Partial Epilepsy
Conditions
Keywords
Partial Epilepsy, eslicarbazepine acetate, Children
Brief summary
To evaluate the effects of eslicarbazepine acetate on cognition in comparison with placebo as adjunctive therapy in children aged 6 to 16 years old with refractory partial-onset seizures.
Detailed description
This will be a 2-part multicentre study in approximately 117 patients. Part I of the study will consist of a 4-week prospective observational baseline period, a 12-week double-blind period (4-week up-titration and 8-week maintenance), and a tapering-off period. After the screening visit (V1), patients will enter the baseline period. At the end of the baseline period (V2), eligible patients will be randomised in a ratio of 2:1 to receive double-blind treatment with Eslicarbazepine acetate or Placebo in addition to concomitant therapy with 1 or 2 Anti-Epileptic Drugs (AEDs). Concomitant AED therapy will be kept stable during the whole study. Initial dose of the study treatment will be 10 mg/kg/day. After 2-weeks on 10 mg/kg/day, the dose will be up-titrated to 20 mg/kg/day (maximum 1200 mg/day). After 2 weeks on 20 mg/kg/day, dose will be up-titrated to 30 mg/kg/day (maximum 1200 mg/day) and patients will receive this dose for 8 weeks. If intolerable adverse events (AEs) occur, the patient can be down-titrated to the previous dose (only 1 down-titration step will be allowed) or discontinued. After the 8-week maintenance period, the study treatment will be tapered off in 10 mg/kg/day 2 week steps. However, if a patient experiences an increase in seizure frequency (e.g. more than 100% increase vs. baseline) during tapering-off, the patient can proceed directly to the open-label part of the study (Part II). After completion of the last 2-week 10 mg/kg/day step, patients will have the option to enter a 1 year open-label treatment (Part II) with Eslicarbazepine acetate (up to 30 mg/kg/day, maximum 1200 mg/day), or will have a 4 week observational follow-up period.
Interventions
Eslicarbazepine acetate (ESL) tablets 200 mg and the matching placebo will be supplied. Treatments will be administered by oral route, once-daily, in the evening. The dose will be rounded to the nearest 100 mg unit. Half tablets may be used for dose adjustment if necessary.
DRUGPlacebo
Treatments will be administered by oral route, once-daily, in the evening.
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
At visit 1 (screening), patient must be/have: * written informed consent by parent or legal guardian and, where applicable, the patient; * age 6 to 16 years, inclusive; * a documented diagnosis of epilepsy for at least 12 months prior to screening; * at least 2 partial onset seizures during the 4 weeks prior to screening despite treatment with 1 to 2 AEDs in a stable dose regimen; * an Intelligence Quotient (IQ) of at least 70; * current treatment with 1 to 2 AEDs (except oxcarbazepine, benzodiazepines other than clobazam and vagus nerve stimulation (VNS)); * excepting epilepsy, patient is judged to be in general good health based on medical history, physical examination and clinical laboratory tests; * in the opinion of the investigator, able to complete the Cognitive Drug Research (CDR) test battery; * in case of a girl of childbearing potential, patient presents a serum B-human chorionic gonadotropin (B hCG) test consistent with a non gravid state and agrees to remain abstinent or use reliable contraception (if used, hormonal contraception must be combined with a barrier method) starting at screening and continuing until at least the post-study visit (PSV). At visit 2 (randomisation), patient must be/have: * at least 2 partial-onset seizures during the 4 week baseline period prior to randomisation (documented in a diary); * in case of a girl of childbearing potential, patient presents a urine B-hCG test consistent with a non-gravid state; * stable dose regimen of concomitant AEDs during the 4 week baseline period; * diaries satisfactorily completed by the patient or his/her caregiver during the baseline period; * satisfactory compliance with the study requirements during the baseline period.
Exclusion criteria
At visit 1 (screening), patients must not be/have: * only simple partial seizures with no motor symptomatology; * primarily generalised seizures; * known rapidly progressive neurological disorders (progressive brain disease, epilepsy secondary to progressive cerebral lesion); * occurrence of seizures too close to count accurately; * history of status epilepticus or cluster seizures (i.e., 3 or more seizures within 30 minutes) within the 3 months prior to screening; seizures of non-epileptic origin; * Lennox-Gastaut syndrome; * West syndrome; * major psychiatric disorders; * seizures of psychogenic origin within the last 2 years; * history of schizophrenia or suicide attempt; * history of attention deficit disorder or other diseases adversely affecting cognitive abilities; * currently treated with oxcarbazepine, benzodiazepines other than clobazam (on a routine or chronic basis) and/or VNS; * known hypersensitivity to carboxamide derivatives (oxcarbazepine or carbamazepine); * uncontrolled cardiac, renal, hepatic, endocrine, gastrointestinal, metabolic, haematological or oncology disorder; * second or third degree atrioventricular blockade; * relevant clinical laboratory abnormalities; * estimated creatinine clearance (CLCR) \<60 mL/min; * pregnancy or nursing; * treatment with eslicarbazepine acetate in any previous study; * participation in other drug clinical trial within the last 2 months; * not ensured capability to perform the trial; * any other condition or circumstance that, in the opinion of the investigator, may compromise the patient's ability to comply with the study protocol. At visit 2 (randomisation), patients must not be / have: • any condition or circumstance that, in the opinion of the investigator, may compromise the patient's ability to comply with the study protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Power of Attention Score to the End of the Double Blind (DB) Period | Visit 1 (-4 weeks for training), Visit 2 (Day 1), Visit 5 (6 weeks), Visit 7 (12 weeks) or at early discontinuation visit (EDV) | Power of Attention was defined as the sum of the reaction time measures from the attentional tasks (simple \[dominant hand only\] reaction time, choice reaction time and digit vigilance speed) in order to assess information processing speed and attention/psychomotor speed.Change from baseline to the end of the double-blind period in Power of Attention will be compared between the treatment groups using an ANCOVA. Non-inferiority of ESL vs Placebo will be assessed by comparing the 95% CI's upper bound of the difference of Least Squares Mean (LSmeans) between treatment groups (ESL-placebo) with 121 ms. If the upper bound is greater than 121 ms then the null hypothesis that the change from baseline in the Power of Attention score in ESL group is at least 121 ms inferior than the placebo group will be rejected. Single Values were calculated the average of post treatment visits (visits 5 and 7or EDV) minus average of baseline visits (visits 1 and 2) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Standardized Seizure Frequency - Part I | Baseline; Titration Period (4 Weeks: V2-V3-V4) | — |
| Change From Baseline in Seizure Frequency During the One-year Open-Label (OL) | Weeks 1 to ≥ 41 weeks | Overall Change from Baseline in Seizure Frequency per week for the One-Year Open-Label Period |
Countries
Italy, Netherlands, Poland, Russia, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Esl (BIA 2-093) Eslicarbazepine acetate (BIA 2-093): ESL 30 mg/kg/day QD (maximum 1200 mg/day). | 83 |
| Placebo Placebo QD | 40 |
| Total | 123 |
Baseline characteristics
| Characteristic | Esl (BIA 2-093) | Placebo | Total |
|---|---|---|---|
| Age, Customized 12-16 Years | 47 participants | 22 participants | 69 participants |
| Age, Customized 6-11 Years | 36 participants | 18 participants | 54 participants |
| Race/Ethnicity, Customized African (Black) | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Caucasian | 83 participants | 39 participants | 122 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized South American | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 36 Participants | 14 Participants | 50 Participants |
| Sex: Female, Male Male | 47 Participants | 26 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 40 | 35 / 83 | 45 / 112 |
| serious Total, serious adverse events | 2 / 40 | 3 / 83 | 8 / 112 |
Outcome results
Primary
Change From Baseline in Power of Attention Score to the End of the Double Blind (DB) Period
Power of Attention was defined as the sum of the reaction time measures from the attentional tasks (simple \[dominant hand only\] reaction time, choice reaction time and digit vigilance speed) in order to assess information processing speed and attention/psychomotor speed.Change from baseline to the end of the double-blind period in Power of Attention will be compared between the treatment groups using an ANCOVA. Non-inferiority of ESL vs Placebo will be assessed by comparing the 95% CI's upper bound of the difference of Least Squares Mean (LSmeans) between treatment groups (ESL-placebo) with 121 ms. If the upper bound is greater than 121 ms then the null hypothesis that the change from baseline in the Power of Attention score in ESL group is at least 121 ms inferior than the placebo group will be rejected. Single Values were calculated the average of post treatment visits (visits 5 and 7or EDV) minus average of baseline visits (visits 1 and 2)
Time frame: Visit 1 (-4 weeks for training), Visit 2 (Day 1), Visit 5 (6 weeks), Visit 7 (12 weeks) or at early discontinuation visit (EDV)
Population: The primary analysis was based on the Cognitive Per-protocol (PP) population - all patients in the Modified Cognitive Intent-to-Treat (ITT) population who completed the 8-week maintenance period and were not Important Protocol Deviations (IPDs) with respect to the primary cognitive endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Power of Attention Score to the End of the Double Blind (DB) Period | 111.085 Milli seconds (ms) | Standard Error 76.4254 |
| Esl (BIA 2-093) | Change From Baseline in Power of Attention Score to the End of the Double Blind (DB) Period | 59.122 Milli seconds (ms) | Standard Error 52.0904 |
p-value: 0.795% CI: [-137.593, 203.993]95% CI lower bound vs non-inf margin
Secondary
Change From Baseline in Seizure Frequency During the One-year Open-Label (OL)
Overall Change from Baseline in Seizure Frequency per week for the One-Year Open-Label Period
Time frame: Weeks 1 to ≥ 41 weeks
Population: Modified Efficacy Intent-to-Treat (ITT) population- all randomized patients who received at least one dose of study treatment after randomization and had at least one post-baseline seizure frequency assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Seizure Frequency During the One-year Open-Label (OL) | -3.03 Seizure per week | Standard Error 31.37 |
Secondary
Change From Baseline in Standardized Seizure Frequency - Part I
Time frame: Baseline; Titration Period (4 Weeks: V2-V3-V4)
Population: Modified Efficacy ITT population - all randomized patients who received at least one dose of study treatment after randomization and had at least one post-baseline seizure frequency assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Standardized Seizure Frequency - Part I | -9.13 Seizures per week | Standard Deviation 75.602 |
| Esl (BIA 2-093) | Change From Baseline in Standardized Seizure Frequency - Part I | -31.03 Seizures per week | Standard Deviation 87.963 |
p-value: <0.795% CI: [-137.593, 203.993]ANCOVA