| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Localization-related, generalized or undetermined whether focal or generalized epileptic syndrome, according to ILAE classification |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| 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 |
|
| 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 document the long-term safety and tolerability of BRV |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the efficacy of BRV during long-term exposure |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible to participate in this study, all of the following criteria must be met as specified.
Inclusion criteria for all subjects
- An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form is signed and dated by the parent(s) or legal representative(s). The Consent form or a specific Assent form, where required, will be signed and dated by minors.
- 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 (including BRV oral solution or tablets) according to the judgment of the Investigator.
- For female subjects, the subject is
1)Not of childbearing potential OR Of childbearing potential, and
Is not sexually active,Has a negative pregnancy test
OR
2)Of childbearing potential, and Is sexually active, Has a negative pregnancy test
- Understands the consequences and potential risks of inadequately protected sexual activity, understands and properly uses contraceptive methods, and is willing to inform the Investigator of any contraception changes. Medically acceptable contraceptive methods for the study include, but are not limited to:
Oral or depot contraceptive treatment with at least ethinylestradiol 30μg per intake or ethinylestradiol 50μg per intake if also taking one of the following: carbamazepine, phenobarbital, primidone, phenytoin, oxcarbazepine, St. John's Wort, or rifampicin
Barrier contraception: intrauterine device, diaphragm with spermicide, male or female condom with spermicide
Abstinence from sexual intercourse
Inclusion criteria for LTFU subjects only
- Male or female subjects having participated in a core study with a confirmed diagnosis of epilepsy and for whom a reasonable benefit from long-term administration of BRV is expected.
Inclusion criteria for directly enrolled subjects only
- Subject is a male or female ≥4 years to <17 years of age.
- Subject has a clinical diagnosis of POS according to the ILAE classification.
- Subject has an EEG compatible with the clinical diagnosis of POS.
- Subject has been observed to have uncontrolled POS after an adequate course of treatment (in the opinion of the Investigator) with at least 1 AED (concurrently or sequentially).
- Subject had at least 1 seizure (POS) during the 3 weeks before the ScrV.
- Subject is taking at least 1 AED. All AEDs need to be at a stable dose for at least 7 days before the ScrV. Vagal nerve stimulator stable for at least 2 weeks before the ScrV is allowed and will be counted as a concomitant AED. 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 |
Subjects are not permitted to enroll in the study if any of the following criteria are met as specified.
Exclusion criteria for all subjects
-Subject is a pregnant or nursing female.
-Subject has severe medical, neurological, or psychiatric disorders or laboratory values, which may have an impact on the safety of the subject.
-Subject has planned participation in any clinical study of another investigational drug or device.
-Subject has any medical condition, which in the Investigator’s opinion, warrants exclusion.
-Subject has >1.5x upper limit of normal (ULN) of any of the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or >1.0xULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome).
-Subject has chronic liver disease.
Exclusion criteria for LTFU subjects only
- Subject had hypersensitivity to BRV or excipients or comparative drugs as stated in this protocol during the course of the core study.
- Subject had poor compliance with the visit schedule or medication intake in the core study.
- Subject ≥6 years of age has a lifetime history of suicide attempt (including actual attempt,interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (“Yes”) to Question 5 of the Columbia-Suicide Severity
Rating Scale (C-SSRS) at the EV. If a subject has active suicidal ideation without a specific plan as indicated by a positive response (“Yes”) to Question 4 of Columbia-Suicide Severity Rating Scale (C-SSRS) at the EV, the subject should be referred immediately to a Mental
Healthcare Professional and may be excluded from the study based upon the Investigator’s judgment of benefit/risk of continuing the subject in the study/on study medication.
Exclusion criteria for directly enrolled subjects only
- Subject has previously received BRV.
- Subject had concomitant use of LEV at the ScrV. In addition, the use of LEV is prohibited for at least 4 weeks prior to the ScrV.
- Subject has epilepsy secondary to a progressive cerebral disease or tumor, or any other progressively neurodegenerative disease. Stable arteriovenous malformations, meningiomas or other benign tumors may be acceptable according to Investigator’s opinion.
- Subject has a history of primary generalized epilepsy.
- Subject has a history of status epilepticus in the month immediately prior to the ScrV or during the Up Titration Period.
- Subject has a history or presence of pseudoseizures.
- Subject is suffering only from febrile seizures.
- Subject is on felbamate with less than 18 months continuous exposure. Subject who has taken felbamate for a combined duration of treatment and wash out of <18 months before the ScrV.
- Subjects treated with vigabatrin who have visual field defects.
- Subject has an allergy to pyrrolidone derivatives or investigational product excipients or a history of multiple drug allergies.
- Subject has any clinically significant acute or chronic illness as determined during the physical examination or from other information available to the Investigator (eg, bone marrow depression, chronic hepatic disease, severe renal impairment, psychiatric disorder).
- Subject has an underlying disease or is receiving a treatment that may interfere with the absorption, distribution, metabolism, and elimination of the study drug.
- Subject has any medical condition that might interfere with his/her study participation (eg, serious infection or scheduled elective surgery).
- Subject has a terminal illness.
- Subject has any clinically significant deviations from reference range values for laboratory parameters as determined by the Investigator.
- Subject has a clinically relevant ECG abnormality according to the Investigator.
- Subject had major surgery within 6 months prior to the ScrV.
- Subject received any investigational drug or device within the 30 days prior to the ScrV. The use of AEDs marketed for adults but not approved for pediatric use is not considered to be “investigational” for the purposes of this study.
- Investigators’ and co Investigators’ children may not be included as subjects in the study.
- Subject has a lifetime history of suicide attempt (including an actual 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 C SSRS Baseline/Screening at the ScrV.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Incidence of treatment-emergent adverse events (TEAEs) during the
study
2. Incidence of treatment-emergent serious adverse events (SAEs)
during the study
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1-2: From Baseline to end of Study (up to 10 years) |
|
| E.5.2 | Secondary end point(s) |
For subjects ≥ 2 years of age (based on daily record card (DRC) data):
1. Absolute change in 28-days adjusted partial-onset seizures (POS)
frequency from Baseline to the end of the Evaluation Period in subjects
with POS only
2. Percent change in 28-days adjusted partial-onset seizures (POS)
frequency from Baseline to the end of the Evaluation Period in subjects
with POS only
3. 50% responder rate for total seizures (all types)
For subjects <2 years of age (based on EEG data [recorded at least 24
hours]) or subjects with typical absence seizures (based on EEG data):
4. Absolute change in average daily frequency of partial-onset-seizures
(POS) in subjects with POS only
5. Percent change in average daily frequency of partial-onset-seizures
(POS) in subjects with POS only
6. 50% responder rate for total seizures (all types) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2: From Baseline to the end of the Evaluation Period (up to 10 years)
3-6: From Baseline to end of Study (up to 10 years)
|
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| To explore direct cost parameters and to assess the effect of BRV on behavior using the Achenbach CBCL and Bayley-III scales |
|
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Belgium |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Mexico |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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