A Study to Evaluate the Pharmacodynamic Activity of E2082 in Adult Participants With Photosensitive Epilepsy

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03686033
• Collaborator: (none)
• Enrollment: 8
• Locations: 5
• Arms: 6
• Actual Duration (Months): 7.6
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary purpose of the study is to assess pharmacodynamic (PD) activity of E2082 as measured by suppression of epileptic photoparoxysmal response (PPR) in the participant's most sensitive eye condition in participants with photosensitive epilepsy, compared to placebo.

Condition or Disease	Intervention/Treatment	Phase
Photosensitive Epilepsy	Drug: Placebo; Drug: E2082	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: The study consists of a crossover design in Treatment Periods 1, 2, and 3, followed by an open-label Treatment Period 4.The study consists of a crossover design in Treatment Periods 1, 2, and 3, followed by an open-label Treatment Period 4.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The study consists of a randomized double-blind design in Treatment Periods 1, 2, and 3, followed by an open-label Treatment Period 4.
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-Blind, Randomized, Crossover, Single-Dose Study With An Open-Label Treatment Period Evaluating Pharmacodynamic Activity of E2082 in Adult Subjects With Photosensitive Epilepsy
• Actual Study Start Date: Oct 31, 2018
• Actual Primary Completion Date: Jun 18, 2019
• Actual Study Completion Date: Jun 18, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo, E2082 2.5 mg, E2082 25 mg, E2082 40 mg Participants will receive a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 1 followed by a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 2 followed by a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between all the treatment periods.	Drug: Placebo; Participants will receive E2082-matched placebo tablets orally.; Drug: E2082; Participants will receive E2082 tablets orally.
Experimental: E2082 2.5 mg, E2082 25 mg, Placebo, E2082 40 mg Participants will receive a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 1 followed by a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 2 followed by a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods.	Drug: Placebo; Participants will receive E2082-matched placebo tablets orally.; Drug: E2082; Participants will receive E2082 tablets orally.
Experimental: E2082 25 mg, Placebo, E2082 2.5 mg, E2082 40 mg Participants will receive a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 1 followed by a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 2 followed by a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods.	Drug: Placebo; Participants will receive E2082-matched placebo tablets orally.; Drug: E2082; Participants will receive E2082 tablets orally.
Experimental: Placebo, E2082 25 mg, E2082 2.5 mg, E2082 40 mg Participants will receive a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 1 followed by a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 2 followed by a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods.	Drug: Placebo; Participants will receive E2082-matched placebo tablets orally.; Drug: E2082; Participants will receive E2082 tablets orally.
Experimental: E2082 2.5 mg, Placebo, E2082 25 mg, E2082 40 mg Participants will receive a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 1 followed by a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 2 followed by a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods.	Drug: Placebo; Participants will receive E2082-matched placebo tablets orally.; Drug: E2082; Participants will receive E2082 tablets orally.
Experimental: E2082 25 mg, E2082 2.5 mg, Placebo, E2082 40 mg Participants will receive a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 1 followed by a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 2 followed by a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods.	Drug: Placebo; Participants will receive E2082-matched placebo tablets orally.; Drug: E2082; Participants will receive E2082 tablets orally.

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in the Photoparoxysmal Response (PPR) Range in the Most Sensitive Eye Condition at 8 Hours Postdose on Day 1 of Each Treatment Period [Baseline (30 minutes-2 hours) and at 8 hours postdose on Day 1 of each treatment period]

   PPR was an electroencephalogram (EEG) trait of spike and spike-wave discharges in response to photic stimulation. Intermittent photic stimulation (IPS)-EEG assessments determine the range of frequencies of IPS that elicited an epileptiform EEG response. Each IPS-EEG assessment was conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open) at ascending and then descending photo stimulation administered at 14 standard frequencies: 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 hertz (Hz). The lower and upper limit of photosensitivity to IPS threshold frequency were determined for each eye condition. From this range, standard photosensitivity response (SPR) was derived. SPR is an integer score that ranges from 0 to 14, with lower scores representing better outcomes. Most sensitive eye condition was defined as one that yielded the largest SPR before dosing.

Secondary Outcome Measures

1. Mean Change From Baseline in PPR Ranges in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Opened) at 8 Hours Postdose on Day 1 of Each Treatment Period [Baseline (30 minutes-2 hours) and at 8 hours postdose on Day 1 of each treatment period]

   PPR was an EEG trait of spike and spike-wave discharges in response to photic stimulation. IPS-EEG assessments determine the range of frequencies of IPS that elicited an epileptiform EEG response. Each IPS-EEG assessment was conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open) at ascending and then descending photo stimulation administered at 14 standard frequencies: 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 Hz. The lower and upper limit of photosensitivity to IPS threshold frequency were determined for each eye condition. From this range, SPR was derived. SPR is an integer score that ranges from 0 to 14, with lower scores representing better outcomes.

2. Time to Onset of Mean Photosensitivity Response in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) up to 8 Hours Postdose on Day 1 of Each Treatment Period [Baseline (30 minutes-2 hours) up to 8 hours postdose on Day 1 of each treatment period]

   Time to onset of mean photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and eyes open condition) was determined from mean and mean change from baseline SPR data across participants. The onset of mean suppression was defined as the first time point at which the mean Response of standardized photosensitivity response (SPR) across participants (not for each participant) was at least 3 units below the mean SPR at baseline. Photosensitivity response were essentially intermittent photosensitivity (intermittent photic stimulation [IPS]) assessments, is a form of visual stimulation, when the participants are flashed with light on their eyes intermittently at different hertz.

3. Maximum Change From Baseline of Photosensitivity Response in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) up to 8 Hours Postdose on Day 1 of Each Treatment Period [Baseline (30 minutes-2 hours) up to 8 hours postdose on Day 1 of each treatment period]

   Maximum change from baseline of photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and eyes open condition) were reported. PPR was an EEG trait of spike and spike-wave discharges in response to photic stimulation. IPS-EEG assessments determine the range of frequencies of IPS that elicited an epileptiform EEG response. Each IPS-EEG assessment was conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open) at ascending and then descending photo stimulation administered at 14 standard frequencies: 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 Hz. The lower and upper limit of photosensitivity to IPS threshold frequency were determined for each eye condition. From this range, SPR was derived. SPR is an integer score that ranges from 0 to 14, with lower scores representing better outcomes.

4. Duration of Mean Photosensitivity Response in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) up to 8 Hours Postdose on Day 1 of Each Treatment Period [Baseline (30 minutes-2 hours) up to 8 hours postdose on Day 1 of each treatment period]

   Duration of mean photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and eyes open condition) was determined from mean and mean change from baseline SPR data across participants. Duration of mean suppression was defined as the difference in hours between the onset of mean suppression and the end of mean suppression of photosensitivity across participants. The onset of mean suppression was defined as the first time point at which the mean SPR across participants was at least 3 units below the mean SPR at baseline. The end of mean suppression was defined as the last time (second time) with two successive reductions in mean SPR across participants of at least 3 units lower than the mean SPR at baseline. Photosensitivity response were essentially IPS assessments, is a form of visual stimulation, when the participants are flashed with light on their eyes intermittently at different hertz.

5. Number of Participants With Complete Suppression, Partial Response, and no Response of Standardized Photosensitivity Response (SPR) up to 8 Hours Postdose on Day 1 of Each Treatment Period [Baseline (30 minutes-2 hours) up to 8 hours postdose on Day 1 of each treatment period]

   Complete suppression, reduction (partial response), and no change (no response) of PPR will be measured. Complete suppression was defined as a SPR reduction to 0 over at least 1 time point for all three eye conditions. Partial response was defined as a reduction in SPR of at least 3 units from baseline for at least 3 time points, and no time points with at least 3 units of increase, in the most sensitive eye condition; without meeting the complete suppression definition. No response was defined as not meeting complete suppression or partial suppression definitions.

6. Change From Baseline in Bond and Lader Visual Analogue Scales (BL-VAS) at 1, 2, 4, 6, and 8 Hours Post-dose in Each Treatment Period [Baseline (30 minutes-2 hours) and at 1,2,4,6 and 8 hours post-dose in each treatment period]

   BL-VAS system was used to assess the extent of damage to the extrapyramidal system and the motor functions that it controls. The BL-VAS monitored the subjective mood of each participant on 16 mood scales. Participants were asked to indicate on the VAS scale ranging from 0 to 100 millimeter (mm) about how they felt at the moment the scale was administered (example, alert/drowsy; calm/excited; content/tensed). The individual responses from the 16 mood scales were then combined to make three subscales: a.) Anxiety, b.) Dysphoria, c.) sedation with each item ranges from 0 to 100 and higher scores indicated better condition.

7. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Up to 28 days after the last dose of study treatment on Day 1 in Treatment Period 4 (approximately Day 71)]

   An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

8. Number of Participants With Clinically Significant Change From Baseline in Vital Signs [Up to 28 days after the last dose of study treatment on Day 1 in Treatment Period 4 (approximately Day 71)]

9. Number of Participants With Clinically Significant Change From Baseline in Laboratory Values [Up to 28 days after the last dose of study treatment on Day 1 in Treatment Period 4 (approximately Day 71)]

10. Cmax: Maximum Observed Plasma Concentration for E2082 [Predose (within 2 hours prior to dosing) to 8 hours postdose on Day 1 of each treatment period]

11. Tmax: Time to Reach Maximum Plasma Concentration (Cmax) for E2082 [Predose (within 2 hours prior to dosing) to 8 hours postdose on Day 1 of each treatment period]

12. AUC (0-8h): Area Under the Plasma Concentration-time Curve From 0 to 8 Hours Post-dose for E2082 [Predose (within 2 hours prior to dosing) to 8 hours postdose on Day 1 of each treatment period]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

1. Diagnosis and/or history of a PPR on EEG.

2. If currently being treated with antiepileptic drug (AED), up to a maximum of 3 concomitant AEDs is allowed provided that doses must have remained stable for at least 4 weeks (or at least 8 weeks if recently initiated) before screening.

3. Reproducible IPS-induced PPR on EEG of at least 3 points on the SPR scale in at least 1 eye condition (eye closure, eyes closed, eyes open) on at least 3 of the EEGs performed at screening.

4. Body mass index (BMI) between 18 to 35 kilogram per square meter (kg/m^2) (inclusive) and a total body weight greater than or equal to (>=) 45 kilogram (kg) at screening.

5. Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour period before screening and before each treatment day.

Exclusion Criteria:

1. Females who are breastfeeding or pregnant at screening or baseline.

2. Male participants who have not had a successful vasectomy, they and their female partners not of childbearing potential, or practicing highly effective contraception throughout the study period and for 28 days after study drug discontinuation. No sperm donation is allowed during the study period and for 28 days after study drug discontinuation.

3. History of nonepileptic seizures (example, metabolic, structural, or pseudoseizures) while on any antiepileptic medication.

4. History of status epilepticus while on any antiepileptic medication(s) within 2 years before screening.

5. Ongoing or history of generalized tonic-clonic seizures (GTCS) within 6 months before screening.

6. Participants who had developed a clinical seizure during previous PPR assessment, or who experiences a clinical seizure during the Screening IPS procedure.

7. Frequent spontaneous background burst or current evidence of proconvulsive activity on EEG (example, increase in spike-wave activity) at screening.

8. Inability to follow restriction on watching television, or use of any device(s) with an animated screen (example, computer, video games, tablets, or smart phone) from the time of arrival at the study center until study procedures are completed for that day.

9. Use of perampanel within 6 weeks before screening.

10. Use of felbamate for less than 2 years or where the dose has not been stable for at least 8 weeks before Visit 1.

11. Use of vigabatrin within 5 months before screening and/or documented evidence of vigabatrin associated clinically significant abnormality in a visual perimetry test.

12. Use of benzodiazepines for non-epilepsy related indications. Intermittent use of benzodiazepines as rescue medication or stable dosage (greater than 4 weeks before screening) for epilepsy indications is allowed.

13. Concomitant use of cannabinoids.

14. Use of concomitant potent cytochrome P450 (CYP)3A inducers or inhibitors within 4 weeks or 5 half-lives, whichever is longer.

15. Vagus nerve stimulation (VNS) implanted within 5 months or changes in parameter within 4 weeks before screening.

16. On a ketogenic diet for which the diet is not a stable regimen for at least 4 weeks before screening.

17. Participants with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

18. A history of prolonged QT syndrome or risk factors for torsade de pointes, or the use of concomitant medications that cause QT prolongation as demonstrated on screening electrocardiogram (ECG).

19. Any suicidal ideation with intent with or without a plan within 6 months before or during screening, and/or any lifetime suicidal behavior.

20. Any psychotic disorder(s) or unstable recurrent affective disorders.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Trials, Inc. and Arkansas Epilepsy Program	Little Rock	Arkansas	United States	72205
2	Consultants in Epilepsy & Neurology, PLLC	Boise	Idaho	United States	83702
3	Johns Hopkins University- School of Medicine	Baltimore	Maryland	United States	21287
4	Washington University Hospital	Saint Louis	Missouri	United States	63110
5	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Eisai Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Apr 12, 2019
• Statistical Analysis Plan - Sep 4, 2019

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT03686033
• Other Study ID Numbers: E2082-A001-201
• First Posted: Sep 26, 2018
• Last Update Posted: Sep 28, 2020
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Eisai Inc.: E2082; Epilepsy; Photosensitive; Anti-epileptic; Seizures; Photoparoxysmal response; PPR
• Additional relevant MeSH terms: Epilepsy; Epilepsy, Reflex

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 4 investigative sites in the United States from 31 October 2018 to 18 June 2019. A total of 8 participants were screened and enrolled, of which 5 participants were randomized and treated, of which, 4 participants completed both crossover and open label treatments in the study.
Pre-assignment Detail	The study was terminated due to safety concerns from a phase 1 study (E2082-J081-001; NCT03402178) and preclinical animal toxicity testing.

Arm/Group Title	Sequence 1: Placebo + E2082 2.5 mg + E2082 25 mg + E2082 40 mg	Sequence 2: E2082 2.5 mg + E2082 25 mg + Placebo + E2082 40 mg	Sequence 3: E2082 25 mg + Placebo + E2082 2.5 mg + E2082 40 mg	Sequence 4: Placebo + E2082 25 mg + E2082 2.5 mg + E2082 40 mg	Sequence 5: E2082 2.5 mg + Placebo + E2082 25 mg + E2082 40 mg	Sequence 6: E2082 25 mg + E2082 2.5 mg + Placebo + E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo (Treatment A) tablet, orally, once on Day 1 in Treatment Period 1, followed by E2082 2.5 milligram (mg) (Treatment B) tablet, orally, once on Day 1 in Treatment Period 2, followed by E2082 25 mg (Treatment C) tablet, orally, once on Day 1 in Treatment Period 3, followed by E2082 40 mg tablet, orally, once on Day 1 in Treatment Period 4 (Open-label). A washout phase of at least 2 weeks was maintained between all the treatment periods.	Participants received, E2082 2.5 mg (Treatment B) tablet, orally, once on Day 1 in Treatment Period 1, followed by E2082 25 mg (Treatment C) tablet, orally, once on Day 1 in Treatment Period 2, followed by E2082-matched placebo (Treatment A) tablet, orally, once on Day 1 in Treatment Period 3, followed by E2082 40 mg tablet, orally, once on Day 1 in Treatment Period 4 (Open-label). A washout phase of at least 2 weeks was maintained between the treatment periods.	Participants received, E2082 25 mg (Treatment C) tablet, orally, once on Day 1 in Treatment Period 1, followed by E2082-matched placebo (Treatment A) tablet, orally, once on Day 1 in Treatment Period 2, followed by E2082 2.5 mg (Treatment B) tablet, orally, once on Day 1 in Treatment Period 3, followed by E2082 40 mg tablet, orally, once on Day 1 in Treatment Period 4 (Open-label). A washout phase of at least 2 weeks was maintained between the treatment periods.	Participants received, E2082-matched placebo (Treatment A) tablet, orally, once on Day 1 in Treatment Period 1, followed by E2082 25 mg (Treatment C) tablet, orally, once on Day 1 in Treatment Period 2, followed by E2082 2.5 mg (Treatment B) tablet, orally, once on Day 1 in Treatment Period 3, followed by E2082 40 mg tablet, orally, once on Day 1 in Treatment Period 4 (Open-label). A washout phase of at least 2 weeks was maintained between the treatment periods.	Participants received, E2082 2.5 mg (Treatment B) tablet, orally, once on Day 1 in Treatment Period 1, followed by E2082-matched placebo (Treatment A) tablet, orally, once on Day 1 in Treatment Period 2, followed by E2082 25 mg (Treatment C) tablet, orally, once on Day 1 in Treatment Period 3, followed by E2082 40 mg tablet, orally, once on Day 1 in Treatment Period 4 (Open-label). A washout phase of at least 2 weeks was maintained between the treatment periods.	Participants received, E2082 25 mg (Treatment C) tablet, orally, once on Day 1 in Treatment Period 1, followed by E2082 2.5 mg (Treatment B) tablet, orally, once on Day 1 in Treatment Period 2, followed by E2082-matched placebo (Treatment A) tablet, orally, once on Day 1 in Treatment Period 3, followed by E2082 40 mg tablet, orally, once on Day 1 in Treatment Period 4 (Open-label). A washout phase of at least 2 weeks was maintained between the treatment periods.
Period Title: Treatment Period 1 (1 Day)
STARTED	1	1	1	1	1	0
COMPLETED	1	1	1	1	1	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (1 Day)
STARTED	1	1	1	1	1	0
COMPLETED	1	1	1	1	1	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (1 Day)
STARTED	1	1	1	1	1	0
COMPLETED	1	1	1	1	0	0
NOT COMPLETED	0	0	0	0	1	0
Period Title: Treatment Period 1 (1 Day)
STARTED	1	1	1	1	0	0
COMPLETED	1	1	1	1	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (1 Day)
STARTED	1	1	1	1	0	0
COMPLETED	1	1	1	1	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (1 Day)
STARTED	1	1	1	1	0	0
COMPLETED	1	1	1	1	0	0
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (1 Day)
STARTED	1	1	1	1	0	0
COMPLETED	1	1	1	1	0	0
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Overall Participants
Arm/Group Description	Participants received E2082-matched placebo (Treatment A) or E2082 2.5 mg (Treatment B) or E2082 25 mg (Treatment C) and E2082 40 mg tablet, orally, once on Day 1 in Treatment Period 1 to 4 as per assigned treatment sequence. A washout phase of at least 2 weeks was maintained between all the treatment periods.
Overall Participants	5
Age, Customized (Count of Participants)
<=18 years	0 0%
Between 18 and 60 years	5 100%
>=60 years	0 0%
Sex: Female, Male (Count of Participants)
Female	4 80%
Male	1 20%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	5 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in the Photoparoxysmal Response (PPR) Range in the Most Sensitive Eye Condition at 8 Hours Postdose on Day 1 of Each Treatment Period
Description	PPR was an electroencephalogram (EEG) trait of spike and spike-wave discharges in response to photic stimulation. Intermittent photic stimulation (IPS)-EEG assessments determine the range of frequencies of IPS that elicited an epileptiform EEG response. Each IPS-EEG assessment was conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open) at ascending and then descending photo stimulation administered at 14 standard frequencies: 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 hertz (Hz). The lower and upper limit of photosensitivity to IPS threshold frequency were determined for each eye condition. From this range, standard photosensitivity response (SPR) was derived. SPR is an integer score that ranges from 0 to 14, with lower scores representing better outcomes. Most sensitive eye condition was defined as one that yielded the largest SPR before dosing.
Time Frame	Baseline (30 minutes-2 hours) and at 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The pharmacodynamic (PD) analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PD data to derive at least 1 PD parameter.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg, tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Baseline	6.80 (4.604)	5.60 (4.336)	6.00 (3.651)	6.50 (1.732)
Change at 8 hours postdose	0.00 (1.517)	1.16 (1.381)	-3.90 (2.928)	-5.25 (0.957)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A: Placebo, Treatment B: E2082 2.5 mg
	Comments	The mixed effects model for the crossover part of the study will include treatment, period, and sequence as fixed effects, baseline (predose) measurement as a covariate, and subject nested within sequence as a random effect. Least Square (LS) Mean Difference was calculated for 2.5 mg versus (vs) Placebo only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 90%; -0.98 to 3.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment A: Placebo, Treatment C: E2082 25 mg
	Comments	The mixed effects model for the crossover part of the study will include treatment, period, and sequence as fixed effects, baseline (predose) measurement as a covariate, and subject nested within sequence as a random effect. LS Mean Difference was calculated for 25 mg vs Placebo only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-4.17
	Confidence Interval	(2-Sided) 90%; -6.35 to -1.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Change From Baseline in PPR Ranges in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Opened) at 8 Hours Postdose on Day 1 of Each Treatment Period
Description	PPR was an EEG trait of spike and spike-wave discharges in response to photic stimulation. IPS-EEG assessments determine the range of frequencies of IPS that elicited an epileptiform EEG response. Each IPS-EEG assessment was conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open) at ascending and then descending photo stimulation administered at 14 standard frequencies: 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 Hz. The lower and upper limit of photosensitivity to IPS threshold frequency were determined for each eye condition. From this range, SPR was derived. SPR is an integer score that ranges from 0 to 14, with lower scores representing better outcomes.
Time Frame	Baseline (30 minutes-2 hours) and at 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The PD analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PD data to derive at least 1 PD parameter.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Eye Closure: Baseline	6.2 (4.09)	6 (3.87)	5.8 (4.65)	5.5 (2.89)
Eye Closure: Change at 8 hours postdose	0.6 (1.66)	0.4 (0.91)	-3.7 (3.93)	-4.3 (1.71)
Eyes Closed: Baseline	5.4 (4.72)	5.6 (4.72)	5.3 (3.2)	6.3 (2.87)
Eyes Closed: Change at 8 hours postdose	1.1 (1.4)	0.7 (1.56)	-3.7 (2.96)	-5.4 (1.62)
Eyes Open: Baseline	5.2 (5.4)	4.6 (4.04)	5 (3.83)	6.3 (4.65)
Eyes Open: Change at 8 hours postdose	0.5 (2.18)	0.8 (1.12)	-3.9 (3.28)	-5.8 (4.09)

3. Secondary Outcome

Title	Time to Onset of Mean Photosensitivity Response in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) up to 8 Hours Postdose on Day 1 of Each Treatment Period
Description	Time to onset of mean photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and eyes open condition) was determined from mean and mean change from baseline SPR data across participants. The onset of mean suppression was defined as the first time point at which the mean Response of standardized photosensitivity response (SPR) across participants (not for each participant) was at least 3 units below the mean SPR at baseline. Photosensitivity response were essentially intermittent photosensitivity (intermittent photic stimulation [IPS]) assessments, is a form of visual stimulation, when the participants are flashed with light on their eyes intermittently at different hertz.
Time Frame	Baseline (30 minutes-2 hours) up to 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The PD analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PD data to derive at least 1 PD parameter.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Eye Closure	NA	NA	1	1
Eyes Closed	NA	NA	1	1
Eyes Opened	NA	NA	1	1

4. Secondary Outcome

Title	Maximum Change From Baseline of Photosensitivity Response in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) up to 8 Hours Postdose on Day 1 of Each Treatment Period
Description	Maximum change from baseline of photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and eyes open condition) were reported. PPR was an EEG trait of spike and spike-wave discharges in response to photic stimulation. IPS-EEG assessments determine the range of frequencies of IPS that elicited an epileptiform EEG response. Each IPS-EEG assessment was conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open) at ascending and then descending photo stimulation administered at 14 standard frequencies: 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 Hz. The lower and upper limit of photosensitivity to IPS threshold frequency were determined for each eye condition. From this range, SPR was derived. SPR is an integer score that ranges from 0 to 14, with lower scores representing better outcomes.
Time Frame	Baseline (30 minutes-2 hours) up to 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The PD analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PD data to derive at least 1 PD parameter.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Eye Closure: Baseline	6.20 (4.087)	6.00 (3.873)	5.75 (4.646)	5.50 (2.887)
Eye Closure: Maximum Change	1.40 (3.912)	1.80 (2.588)	-4.50 (3.697)	-5.25 (2.500)
Eyes Closed: Baseline	5.40 (4.722)	5.60 (4.722)	5.25 (3.202)	6.25 (2.872)
Eyes Closed: Maximum Change	1.80 (2.588)	2.00 (2.345)	-4.25 (2.630)	-6.25 (2.872)
Eyes Opened: Baseline	5.20 (5.404)	4.60 (4.037)	5.00 (3.830)	6.25 (4.646)
Eyes Opened: Maximum Change	2.00 (3.240)	1.80 (3.633)	-4.25 (3.304)	-6.25 (4.646)

5. Secondary Outcome

Title	Duration of Mean Photosensitivity Response in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) up to 8 Hours Postdose on Day 1 of Each Treatment Period
Description	Duration of mean photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and eyes open condition) was determined from mean and mean change from baseline SPR data across participants. Duration of mean suppression was defined as the difference in hours between the onset of mean suppression and the end of mean suppression of photosensitivity across participants. The onset of mean suppression was defined as the first time point at which the mean SPR across participants was at least 3 units below the mean SPR at baseline. The end of mean suppression was defined as the last time (second time) with two successive reductions in mean SPR across participants of at least 3 units lower than the mean SPR at baseline. Photosensitivity response were essentially IPS assessments, is a form of visual stimulation, when the participants are flashed with light on their eyes intermittently at different hertz.
Time Frame	Baseline (30 minutes-2 hours) up to 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The PD analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PD data to derive at least 1 PD parameter.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Eye Closure: Duration	NA	NA	7	7
Eyes Closed: Duration	NA	NA	7	7
Eyes Opened: Duration	NA	NA	7	7

6. Secondary Outcome

Title	Number of Participants With Complete Suppression, Partial Response, and no Response of Standardized Photosensitivity Response (SPR) up to 8 Hours Postdose on Day 1 of Each Treatment Period
Description	Complete suppression, reduction (partial response), and no change (no response) of PPR will be measured. Complete suppression was defined as a SPR reduction to 0 over at least 1 time point for all three eye conditions. Partial response was defined as a reduction in SPR of at least 3 units from baseline for at least 3 time points, and no time points with at least 3 units of increase, in the most sensitive eye condition; without meeting the complete suppression definition. No response was defined as not meeting complete suppression or partial suppression definitions.
Time Frame	Baseline (30 minutes-2 hours) up to 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The PD analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PD data to derive at least 1 PD parameter.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Complete Suppression	0 0%	0 NaN	2 NaN	2 NaN
Partial Response	0 0%	0 NaN	0 NaN	2 NaN
No Response	5 100%	5 NaN	2 NaN	0 NaN

7. Secondary Outcome

Title	Change From Baseline in Bond and Lader Visual Analogue Scales (BL-VAS) at 1, 2, 4, 6, and 8 Hours Post-dose in Each Treatment Period
Description	BL-VAS system was used to assess the extent of damage to the extrapyramidal system and the motor functions that it controls. The BL-VAS monitored the subjective mood of each participant on 16 mood scales. Participants were asked to indicate on the VAS scale ranging from 0 to 100 millimeter (mm) about how they felt at the moment the scale was administered (example, alert/drowsy; calm/excited; content/tensed). The individual responses from the 16 mood scales were then combined to make three subscales: a.) Anxiety, b.) Dysphoria, c.) sedation with each item ranges from 0 to 100 and higher scores indicated better condition.
Time Frame	Baseline (30 minutes-2 hours) and at 1,2,4,6 and 8 hours post-dose in each treatment period

Outcome Measure Data

Analysis Population Description

The PD analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PD data to derive at least 1 PD parameter.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Anxiety: Baseline	29.42 (22.731)	29.42 (22.731)	24.33 (22.712)	24.33 (22.712)
Anxiety: Change at 1 hour post-dose	-7.36 (23.099)	-9.44 (19.550)	-0.37 (0.386)	-2.40 (3.382)
Anxiety: Change at 2 hours post-dose	2.84 (8.996)	-10.04 (20.028)	-1.05 (2.684)	19.73 (42.748)
Anxiety: Change at 4 hours post-dose	2.82 (8.885)	-8.96 (18.512)	0.10 (1.010)	-0.10 (4.017)
Anxiety: Change at 6 hours post-dose	-0.72 (3.883)	-9.70 (21.895)	-0.87 (2.766)	-0.42 (4.452)
Anxiety: Change at 8 hours post-dose	-0.72 (3.935)	5.92 (43.792)	18.78 (35.818)	-0.85 (3.171)
Dysphoria: Baseline	33.58 (23.032)	33.58 (23.032)	36.23 (25.703)	36.23 (25.703)
Dysphoria: Change at 1 hour post-dose	-4.44 (7.134)	-0.50 (6.536)	0.50 (0.883)	2.28 (4.110)
Dysphoria: Change at 2 hours post-dose	1.80 (3.616)	-1.62 (2.909)	2.68 (3.886)	3.30 (3.503)
Dysphoria: Change at 4 hours post-dose	-0.26 (1.137)	-1.94 (3.889)	2.47 (3.661)	2.55 (3.486)
Dysphoria: Change at 6 hours post-dose	-0.88 (3.397)	1.56 (3.591)	2.30 (3.866)	0.02 (2.334)
Dysphoria: Change at 8 hours post-dose	0.30 (6.288)	-2.36 (3.965)	-0.30 (1.137)	-0.40 (1.337)
Sedation: Baseline	28.90 (18.748)	28.90 (18.748)	31.90 (20.215)	31.90 (20.215)
Sedation: Change at 1 hour post-dose	4.36 (5.963)	6.20 (4.933)	6.45 (3.724)	5.98 (4.131)
Sedation: Change at 2 hours post-dose	9.44 (9.060)	7.23 (7.032)	7.40 (4.291)	8.18 (5.702)
Sedation: Change at 4 hours post-dose	5.50 (5.247)	2.84 (6.993)	11.55 (9.627)	6.08 (4.219)
Sedation: Change at 6 hours post-dose	0.58 (2.567)	2.70 (9.281)	7.08 (4.424)	10.30 (12.258)
Sedation: Change at 8 hours post-dose	1.08 (3.976)	0.50 (6.615)	2.38 (3.256)	9.53 (9.466)

8. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Time Frame	Up to 28 days after the last dose of study treatment on Day 1 in Treatment Period 4 (approximately Day 71)

Outcome Measure Data

Analysis Population Description

The safety analysis set was the group of participants who received at least 1 dose of study drug and have at least 1 postdose safety assessment.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Count of Participants [Participants]	2 40%	2 NaN	1 NaN	2 NaN

9. Secondary Outcome

Title	Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Time Frame	Up to 28 days after the last dose of study treatment on Day 1 in Treatment Period 4 (approximately Day 71)

Outcome Measure Data

Analysis Population Description

The safety analysis set was the group of participants who received at least 1 dose of study drug and have at least 1 postdose safety assessment.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	0 NaN

10. Secondary Outcome

Title	Number of Participants With Clinically Significant Change From Baseline in Laboratory Values
Time Frame	Up to 28 days after the last dose of study treatment on Day 1 in Treatment Period 4 (approximately Day 71)

Outcome Measure Data

Analysis Population Description

The safety analysis set was the group of participants who received at least 1 dose of study drug and have at least 1 postdose safety assessment.

Arm/Group Title	Treatment A: Placebo	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	5	4	4
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	0 NaN

11. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for E2082
Time Frame	Predose (within 2 hours prior to dosing) to 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PK data to derive at least 1 PK parameter.

Arm/Group Title	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	4	4
Mean (Standard Deviation) [nanogram per milliliter (ng/mL)]	100 (25.1)	617 (30.3)	851 (91.8)

12. Secondary Outcome

Title	Tmax: Time to Reach Maximum Plasma Concentration (Cmax) for E2082
Time Frame	Predose (within 2 hours prior to dosing) to 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The PK analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PK data to derive at least 1 PK parameter.

Arm/Group Title	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	4	4
Median (Full Range) [hour]	3.93	3.96	3.99

13. Secondary Outcome

Title	AUC (0-8h): Area Under the Plasma Concentration-time Curve From 0 to 8 Hours Post-dose for E2082
Time Frame	Predose (within 2 hours prior to dosing) to 8 hours postdose on Day 1 of each treatment period

Outcome Measure Data

Analysis Population Description

The PK analysis set was the group of randomized participants who received at least 1 dose of study drug and have sufficient PK data to derive at least 1 PK parameter.

Arm/Group Title	Treatment B: E2082 2.5 mg	Treatment C: E2082 25 mg	Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.	Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
Measure Participants	5	4	4
Mean (Standard Deviation) [hour*nanogram per milliliter (h*ng/mL)]	633 (142)	3990 (344)	5750 (787)

Adverse Events

Time Frame	Up to 28 days after the last dose of study treatment on Day 1 in Treatment Period 4 (approximately Day 71)
Arm/Group Title	Treatment A: Placebo		Treatment B: E2082 2.5 mg		Treatment C: E2082 25 mg		Open-label Treatment: E2082 40 mg
Arm/Group Description	Participants received, E2082-matched placebo tablet, orally, once on Day 1 as per assigned Treatment sequence in Treatment Period 1, 2, or 3.		Participants received, E2082 2.5 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.		Participants received, E2082 25 mg tablet, orally, once on Day 1 as per assigned treatment sequence in Treatment Period 1, 2, or 3.		Participants received, E2082 40 mg tablet, orally, once on Day 1 of Treatment Period 4 in all the sequences.
All Cause Mortality
	Treatment A: Placebo		Treatment B: E2082 2.5 mg		Treatment C: E2082 25 mg		Open-label Treatment: E2082 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/4 (0%)		0/4 (0%)
Serious Adverse Events
	Treatment A: Placebo		Treatment B: E2082 2.5 mg		Treatment C: E2082 25 mg		Open-label Treatment: E2082 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/5 (20%)		0/5 (0%)		0/4 (0%)		0/4 (0%)
Eye disorders
Eye movement disorder	1/5 (20%)		0/5 (0%)		0/4 (0%)		0/4 (0%)
Nervous system disorders
Disturbance in attention	1/5 (20%)		0/5 (0%)		0/4 (0%)		0/4 (0%)
Dysarthria	1/5 (20%)		0/5 (0%)		0/4 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Treatment A: Placebo		Treatment B: E2082 2.5 mg		Treatment C: E2082 25 mg		Open-label Treatment: E2082 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		2/5 (40%)		1/4 (25%)		2/4 (50%)
Infections and infestations
Upper respiratory tract infection	1/5 (20%)		1/5 (20%)		0/4 (0%)		0/4 (0%)
Nervous system disorders
Dizziness	0/5 (0%)		1/5 (20%)		0/4 (0%)		0/4 (0%)
Dysarthria	1/5 (20%)		0/5 (0%)		0/4 (0%)		1/4 (25%)
Headache	1/5 (20%)		0/5 (0%)		0/4 (0%)		0/4 (0%)
Somnolence	1/5 (20%)		1/5 (20%)		0/4 (0%)		2/4 (50%)
Psychiatric disorders
Aggression	1/5 (20%)		0/5 (0%)		0/4 (0%)		0/4 (0%)
Anger	1/5 (20%)		0/5 (0%)		0/4 (0%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/5 (0%)		0/5 (0%)		1/4 (25%)		0/4 (0%)

Limitations/Caveats

The study was terminated due to safety concerns from a phase 1 study (E2082-J081-001; NCT03402178) and preclinical animal toxicity testing.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.