| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Partial onset seizures with or without secondary generalization. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10015037 |
| E.1.2 | Term | Epilepsy |
|
| 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 |
| The primary objective of this study is to evaluate the efficacy of BRV in the conversion to monotherapy at the doses of 50 and 100 mg/day (administered in two equal doses per day) in subjects with partial onset seizures when compared to a historical pseudo-placebo control group. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of BRV in subjects undergoing conversion to monotherapy for POS.
• To explore direct medical resources use and indirect cost parameters.
• To explore the impact of BRV on different Patient Reported Outcomes (PRO): The Quality of Life Inventory in Epilepsy (QOLIE-31-P), the Hospital Anxiety and Depression Scale (HADS), the EQ-5D, and a Patient-reported Global Evaluation Scale (GES).
• To explore the impact of BRV on the Investigator’s GES.
• To obtain a description of the patient’s self-reported health status.
• To explore the population pharmacokinetics of BRV in monotherapy.
• To collect blood samples for genotyping of SV2-and epilepsy-related genes (for a pooled analysis at the program level). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• An IEC/IRB approved written informed consent signed and dated by the subject or by parent(s) or legal representative. The consent form or a specific assent form, where required, will be signed and dated by minors.
• Subjects from 16 to 75 years, both inclusive. Subjects under 18 years may only be included where permitted legally and ethically accepted.
• Subjects with a body weight ≥ 45 kg.
• Female subjects without childbearing potential (pre-menarcheal, post-menopausal for at least 2 years, bilateral oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with childbearing potential are eligible if they use a medically accepted contraceptive method. Oral or depot contraceptive treatment with at least 30 μg [or 50 μg ethinylestradiol per intake if associated with carbamazepine (or other strong enzyme inducers e.g. oxcarbazepine)] must be used in conjunction with a barrier method. Monogamous relationship with vasectomized partner or double-barrier contraception are acceptable methods. The subject must understand the consequences and potential risks of inadequately protected sexual activity, be educated about and understand the proper use of contraceptive methods, and undertake to inform the Investigator of any potential change in status. Sexual inactivity might be accepted on a case-by-case basis.
• Subject/legally acceptable representative considered as reliable and capable of adhering to the protocol (e.g. able to understand and complete diaries), visit schedule or medication intake according to the judgment of the Investigator.
• Well-characterized partial onset seizures according to the ILAE classification (1981) or focal epilepsy or epileptic syndrome according to the ILAE classification (1989).
• Presence of an EEG compatible with the clinical diagnosis of focal epilepsy in the last 5 years. If an EEG has not been performed within the last 5 years, a Baseline EEG must be performed before Visit 3.
• Presence of a brain CT Scan or MRI performed within the last 2 years. If a CT Scan or MRI has not been performed within the last 2 years, a Baseline exam must be performed before Visit 3.
• Subjects with a history of inadequately controlled partial onset seizures that may be classified as simple or complex whether or not secondarily generalized (type I seizures according to the ILAE classification, 1981).
• Subjects having at least 2 but not exceeding 40 partial onset seizures, whether or not secondarily generalized per 4 weeks during the 8-week Baseline Period. (NOTE: Aura is a subjective ictal phenomenon, usually visual, visceral or auditory, that in a given subject may precede an observable seizure. When it occurs by itself it constitutes a simple partial sensory seizure. Auras followed by an observable seizure should only be counted as one event and receive the ILAE code of the observable seizure while stand-alone auras should be counted as a seizure and receive the corresponding ILAE code (1981)).
• Subjects must be on a stable dose of at least 1 but no more than 2 concomitant AEDs for at least 4 weeks before Baseline (Visit 1) and expected to remain on a stable dose until the tapering period commences.
• If a second AED is taken, its dose must be ≤ 50% of the minimum recommended maintenance dose approved in the US for at least 4 weeks before Baseline (Visit 1). |
|
| E.4 | Principal exclusion criteria |
• Seizure type IA simple partial non-motor as only seizure type.
• History or presence of seizures occurring too frequently or indistinctly separated to be reliably counted, during the 6 months preceding Visit 1 or during Baseline.
• History or presence of status epilepticus during the 1 year preceding Visit 1 or during Baseline.
• History or presence of pseudo-seizures.
• Subjects on felbamate with less than 18 months continuous exposure before Visit 1. Subjects having been on felbamate are eligible if the combined duration of treatment and wash-out is ≥ 18 months.
• Subjects currently on vigabatrin. Subjects having been on vigabatrin if no visual fields examination report available including standard static (Humphrey or Octopus) or kinetic perimetry (Goldman) or if results of these examinations are abnormal.
• Subjects who have received treatment with phenobarbital or primidone within 3 months prior to Visit 1 and subjects who have received treatment with benzodiazepines within 1 month prior to Visit 1. Subjects with VNS are excluded unless their device has been documented to be inactivated for at least 28 days prior to Visit 1.
• Subjects taking any drug with possible relevant CNS effects except if stable from at least 1 month before Visit 1 and expected to be kept stable during the study.
• Subjects taking any drug that may significantly influence the metabolism of BRV (CYP2C or CYP3A potent inducers/inhibitors) except if the dose has been kept stable at least one month before Visit 1, and is expected to be kept stable during the study.
• History of cerebrovascular accident (CVA), including transient ischemic attack (TIA), in the last 6 months.
• Subjects suffering from severe cardiovascular disease or peripheral vascular disease.
• Presence of any sign (clinical or imaging techniques) suggesting rapidly progressing (i.e. not expected to stay stable during trial participation) brain disorder or brain tumor. Stable arteriovenous malformations, meningiomas or other benign tumors may be acceptable.
• Any clinical conditions (e.g. bone marrow depression, chronic hepatic disease and/or severe renal impairment) which impair reliable participation in the trial or necessitate the use of medication not allowed by protocol.
• Presence of a terminal illness.
• Presence of a serious infection.
• Subjects with history of severe adverse hematologic reaction to any drug.
• Subjects suffering from severe disturbance of haemostasis. Impaired hepatic function: ALT/SGPT, AST/SGOT, alkaline phosphatase, gamaGT values of more than three times the upper limit of the reference range. A result of gamaGT exceeding 3 times the upper limit can only be accepted if attributable to hepatic enzyme induction caused by concomitant antiepileptic treatment and other hepatic enzymes are below 3 times the upper limit of the reference range.
• Subjects having clinically significant deviations from reference range values for laboratory parameters: creatinine clearance calculated < 50 mL/min, platelets < 100,000/μL, or neutrophil cells < 1,800/μL).
• Clinically significant ECG abnormalities according to the Investigator.
• History of suicide attempt.
• Ongoing psychiatric disease other than mild controlled disorder.
• Subjects who are institutionalized due to judicial reasons.
• Known allergic reaction or intolerance to pyrrolidone derivatives and/or investigational product excipients (BRV excipients are as follows: Croscarmellose sodium, lactose, beta cyclodextrin, magnesium stearate, Opadry TM {hydroxypropylmethylcellulose, macrogel, PEG, sodium saccharinate, talc and titanium dioxide}. Placebo excipients are: Lactose, magnesium stearate, microcristalline cellulose, aerosil and opadry TM).
• Known multiple drug allergies or severe drug allergy.
• Pregnant or lactating women.
• Known alcohol or drug addiction or abuse within the last 2 years.
• Subjects taking part in another clinical/pharmacological trial in the month preceding Visit 1.
• Investigators, co-investigators, their spouses or children or any trial collaborators.
• Subjects previously treated with BRV.
• Subjects previously screened within this trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Variables:
The primary efficacy end point is the cumulative exit rate at 112 days after the beginning of the tapering phase (at Visit 4) of the Baseline AED(s).
Safety Variables:
• Adverse events reporting.
• Laboratory tests (blood chemistry, hematology, urinalysis, pregnancy testing, thyroid profile analysis).
• Electrocardiogram (ECG).
• Physical and neurological examinations.
• Vital signs including orthostatic measurements.
• Body weight.
Pharmacokinetic Variables:
• BRV (parent compound only) plasma levels.
• Concomitant AED (and/or relevant metabolites) plasma levels. |
|
| 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 | Yes |
| 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 | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
|
| 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
|
| Last visit of the last subject undergoing the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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