Partial Epilepsy
Conditions
Keywords
refractory, partial, epilepsy
Brief summary
The primary objective of the study is to evaluate the efficacy of eslicarbazepine acetate once-daily at doses of 400 mg, 800 mg and 1200 mg compared with placebo as adjunctive therapy in patients with refractory partial epilepsy over a 12-week maintenance period. Patients who complete Part I may enter a 1-year open-label extension.
Detailed description
Part I was a 22-week parallel-group, randomized, placebo-controlled period (8 weeks baseline, 2 weeks double-blind titration, and 12 weeks maintenance). After completing the baseline period, patients were randomized in a 1:1:1:1 ratio to 1 of the 3 ESL dose levels or to placebo. Part II was a 1-year open-label extension for patients who had completed Part I. The starting dose was 800 mg once daily and could be titrated up or down at 400-mg intervals between 400 and 1200 mg.
Interventions
oral tablets
DRUGplacebo
once daily placebo comparator
DRUGESL - Part II
Eslicarbazepine acetate was supplied as scored 800-mg tablets for daily oral administration.
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
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 |
|---|---|---|
| PART I - Seizure Frequency | 12-week maintenance period | The primary efficacy endpoint is the natural log transformation of the seizure frequency per 4 weeks. The primary efficacy analysis was based on the ITT population. Efficacy analyses were performed chiefly using data from the 12-week maintenance period in Part I of the study. The primary efficacy variable is the ln transformation of the seizure frequency per 4 weeks. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA that models seizure frequency as a function of baseline seizure frequency and treatment. |
| PART II - Nº of Treatment-Emergent Adverse Events (TEAE) | 1 year | Safety assessments were based primarily on AEs (Number of patients who experienced at least one AEs), and on whether these were related to the study medication, were serious, led to permanent discontinuation of study participation, or led to death. |
Countries
Portugal
Participant flow
Recruitment details
STUDY DATES: PART I - From: 01 Sep 2004 To: 19 Dec 2006; PART II - From: 02 February 2005 To: 29 January 2008 Patients were screened at 46 sites in 13 countries for Part I and Patients from 42 sites in 12 countries continued in part II.;
Pre-assignment details
Part I was a 22-week parallel-group, randomized, placebo controlled period. After completing the baseline period, patients were randomized in a 1:1:1:1 ratio to 1 of the 3 ESL dose levels or to placebo. For Part I 400 patients were planned; of 503 patients screened, 395 were randomized. 325 patients who completed Part I were enrolled in Part II.
Participants by arm
| Arm | Count |
|---|---|
| ESL 1200 mg Once Daily eslicarbazepine acetate : oral tablets | 98 |
| ESL 400 mg Once Daily eslicarbazepine acetate : oral tablets | 96 |
| ESL 800 mg Once Daily eslicarbazepine acetate : oral tablets | 101 |
| Placebo placebo : once daily placebo comparator | 100 |
| Total | 395 |
Baseline characteristics
| Characteristic | ESL 1200 mg Once Daily | ESL 400 mg Once Daily | ESL 800 mg Once Daily | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 98 Participants | 96 Participants | 101 Participants | 98 Participants | 393 Participants |
| Sex: Female, Male Female | 46 Participants | 57 Participants | 50 Participants | 48 Participants | 201 Participants |
| Sex: Female, Male Male | 52 Participants | 39 Participants | 51 Participants | 52 Participants | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 59 / 100 | 75 / 96 | 84 / 101 | 78 / 98 | 270 / 325 |
| serious Total, serious adverse events | 0 / 100 | 4 / 96 | 6 / 101 | 2 / 98 | 28 / 325 |
Outcome results
Primary
PART II - Nº of Treatment-Emergent Adverse Events (TEAE)
Safety assessments were based primarily on AEs (Number of patients who experienced at least one AEs), and on whether these were related to the study medication, were serious, led to permanent discontinuation of study participation, or led to death.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ESL 1200 mg Once Daily | PART II - Nº of Treatment-Emergent Adverse Events (TEAE) | 270 participants |
| ESL 400 mg Once Daily | PART II - Nº of Treatment-Emergent Adverse Events (TEAE) | 151 participants |
| ESL 800 mg Once Daily | PART II - Nº of Treatment-Emergent Adverse Events (TEAE) | 240 participants |
| Placebo | PART II - Nº of Treatment-Emergent Adverse Events (TEAE) | 194 participants |
| TEAE Leading to Discontinuation | PART II - Nº of Treatment-Emergent Adverse Events (TEAE) | 37 participants |
| Serious TEAE | PART II - Nº of Treatment-Emergent Adverse Events (TEAE) | 28 participants |
| TEAE Leading to Death | PART II - Nº of Treatment-Emergent Adverse Events (TEAE) | 3 participants |
Primary
PART I - 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 the ITT population. Efficacy analyses were performed chiefly using data from the 12-week maintenance period in Part I of the study. The primary efficacy variable is the ln transformation of the seizure frequency per 4 weeks. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA that models seizure frequency as a function of baseline seizure frequency and treatment.
Time frame: 12-week maintenance period
Population: The primary efficacy analysis was an ANCOVA that assessed reduction in seizure frequency per 4 weeks for the ITT population during the 12-week maintenance period
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ESL 1200 mg Once Daily | PART I - Seizure Frequency | 7 ln (Seizures) per 4 weeks |
| ESL 400 mg Once Daily | PART I - Seizure Frequency | 8.7 ln (Seizures) per 4 weeks |
| ESL 800 mg Once Daily | PART I - Seizure Frequency | 7.1 ln (Seizures) per 4 weeks |
| Placebo | PART I - Seizure Frequency | 9.8 ln (Seizures) per 4 weeks |