-Lasmiditan Base on Quantitative Whole-Body Autoradiographic Data in 
Rats. Covance Laboratories, Inc.; Madison, Wisconsin; 2016. 
4. Gibaldi M, Perrier D. Pharmacokinetics. 2nd edition. New York, NY: Marcel 
Dekker Inc.; 1982. 
5. Department of Health and Human Services, Food and Drug Administration. 
International Conference on Harmonisation; Guidelines on Structure and Content 
of Clinical Study Reports; Availability. Federal Register. 
1996;61(138):37320-37343. 
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APPENDIX A - CLINICAL LABORATORY EVALUATIONS 
Clinical Chemistry Panel (Fasted): Complete Blood Count: 
Urinalysis: 
Alanine aminotransferase 
Hematocrit 
Bilirubin 
Albumin 
Hemoglobin 
Color and appearance 
Alkaline phosphatase 
Mean corpuscular hemoglobin 
Glucose 
Aspartate aminotransferase 
Blood urea nitrogen 
Mean corpuscular hemoglobin 
concentration 
Ketones 
Leukocyte esterase 
Calcium 
Mean corpuscular volume 
Nitrite 
Chloride 
Platelet count 
Occult blood 
Cholesterol 
Red blood cell (RBC) count 
pH and specific gravity 
Creatinine 
RBC distribution width 
Protein 
Glucose 
White blood cell (WBC) count 
Urobilinogen 
Iron 
Phosphorus  
Potassium 
Sodium 
WBC differential (absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Microscopic exam including 
bacteria, casts, crystals, 
epithelial cells, RBCs, and 
WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
Total bilirubin 
 
 
Total protein 
 
 
Triglycerides 
 
 
Uric acid 
 
 
 
 
 
 
 
 
Drug Screen: 
Other Tests: 
Hormone panel – females 
only: 
Including but not limited to the 
following: 
Hepatitis B surface antigen 
Hepatitis C virus antibody 
Follicle-stimulating hormone 
(postmenopausal females only) 
Alcohol (ethanol; via breathalyzer; 
at Check-in only) 
Amphetamines 
Human Immunodeficiency Virus 
antibody 
Serum pregnancy test (human 
chorionic gonadotropin) 
Barbiturates 
Benzodiazepines 
 
 
Cannabinoids 
 
 
Cocaine (metabolite) 
 
 
Methadone 
 
 
Opiates 
 
 
Phencyclidine 
Cotinine 
 
 
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APPENDIX B - BLOOD SAMPLING SUMMARY 
Purpose 
Maximum Blood Volume 
per Sample (mL) 
Maximum Number of 
Blood Samples 
Maximum Total 
Volume (mL) 
Serology 
4 
1 
4 
Pharmacokinetic and total 
radioactivity sampling 
10 
23 
230 
Metabolism sampling 
10 
7 
70 
Clinical laboratory tests 
8 
4 
32 
Pregnancy tests 
4 
2 
8 
FSH tests 
4 
1 
4 
Total 
 
 
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APPENDIX C - ADVERSE EVENTS 
1 ADVERSE EVENTS 
1.1 Definition of Adverse Events 
An adverse event (AE; or adverse experience) is defined as any untoward medical 
occurrence experienced by a patient or healthy subject, whether or not considered drug 
related by the Investigator (or designee). A treatment-emergent AE is an AE that is reported 
after a dose of study drug. 
 
The following are all AEs: 
• 
unfavorable changes in general condition; 
• 
subjective or objective signs/symptoms; 
• 
concomitant diseases or accidents; 
• 
clinically relevant adverse changes in laboratory parameters 
observed in a subject during a clinical study. 
 
Adverse events comprise all disturbances of general health status, subjective and 
objective disease symptoms (including laboratory abnormalities), and accidents observed 
in the context of a clinical trial, irrespective of a possible causal relationship with the 
administration of the trial substance. Events occurring in the framework of a clinical trial 
during drug-free and post-treatment periods, under placebo, or in a reference group 
receiving drug or nondrug therapy are also to be designated as AEs. 
1.2 Categorization of Adverse Events 
The severity of AEs will be categorized as follows: 
• 
MILD = of little concern to the subject and/or of no clinical 
significance, is not expected to affect the subject’s health or 
well-being; 
• 
MODERATE = discomforting enough to cause interference with 
or change in usual activities, is likely to require medical 
intervention or close follow-up; 
• 
SEVERE = incapacitating or causing inability to work or 
participate in many or all usual activities, is of concern to the 
subject or poses substantial risk to the subject’s health or 
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well-being, is likely to require medical intervention or close 
follow-up. 
 
The Investigator (or designee) will make a determination of the relationship of the AE to 
the study drug using a 2-category system according to the following guidelines: 
• 
Reasonable Possibility = a plausible temporal relationship exists 
between the AE onset and administration of the investigational 
product, and the AE cannot be readily explained by the subject’s 
clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be 
possibly related, based on the known therapeutic and 
pharmacologic actions or AE profile of the investigational product. 
In case of cessation or reduction of the dose, the AE may abate or 
resolve and it may reappear upon rechallenge. 
• 
No Reasonable Possibility = evidence exists that the AE has an 
etiology other than the investigational product and/or no plausible 
temporal relationship exists between the AE onset and 
administration of the investigational product.  
For SAEs, an alternative causality must be provided (e.g., pre-
existing condition, underlying disease, intercurrent illness, or 
concomitant medication). 
 
An AE is associated with the use of the drug if there is a reasonable possibility that the 
experience may have been caused by the drug. 
 
The following categories will be used for the action taken with the study drug for the AE: 
drug withdrawn, dose not changed, drug interrupted, unknown, and not applicable. 
 
The following categories will be used for the outcome of the AE: resolved, resolved with 
sequelae, ongoing, fatal, and unknown. 
1.3 Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported 
immediately to the Investigator (or designee) or Sponsor, including pregnancy in female 
partners of male subjects. The pregnancy may be followed to term or outcome and this 
outcome may be reported to the Sponsor. Pregnancy, in and of itself, is not regarded as an 
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AE or serious AE (SAE) unless the birth results in a congenital anomaly/birth defect or 
there is suspicion that the study medication may have interfered with the effectiveness of 
a contraceptive medication or method. 
1.4 Definition of Serious Adverse Events 
An SAE (by Food and Drug Administration [FDA] definition) is any adverse drug 
experience occurring at any dose that results in any of the following outcomes: 
• 
death; 
• 
a life-threatening adverse drug experience (i.e., places the subject, 
in the view of the Investigator (or designee), at immediate risk of 
death); 
• 
inpatient hospitalization or prolongation of existing hospitalization; 
• 
a persistent or significant disability/incapacity; 
• 
a congenital anomaly/birth defect; 
• 
important medical event that may require medical or surgical 
intervention to prevent one of the above outcomes. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. All SAEs must be 
collected that occur after the subject signs the Informed Consent Form. 
1.5 Unexpected Adverse Drug Experience 
An unexpected adverse drug experience is any adverse drug experience, the specificity or 
severity of which is not consistent with the current Investigator Brochure (IB) or, if an IB 
is not required or available, the specificity or severity of which is not consistent with the 
risk information described in the general investigational plan or elsewhere in the current 
application, as amended. 
1.6 Reporting 
Food and Drug Administration-reportable AEs are AEs that are associated with the use of 
the drug and are serious and unexpected. Food and Drug Administration-reportable AEs 
will be reported by the clinical site to the Sponsor, Medical Monitor assigned by the 
Sponsor, and the responsible Institutional Review Board (IRB). 
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The Sponsor and Medical Monitor will be notified in writing (e.g., facsimile) within 
24 hours of when an AE that is potentially FDA-reportable is first recognized or reported. 
 
Subsequently, a written confirmation or summary of the AE (using FDA Form 3500A, or 
equivalent) will be sent to the Sponsor within 3 working days of the original notification. 
(Instructions for completion of FDA Form 3500A may be obtained from the FDA 
website at www.fda.gov/medwatch/how.htm.). 
 
The IRB will be notified of any FDA-reportable AE within the timeframe required by the 
IRB. The IRB Serious and Unexpected Adverse Experience Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the 
AE.  
 
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