Clinical trial NCT03040362
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2017-04-20; Completion date: 2017-05-06
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will be an open-label, nonrandomized, absorption, metabolism, and excretion study of \[14C\]-lasmiditan administered as a 200-milligrams (mg) (approximately 100 microcuries\[µCi\]) oral solution to 8 healthy males and females, following at least a 10 hour fast from food 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 males and females.

Detailed description:

Arms: arm 1: \[14C\]-lasmiditan administered as a 200 mg (approximately 100 µCi) oral solution
Interventions: intervention 1: [14C]-lasmiditan
Intervention descriptions: intervention 1: \[14C\]-lasmiditan as a 200 mg (approximately 100 µCi) oral solution

Protocol documents:
Prot_000.pdf: 
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 
Page 1 of 48 
 
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 
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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 
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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 
Page 4 of 48 
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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CONFIDENTIAL 
Protocol COL MIG-110 
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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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CoLucid Pharmaceuticals, Inc. 
Clinical Protocol 
Covance Study 8331469 
CONFIDENTIAL 
Protocol COL MIG-110 
Final 1.0:23 January 2017 
Page 7 of 48 
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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CoLucid Pharmaceuticals, Inc. 
Clinical Protocol 
Covance Study 8331469 
CONFIDENTIAL 
Protocol COL MIG-110 
Final 1.0:23 January 2017 
Page 8 of 48 
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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CoLucid Pharmaceuticals, Inc. 
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Covance Study 8331469 
CONFIDENTIAL 
Protocol COL MIG-110 
Final 1.0:23 January 2017 
Page 9 of 48 
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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CoLucid Pharmaceuticals, Inc. 
Clinical Protocol 
Covance Study 8331469 
CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0:23 January 2017 
Page 10 of 48 
 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
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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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Protocol COL MIG-110 
 
 
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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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CoLucid Pharmaceuticals, Inc. 
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Protocol COL MIG-110 
 
 
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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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Protocol COL MIG-110 
 
 
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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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Protocol COL MIG-110 
 
 
Final 1.0:23 January 2017 
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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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8331469 
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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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
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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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 33 of 48 
 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 34 of 48 
 
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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CoLucid Pharmaceuticals, Inc. 
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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 35 of 48 
 
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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Clinical Protocol 
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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 36 of 48 
 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 37 of 48 
 
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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CoLucid Pharmaceuticals, Inc. 
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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 38 of 48 
 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 39 of 48 
 
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. 
Clinical Protocol 
Covance Study 8331469 
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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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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Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 43 of 48 
 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 44 of 48 
 
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 
 
 
348 
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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 45 of 48 
 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 46 of 48 
 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 47 of 48 
 
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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CONFIDENTIAL 
Protocol COL MIG-110 
 
 
Final 1.0: 23 January 2017 
Page 48 of 48 
 
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.  
 
Page 49 of 49

SAP_001.pdf: 
Statistical Analysis Plan 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: 06-Jun-2017 
 
 
 


Clinical Study Report 
CoLucid Reference: COL MIG-110 
 
 
CONFIDENTIAL
16.1.9 
Documentation of Statistical Methods 
Final
Page 1 of 18
Approval Date: 26-Mar-2018 GMT


Final: 06 June 2017 
 
Page 1 of 17
STATISTICAL ANALYSIS PLAN 
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 
Statistical Analysis Plan Status: Final 
Statistical Analysis Plan Date: 06 June 2017 
Study Drug: [14C]-Lasmiditan  
Sponsor Reference Number: COL MIG-110 
Covance Study Number: 8331469 
Clinical Phase 1 
Sponsor:
CoLucid Pharmaceuticals, Inc. 
222 Third Street, Suite 1320 
Cambridge, Massachusetts 02142 
United States 
Study Site: 
Covance Clinical Research Unit Inc. 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
United States 
Sponsor Signatory: 
 
 
Telephone:  
 
Principal Investigator: 
 
Telephone:  
 
Page 2 of 18
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Statistical Analysis l' Jan 
Covance Study: 8331469 
CONFIDENTJJ\L 
Sponsor Reference: COL MIG-(fl) 
1 STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES 
By signing this page when the Statistical Analysis Plan (SAP) is considered final, the signatories 
agree to the statistical and pharmacokinetic (PK) analyses to be perfo1med ror this study, and to 
the basic format of the tables, figll'es, and listings (TFLs). Once the SAP has been signed;· 
programming of the TFLs based upon this document can proceed. Any modifications to the SAP 
and TFLs made after signing may result in a work-scope change. 
Covance approval: 
 
Sponsor approval: 
 
 
 
 
 
 
 
 
CoLucid Pharmaceuticals, Inc. 
Final: 06 June 2017 
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Statistical Analysis Plan  
CONFIDENTIAL 
Covance Study: 8331469 
Sponsor Reference: COL MIG-110 
Final: 06 June 2017 
 
Page 3 of 17
2  TABLE OF CONTENTS 
1  
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................... 2 
2  
TABLE OF CONTENTS ................................................................................................... 3 
3  
ABBREVIATIONS ............................................................................................................ 4 
4  
INTRODUCTION .............................................................................................................. 6 
5  
STUDY OBJECTIVES ...................................................................................................... 6 
6  
STUDY DESIGN ............................................................................................................... 7 
7  
TREATMENT .................................................................................................................... 8 
8  
SAMPLE SIZE JUSTIFICATION ..................................................................................... 8 
9  
DEFINITION OF ANALYSIS POPULATIONS .............................................................. 8 
10  STATISTICAL METHODOLOGY ................................................................................... 9 
10.1  General ......................................................................................................................... 9 
10.1.1  Definition of Baseline and Change from Baseline ............................................. 9 
10.1.2  Repeat and Unscheduled Readings .................................................................... 9 
10.2  Demographics and Subject Disposition ..................................................................... 10 
10.3  Pharmacokinetic Assessment ..................................................................................... 10 
10.3.1  Pharmacokinetic Analysis ................................................................................ 10 
10.3.2  Presentation of Pharmacokinetic Data ............................................................. 15 
10.4  Safety and Tolerability Assessments ......................................................................... 15 
10.4.1  Adverse Events ................................................................................................. 15 
10.4.2  Clinical Laboratory Parameters ........................................................................ 16 
10.4.3  Vital Signs ........................................................................................................ 16 
10.4.4  Electrocardiogram ............................................................................................ 16 
10.4.5  Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 16 
10.4.6  Other Assessments ........................................................................................... 16 
10.4.7  Safety and Tolerability Statistical Methodology .............................................. 16 
11  INTERIM ANALYSES .................................................................................................... 16 
12  CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 17 
13  DATA PRESENTATION ................................................................................................ 17 
13.1 Insufficient Data for Presentation ............................................................................... 17 
14  REFERENCES ................................................................................................................. 17 
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3  ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
ADaM 
analysis data model 
AE
adverse event
CDISC 
Clinical Data Interchange Standards Consortium 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV% 
coefficient of variation 
EC
Early Clinical
ECG
electrocardiogram
ICH 
International Conference on Harmonisation 
MedDRA 
Medical Dictionary for Regulatory Activities 
QTc 
QT correction; QT interval corrected for heart rate 
QTcF 
QTc calculated using the Fridericia correction  
SAP 
Statistical Analysis Plan 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
%AUCextrap 
percentage of AUC that is due to extrapolation from the time of the 
last quantifiable concentration to infinity 
%FR 
Percent of dose recovered in feces over a sampling interval 
%UR 
Percent of dose recovered in urine over a sampling interval 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
AUC0-tlast 
area under the concentration-time curve from time zero to the time 
of the last quantifiable concentration 
Aef 
Amount excreted in feces over a sampling interval 
Aeu 
Amount excreted in urine over a sampling interval 
BLQ 
below the limit of quantification 
BMI
body mass index
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CL/F 
apparent total clearance 
Cmax 
maximum observed plasma concentration 
CLR
Renal clearance
LLOQ 
lower limit of quantification 
LS
least squares
PK
pharmacokinetic
PT
preferred term
R2 -adjusted 
adjusted coefficient of variation for goodness of fit 
SD
standard deviation
SOC 
system organ class 
t½ 
apparent terminal elimination half-life 
tlast 
Time of last quantifiable concentration 
tmax 
time of maximum observed concentration 
TRA
total radioactivity
Vz/F 
apparent volume of distribution during the terminal phase 
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Statistical Analysis Plan  
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4  INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 dated 
23 January 2017). 
This SAP describes the planned analysis of the safety, tolerability, and PK data from this study. 
A detailed description of the planned TFLs to be presented in the Clinical Study Report (CSR) is 
provided in the accompanying TFL shell document. 
The intent of this document is to provide guidance for the statistical analyses of PK data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between CoLucid Pharmaceuticals, Inc. and Covance Early Clinical (EC) 
Biometrics. A limited amount of information concerning this study (eg, objectives, study design) 
is given to help the reader’s interpretation. This SAP must be finalised prior to the lock of the 
clinical database for this study. When the SAP and TFL shells are agreed upon and finalized, 
they will serve as the template for this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between CoLucid Pharmaceuticals, Inc. and Covance EC Biometrics and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline entitled, “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH E3 guideline entitled, “Guidance for Industry: 
Structure and Content of Clinical Study Reports.”1,2 
5  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 Ci) [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.
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6  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 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. 
Figure 1. Study Design Schematic 
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. 
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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 in the 
protocol), 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. 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 in the protocol. 
7  TREATMENT 
The treatment administered will be a single dose of 200 mg (approximately 100 Ci) 
[14C]-lasmiditan 
8  SAMPLE SIZE JUSTIFICATION 
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. 
9  DEFINITION OF ANALYSIS POPULATIONS 
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. 
The PK Population will consist of all subjects who received at least 1 dose of study drug and 
have evaluable PK data. A subject will be excluded from the PK summary statistics and 
statistical analysis if the subject has an adverse event (AE) of vomiting that occurs at or before 2 
times median time to maximum concentration.  
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Details of subject assignment to the analysis populations will be listed. 
The All Subjects Population will consist of any subjects who enrolled on to the study (signed 
informed consent) and had study assessments recorded on the database as per the protocol. The 
All Subjects Population will include the Safety Population.  
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Statistical Analysis Plan  
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10 
STATISTICAL METHODOLOGY 
10.1 General 
Data listings will be provided for the All Subjects Population. Summary statistics and statistical 
analyses will be performed for subjects included in the relevant analysis populations 
(Safety/PK).  
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation, arithmetic coefficient of variation (CV%), median, minimum, maximum, and number. 
For log-normal data (eg, the PK parameters: areas under the concentration-time curve [AUCs] 
and maximum observed concentration [Cmax]), the geometric mean and geometric CV% will also 
be presented. For categorical data, frequency counts and percentages will be presented. Data 
listings will be provided for all subjects up to the point of withdrawal, with any subjects 
excluded from the relevant population highlighted. For the calculation of summary statistics and 
statistical analysis, unrounded data will be used. 
Missing values will not be imputed. 
Data analysis will be performed using SAS® Version 9.3 or higher. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilised to ensure 
compliance with CDISC standards. 
10.1.1 Definition of Baseline and Change from Baseline 
Baseline for each parameter is defined as the last value measured prior to dosing, including 
repeat (vital signs or ECG) and unscheduled (clinical laboratory parameters) readings (see 
Section 10.1.2 for definitions of repeat and unscheduled readings).  
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate. 
10.1.2 Repeat and Unscheduled Readings 
Repeat readings occur when the original vital signs or ECG result requires confirmation. Repeat 
readings are labelled as ‘Repeat’ in the listings and replace the original readings in all summaries 
and changes from baseline presentations and calculations. Prior to dosing, all readings taken in 
addition to the original reading are defined as predose repeats. Postdose repeat readings are 
defined as readings collected within 15 minutes of the actual time of the original reading.  
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Statistical Analysis Plan  
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With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
Unscheduled readings are labelled as ‘Unscheduled’ in the listings. Because unscheduled 
postdose readings are not associated with any scheduled timepoint, they are excluded from all 
summaries (with the exception that they may be used as baseline, as stated in Section 10.1.1). 
10.2 Demographics and Subject Disposition 
The demographic variables age, sex, race, ethnicity, body weight, height, and body mass index 
will be summarised and listed. Subject disposition will be summarised and listed. 
10.3 Pharmacokinetic Assessment 
10.3.1 Pharmacokinetic Analysis 
The following pharmacokinetic parameters will be determined, where possible, based on the 
plasma concentrations of lasmiditan, metabolites M3, M7, M8, and M18 and total radioactivity 
in whole blood and plasma, using non-compartmental methods performed using Phoenix 
WinNonlin (Certara United States, Inc.) version 6.4 or higher: 
Parameter
Definition
AUC0-tlast 
Area under the concentration-time curve from time 0 to the time of last 
measurable concentration (tlast), calculated using the linear trapezoidal 
rule for increasing concentrations and the logarithmic rule for decreasing 
concentrations 
AUC0- 
Area under the concentration-time curve from time 0 extrapolated to 
infinity 
%AUC(tlast-∞) 
Percentage of AUC that is due to extrapolation from the last measurable 
concentration to infinity 
Cmax 
Maximum observed concentration 
tmax 
Time of maximum observed concentration 
tlast 
Time of last quantifiable concentration 
t1/2 
Apparent terminal elimination half-life 
z
Apparent terminal elimination rate constant, where z is the magnitude 
of the slope of the linear regression of the log concentration versus time 
profile during the terminal phase 
CL/F 
Apparent oral clearance (calculated for lasmitidan only) 
Vz/F 
Apparent volume of distribution during the terminal elimination phase 
(calculated for lasmitidan only) 
AUC Ratio  
(Blood /Plasma) 
AUC0-∞ of total radioactivity in whole blood/AUC0-∞ of total 
radioactivity in plasma 
AUC Ratio 
(Lasmitidan/TRA) 
AUC0-∞ of lasmitidan in plasma/AUC0-∞ of total radioactivity in plasma 
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AUC Ratio 
(Metabolite/TRA) 
AUC0-∞ of metabolite in plasma/AUC0-∞ of total radioactivity in plasma 
(calculated for each metabolite) 
M:P AUC Ratio 
Metabolite to lasmitidan (parent) ratio calculated as: 
AUC0-∞ metabolite/AUC0-∞ lasmitidan 
AUC0-, CL/F, and Vz/F will be calculated based on predicted Clast. 
In addition, the following PK parameters will be calculated, whenever possible, for each subject 
based on the urine concentrations of lasmitidan, metabolites M3, M7, M8, M18 and total 
radioactivity. Parameters for lasmitidan and metabolites will be reported by the Covance Early 
Clinical Biometrics PK group; parameters for total radioactivity will be reported by the Covance 
Radioanalysis group.  
Parameter
Definition
Aeu 
Amount excreted in urine over a sampling interval, calculated as the 
sample weight (g) for the interval * concentration in urine. A 
specific gravity of 1 g/mL is assumed for urine. 
Total Aeu 
Cumulative amount excreted in urine, calculated as the sum of the 
Aeu for all sampling intervals 
CLR 
Renal clearance, where CLR = Total Aeu 0-x h/AUC0-x h (where x is 
the time of the last interval collected; calculated for lasmitidan 
only) 
%UR 
Percent of lasmitidan dose recovered in urine over a sampling 
interval, where %UR = 100 * (Aeu lasmitidan/lasmitidan dose) 
%UR for metabolites will be calculated as follows: 
%UR = 100 * (Aeu metabolite/(lasmitidan dose)) 
Total %UR 
Cumulative percent of dose recovered in urine, calculated as the 
sum of %UR for all sampling intervals 
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The following PK parameters will be calculated, whenever possible, for each subject based on 
the fecal concentrations of total radioactivity. Parameters for total radioactivity will be reported 
by the Covance Radioanalysis group. 
Parameter
Definition
Aef 
Amount excreted in feces over a sampling interval 
Total Aef 
Cumulative amount excreted in feces, calculated as the sum of the 
Aef for all sampling intervals 
% FR 
Percent of dose recovered in feces over a sampling interval, where 
%FR = 100 * (Aef/dose) 
Total % FR 
Cumulative percent of dose recovered in feces, calculated as the 
sum of %FR for all sampling intervals 
Additional pharmacokinetic parameters may be determined where appropriate. 
Pharmacokinetic analysis will, where possible, be carried out using actual post dose times 
recorded in the raw data. If actual times are missing, nominal times may be used with sponsor 
approval.  
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
Cmax and tmax will be obtained directly from the concentration-time profiles.   
For multiple peaks, the highest post dose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest tmax will be reported.  
AUC0-t or other common partial area may be used to determine ratios if AUC0-∞ cannot be 
calculated. 
The amount excreted in urine (Aeu) for each urine collection interval will be calculated as the 
product of urine concentration and urine weight (assuming specific gravity is approximately 1); 
Total Aeu0-x h will be calculated by summing the Aeu values for each collection interval over the 
study collection period, where x is the end time of the last collection interval. 
The percent of the dose excreted (%UR) will be calculated for each urine collection interval (i) 
according to the following formula: 
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Statistical Analysis Plan  
 
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100
×
dose
)i(
A
=
)i(
UR
%
eu
 
Total %UR will be calculated by summing the %UR values for each collection interval over the 
study collection period. 
CLR will be calculated over 0-x h according to the following formula: 
h
x
-
0
h
x
-
0
R
AUC
Aeu
Total
=
CL
 
10.3.1.1 Criteria for handling concentrations below the limit of quantification in 
Pharmacokinetic analysis 
 Concentration values that are below the level of quantification (BLQ) will be set to zero, 
with defined exceptions as follows; 
 Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
 If there are late positive concentration values following 2 BLQ concentration values in the 
apparent terminal phase, these values will be evaluated. If these values are considered to 
be anomalous, they will be set to missing. 
 If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis. 
 If a predose concentration is missing, it may be set to zero with sponsor approval 
10.3.1.2 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life 
 Number of Data Points 
At least three data points will be included in the regression analysis and preferably should not 
include Cmax. 
 Goodness of Fit 
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Statistical Analysis Plan  
 
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When assessing terminal elimination phases, the R2 adjusted (adjusted coefficient of variation for 
goodness of fit) value will be used as a measure of the goodness of fit of the data points to the 
determined line.  
An elimination half-life will only be calculated if the R2 adjusted value of the regression line is 
greater than or equal to 0.7. 
 Period of Estimation 
Time period used for the estimation of apparent terminal elimination half-lives, where possible, 
will be over at least two half-lives.  
Where an elimination half-life is estimated over a time period of less than two half-lives, it will 
be flagged in the data listings at the discretion of the pharmacokineticist, and the robustness of 
the value should be discussed in the study report. 
 
10.3.1.3 Calculation of AUC 
 The minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive concentrations above the lower limit of quantification (LLOQ), with at least 
one of these concentrations following Cmax.  
 For any partial AUC determination (i.e. AUC0-x h), nominal time will generally be used 
for the end of the interval. Actual times for partial AUC intervals may be used at the 
discretion of the Pharmacokineticist.  
 AUC0- values where the percentage extrapolation is less than 20% will be reported. 
AUC0- values where the percentage extrapolation is between 20 to 30% will be flagged 
and included in the descriptive statistics, whilst AUC0- values where the percentage 
extrapolation is greater than 30% will be reported but excluded from descriptive 
statistics.   
 If AUC0-∞ cannot be determined for all subjects, an alternative AUC measure, such as 
AUC to a fixed time point, may be used in the calculation of ratios. 
 
10.3.1.4 Anomalous Values 
If a value is considered to be anomalous due to being inconsistent with the expected 
pharmacokinetic profile, it may be appropriate to exclude this point from the pharmacokinetic 
analysis. However, the exclusion of data must have strong justification and will be documented 
in the raw data and study report. 
 
Embedded BLQ values may be considered anomalous depending on the route of administration 
and the characteristics of the drug. 
 
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Statistical Analysis Plan  
 
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Positive predose value(s) greater than 5% of Cmax may be excluded from the summary statistics 
of PK tables and statistical analysis at the discretion of the Pharmacokineticist. 
 
10.3.2 Presentation of Pharmacokinetic Data 
10.3.2.1 Presentation of Pharmacokinetic Plasma Drug Concentration Data 
The following rules will be applied if there are values that are BLQ or if there are missing values 
(e.g., no result [NR]) in a concentration data series to be summarized. 
 For the calculation of summary statistics, BLQ values will be set to zero. 
 If an embedded BLQ value is considered anomalous within the concentration-time profile, 
this value will be excluded from the summary statistics. 
 Where there is NR, these will be set to missing. 
 If there are less than three values in the data series, only the min, max and N will be 
presented. The other summary statistics will be denoted as not calculated (NC). BLQ is 
considered a value. 
 If all the values are BLQ, then the arithmetic mean, arithmetic SD, median, min and max 
will be presented as zero, and the geometric mean and geometric CV% will be denoted as 
NC. 
 If the value of the arithmetic mean or median is below the lower limit of quantification, 
these values will be presented as zero and the geometric mean and geometric CV% will 
be denoted as NC. 
 
10.3.2.2 Presentation of Pharmacokinetic Parameters 
 For the calculation of summary statistics of PK parameters, all NR and NC values in a data 
series will be set to missing. 
 The AUC values will be set to NC if they have been calculated using fewer than three 
concentrations, and/or three concentrations if the last is Cmax. 
10.4 Safety and Tolerability Assessments 
10.4.1 Adverse Events 
All AEs will be listed. The TEAEs will be summarised by treatment, severity, and relationship to 
the study drug. The frequency (the number of TEAEs, the number of subjects experiencing a 
TEAE, and the percentage of subjects experiencing a TEAE) of TEAEs will be summarised by 
treatment, and by Medical Dictionary for Regulatory Activities system organ class and preferred 
term. The summary and frequency TEAE tables will be presented for all causalities and for those 
TEAEs considered related to the study drug (those that have a relationship of reasonable 
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Statistical Analysis Plan  
 
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possibility). Any severe or serious AEs will be tabulated. For any AEs that change severity 
ratings the AE will be included only once under the maximum severity rating in the summaries.    
10.4.2 Clinical Laboratory Parameters 
Clinical chemistry, complete blood count (CBC) and urinalysis data will be listed. In addition, all 
clinical chemistry, CBC, and urinalysis data outside the clinical reference ranges will be listed by 
parameter and treatment. 
Values for any clinical chemistry, CBC, and urinalysis values outside the clinical reference 
ranges will be flagged on the individual subject data listings. 
10.4.3 Vital Signs 
The vital signs data will be summarised by treatment, together with changes from baseline.  .  
Vital signs values outside the clinical reference ranges will be flagged on the individual subject 
data listings. 
Orthostatic decreases of >20 mmHg for systolic blood pressure or >10 mmHg for diastolic blood 
pressure or an increase in heart rate of >30 bpm are considered to be of potential clinical concern 
and will also be highlighted on the individual data listings. Repeat and unscheduled readings will 
be handled as defined in Section 10.1.2. Orthostatic change is the standing value, minus the 
supine value taken prior to the standing value. 
10.4.4 Electrocardiogram 
The ECG data will be listed only.  
10.4.5 Columbia Suicide Severity Rating Scale (C-SSRS) 
Data from the C-SSRS questionnaire will be listed only. 
10.4.6 Other Assessments 
All other safety assessments not detailed in this section such as medical history etc. will be listed 
but not summarised or statistically analysed. 
 
10.4.7 Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
11  
INTERIM ANALYSES 
No interim statistical analyses are planned. 
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Statistical Analysis Plan  
 
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12  
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
There were no changes from the protocol-specified statistical analyses. 
13  
DATA PRESENTATION 
13.1 Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.” 
14  
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
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