Partial Epilepsy
Conditions
Keywords
Refractory, partial, epilepsy, efficacy, eslicarbazepine, safety
Brief summary
The purpose of this study is to determine whether Eslicarbazepine acetate (BIA 2-093) is an effective adjunct therapy in the treatment of refractory partial seizures
Detailed description
The study was designed to include 3 parts; only the first part is described in this report. Part I of the study was an international, randomized, placebo-controlled, double-blind, parallel group, multicenter clinical study conducted in 19 countries at 173 sites in 653 subjects with refractory simple partial or complex partial seizures, with or without secondary generalization. After screening procedures and confirming eligibility, subjects entered Part I of the study, which consisted of 3 periods. The first period was an 8 week observation baseline period (Week -8 to Week -1) during which subjects were instructed on how to complete the seizure diary. At the end of the 8 week observational baseline period, eligible subjects were randomized in a 1:1:1 allocation ratio to 1 of 3 treatment groups (with a blinded treatment assignment): * Placebo * ESL 800 mg QD * ESL 1200 mg QD Subjects then entered the second period of Part 1, the 2 week, double blind, up titration period (Week 1 to Week 2). During this period, subjects in the ESL 800 mg group received ESL 400 mg QD, subjects in the ESL 1200 mg group received ESL 800 mg QD, and subjects in the placebo group received placebo QD. Subjects then entered the third period of Part I, the 12 week, double-blind, maintenance period (Week 3 to Week 14) where subjects in the ESL 800 mg group received ESL 800 mg QD, subjects in the ESL 1200 mg group received ESL 1200 mg QD, and subjects in the placebo group received placebo QD. At the completion of the maintenance period, subjects who did not enter Part II were to be tapered off study drug while maintaining the blind according to the following down titration procedure: subjects on 800 mg were down titrated to 400 mg for a duration of 2 weeks, and subjects on 1200 mg were down titrated to 800 mg for 1 week and then down-titrated to 400 mg for 1 week and subjects in the placebo group received placebo QD for 2 weeks. During Part I, 1 to 2 concomitant AEDs were allowed in this study and were to be kept stable during the course of the study.
Interventions
DRUG800 mg QD Eslicarbazepine acetate
Oral, 800 mg QD, 2-week titration period and 12-week maintenance period
DRUG1200 mg QD Eslicarbazepine acetate
Oral, 1200 mg QD, 2-week titration followed by 12-week maintenance period
DRUGPlacebo
Placebo tablet given QD
Sponsors
Sumitomo Pharma America, Inc.
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
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
At V1 (screening), patient must be/have: 1. Written informed consent signed by patient. 2. Aged 16 years or more (patients under 18 years of age require parental/legal representative consent). In North America as well as in other participating countries, when appropriate and/or required by state or local law, minor patients must give written informed assent prior to participation in the study. 3. A documented diagnosis of epilepsy since at least 12 months prior to screening. 4. At least 4 partial-onset seizures (including subtypes of simple partial, complex partial and partial seizures evolving to secondarily generalised) on the 4 weeks prior to screening. 5. Currently treated with 1 or 2 AEDs (any except OXC), in a stable dose regimen during at least 1 month prior to screening. Patients using vigabatrin should have been on this medication for at least 1 year with no deficit in visual field identified (a confirmatory test should be available within 1 month before study entry). The device for VNS should be implanted at least 6 months before screening; parameters need to be stable for at least 1 month prior to screening (VNS will not be counted as concomitant AED). 6. Excepting epilepsy, patient is judged to be in general good health based on medical history, physical examination findings, and clinical laboratory test results. 7. Post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation. In case of women of childbearing potential (WOCBP), patient must present a serum beta-human chorionic gonadotropin (B-hCG) test consistent with a non gravid state and agree to remain abstinent or use reliable contraception (hormonal contraception should be combined with a barrier method) beginning at screening and continuing at least to the PSV. At V2 (randomisation), patient must have: 8. At least 8 partial-onset seizures during baseline with at least 3 partial-onset seizures in each 4-week section of the 8-week baseline period prior to randomisation (documented in a diary) and no seizure-free interval exceeding 28 consecutive days. 9. In case of WOCBP, patient must present a urine B-hCG test consistent with a non gravid state. 10. Diaries satisfactorily completed by the patient or his/her caregiver. 11. Satisfactorily complied with the study requirements during the baseline period (including no changes in concomitant AED therapy should have occurred in the baseline period).
Exclusion criteria
At V1 (screening), patients must not be/have: 1. Only simple partial seizures with no motor symptomatology (classified as A2 4 according to the International Classification of Epileptic Seizures). 2. Primarily generalised seizures. 3. Known progressive neurological disorders (progressive brain disease; epilepsy secondary to progressive cerebral lesion). 4. Occurrence of seizures too close to count accurately. 5. History of status epilepticus or cluster seizures (i.e., 3 or more seizures within 30 minutes) within the 3 months prior to screening. 6. Seizures of non-epileptic origin. 7. Seizures of psychogenic origin within the last 2 years. 8. Major psychiatric disorders. 9. Documented diagnosis of schizophrenia with accompanying documented history of at least 1 acute psychosis episode within the last 2 years) or history of suicide attempt. 10. Currently treated with OXC. 11. Using benzodiazepines on more than an occasional basis (defined as more than 2 times per week), except when used chronically as AED. 12. Known exposure to Eslicarbazepine acetate from previous study. o Previous use of Eslicarbazepine acetate or participation in a clinical study with Eslicarbazepine acetate (patients not exposed to Eslicarbazepine acetate \[e.g., screen failed\] are allowed). 13. Known hypersensitivity to carboxamide derivatives. 14. History of abuse of alcohol, drugs or medications within the last 2 years. 15. Uncontrolled cardiac, renal, hepatic, endocrine, gastrointestinal, metabolic, haematological or oncology disorder. 16. Second or third-degree atrioventricular blockade not corrected with a pacemaker. 17. Relevant clinical laboratory abnormalities (e.g., sodium \<130 mmol/L, alanine or aspartate transaminases \>2.0 times the upper limit of the normal, white blood cell \[WBC\] count \<3,000 cells/mm3) or for patients of Asian ancestry, positive HLA B\*1502 test. 18. Estimated creatinine clearance \<60 mL/min \[men: (140-age) x weight/serum creatinine x 72; women: (0.85) (140-age) x weight/serum creatinine x 72. Age in years, weight in kg, and serum creatinine in mg/dL\]. 19. Pregnant or nursing. 20. Participation in other drug clinical trial within the last 2 months or received an investigational drug within 5 half-lives of this other product, whichever is longer. Patient(s) who are known to have not taken any doses of study drug(s) in earlier study(ies) (e.g. screen-failures) are allowed without any time limitation. 21. Not ensured capability to perform the trial. 22. Any other condition or circumstance that, in the opinion of the Investigator, may compromise the patient's ability to comply with the study protocol. 23. Currently treated with VNS, but implanted \<6 months before screening or parameters not stable for at least 1 month prior to screening. At V2 (randomisation), patients must not be/have: 24. Inadequate compliance to concomitant AEDs during the 8-week baseline period or to screening
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Seizure Frequency Over the 12-week Maintenance Period. | 12-week maintenance period (Week 3 to week 14) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Responders | Baseline (Week-8 through Week -1) and Maintenance period (Week 3 to week 14) | Subjects who had at least a 50% reduction from baseline in standardized seizure frequency during the maintenance period were classified as responders. |
Countries
Argentina, Belgium, Brazil, Canada, Cyprus, France, Germany, Greece, Italy, Poland, United States
Participant flow
Recruitment details
A total of 173 investigational sites in 19 countries (North America, 89 sites; Rest-of-World \[ROW\], 84 sites) screened and enrolled subjects. Of these, 160 sites randomized subjects into the study. Studied period (years): * First subject first visit: 02 December 2008 * Last subject last visit: 12 January 2012 (Part I)
Pre-assignment details
The first period was an 8-week observation baseline period (Week -8 to Week -1) during which subjects were instructed on how to complete the seizure diary. At the end of the 8 week observational baseline period, eligible subjects were randomized in a 1:1:1 allocation ratio to 1 of 3 treatment groups (with a blinded treatment assignment)
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo tablets QD orally | 224 |
| 800 mg QD The study drug was a conventional immediate-release tablet of eslicarbazepine (ESL) and provided as either 400 mg or 800 mg dosage strengths (the 800 mg tablets were not used in North America). The composition was directly proportional between the strengths. The excipients used were standard pharmaceutical excipients of compendial grade, widely used in the pharmaceutical industry. The medication was taken orally. | 216 |
| 1200 mg QD The study drug was a conventional immediate-release tablet of eslicarbazepine (ESL) and provided as either 400 mg or 800 mg dosage strengths (the 800 mg tablets were not used in North America). The composition was directly proportional between the strengths. The excipients used were standard pharmaceutical excipients of compendial grade, widely used in the pharmaceutical industry. The medication was taken orally. | 210 |
| Total | 650 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative Reasons | 1 | 2 | 1 |
| Overall Study | Adverse Event | 9 | 21 | 45 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 |
| Overall Study | Non-Compliance with Study Drug | 5 | 1 | 3 |
| Overall Study | other reasons | 8 | 8 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 3 |
| Overall Study | Pregnancy | 2 | 1 | 0 |
| Overall Study | Protocol Violation | 4 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 7 | 7 | 12 |
Baseline characteristics
| Characteristic | 1200 mg QD | Total | Placebo | 800 mg QD |
|---|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 11 Participants | 3 Participants | 2 Participants |
| Age, Categorical >=65 years | 2 Participants | 8 Participants | 3 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 202 Participants | 631 Participants | 218 Participants | 211 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 39 Participants | 126 Participants | 46 Participants | 41 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 24 Participants | 8 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 29 Participants | 87 Participants | 28 Participants | 30 Participants |
| Race (NIH/OMB) White | 134 Participants | 413 Participants | 142 Participants | 137 Participants |
| Sex: Female, Male Female | 105 Participants | 324 Participants | 112 Participants | 107 Participants |
| Sex: Female, Male Male | 105 Participants | 326 Participants | 112 Participants | 109 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 | 125 / 224 | 145 / 216 | 163 / 210 |
| serious Total, serious adverse events | 7 / 224 | 14 / 216 | 3 / 210 |
Outcome results
Primary
Seizure Frequency Over the 12-week Maintenance Period.
Time frame: 12-week maintenance period (Week 3 to week 14)
Population: Intent-to-treat (ITT) population was the primary population for the analysis of efficacy; ITT included all randomized subjects who received at least one dose of study treatment after randomization and had at least one post-baseline seizure frequency assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (ITT Population) | Seizure Frequency Over the 12-week Maintenance Period. | 7.88 Nº Standardized Seizures by 4 weeks | Standard Error 0.49 |
| ESL 800 mg QD (ITT Population) | Seizure Frequency Over the 12-week Maintenance Period. | 6.54 Nº Standardized Seizures by 4 weeks | Standard Error 0.41 |
| ESL 1200 mg QD (ITT Population) | Seizure Frequency Over the 12-week Maintenance Period. | 6.00 Nº Standardized Seizures by 4 weeks | Standard Error 0.4 |
p-value: 0.058ANCOVA
p-value: 0.004ANCOVA
Secondary
Proportion of Responders
Subjects who had at least a 50% reduction from baseline in standardized seizure frequency during the maintenance period were classified as responders.
Time frame: Baseline (Week-8 through Week -1) and Maintenance period (Week 3 to week 14)
Population: Intent-to-treat (ITT) population was the primary population for the analysis of efficacy; ITT included all randomized subjects who received at least one dose of study treatment after randomization and had at least one post-baseline seizure frequency assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (ITT Population) | Proportion of Responders | 23.1 percentage of participants |
| ESL 800 mg QD (ITT Population) | Proportion of Responders | 30.5 percentage of participants |
| ESL 1200 mg QD (ITT Population) | Proportion of Responders | 42.6 percentage of participants |
p-value: 0.068ANCOVA
p-value: 0.001ANCOVA