Partial Epilepsy
Conditions
Keywords
epilepsy
Brief summary
The primary objective was to evaluate the efficacy of eslicarbazepine acetate (ESL) administered once daily at 1200 mg or 800 mg, compared with placebo as adjunctive therapy in patients with refractory partial epilepsy over a 12-week maintenance period.
Detailed description
This was a phase III, 2-part multicenter study. Part I was an 26-week parallel-group, randomized, placebo-controlled design consisting of an 8 week baseline period, a 2 week double-blinded titration period, 12 week maintenance period, and a 4 week tapering-off period. After completing the baseline period, patients were randomized in a 1:1:1 ratio to 1 of the 2 ESL daily dose levels (1200 or 800 mg) or placebo. Part II was a 1-year open-label extension for patients who had completed Part I. Starting at 800 mg/day, the dosage could be titrated at 400 mg intervals down to a minimum of 400 mg/day or up to a maximum of 1200 mg/day. Patients who completed Part II could participate in a study extension and continue treatment with ESL until marketing authorization is obtained or clinical development is discontinued, with visits scheduled at the discretion of the investigator but at least every 6 months. Results from Part I & II were presented in two separate reports.
Interventions
oral tablet, 800 mg or 1200 mg once daily
DRUGplacebo (Part I)
once daily placebo comparator
DRUGESL - Open-label Extension (Part II)
Part II was a 1-year open-label extension for patients who had completed Part I. Starting at 800 mg/day, the dosage could be titrated at 400 mg intervals down to a minimum of 400 mg/day or up to a maximum of 1200 mg/day
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* written informed consent signed by patient * aged 18 years or more * documented diagnosis of simple or complex partial seizures with or without secondary generalisation since at least 12 months prior to screening * at least 4 partial seizures in each 4 week period during the last 8 weeks prior to screening, currently treated with 1 or 2 AEDs (any except oxcarbazepine and felbamate), in a stable dose regimen during at least 2 months prior to screening (patients using vigabatrin should have been on this medication for at least 1 year with no deficit in visual field identified) * excepting epilepsy, patient is judged to be in general good health based on medical history, physical examination and laboratory tests * post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation; in case of woman of childbearing potential, patient must present a serum beta-hCG test consistent with a non-gravid state and agree to remain abstinent or use reliable contraception (oral contraception should be combined with a barrier method)
Exclusion criteria
* only simple partial seizures with no motor symptomatology (classified as A2-4 according to the International Classification of Epileptic Seizures) that are not video-EEG documented * primarily generalised epilepsy * known rapid progressive neurological disorder; 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 psychogenic origin within the last 2 years * history of schizophrenia or suicide attempt * currently on or with exposure to felbamate or oxcarbazepine more within one month of screening * using benzodiazepines on more than on an occasional basis (except when used chronically as AED) * previous use of ESL or participation in a clinical study with ESL * known hypersensitivity to carbamazepine, oxcarbazepine or chemically related substances * history of abuse of alcohol, drugs or medications within the last 2 years * uncontrolled cardiac, renal, hepatic, endocrine, gastrointestinal, metabolic, haematological or oncology disorder * second or third-degree atrioventricular blockade not corrected with a pacemaker * relevant clinical laboratory abnormalities
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Seizure Frequency | 12 weeks | The primary efficacy endpoint is the natural log transformation of the seizure frequency per 4 weeks. The primary efficacy analysis was based on results for the ITT population during the 12-week maintenance period. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA model with treatment as a factor and seizure frequency as a covariate |
| PART II: Nº of Treatment-Emergent Adverse Events (TEAE) | 1-year | The primary objective for Part II of the study was to evaluate the safety and tolerability of eslicarbazepine acetate (ESL, BIA 2-093) at doses titrated to an efficacy or safety endpoint over a 1-year open-label period. Safety assessments were based primarily on AEs (Number of participants with at least one treatment-emergent adverse events are reported); assessment of AEs was based on treatment relatedness, action taken on study drug, outcome, and causality. |
Countries
Portugal
Participant flow
Recruitment details
Patients were screened at 39 sites in 3 countries. STUDY DATES: PART I: from: 14 Dec 2004 to: 19 Jan 2007 PART II: from 21 June 2005 to 22 January 2008
Pre-assignment details
The duration of Part I was 26 weeks, including the 8-week baseline period. After completing the baseline period, patients were randomized in a 1:1:1 ratio to 1 of the 2 ESL daily dose levels (1200 or 800 mg) or placebo.Part II was a 1-year open-label extension for patients who had completed Part I
Participants by arm
| Arm | Count |
|---|---|
| ESL 1200mg Daily ESL 1200mg daily
eslicarbazepine acetate : oral tablet, 800 mg or 1200 mg once daily | 80 |
| ESL 800mg Daily ESL 800mg daily
eslicarbazepine acetate : oral tablet, 800 mg or 1200 mg once daily | 85 |
| Placebo placebo
placebo : once daily placebo comparator | 88 |
| Total | 253 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| PART I | Lost to Follow-up | 0 | 0 | 1 | 0 |
| PART II | Adverse Event | 0 | 0 | 0 | 10 |
| PART II | Not Know | 0 | 0 | 0 | 20 |
| PART II | Patient non-compliance | 0 | 0 | 0 | 4 |
| PART II | Physician Decision | 0 | 0 | 0 | 1 |
| PART II | Pregnancy | 0 | 0 | 0 | 1 |
| PART II | Withdrawal by Subject | 0 | 0 | 0 | 8 |
Baseline characteristics
| Characteristic | ESL 1200mg Daily | ESL 800mg Daily | Placebo | Total |
|---|---|---|---|---|
| Age, Customized <=18 years | 2 participants | 2 participants | 2 participants | 6 participants |
| Age, Customized >=65 years | 2 participants | 1 participants | 3 participants | 6 participants |
| Age, Customized Between 18 and 65 years | 76 participants | 82 participants | 83 participants | 241 participants |
| Sex: Female, Male Female | 45 Participants | 50 Participants | 45 Participants | 140 Participants |
| Sex: Female, Male Male | 35 Participants | 35 Participants | 43 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 31 / 87 | 41 / 85 | 57 / 80 | 80 / 194 |
| serious Total, serious adverse events | 0 / 87 | 0 / 85 | 1 / 80 | 11 / 194 |
Outcome results
Primary
PART II: Nº of Treatment-Emergent Adverse Events (TEAE)
The primary objective for Part II of the study was to evaluate the safety and tolerability of eslicarbazepine acetate (ESL, BIA 2-093) at doses titrated to an efficacy or safety endpoint over a 1-year open-label period. Safety assessments were based primarily on AEs (Number of participants with at least one treatment-emergent adverse events are reported); assessment of AEs was based on treatment relatedness, action taken on study drug, outcome, and causality.
Time frame: 1-year
Population: There was no sample size estimate for Part II. Part II was a 1-year open-label extension for patients who had completed Part I and was willing to continue treatment in Part II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | PART II: Nº of Treatment-Emergent Adverse Events (TEAE) | 112 participants |
| ESL 800 mg | PART II: Nº of Treatment-Emergent Adverse Events (TEAE) | 40 participants |
| ESL 1200 mg | PART II: Nº of Treatment-Emergent Adverse Events (TEAE) | 94 participants |
| Treatment-related Treatment-emergent Adverse Event | PART II: Nº of Treatment-Emergent Adverse Events (TEAE) | 66 participants |
| TEAE Leading to Discontinuation From the Study | PART II: Nº of Treatment-Emergent Adverse Events (TEAE) | 9 participants |
| Treatment Emergent Serious Adverse Event | PART II: Nº of Treatment-Emergent Adverse Events (TEAE) | 11 participants |
| TEAE Leading to Death | PART II: Nº of Treatment-Emergent Adverse Events (TEAE) | 2 participants |
Primary
Seizure Frequency
The primary efficacy endpoint is the natural log transformation of the seizure frequency per 4 weeks. The primary efficacy analysis was based on results for the ITT population during the 12-week maintenance period. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA model with treatment as a factor and seizure frequency as a covariate
Time frame: 12 weeks
Population: The primary efficacy analysis was based on the ITT population.The intent-to-treat (ITT) population included all randomized patients with at least one dose of investigational product and at least one post-baseline seizure frequency assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Seizure Frequency | 7.3 ln (Seizures) per 4 weeks |
| ESL 800 mg | Seizure Frequency | 5.7 ln (Seizures) per 4 weeks |
| ESL 1200 mg | Seizure Frequency | 5.5 ln (Seizures) per 4 weeks |