| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015037 |
| E.1.2 | Term | Epilepsy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| 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 evaluate the safety and tolerability of BRV 200mg/day administered intravenously as an infusion or a bolus, according to an initiation or a conversion scheme, during repeated dosing (100mg/administration bid for 4.5 days) as an adjunctive treatment in adult subjects suffering from localization-related or generalized epilepsy |
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| E.2.2 | Secondary objectives of the trial |
| • To collect data on health care resource utilization |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. An Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved written Informed Consent form signed and dated by the subject or by parent(s) or legal representative(s). The consent form or a specific Assent form, where required, will be signed and dated by minors.
2. Subjects from 16 to 70 years, both inclusive. Subjects under 18 years of age may only be included where legally permitted and ethically accepted. In the Czech Republic and Germany, subjects <18 years of age are not allowed to participate. In the Czech Republic, subjects >65 years of age are not allowed to participate.
3. Subjects with a body weight ≥40kg.
4. Female subjects without childbearing potential (premenarcheal, postmenopausal for at least 2 years, bilateral oophorectomy, tubal ligation, or 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 30μg (or 50μg ethinylestradiol per intake if associated with carbamazepine [or other strong enzyme inducers eg, phenobarbital, primidone, oxcarbazepine]) must be used in conjunction with a barrier method. Monogamous relationship with partner vasectomized for at least 3 months 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 based upon Investigator’s judgment.
5. Subject/legal representative considered as reliable and capable of adhering to the protocol (eg, able to understand and complete diaries), visit schedule, or medication intake according to the judgment of the Investigator.
6. Subjects with well-characterized focal or generalized epilepsy or epileptic syndrome according to the ILAE classification.
7. Inpatients and outpatients with a history of POS whether or not secondarily generalized or primary generalized seizures (Type I or II seizures according to the ILAE classification).
8. Subjects being uncontrolled while treated with 1 to 2 permitted concomitant AED(s). Vagal nerve stimulation (VNS) is allowed and will be counted as a concomitant AED.
9. Permitted concomitant AEDs and VNS (implanted for at least 9 months) being stable and at optimal dosage for the subject from at least 1 month (3 months for phenobarbital and primidone) before V1 and expected to be kept stable during the Run-In and Evaluation Periods. Benzodiazepines taken more than once a week (for any indication) will be considered as a concomitant AED. |
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| E.4 | Principal exclusion criteria |
1. Mentally impaired subjects unable to understand the study purpose
2. History or presence of status epilepticus during 1 year preceding V1 or during Baseline.
3. Subjects on felbamate with less than 18 months continuous exposure before V1. Subjects having been on felbamate are eligible if the combined duration of treatment and wash-out is ≥18 months.
4. Subjects currently on vigabatrin. Subjects having been on vigabatrin if no visual fields examination report available including standard static (Humphrey or Octopus) or cinetic perimetry (Goldman) or if results of these examinations are abnormal.
5. Subject 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 Run-in and Evaluation Periods.
6. 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 1 month before V1, and is expected to be kept stable during the Run-in and Evaluation Periods.
7. History of cerebrovascular accident (CVA), including transient ischemic attack (TIA), in the last 6 months.
8. Subjects suffering from severe cardiovascular disease or peripheral vascular disease.
9. 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.
10. 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.
11. Presence of a terminal illness.
12. Presence of a serious infection.
13. Subjects with history of severe adverse hematologic reaction to any drug.
14. Subjects suffering from severe disturbance of hemostasis.
15. Subject has impaired liver functions: values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase are more than twice the upper limit of the reference range.
16. Subject 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).
17. Clinically significant ECG abnormalities according to the Investigator.
18. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at V1.
19. In the Investigator’s medical judgment, any current suicidal ideation or other serious psychiatric disorders (ie, bipolar disorder, severe depression, psychosis) requiring or having required hospitalization or medication.
20. Known allergic reaction or intolerance to pyrrolidone derivatives and/or investigational product excipients.
21. Known multiple drug allergies or severe drug allergy.
22. Pregnant or lactating women.
23. Known alcohol or drug addiction or abuse within the last two years.
24. Subject institutionalized under judicial decision.
25. Problems of venous accessibility
26. Subject taking part in another clinical/pharmacological trial in the month preceding enrolment (V1).
27. Investigators, co-investigators, their spouses or children or any trial collaborators.
28. Subject previously treated with BRV.
29. Subject previously screened within this trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Variables
The safety assessment will be made using:
• AEs, with special attention to injection-related AEs (local site and systemic reactions) and seizure worsening
• Seizure counts
• Laboratory tests (hematology, biochemistry, urinalysis, and BRV and AED plasma concentrations)
• ECGs including cardiac telemetry
• Vital signs (including orthostatic measurement), body weight, and height
• Physical and neurological examinations
• Psychiatric and mental status |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
| • Health care resource utilization data (concomitant medications, medical procedures, hospital stays, and health care provider consultations not foreseen by the protocol) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| 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 | 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 1 week double blind during the Run in period |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 21 |
| 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 | No |
| 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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| The end of study is defined as the date of Last Patient Last Visit (LPLV) |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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