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A Study to Evaluate the Pharmacodynamic Activity of E2730 in Adult Participants With Photosensitive Epilepsy

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ClinicalTrials.gov Identifier: NCT03603639
Recruitment Status : Terminated (The study was stopped due to efficacy reasons.)
First Posted : July 27, 2018
Last Update Posted : May 2, 2019
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.

Brief Summary:
The primary purpose of the study is to assess the pharmacodynamic (PD) activity of E2730 as measured by suppression of epileptic photoparoxysmal response (PPR) in the participant's most sensitive eye condition in participants with photosensitive epilepsy.

Condition or disease Intervention/treatment Phase
Photosensitive Epilepsy Drug: Placebo Drug: E2730 Phase 2

Detailed Description:

Adult participants with epilepsy will be enrolled in this study. This study will consist of 2 phases: Prerandomization and Randomization Phase.

The Prerandomization Phase will consist of a Screening Period (up to 3 weeks), during which each participant's study eligibility will be determined and baseline assessments will be conducted. The Randomization Phase will consist of 3 Treatment Periods with a single dose in each period (placebo, E2730 40 mg, or E2730 120 mg), each separated by a 3-week washout interval for a total of approximately 6 weeks, and a Follow-up Period (3 weeks after the last dose of study drug).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Double-Blind, Randomized, Cross-Over Study Evaluating Pharmacodynamic Activity of E2730 in Adult Subjects With Photosensitive Epilepsy
Actual Study Start Date : June 28, 2018
Actual Primary Completion Date : February 13, 2019
Actual Study Completion Date : February 13, 2019


Arm Intervention/treatment
Experimental: Placebo, E2730 40 mg, E2730 120 mg
Participants will receive a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 1 followed by a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 2 followed by a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods.
Drug: Placebo
Participants will receive E2730-matched placebo capsule, orally.

Drug: E2730
Participants will receive E2730 capsule, orally.

Experimental: E2730 40 mg, E2730 120 mg, Placebo
Participants will receive a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 1 followed by a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 2 followed by a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods.
Drug: Placebo
Participants will receive E2730-matched placebo capsule, orally.

Drug: E2730
Participants will receive E2730 capsule, orally.

Experimental: E2730 120 mg, Placebo, E2730 40 mg
Participants will receive a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 1 followed by a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 2 followed by a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods.
Drug: Placebo
Participants will receive E2730-matched placebo capsule, orally.

Drug: E2730
Participants will receive E2730 capsule, orally.

Experimental: Placebo, E2730 120 mg, E2730 40 mg
Participants will receive a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 1 followed by a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 2 followed by a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods.
Drug: Placebo
Participants will receive E2730-matched placebo capsule, orally.

Drug: E2730
Participants will receive E2730 capsule, orally.

Experimental: E2730 40 mg, Placebo, E2730 120 mg
Participants will receive a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 1 followed by a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 2 followed by a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods.
Drug: Placebo
Participants will receive E2730-matched placebo capsule, orally.

Drug: E2730
Participants will receive E2730 capsule, orally.

Experimental: E2730 120 mg, E2730 40 mg, Placebo
Participants will receive a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 1 followed by a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 2 followed by a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods.
Drug: Placebo
Participants will receive E2730-matched placebo capsule, orally.

Drug: E2730
Participants will receive E2730 capsule, orally.




Primary Outcome Measures :
  1. Mean Change from Baseline in the Photoparoxysmal Response (PPR) Range in the Most Sensitive Eye Condition [ Time Frame: 30 minutes to 2 hours pre-dose (Baseline), and at 1, 2, 4, 6, and 8 hours post-dose ]
    PPR is an electroencephalogram (EEG ) trait of spike and spike-wave discharges in response to photic stimulation. EEG data will be analyzed to determine the change in PPR following the intake of study treatment.


Secondary Outcome Measures :
  1. Mean Change from Baseline in PPR Ranges in Each of the 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) [ Time Frame: 30 minutes to 2 hours pre-dose (Baseline), and at 1, 2, 4, 6, and 8 hours post-dose ]
    PPR is an EEG trait of spike and spike-wave discharges in response to photic stimulation. EEG data will be analyzed to determine the change in PPR following the intake of study treatment.

  2. Time to Onset of Photosensitivity Response in all 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) [ Time Frame: 30 minutes to 2 hours pre-dose, and at 1, 2, 4, 6, and 8 hours post-dose ]
    Photosensitivity response is 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 (Hz).

  3. Maximum Change from Baseline of Photosensitivity Response in all 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) [ Time Frame: 30 minutes to 2 hours pre-dose, and at 1, 2, 4, 6, and 8 hours post-dose ]
    Photosensitivity response is essentially intermittent photosensitivity (IPS) assessments, is a form of visual stimulation, when the participants are flashed with light on their eyes intermittently at different when the participants are flashed with light on their eyes intermittently at different Hz.

  4. Duration of Photosensitivity Response in all 3 Eye Conditions (Eye Closure, Eyes Closed, and Eyes Open Condition) [ Time Frame: 30 minutes to 2 hours pre-dose, and at 1, 2, 4, 6, and 8 hours post-dose ]
    Photosensitivity response is essentially intermittent photosensitivity (IPS) assessments, is a form of visual stimulation, when the participants are flashed with light on their eyes intermittently at different when the participants are flashed with light on their eyes intermittently at different Hz.

  5. Percentage of Participants with Complete Suppression, Partial Response, and no Response of PPR [ Time Frame: 30 minutes to 2 hours pre-dose, and at 1, 2, 4, 6, and 8 hours post-dose ]
    Complete suppression, reduction (partial response) and no change (no response) of PPR will be measured. Complete suppression is defined as a standardized photosensitivity response (SPR) reduction to 0 over at least 1 time point for all three eye conditions. Partial suppression is 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 is defined as the response not meeting complete suppression or partial suppression definitions.

  6. Number of Participants with AEs or Changes in the Neurological Examination [ Time Frame: Approximately 7 weeks ]
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

  7. Number of Participants with Clinically Significant Change in Vital Signs, Serum Chemistries, Complete Blood Counts, or Liver Function Tests after Single Doses of E2730 Compared to Placebo [ Time Frame: Approximately 7 weeks ]
    Vital signs include systolic and diastolic blood pressure, pulse, respiratory rate, body temperature and weight. Liver function tests parameters include alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, total bilirubin.

  8. Maximum Observed Drug Concentration (Cmax) of E2730 and its N-acetyl metabolite, M1 in Plasma [ Time Frame: Pre-dose, 1, 2, 4, 6, and 8 hours post-dose ]
    Maximum observed drug concentration of E2730 and its N-acetyl metabolite, M1 in Plasma will be measured.

  9. Area Under the Concentration Versus Time Curve From Zero to 8 Hours (AUC[0-8h]) of E2730 and its N-acetyl metabolite, M1 in Plasma [ Time Frame: Pre-dose, 1, 2, 4, 6, and 8 hours post-dose ]
    Area under the concentration versus time curve from zero to 8 hours of E2730 and its N-acetyl metabolite, M1 in plasma will be measured.

  10. Time to Reach Maximum Drug Concentration (tmax) of E2730 and its N-acetyl metabolite, M1 in Plasma [ Time Frame: Pre-dose, 1, 2, 4, 6, and 8 hours post-dose ]
    Time to reach maximum drug concentration of E2730 and its N-acetyl metabolite, M1 in plasma will be measured.

  11. Relationship between Area Under the Concentration Versus Time Curve From Zero to 8 Hours (AUC[0-8h]) and Time to Onset of PPR [ Time Frame: Pre-dose, 1, 2, 4, 6, and 8 hours post-dose ]
    Relationship between area under the concentration versus time curve from zero to 8 hours and time to onset of PPR will be measured.

  12. Relationship between Area Under the Concentration Versus Time Curve From Zero to 8 Hours (AUC[0-8h]) and Maximum Change in PPR [ Time Frame: Pre-dose, 1, 2, 4, 6, and 8 hours post-dose ]
    Relationship between area under the concentration versus time curve from zero to 8 hours and maximum change in PPR will be measured.

  13. Relationship between Area Under the Concentration Versus Time Curve From Zero to 8 Hours (AUC[0-8h]) and Duration of PPR [ Time Frame: Pre-dose, 1, 2, 4, 6, and 8 hours post-dose ]
    Relationship between area under the concentration versus time curve from zero to 8 hours and duration of PPR will be measured.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female 18 to 60 years old at the time of informed consent.
  2. A diagnosis and history of a PPR on EEG with or without a diagnosis of epilepsy.
  3. Currently taking up to a maximum of 3 concomitant antiepileptic drugs (AEDs). If taking concomitant AED(s), the dose must have remained stable for at least 4 weeks prior to Screening.
  4. A reproducible intermittent photic stimulation (IPS)-induced PPR on EEG of at least 3 points on a frequency assessment scale (SPR) in at least 1 eye condition on at least 3 of the EEGs performed at Screening.
  5. A body mass index (BMI) between 18 to 35 kilogram per square meter (kg/m^2) and a total body weight greater than or equal to 45 kilograms (kg) at the time of Screening.

Exclusion Criteria:

  1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 international units per liter [IU/L] or equivalent units of ß-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
  2. History of nonepileptic seizures (eg, metabolic, structural, or pseudoseizures) while on any antiepileptic medication(s).
  3. History of status epilepticus while on any antiepileptic medication(s) within 2 years prior to Screening.
  4. Ongoing or history of generalized tonic-clonic seizures within 6 months prior to Screening.
  5. Previously developed or who experienced a clinical seizure during prior PPR assessment or Screening IPS procedure, respectively.
  6. Use of AEDs that affect gama-aminobutyric acid (GABA) (GABAergic AEDs) (such as tiagabine, vigabatrin, gabapentin, pregabalin) within 3 months prior to Screening.
  7. Multiple drug allergies or a severe drug reaction to AED(s), including dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
  8. An active central nervous system (CNS) infection, demyelinating disease, degenerative neurological disease or any CNS disease deemed to be progressive during the course of the study that may confound the interpretation of the study results.
  9. Concomitant use of cannabinoids.
  10. Inability to follow restriction on watching television, or use of any device with an animated screen (ie, computer, video games, tablets).
  11. A history of prolonged QT syndrome or risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT Syndrome), or the use of concomitant medications that prolonged the QT/corrected QT (QTc) interval; or prolonged QT/QTc interval (QTc greater than [>] 450 millisecond [msec]) demonstrated on electrocardiograms (ECG) at Screening or baseline (based on average of triplicate ECGs).
  12. Any suicidal ideation with intent with or without a plan within 6 months before Screening or during Screening (ie, answering "Yes" to questions 4 or 5 on the suicidal ideation section of the Columbia-Suicide Severity Rating Scale [C-SSRS]).
  13. Any lifetime suicidal behavior (per the suicidal behavior section of the C-SSRS).
  14. Any psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
  15. Frequent spontaneous background burst or current evidence of proconvulsive activity on EEG (eg, increase in spike-wave activity) at Screening.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03603639


Locations
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United States, Arkansas
Clinical Trials, Inc. and Arkansas Epilepsy Program
Little Rock, Arkansas, United States, 72205
United States, Idaho
Consultants in Epilepsy & Neurology, PLLC
Boise, Idaho, United States, 83702
United States, Maryland
Johns Hopkins University- School of Medicine
Baltimore, Maryland, United States, 21287
United States, Missouri
Washington University Hospital
Saint Louis, Missouri, United States, 63110
United States, Pennsylvania
Unniversity of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Eisai Inc.
Investigators
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Study Director: Medical Director Eisai Inc.

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Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT03603639     History of Changes
Other Study ID Numbers: E2730-A001-201
First Posted: July 27, 2018    Key Record Dates
Last Update Posted: May 2, 2019
Last Verified: July 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc.:
E2730
Epilepsy
Photosensitive
Seizures
PPR
Anti-epileptic

Additional relevant MeSH terms:
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Epilepsy
Epilepsy, Reflex
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases