| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| E2007 is given as adjunctive therapy in patients with refractory partial seizures |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To determine the maximal tolerated dose (MTD) of E2007 when added to concomitant antiepileptic drugs (AEDs), given bid or qd to patients with refractory partial onset seizures (including secondarily generalized seizures).
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| E.2.2 | Secondary objectives of the trial |
1.To evaluate the overall safety of E2007 in the treated population.
2.To analyze pharmacokinetic variables
3.To evaluate the efficacy of E2007 for the control of partial-onset seizures by the proportion of patients experiencing a > 50% reduction in partial seizure frequency from Baseline to the Maintenance Phase (total and per dose group).
4.To determine effects of E2007 on mood as measured by the Profile of Mood States (POMS) test.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Written informed consent signed by patient or legal guardian prior to entering the study or undergoing any study procedures.
2) Patients, who are reliable and willing to make themselves available for the study period and are able to record seizures and report adverse events themselves or have a caregiver who can record and report the events.
3) Male and female patients will be eligible for enrollment. Females should be either of non-childbearing potential as a result of surgery, radiational therapy, menopause (one year post onset), or of childbearing potential and practicing a medically acceptable method of contraception (eg, abstinence, a barrier method plus spermicide, or IUD) for at least three months before Visit 1 (Screening) and for two months after the end of the study. They must also have a negative serum β-hCG at Screening. Pregnant and/or lactating females are excluded. Those women using hormonal contraceptives must also be using an additional approved method of contraception (eg, a barrier method plus spermicide, or IUD) starting with the Baseline Phase and continuing throughout the entire study period. (revised per Amendment 01).
4) Patients, who are between the ages of 18 and 70 years of age, inclusive.
5) Are of 40 kg (88 lb) of weight or more.
6) Have the diagnosis of epilepsy with partial-onset seizures with or without secondarily generalized seizures according with the International League Against Epilepsy’s Classification of Epileptic Seizures (1981).9 (See Appendix 4) Diagnosis should have been established by clinical history, electroencephalogram (EEG) and computed tomography/magnetic resonance imaging (CT/MRI) of the brain performed within the last 10 years and consistent with localization-related epilepsy.
7) Have uncontrolled partial seizures despite having been treated with at least three different AEDs (given concurrently or sequentially) for at least 2 years.
8) To be enrolled, patient must have averaged at least 4 partial seizures per month, with no 21-day seizure-free period during the 2 months preceding randomization. To be randomized, the patient must have had at least 3 seizures during the prospective Baseline Phase (28 days), with no 21-day seizure-free period. This should be documented in the form of medical history, medical records, or photocopied records of the patient diary/patient chart. Simple partial seizures without motor signs will not be counted towards this inclusion criterion.
9) Patients, who are currently being treated with one or a maximum of two licensed AEDs and are known to take their medication(s) as directed.
10) Are on a stable dose(s) of the same AED(s) for the 2 months prior to Visit 1.
11) If using a vagal nerve stimulator, it must have been implanted for at least 5 months prior to Visit 1. Stimulator parameters may not be changed for at least 1 month prior to Visit 1 or thereafter during the study. Magnet use will be allowed and documented throughout the study.
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| E.4 | Principal exclusion criteria |
1) Have participated in a study involving administration of an investigational compound within one month of Visit 1 (Screening), or within 5 half-lives of the previous investigational compound, whichever is longer.
2) Presence of non-motor simple partial seizures only.
3) Presence of primary generalized epilepsies or seizures, such as absences, myoclonic epilepsies, Lennox-Gastaut syndrome.
4) History of status epilepticus in the past year or seizure clusters where individual seizures cannot be counted.
5) Show evidence of clinically significant disease (cardiac, respiratory, gastrointestinal, renal disease, etc) that in the opinion of the Investigator(s) could affect the patient’s safety or trial conduct.
6) Show evidence of significant active hepatic disease. Stable elevations of liver enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) due to concomitant medication(s) will be allowed if they are less than 2 times the upper limit of normal (ULN).
7) Show evidence of significant active hematological disease. White blood cell (WBC) count cannot be ≤ 2500/µL (2.50 1E+09/L) or an absolute neutrophil count ≤ 1000/µL (1.00 1E+09/L) (revised per Amendment 03).
8) Clinically significant ECG abnormality, including prolonged QTc defined as ≥ 450 msec for males and ≥ 470 msec for females.
9) Presence of major active psychiatric disease. Patients taking a stable dose of selective serotonin reuptake inhibitor (SSRI) antidepressant will be allowed (except fluvoxamine).
10) Presence of a progressive central nervous system (CNS) disease, including degenerative CNS diseases and tumors.
11) Have a history of psychogenic seizures.
12) Have a history of drug abuse in the past 2 years and/or positive finding on urinary drug screening, other than prescribed medication.
13) Have a history of alcohol abuse in the past 2 years, and/or positive finding on urinary drug screen.
14) Have had multiple drug allergies (dermatological, hematological or organ toxicity) or one or more severe drug reactions.
15) Allergy to lactose.
16) Concomitant use of felbamate or use of felbamate within 2 months prior to Visit 1.
17) Concomitant use of vigabatrin. Patients that took vigabatrin in the past must be off vigabatrin for at least 5 months prior to Visit 1 and must not have evidence of a clinically significant abnormality in a visual perimetry test.
18) Concomitant use or use within the previous 4 weeks prior to Visit 1 of neuroleptics, monoamine oxidase (MAO) inhibitors, barbiturates (except for seizure control indication), benzodiazepines (other than occasional intermittent use), and narcotic analgesics.
19) Frequent need of rescue benzodiazepines (one or more times a month).
In patients undergoing ophthalmological testing (in selected US centers only), the following additional exclusion criteria will apply (revised per Amendment 03):
1) Abnormal, clinically significant, ophthalmological examination.
2) History of ophthalmological disorder that could affect visual acuity, color vision, or visual field.
3) History of diabetes.
4) History of temporal lobectomy or other intracranial surgery that could affect the visual field.
5) Treatment with major ophthalmic formulations, plaquenil (hydroxychloroquine), or mellaril (thioridizine).
6) Previous treatment with vigabatrin.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy assessment will be done through the following means:
1) Seizure counts: using the patient’s diary. This diary should be completed by the patient or the designated caregiver.
2) Clinical Global Impression of Change: completed at Visit 2 and Visit 7, and during the Premature Discontinuation Visit, if applicable (see protocol Appendix 5).
3) Patient’s Global Impression of Change: completed at Visit 2 and Visit 7, and during the Premature Discontinuation Visit, if applicable (see protocol Appendix 6).
4) Seizure Severity Questionnaire: completed at Visit 2 and Visit 7 and during the Premature Discontinuation Visit, if applicable (see protocol Appendix 7).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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