The Effects of Lasmiditan on Simulated Driving Performance - Healthy Participants

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03012334
• Collaborator: Algorithme Pharma Inc (Industry), Cognitive Research Corporation (Industry), CoLucid Pharmaceuticals (Industry)
• Enrollment: 90
• Location: 1
• Arms: 5
• Actual Duration (Months): 4.7
• Patients Per Site Per Month: 19.2

Study Details

Study Description

Brief Summary

This will be a randomized, single dose, double-blind, placebo-controlled, Latin-square design with 5-period (full) crossover study with participants randomized to treatment sequences. Participants will complete all 5 Periods.

During each Period, participants will come to the clinical research unit (CRU) and remain overnight before being dosed with a single dose of either lasmiditan, alprazolam, or placebo in the morning. Cognitive testing and driving simulation will be conducted post dosing. Participants will have a washout of at least 5 days between each Period.

This study is designed to test non-inferiority of lasmiditan doses relative to placebo, with an alprazolam test versus placebo to confirm the sensitivity of the simulator to detect treatment effects.

Condition or Disease	Intervention/Treatment	Phase
Migraine	Drug: Lasmiditan; Drug: Alprazolam; Other: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: A Phase I, Randomized, Double-Blind, Placebo-Controlled, 5-Period, Cross-Over Study Assessing the Effects of Lasmiditan on Simulated Driving Performance in Normal Healthy Volunteers
• Actual Study Start Date: Jan 16, 2017
• Actual Primary Completion Date: Jun 8, 2017
• Actual Study Completion Date: Jun 8, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lasmiditan 50mg (milligrams) Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Drug: Lasmiditan; Dose is based on treatment sequence in 5-way crossover; Other Names: LY573144
Experimental: Lasmiditan 100mg Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Drug: Lasmiditan; Dose is based on treatment sequence in 5-way crossover; Other Names: LY573144
Experimental: Lasmiditan 200mg Participants received 200mg of Lasmiditan tablets given as single doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Drug: Lasmiditan; Dose is based on treatment sequence in 5-way crossover; Other Names: LY573144
Active Comparator: Alprazolam 1mg Participants received 1mg of Alprazolam tablets as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Drug: Alprazolam; Active comparator based on treatment sequence in 5-way crossover
Placebo Comparator: Placebo Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Other: Placebo; Placebo comparator based on treatment sequence in 5-way crossover

Outcome Measures

Primary Outcome Measures

1. Simulated Driving Performance in Healthy Participants as Measured by Standard Deviation of Lateral Position (SDLP) Using the Cognitive Research Corporation Driving Simulator-MiniSim (CRCDS-MiniSim) [Approximately 90 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence]

   The standard deviation of lateral position (SDLP) is the primary parameter used as stable measure of driving performance with high test-retest reliability. It measures the driver's ability to stay in a constant position within the driving lane. Variations in the lateral position are recorded and analyzed. SDLP, was analyzed using a mixed model with fixed effects for sequence, period, and treatment, and a random effect for participant within sequence. A variance component covariance structure and Kenward-Roger degrees of freedom was used.

Secondary Outcome Measures

1. Karolinska Sleepiness Scale (KSS) Score [Approximately 85 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence]

   The KSS is used to assess subjective level of sleepiness. This is a participant self-report measure of situational sleepiness and provides an assessment of alertness/sleepiness at a particular point in time. It is a 9-point categorical Likert scale on which the participant rates sleepiness from 1 (very alert) to 9 (very sleepy/fighting sleep), with higher scores indicating more sleepiness and lower scores indicating more alertness.

2. Percentage of Participants With Self-Reported Readiness to Drive [Approximately 85 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence]

   On each dosing day participants were asked "Right now do you feel safe to drive?". Pair-wise comparisons for readiness to drive were analyzed using McNemar test.

3. Motivational and Self-Appraisal Visual Analog Scale (VAS) [Approximately 2.5 hours post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence]

   After completing the driving simulation, participants assessed their own performance and their level of motivation to perform at their best during the driving simulation. Participants responded to 2 questions: 1. How well do you think you drove for the last 60 minutes? 2. How motivated did you feel to drive at your best during the last 60 minutes of driving?. Participants recorded their response to each question by writing a vertical line on a 100 millimeters (mm) horizontal, linear visual analog scale indicating their level of performance (Not Satisfactory to Satisfactory) and motivation (Not Motivated to Motivated). Scores on the 100 mm linear scale were measured to the nearest millimeter from the left. Scores ranged from 0-100 mm, with higher scores indicating motivated and satisfactory and lower scores indicating not motivated and not satisfactory.

4. Number of Correct Responses in Driving Performance Using CogScreen Symbol Digit Coding (SDC) Test [Approximately 85 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence]

   The SDC Test, a digit symbol substitution test that is sensitive to changes in information processing speed, provides measures of response speed and accuracy. The test was administered prior to the simulated driving sessions. The principal test score measures the number of correct responses in 120 seconds. SDC was used in this study to measure attention, visual scanning, working memory, and speed of information processing. Scores range from 0 (No correct responses). A higher score indicates greater processing speed.

5. Driving Performance Using the CRCDS-MiniSim - Lane Exceedance [Approximately 90 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence]

   The CRCDS-MiniSim is a PC-based research driving simulator that provides a realistic automotive driving environment. The present study employs the Country Vigilance-Divided Attention (CVDA) driving scenario, a 62.1 mile (100 km), monotonous, two lane highway driving task that includes a secondary visual vigilance task (DA). The monotonous Country Vigilance scenario has been demonstrated to be sensitive to detect the effects of fatigue or sleepiness on driving performance. Lane exceedance is the number of lane exceedances, an indication of lane position control, (i.e., the driver's ability to stay within his/her lane), as measured by the number of times that the front left or right tire of the vehicle crosses over the right or left lane boundary.

6. Driving Performance Using the CRCDS-MiniSim - Speed Deviation [Approximately 90 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence]

   The CRCDS-MiniSim is a PC-based research driving simulator that provides a realistic automotive driving environment. The present study employs the Country Vigilance-Divided Attention (CVDA) driving scenario, a 62.1 mile (100 km), monotonous, two lane highway driving task that includes a secondary visual vigilance task (DA). The monotonous Country Vigilance scenario has been demonstrated to be sensitive to detect the effects of fatigue or sleepiness on driving performance. Speed deviation is a measure of intra-individual variability. Measures that assess an individual's failure to maintain consistent performance are more sensitive to sedation than are measures of absolute performance.

Other Outcome Measures

1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up To 35 days]

   Data presented are the number of participants who experienced 1 or more AEs (all causalities and drug-related) and serious AEs (SAEs). A summary of SAEs and other non-serious AEs, regardless of causality is located in the Reported Adverse Events section of this record.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Able and willing to voluntarily consent to participate in this study and provide written informed consent prior to start of any study-specific procedures.

• Males and females between the ages of 21 and 50 years of age (inclusive). No more than 60% of one gender will be enrolled in the study.

• Body Mass Index (BMI) between 18 and 32 kilograms per meter squared (kg/m²) (inclusive).

• Participant is able to reliably perform study assessments (Standard Deviation of Lateral Position (SDLP) no higher than 1 standard deviation greater than the mean for normal healthy adults completing the practice scenario; Symbol Digit Coding (SDC) Correct no less than 1 standard deviation below the mean for healthy adults in their age range); demonstrates the ability to understand task instructions, and is physically capable (e.g., adequate manual dexterity, vision, and hearing) and cognitively capable of performing study tasks.

• Participant possesses a valid driver's license and is an active driver. Drives a minimum of 10,000 miles (about 16,000 km) per year for the previous 3 years.

• Participant must also demonstrate simulator sickness questionnaire scores which are not indicative of simulator sickness as defined in the driving simulation operations manual.

• Participant has a regular sleep pattern, is not engaged in shift-work, and in general, has at least 7 hours of sleep each night (bedtime occurs between 21:00 and 24:00 hours).

• Participant has a score < 10 on the Epworth Sleepiness Scale.

• Use of a medically highly effective form of birth control during the study and for thirty (30) days:

• Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

• History or presence of clinically significant condition that, in the opinion of the Investigator, would jeopardize the safety of the participant or the validity of the study results.

• A history within 2 years of, or current treatment for, a sleeping disorder (including excessive snoring, obstructive sleep apnea), or a chronic painful condition that interferes with the participant's sleep.

• A history of difficulty either falling asleep or staying asleep in the previous 3 months, that is considered clinically significant by the investigator.

• Participant has a history or diagnosis of any of the following conditions:

• Primary or secondary insomnia

• Narcolepsy

• Cataplexy (familial or idiopathic)

• Circadian Rhythm Sleep Disorder

• Parasomnia including nightmare disorder, sleep terror disorder, sleepwalking disorder, and rapid eye movement behavior disorder

• Sleep-related Breathing Disorder (obstructive or central sleep apnea syndrome, central alveolar hypoventilation syndrome)

• Periodic Limb Movement Disorder

• Restless Legs Syndrome

• Primary Hypersomnia

• Excessive Daytime Sleepiness (EDS)

• Participant has visual or auditory impairment which in the opinion of the investigator would interfere with study related procedures or study conduct.

• Expected to use any other medication or dietary supplement to promote sleep including over- the-counter sleep medications, during their participation in the study.

• Participant consumes excessive amounts of coffee, tea, cola, or other caffeinated beverages per day.

• Participant has traveled across 1 or more time zones (transmeridian travel) in the last 2 weeks prior to randomization or is expected to travel across 1 or more time zones during the study.

• Expected to work on a rotating shift during their participation in the study.

• Participant works a night shift.

• History or presence of seizure disorder.

• History of urinary retention, angle closure glaucoma, or increased ocular pressure.

• History of gastrointestinal tract surgery, except for appendectomy.

• Has abnormal finding on the physical exam, medical history, electrocardiogram (ECG), or clinical laboratory results at Screening, that are considered clinically significant by the investigator.

• Presence of out-of-range cardiac interval on the screening ECG or other clinically significant ECG abnormalities

• History of orthostatic hypotension, fainting spells, or blackouts, that are considered clinically significant by the investigator.

• The presence of chronic or acute infections, that are considered clinically significant by the investigator.

• History of allergy/hypersensitivity (including drug allergies) that are deemed relevant to the study as judged by the Investigator.

• Use of psychoactive prescription or non-prescription medications, psychoactive nutritional supplements or herbal preparations within 2 weeks or 5 half-lives (whichever is longer) of admission to the clinical research unit (CRU) on Day -1.

• Has received any previous study drug within 30 days prior to the first dose of this study drug.

• Is a smoker of more than 10 cigarettes or eCigarettes, or 3 cigars or 3 pipes per day, and is unable to refrain from smoking while confined to the CRU.

• Has any history of dependency or treatment for substance abuse within the past 2 years.

• Participant with a history of alcoholism or who consumes excessive amounts of alcohol.

• Participants who consume alcohol on a regular basis (i.e., ≥ 5 times/week) before bedtime will be excluded from the study.

• Inability to comply with the dietary regimen of the clinical research center.

• Pregnancy / positive pregnancy test.

• Planning to become pregnant during the study or within 1 month of study completion.

• Inability to use adequate contraception during the study. It is recommended that adequate contraception be used for 30 days following completion of the study.

• Has a positive screen for alcohol or other drugs of abuse (amphetamines, methamphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates).

• Has a history for Hepatitis B, Hepatitis C , or Human Immunodeficiency Virus (HIV) at Screening or has been previously treated for Hepatitis B, Hepatitis C, or HIV.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Algorithme Pharma	Mount Royal	Quebec	Canada	H3P3P1

Sponsors and Collaborators

• Eli Lilly and Company
• Algorithme Pharma Inc
• Cognitive Research Corporation
• CoLucid Pharmaceuticals

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

• Statistical Analysis Plan - Jun 23, 2017
• Study Protocol - Dec 6, 2016

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT03012334
• Other Study ID Numbers: 16883; COL MIG-106; H8H-CD-LAHG
• First Posted: Jan 6, 2017
• Last Update Posted: Jan 10, 2020
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Alprazolam; Lasmiditan

Study Results

Participant Flow

Pre-assignment Detail	Crossover study with five study periods, each participant received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and Placebo as per the dosing sequence in each period. The washout period between dosing in consecutive study periods was at least 7 days.

Arm/Group Title	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6	Sequence 7	Sequence 8	Sequence 9	Sequence 10
Arm/Group Description	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 50 mg, Period 2: Lasmiditan 100 mg, Period 3: Placebo, Period 4: Lasmiditan 200 mg and Period 5: Alprazolam 1 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 100 mg, Period 2: Lasmiditan 200 mg, Period 3: Lasmiditan 50 mg, Period 4: Alprazolam 1 mg and Period 5: Placebo	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 200 mg, Period 2: Alprazolam 1 mg, Period 3: Lasmiditan 100 mg, Period 4: Placebo and Period 5: Lasmiditan 50 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Alprazolam 1 mg, Period 2: Placebo, Period 3: Lasmiditan 200 mg, Period 4: Lasmiditan 50 mg and Period 5: Lasmiditan 100 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Placebo, Period 2: Lasmiditan 50 mg, Period 3: Alprazolam 1 mg, Period 4: Lasmiditan 100 mg and Period 5: Lasmiditan 200 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Alprazolam 1 mg, Period 2: Lasmiditan 200 mg, Period 3: Placebo, Period 4: Lasmiditan 100 mg and Period 5: Lasmiditan 50 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Placebo, Period 2: Alprazolam 1 mg, Period 3: Lasmiditan 50 mg, Period 4: Lasmiditan 200 mg and Period 5: Lasmiditan 100 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 50 mg, Period 2: Placebo, Period 3: Lasmiditan 100 mg, Period 4: Alprazolam 1 mg and Period 5: Lasmiditan 200 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 100 mg, Period 2: Lasmiditan 50 mg, Period 3: Lasmiditan 200 mg, Period 4: Placebo and Period 5: Alprazolam 1 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 200 mg, Period 2: Lasmiditan 100 mg, Period 3: Alprazolam 1 mg, Period 4: Lasmiditan 50 mg and Period 5: Placebo
Period Title: Period 1
STARTED	9	9	9	9	9	9	9	9	9	9
COMPLETED	9	9	9	9	9	9	9	9	9	8
NOT COMPLETED	0	0	0	0	0	0	0	0	0	1
Period Title: Period 1
STARTED	9	9	9	9	9	9	9	9	9	8
COMPLETED	9	8	8	9	9	9	9	8	9	8
NOT COMPLETED	0	1	1	0	0	0	0	1	0	0
Period Title: Period 1
STARTED	9	8	8	9	9	9	9	8	9	8
COMPLETED	9	8	8	9	9	9	9	8	9	8
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0
Period Title: Period 1
STARTED	9	8	8	9	9	9	9	8	9	8
COMPLETED	9	8	8	9	9	9	8	8	8	8
NOT COMPLETED	0	0	0	0	0	0	1	0	1	0
Period Title: Period 1
STARTED	9	8	8	9	9	9	8	8	8	8
COMPLETED	9	8	8	9	9	9	8	8	8	8
NOT COMPLETED	0	0	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6	Sequence 7	Sequence 8	Sequence 9	Sequence 10	Total
Arm/Group Description	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 50 mg, Period 2: Lasmiditan 100 mg, Period 3: Placebo, Period 4: Lasmiditan 200 mg and Period 5: Alprazolam 1 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 100 mg, Period 2: Lasmiditan 200 mg, Period 3: Lasmiditan 50 mg, Period 4: Alprazolam 1 mg and Period 5: Placebo	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 200 mg, Period 2: Alprazolam 1 mg, Period 3: Lasmiditan 100 mg, Period 4: Placebo and Period 5: Lasmiditan 50 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Alprazolam 1 mg, Period 2: Placebo, Period 3: Lasmiditan 200 mg, Period 4: Lasmiditan 50 mg and Period 5: Lasmiditan 100 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Placebo, Period 2: Lasmiditan 50 mg, Period 3: Alprazolam 1 mg, Period 4: Lasmiditan 100 mg and Period 5: Lasmiditan 200 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Alprazolam 1 mg, Period 2: Lasmiditan 200 mg, Period 3: Placebo, Period 4: Lasmiditan 100 mg and Period 5: Lasmiditan 50 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Placebo, Period 2: Alprazolam 1 mg, Period 3: Lasmiditan 50 mg, Period 4: Lasmiditan 200 mg and Period 5: Lasmiditan 100 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 50 mg, Period 2: Placebo, Period 3: Lasmiditan 100 mg, Period 4: Alprazolam 1 mg and Period 5: Lasmiditan 200 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 100 mg, Period 2: Lasmiditan 50 mg, Period 3: Lasmiditan 200 mg, Period 4: Placebo and Period 5: Alprazolam 1 mg	Participants received Lasmiditan (50 milligrams (mg), 100mg, and 200mg), Alprazolam 1mg and placebo as per the below dosing schedule. Period 1: Lasmiditan 200 mg, Period 2: Lasmiditan 100 mg, Period 3: Alprazolam 1 mg, Period 4: Lasmiditan 50 mg and Period 5: Placebo	Total of all reporting groups
Overall Participants	9	9	9	9	9	9	9	9	9	9	90
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	90 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	3 33.3%	4 44.4%	5 55.6%	6 66.7%	5 55.6%	6 66.7%	4 44.4%	2 22.2%	4 44.4%	7 77.8%	46 51.1%
Male	6 66.7%	5 55.6%	4 44.4%	3 33.3%	4 44.4%	3 33.3%	5 55.6%	7 77.8%	5 55.6%	2 22.2%	44 48.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 22.2%	2 22.2%	1 11.1%	3 33.3%	2 22.2%	3 33.3%	2 22.2%	0 0%	0 0%	0 0%	15 16.7%
Not Hispanic or Latino	7 77.8%	7 77.8%	8 88.9%	6 66.7%	7 77.8%	6 66.7%	7 77.8%	9 100%	9 100%	9 100%	75 83.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%	1 11.1%	0 0%	0 0%	2 2.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 11.1%	0 0%	1 11.1%	1 11.1%	0 0%	0 0%	0 0%	0 0%	0 0%	1 11.1%	4 4.4%
White	8 88.9%	9 100%	8 88.9%	8 88.9%	8 88.9%	9 100%	9 100%	8 88.9%	9 100%	8 88.9%	84 93.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Canada	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	90 100%

Outcome Measures

1. Primary Outcome

Title	Simulated Driving Performance in Healthy Participants as Measured by Standard Deviation of Lateral Position (SDLP) Using the Cognitive Research Corporation Driving Simulator-MiniSim (CRCDS-MiniSim)
Description	The standard deviation of lateral position (SDLP) is the primary parameter used as stable measure of driving performance with high test-retest reliability. It measures the driver's ability to stay in a constant position within the driving lane. Variations in the lateral position are recorded and analyzed. SDLP, was analyzed using a mixed model with fixed effects for sequence, period, and treatment, and a random effect for participant within sequence. A variance component covariance structure and Kenward-Roger degrees of freedom was used.
Time Frame	Approximately 90 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug and have evaluable data for simulated driving performance.

Arm/Group Title	Placebo	Lasmiditan 50mg	Lasmiditan 100mg	Lasmiditan 200mg	Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 1mg of Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
Measure Participants	85	87	86	89	85
Mean (Standard Deviation) [Centimeters (cm)]	28.77 (6.73)	38.52 (12.39)	44.03 (13.55)	50.24 (13.76)	51.48 (14.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 50mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Doses of lasmiditan were considered non-inferior to placebo if the upper 95% confidence limit on the difference in Standard Deviation of Lateral Position (SDLP) between that dose and placebo was less than 4.4 cm and lower doses also did not exceed the non-inferiority (NI) margin.
Statistical Test of Hypothesis	p-Value	<.001
	Comments	P-value is obtained from mixed effect model for testing difference versus placebo equals to zero.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	9.86
	Confidence Interval	(2-Sided) 95%; 7.39 to 12.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 100mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Doses of lasmiditan were considered non-inferior to placebo if the upper 95% confidence limit on the difference in SDLP between that dose and placebo was less than 4.4 cm and lower doses also did not exceed the non-inferiority (NI) margin.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is obtained from mixed effect model for testing difference versus placebo equals to zero.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	15.35
	Confidence Interval	(2-Sided) 95%; 12.87 to 17.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 200mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Doses of lasmiditan were considered non-inferior to placebo if the upper 95% confidence limit on the difference in SDLP between that dose and placebo was less than 4.4 cm and lower doses also did not exceed the non-inferiority (NI) margin.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is obtained from mixed effect model for testing difference versus placebo equals to zero.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	21.06
	Confidence Interval	(2-Sided) 95%; 18.60 to 23.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	22.71
	Confidence Interval	(2-Sided) 95%; 20.23 to 25.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 50mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-12.85
	Confidence Interval	(2-Sided) 95%; -15.32 to -10.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 100mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-7.36
	Confidence Interval	(2-Sided) 95%; -9.84 to -4.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 200mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95%; -4.11 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Karolinska Sleepiness Scale (KSS) Score
Description	The KSS is used to assess subjective level of sleepiness. This is a participant self-report measure of situational sleepiness and provides an assessment of alertness/sleepiness at a particular point in time. It is a 9-point categorical Likert scale on which the participant rates sleepiness from 1 (very alert) to 9 (very sleepy/fighting sleep), with higher scores indicating more sleepiness and lower scores indicating more alertness.
Time Frame	Approximately 85 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug and have evaluable data for karolinska sleepiness scale.

Arm/Group Title	Placebo	Lasmiditan 50mg	Lasmiditan 100mg	Lasmiditan 200mg	Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 1mg of Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
Measure Participants	85	87	86	89	85
Mean (Standard Deviation) [Units on a scale]	2.8 (1.35)	4.4 (1.85)	5.1 (1.89)	5.7 (1.94)	6.2 (1.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 50mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; 1.1744 to 2.0335
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 100mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; 1.8306 to 2.6926
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 200mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; 2.4239 to 3.2800
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; 2.9568 to 3.8193
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 50mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -2.2137 to -1.3546
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 100mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -1.5574 to -0.6956
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 200mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0142
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -0.9642 to -0.1081
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Self-Reported Readiness to Drive
Description	On each dosing day participants were asked "Right now do you feel safe to drive?". Pair-wise comparisons for readiness to drive were analyzed using McNemar test.
Time Frame	Approximately 85 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug and have evaluable data for self-reported readiness to drive.

Arm/Group Title	Placebo	Lasmiditan 50mg	Lasmiditan 100mg	Lasmiditan 200mg	Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 1mg of Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
Measure Participants	85	87	86	89	85
Number [Percentage of Participants]	100 1111.1%	80 888.9%	67.9 754.4%	55.3 614.4%	43.5 483.3%

4. Secondary Outcome

Title	Motivational and Self-Appraisal Visual Analog Scale (VAS)
Description	After completing the driving simulation, participants assessed their own performance and their level of motivation to perform at their best during the driving simulation. Participants responded to 2 questions: 1. How well do you think you drove for the last 60 minutes? 2. How motivated did you feel to drive at your best during the last 60 minutes of driving?. Participants recorded their response to each question by writing a vertical line on a 100 millimeters (mm) horizontal, linear visual analog scale indicating their level of performance (Not Satisfactory to Satisfactory) and motivation (Not Motivated to Motivated). Scores on the 100 mm linear scale were measured to the nearest millimeter from the left. Scores ranged from 0-100 mm, with higher scores indicating motivated and satisfactory and lower scores indicating not motivated and not satisfactory.
Time Frame	Approximately 2.5 hours post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug and have evaluable data for visual analog scale.

Arm/Group Title	Placebo	Lasmiditan 50mg	Lasmiditan 100mg	Lasmiditan 200mg	Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 1mg of Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
Measure Participants	85	87	86	89	85
VAS Motivation	78.0 (18.48)	65.6 (26.21)	53.7 (30.98)	49.9 (33.70)	47.6 (33.86)
VAS Self-appraisal	77.2 (15.96)	51.2 (27.03)	39.8 (27.82)	30.8 (25.17)	24.7 (26.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 50mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-12.6
	Confidence Interval	(2-Sided) 95%; -18.6895 to -6.5006
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 100mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-24.2
	Confidence Interval	(2-Sided) 95%; -30.3631 to -18.1357
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 200mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-28.4
	Confidence Interval	(2-Sided) 95%; -34.4420 to -22.2897
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-30.4
	Confidence Interval	(2-Sided) 95%; -36.5068 to -24.2770
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 50mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	17.8
	Confidence Interval	(2-Sided) 95%; 11.7029 to 23.8908
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 100mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0489
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	6.1
	Confidence Interval	(2-Sided) 95%; 0.0297 to 12.2554
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 200mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5123
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 95%; -4.0500 to 8.1021
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 50mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-26.4
	Confidence Interval	(2-Sided) 95%; -32.4956 to -20.3628
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 100mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-37.8
	Confidence Interval	(2-Sided) 95%; -43.9270 to -31.7537
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 200mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-46.8
	Confidence Interval	(2-Sided) 95%; -52.8147 to -40.7268
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-52.6
	Confidence Interval	(2-Sided) 95%; -58.6490 to -46.4682
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 50mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	26.1
	Confidence Interval	(2-Sided) 95%; 20.0635 to 32.1953
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 100mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	14.7
	Confidence Interval	(2-Sided) 95%; 8.6325 to 20.8040
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 200mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0605
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	5.8
	Confidence Interval	(2-Sided) 95%; -0.2560 to 11.8317
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Correct Responses in Driving Performance Using CogScreen Symbol Digit Coding (SDC) Test
Description	The SDC Test, a digit symbol substitution test that is sensitive to changes in information processing speed, provides measures of response speed and accuracy. The test was administered prior to the simulated driving sessions. The principal test score measures the number of correct responses in 120 seconds. SDC was used in this study to measure attention, visual scanning, working memory, and speed of information processing. Scores range from 0 (No correct responses). A higher score indicates greater processing speed.
Time Frame	Approximately 85 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug and have evaluable data for driving performance.

Arm/Group Title	Placebo	Lasmiditan 50mg	Lasmiditan 100mg	Lasmiditan 200mg	Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 1mg Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
Measure Participants	85	87	86	89	85
Mean (Standard Deviation) [Responses]	72.8 (10.18)	68.1 (10.19)	66.0 (8.78)	64.1 (8.07)	61.7 (10.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 50mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 95%; -6.14 to -2.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 100mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-6.9
	Confidence Interval	(2-Sided) 95%; -8.58 to -5.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 200mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-8.9
	Confidence Interval	(2-Sided) 95%; -10.52 to -7.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-11.2
	Confidence Interval	(2-Sided) 95%; -12.81 to -9.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 50mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	6.7
	Confidence Interval	(2-Sided) 95%; 5.02 to 8.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 100mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	4.2
	Confidence Interval	(2-Sided) 95%; 2.58 to 5.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 200mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.007
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; 0.64 to 3.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Driving Performance Using the CRCDS-MiniSim - Lane Exceedance
Description	The CRCDS-MiniSim is a PC-based research driving simulator that provides a realistic automotive driving environment. The present study employs the Country Vigilance-Divided Attention (CVDA) driving scenario, a 62.1 mile (100 km), monotonous, two lane highway driving task that includes a secondary visual vigilance task (DA). The monotonous Country Vigilance scenario has been demonstrated to be sensitive to detect the effects of fatigue or sleepiness on driving performance. Lane exceedance is the number of lane exceedances, an indication of lane position control, (i.e., the driver's ability to stay within his/her lane), as measured by the number of times that the front left or right tire of the vehicle crosses over the right or left lane boundary.
Time Frame	Approximately 90 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug and have evaluable data for driving performance.

Arm/Group Title	Placebo	Lasmiditan 50mg	Lasmiditan 100mg	Lasmiditan 200mg	Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 1mg of Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
Measure Participants	85	87	86	89	85
Mean (Standard Deviation) [Lane Exceedances]	2.288 (1.3406)	3.716 (1.3336)	4.301 (1.1496)	4.884 (0.8359)	4.841 (0.8575)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 50mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1.439
	Confidence Interval	(2-Sided) 95%; 1.2198 to 1.6583
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 100mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.018
	Confidence Interval	(2-Sided) 95%; 1.7981 to 2.2380
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 200mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.572
	Confidence Interval	(2-Sided) 95%; 2.3536 to 2.7909
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	2.553
	Confidence Interval	(2-Sided) 95%; 2.3331 to 2.7730
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 50mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.114
	Confidence Interval	(2-Sided) 95%; -1.3333 to -0.8948
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 100mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.535
	Confidence Interval	(2-Sided) 95%; -0.7549 to -0.3151
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 200mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8629
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.019
	Confidence Interval	(2-Sided) 95%; -0.1995 to 0.2379
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Other Pre-specified Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Data presented are the number of participants who experienced 1 or more AEs (all causalities and drug-related) and serious AEs (SAEs). A summary of SAEs and other non-serious AEs, regardless of causality is located in the Reported Adverse Events section of this record.
Time Frame	Up To 35 days

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug.

Arm/Group Title	Placebo	Lasmiditan 50mg	Lasmiditan 100mg	Lasmiditan 200mg	Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 1mg of Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
Measure Participants	85	87	86	89	85
Other AEs	8 88.9%	34 377.8%	47 522.2%	62 688.9%	71 788.9%
SAEs	1 11.1%	0 0%	0 0%	0 0%	0 0%

8. Secondary Outcome

Title	Driving Performance Using the CRCDS-MiniSim - Speed Deviation
Description	The CRCDS-MiniSim is a PC-based research driving simulator that provides a realistic automotive driving environment. The present study employs the Country Vigilance-Divided Attention (CVDA) driving scenario, a 62.1 mile (100 km), monotonous, two lane highway driving task that includes a secondary visual vigilance task (DA). The monotonous Country Vigilance scenario has been demonstrated to be sensitive to detect the effects of fatigue or sleepiness on driving performance. Speed deviation is a measure of intra-individual variability. Measures that assess an individual's failure to maintain consistent performance are more sensitive to sedation than are measures of absolute performance.
Time Frame	Approximately 90 minutes post dose, on Day 1, 7, 14, 21, or 28 depending upon the assigned treatment sequence

Outcome Measure Data

Analysis Population Description

All randomized participants who received study drug and have evaluable data for driving performance.

Arm/Group Title	Placebo	Lasmiditan 50mg	Lasmiditan 100mg	Lasmiditan 200mg	Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.	Participants received 1mg of Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
Measure Participants	85	87	86	89	85
Mean (Standard Deviation) [meter per second (m/sec)]	0.635 (0.2716)	0.814 (0.3475)	0.935 (0.5696)	1.013 (0.4581)	1.238 (0.5856)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 50mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.180
	Confidence Interval	(2-Sided) 95%; 0.0849 to 0.2746
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 100mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.303
	Confidence Interval	(2-Sided) 95%; 0.2082 to 0.3985
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lasmiditan 200mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.372
	Confidence Interval	(2-Sided) 95%; 0.2770 to 0.4662
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.603
	Confidence Interval	(2-Sided) 95%; 0.5080 to 0.6983
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 50mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.423
	Confidence Interval	(2-Sided) 95%; -0.5183 to -0.3286
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 100mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.300
	Confidence Interval	(2-Sided) 95%; -0.3949 to -0.2047
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Lasmiditan 200mg, Alprazolam 1mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.232
	Confidence Interval	(2-Sided) 95%; -0.3261 to -0.1370
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up To 35 days
Adverse Event Reporting Description	All randomized participants who received study drug.
Arm/Group Title	Placebo		Lasmiditan 50mg		Lasmiditan 100mg		Lasmiditan 200mg		Alprazolam 1mg
Arm/Group Description	Participants received placebo tablets identical to Lasmiditan, administered as single oral dose on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.		Participants received 50mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.		Participants received 100mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.		Participants received 200mg of Lasmiditan tablets given as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.		Participants received 1mg of Alprazolam tablets as single oral doses on Day 1, 7, 14, 21, or 28 (dependent upon the assigned treatment sequence) in the morning.
All Cause Mortality
	Placebo		Lasmiditan 50mg		Lasmiditan 100mg		Lasmiditan 200mg		Alprazolam 1mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/85 (0%)		0/87 (0%)		0/86 (0%)		0/89 (0%)		0/85 (0%)
Serious Adverse Events
	Placebo		Lasmiditan 50mg		Lasmiditan 100mg		Lasmiditan 200mg		Alprazolam 1mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/85 (1.2%)		0/87 (0%)		0/86 (0%)		0/89 (0%)		0/85 (0%)
Nervous system disorders
Cerebellar haematoma	1/85 (1.2%)	1	0/87 (0%)	0	0/86 (0%)	0	0/89 (0%)	0	0/85 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Lasmiditan 50mg		Lasmiditan 100mg		Lasmiditan 200mg		Alprazolam 1mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/85 (9.4%)		34/87 (39.1%)		47/86 (54.7%)		62/89 (69.7%)		71/85 (83.5%)
Gastrointestinal disorders
Nausea	0/85 (0%)	0	3/87 (3.4%)	3	5/86 (5.8%)	5	6/89 (6.7%)	6	3/85 (3.5%)	3
General disorders
Fatigue	2/85 (2.4%)	2	15/87 (17.2%)	15	10/86 (11.6%)	11	7/89 (7.9%)	7	14/85 (16.5%)	14
Nervous system disorders
Dizziness	1/85 (1.2%)	1	14/87 (16.1%)	14	18/86 (20.9%)	18	36/89 (40.4%)	37	26/85 (30.6%)	26
Headache	3/85 (3.5%)	3	8/87 (9.2%)	8	3/86 (3.5%)	3	5/89 (5.6%)	6	6/85 (7.1%)	6
Hypoaesthesia	0/85 (0%)	0	1/87 (1.1%)	1	4/86 (4.7%)	4	5/89 (5.6%)	5	0/85 (0%)	0
Lethargy	0/85 (0%)	0	3/87 (3.4%)	3	4/86 (4.7%)	4	7/89 (7.9%)	7	3/85 (3.5%)	3
Somnolence	2/85 (2.4%)	2	10/87 (11.5%)	10	23/86 (26.7%)	23	38/89 (42.7%)	38	45/85 (52.9%)	45
Respiratory, thoracic and mediastinal disorders
Hiccups	0/85 (0%)	0	0/87 (0%)	0	0/86 (0%)	0	0/89 (0%)	0	5/85 (5.9%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Details of the Study and its results shall not be publicized in any form without prior consent of the Sponsor. Such approval is necessary to prevent premature disclosure of trade secrets and other confidential information.