| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Partial onset seizures (seizure activity initiating from one side of brain) |
|
| 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 | 10061334 |
| E.1.2 | Term | Partial seizures |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 efficacy of BRV at doses of 100 and 200mg/day compared to PBO as adjunctive treatment in adult focal epilepsy subjects with partial onset seizures not fully controlled despite current treatment with 1 or 2 concomitant AEDs. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the safety and tolerability of BRV. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form is signed and dated by the subject or by the parent(s) or legal representative. The consent form or a specific assent form, where required, will be signed and dated by minors
2 Subject/legal representative is considered 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
3 Subjects (male or female) from 16 to 80 years, both inclusive. Subjects under 18 years may only be included where legally permitted and ethically accepted
4 Subjects with a body weight ≥40kg
5 Female subjects without childbearing potential (premenarcheal, postmenopausal 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 30μg ethinylestradiol per intake [or 50μg ethinylestradiol per intake if associated with any strong enzyme inducer (eg carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. John’s Wort, rifampicin)], 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. Abstinence will be considered as an acceptable method of contraception if the Investigator can document that the subject agrees to be compliant
6 Well-characterized focal epilepsy/epileptic syndrome according to the 1989 International League Against Epilepsy (ILAE) classification
7 Presence of an EEG reading compatible with the clinical diagnosis of focal epilepsy within the last 5 years
8 Presence of a brain MRI/computed tomography (CT) scan performed within the last 2 years
9 Subjects having at least 8 Type I seizures [POS; focal seizures (according to the 1981 ILAE classification)] during the 8-week Baseline Period with at least 2 Type I seizures during each 4-week interval of the Baseline Period
10 Subjects having at least 2 partial onset seizures whether or not secondarily generalized per month during the 3 months preceding V1
11 Subjects being uncontrolled while treated by 1 or 2 permitted concomitant AED(s). Vagal Nerve Stimulation (VNS) is allowed and will be counted as a concomitant AED
12 Permitted concomitant AED(s) and VNS being stable and at optimal dosage for the subject from at least 1 month (3 months for phenobarbital, phenytoin, and primidone) before V1 and expected to be kept stable during the Baseline and Treatment Period. Benzodiazepine taken more than once a week (for any indication) will be considered as a concomitant AED |
|
| E.4 | Principal exclusion criteria |
1 Subject previously randomized within this study or any other prior study with BRV as a dosing arm
2 Seizure type IA (1981 ILAE classification) nonmotor as only seizure type
3 Subject has participated in another study of an investigational medication (or a medical device) within the last 30 days or is currently participating in another study of an investigational medication (or a medical device)
4 Subject is currently treated with LEV
5 Subject has taken LEV within 90 days prior to V1
6 Subject has any medical or psychiatric condition that, in the opinion of the Investigator, could jeopardize or would compromise the subject’s ability to participate in this study
7 Subject has a known hypersensitivity to any components of the investigational medicinal product or comparative drugs as stated in this protocol
8 Subject not able to read and understand the informed consent form, assent form, or seizure diary card instructions
9 Subject has obvious cognitive impairment or mental retardation as per Investigator assessment
10 Subjects whose seizures could not be reliably counted on a regular basis due to their fast and repetitive occurrence (clusters or flurries)
11 Subject has history or presence of status epilepticus during the year preceding V1 or during Baseline
12 Subject has history or presence of known psychogenic nonepileptic seizures
13 Subject on felbamate with less than 18 months exposure before V1
14 Subject currently on vigabatrin. Subject with history of vigabatrin use but either no visual fields examination report available including standard static (Humphrey or Octopus) or kinetic perimetry (Goldman) or results of these examinations are abnormal
15 Subject taking any drug with possible central nervous system (CNS) effects except if stable from at least 1 month before V1 and expected to be kept stable during the Treatment Period
16 Subject taking any drug that may significantly influence the metabolism of BRV cytochrome P450 (potent inducers) except if the dose has been kept stable at least 1 month before V1, and is expected to be kept stable during the Treatment Period
17 Subject has history of cerebrovascular accident, including transient ischemic attack, in the last 6 months
18 Subject is suffering from severe cardiovascular disease or peripheral vascular disease
19 Subject has presence of any sign (clinical or imaging techniques) suggesting rapidly progressing (ie, not expected to stay stable during study participation) brain disorder or brain tumor. Stable arteriovenous malformations, meningiomas, or other benign tumors may be acceptable.
20 Subject has any clinical conditions (eg, bone marrow depression, chronic hepatic disease, and/or severe renal impairment) which impair reliable participation in the study or necessitate the use of medication not allowed by protocol
21 Subject has presence of a terminal illness
22 Subject has presence of a serious infection
23 Subject has history of severe adverse hematologic reaction to any drug
24 Subject is suffering from severe disturbance of hemostasis
25 Subject has impaired hepatic function: ALT/SGPT (alanine aminotransferase/serum glutamic pyruvate transaminase), AST/SGOT (aspartate aminotransferase/serum glutamic oxaloacetic transaminase), alkaline phosphatase of more than 2 times the upper limit of the reference range
26 Gamma-glutamyltransferase (GGT) values of more than 3 times the upper limit of the reference range. A result of GGT 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 2 times the upper limit of the reference range
27 Subject has clinically significant deviations from reference range values for laboratory parameters: creatinine clearance calculated <30mL/min, platelets <100,000/μL, or neutrophil cells <1,800/μL
28 Subject has clinically significant ECG abnormalities according to the Investigator
29 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 Screening
30 Subject has ongoing psychiatric disease other than mild controlled disorder
31 Subject has known allergic reaction or intolerance to pyrrolidine derivatives and/or investigational product excipients
32 Subject has known multiple drug allergies or severe drug allergy
33 Subject is pregnant or lactating woman
34 Subject has known alcohol or drug addiction or abuse within the last 2 years
35 Investigators, co-Investigators, their spouses or children, or any study collaborators. If the Investigator has any other doubts concerning the eligibility, he/she should consult UCB Study Physician or representative for clarification |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Partial onset seizure (POS) (Type I seizures ) frequency over the
Treatment Period standardized to a 28-day duration. The primary
efficacy outcome for USA will be percent reduction in POS frequency over placebo based on analysis of covariance. The primary outcome for European authorities will be the 50% responder rate based on percent reduction in weekly POS frequency from Baseline to the Treatment Period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline to 12-week Treatment Period |
|
| E.5.2 | Secondary end point(s) |
| To assess the safety and tolerability of BRV. Safety variables are AEs, laboratory tests (blood chemistry, hematology, urinalysis, and pregnancy test), ECG, vital signs, body weight, physical examination, neurological examination, mental status, and psychiatric status. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 133 |
| 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 |
| Brazil |
| Hong Kong |
| India |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Taiwan |
| United States |
| Canada |
|
| 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
|
| The end of the study is defined as the date of the last visit of the last subject in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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