Safety and Efficacy of Eslicarbazepine Acetate Monotherapy in Subjects With Partial Epilepsy Not Well Controlled by Current Antiepileptic Drugs

Study Overview
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Brief Summary
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This is an 18-week, double-blind, multicenter study with gradual conversion from previous antiepileptic therapy to eslicarbazepine acetate monotherapy in subjects with partial epilepsy.

Detailed Description
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This is an 18-week, double-blind, randomized, historical control, multicenter study with gradual conversion to monotherapy in subjects with partial onset seizures who are not well controlled by current AEDs. The 18 week double-blind treatment period consists of a 2-week period for titration of study drug, 6-week period for taper or conversion off AEDs, and a 10-week monotherapy period. Subjects not entering an optional open-label extension study will enter a 1-week period to taper off study drug followed by an end of study visit (week 19). This study was previously posted by Sepracor Inc. In October 2009, Sepracor Inc. was acquired by Dainippon Sumitomo Pharma., and in October 2010, Sepracor Inc's name was changed to Sunovion Pharmaceuticals Inc.

Official Title
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Double-Blind, Randomized, Historical Control Study of the Safety and Efficacy of Eslicarbazepine Acetate Monotherapy in Subjects With Partial Epilepsy Not Well Controlled by Current Antiepileptic Drugs

Conditions
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Epilepsy With Simple or Complex Partial Onset Seizures

Intervention / Treatment
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* Drug: Eslicarbazepine acetate
* Drug: Eslicarbazepine acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of partial epilepsy as defined in the Classification of Seizures of the International League Against Epilepsy (ILAE) (simple partial seizures with observable motor component, or complex, with or without secondary generalization) a. Medical history of seizures; b. Absence of confounding factors (pseudoseizures, syncope); c. Documented EEG recording (done within 5 years prior to screening) consistent with focal onset epilepsy. Documented CT or MRI scan conducted within 10 years prior to screening, showing the absence of a progressive structural abnormality (eg, tumor). Mesial temporal sclerosis is acceptable. ≥4 partial onset seizures during the 8 weeks prior screening with no 28-day seizure free period. Stable treatment with 1-2 AEDs during the last 4 weeks prior to screening. Subjects must have the ability to comprehend the informed consent form and be willing to provide informed consent. For subjects who are unable to comprehend the written consent, a witness/caregiver who is able to describe and provide an understanding of the informed consent to the subject must sign the consent form on behalf of the subject. Subjects must give written informed consent prior to participation in the study. For subjects <18 years of age, the informed consent must be signed by the subject's parent or legal guardian, and, when appropriate and/or required by state or local law, minor subjects must give written informed assent prior to participation in the study. Subjects of Asian ancestry are required to give written informed consent for genotyping. All subjects must sign a HIPAA Form. All females of child bearing potential must also sign the Women of Childbearing Potential Addendum. A female subject is eligible to enter and participate in the study if she is of: a. Non-childbearing potential (ie, physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); b. Child-bearing potential (all females ≤65 years of age), has a negative pregnancy test at screening and agrees to satisfy contraception requirements. Exclusion Criteria: Subjects with only simple partial seizures without a motor component. Presence of generalized seizure syndromes (eg, juvenile myoclonic epilepsy or Lennox-Gastaut syndrome). History of pseudo-seizures. Current seizures related to an acute medical illness. Seizures secondary to metabolic, toxic or infectious disorder or drug abuse. Status epilepticus within 2 years prior to screening. Seizures only occurring in a cluster pattern. Subjects taking 2 of the following sodium channel blocking AEDs: phenytoin, carbamazepine, oxcarbazepine, or lamotrigine. Subjects taking 2 AEDs with both being in the upper dose range (defined as approximately two-thirds of the defined daily dose). Subjects taking more than 2 AEDs. Subjects with progressive structural central nervous system lesion or progressive encephalopathy. Psychiatric exclusion criteria: subjects with history of suicide attempt in last 2 years; major depressive episode within last 6 months; abuse of alcohol or substance abuse in last 2 years; significant psychiatric disorder or recurrent episodes of severe depression within 2 years prior to screening. Medical exclusion criteria: known renal insufficiency or subject with estimated creatinine clearance [CrCL] <60 mL/min based on serum creatinine using the Cockcroft-Gault formula. Clinical and laboratory exclusion criteria: Subjects of Asian ancestry who tests positive for the presence of the HLA-B*1502 allele. Subjects who have been on benzodiazepines, phenobarbital, or primidone on a regular basis within 3 months prior to screening. Subjects taking antipsychotics, tricyclic antidepressants, anxiolytics, sedative hypnotics including non-benzodiazepines, central opioid agonists/antagonists, monoamine oxidase inhibitors (MAOIs) within at least 5 half lives (or for at least 2 weeks whichever is longer) prior to randomization. Subjects presently on felbamate or vigabatrin Female subjects who are currently breastfeeding or intending to breastfeed during study period.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eslicarbazepine 1600 mg QD<br>Subjects randomized to 1600 mg QD of eslicarbazepine acetate will titrate from 600 mg QD (Day 0) to 1200 mg QD (Week 1) to 1600 mg QD (Weeks 2-18) Subjects may continue in an open-label extension study with a starting dose of 1600 mg QD, or taper off study drug at the completion of this study The treatment period for subjects entering the open label extension study is up to 9 study visits over 18 weeks. The treatment period for subjects not entering the open-label extension study is up to 10 study visits over 19 weeks. | Drug: Eslicarbazepine acetate<br>* 1600 mg QD<br>|
| Experimental: Eslicarbazepine 1200 mg QD<br>Subjects randomized to 1200 mg QD eslicarbazepine acetate will titrate from 400 mg QD (Day 0) to 800 mg QD (week 1) to 1200 mg QD (weeks 2-18) Subjects may continue in an open-label extension study with a starting dose of 1600 mg QD, or taper off study drug at the completion of this study The treatment period for subjects entering the open label extension study is up to 9 study visits over 18 weeks. The treatment period for subjects not entering the open-label extension study is up to 10 study visits over 19 weeks. | Drug: Eslicarbazepine acetate<br>* 1200 mg QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative 112-day Exit Rate as Estimated by Kaplan-Meier Method | Cumulative exit rate was defined as the proportion of subjects meeting at least one of the five exit criteria over a 16-wk study period (start of Antiepilectic Drugs(AED) taper/conv.period (Wk 3 to end of double blind monotherapy period (Wk 18)):1.One episode of status epilepticus.2.One secondary general partial seizure (in subjects who did not have gen. seizures during 6 months prior to screening).3.A two fold increase in any consecutive 28 day seizure rate compared to the highest consecutive 28 day seizure rate during the 8 wk baseline period. 4.A two fold increase in any consecutive 2 day seizure rate compared to the highest consecutive 2 day seizure rate during the 8 wk baseline period. If the highest number of seizures in any consecutive 2 day period during the 8 wk baseline was 1 then 3 seizures in a consecutive 2 day period was required to exit.5.Worsening of seizures or increase in seizure frequency considered serious or requiring intervention as judged by the Investigator. | Week 3 to Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects That Are Seizure-free During the 10-week Double-blind Monotherapy Treatment Period. | Seizure-free subjects during the monotherapy period were determined as subjects who had seizure assessments during the monotherapy period, and did not have any seizures in the 10 weeks between Visits 6 and 9 (Weeks 9 through 18). Subjects who discontinued during this period were considered not seizure-free even if they were seizure-free at the time of discontinuation, i.e., to be considered seizure-free, subjects must complete the 10-week period without any seizures. | Weeks 9 through 18 | 
| Percentage of Subjects Seizure-free During the Last 4 Weeks on Eslicarbazepine Acetate Monotherapy. | Seizure-free subjects during the last four weeks of monotherapy were determined as subjects who had seizure assessments during the 4 weeks between Visits 8 and 9 (Weeks 15 through 18), and did not have any seizures. | Weeks 15 through 18 | 
| Completion Rate | Subjects completing the study were determined as subjects who completed the 18 weeks of double-blind treatment. | Week 1 to Week 18 | 
| Completion Rate During the 10 Weeks of Monotherapy | Monotherapy completion rate was defined as the proportion (%) of subjects entering the monotherapy period who completed the 10 weeks of monotherapy treatment. | Weeks 8 through 18 | 
| Time on Eslicarbazepine Acetate Monotherapy. | The start of the monotherapy period was defined as the date of termination of all other AEDs while taking study monotherapy medication. Time on monotherapy was defined from the start of monotherapy period to the last dose of monotherapy treatment. | Week 8 to Week 18 | 
| Change in Seizure Frequency From Baseline. | The relative (%) change in standardized seizure frequency was evaluated for four periods: titration (Weeks 1 to 2), AED taper/conversion (Weeks 3 to 8), monotherapy (Weeks 9 to 18), and double-blind (Weeks 1 to 18). | Week 0 to Week 18, Double-blind: weeks 1to 18; baseline:weeks-8 to -1; Titration: weeks 1 to 2; AED taper/conversion:weeks 3 to 8; monotherapy: weeks 9 to 18 | 
| Responder Rate (Proportion [%] of Subjects With a ≥50% Reduction of Seizure Frequency From Baseline). | Responder rate was defined as the proportion (%) of subjects with a ≥ 50% reduction of seizure frequency from baseline. This analysis was done for the titration (Weeks 1 to 2), AED taper/conversion (Weeks 3 to 8), monotherapy (Weeks 9 to 18), and double-blind (Weeks 1 to 18) periods. | Week 0 to Week 18, Double blind: weeks to 8; baseline:weeks -8 to -1; titration: weeks 1 to 2; AED taper/conversion: weeks 3 to 8; monotherapy: weeks 9 to 18 | 
| Percentage of Subjects Reaching Each of the Exit Events. | The percentage of subjects reaching each of the 5 exit criteria. 1.One episode of status epilepticus.2.One secondary general partial seizure (in subjects who did not have gen. seizures during 6 months prior to screening).3.A two fold increase in any consecutive 28 day seizure rate compared to the highest consecutive 28 day seizure rate during the 8 wk baseline period. 4.A two fold increase in any consecutive 2 day seizure rate compared to the highest consecutive 2 day seizure rate during the 8 wk baseline period. If the highest number of seizures in any consecutive 2 day period during the 8 wk baseline was 1 then 3 seizures in a consecutive 2 day period was required to exit.5.Worsening of seizures or increase in seizure frequency considered serious or requiring intervention as judged by the Investigator. | Week 1 to Week 18 | 
| Change in Total Score From Baseline in 31-Item Quality of Life in Epilepsy (QOLIE-31). | The QOLIE-31 overall score was obtained by using a weighted average of multi-item scale scores. The recorded responses were converted to 0-100 point scales. The mean of the individual item scores in each subgroup were calculated, with higher converted scores reflecting better quality of life. | Week 0 to Week 18, baseline: day 0: End of AED taper/conversion period: end of week 8; End of monotherapy period: end of week 18 | 
| Change in Total Score From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS). | The total score of MADRS is defined as the sum of all individual symptom scores, ranging from 0 to 60, higher score indicates more severe depression. Each of the 10 symptoms of depression on MADRS was measured on a scale of 0 to 6 with 0 representing the lowest severity of the symptom and 6 representing the highest severity | Week 0 to Week 18; Baseline: day 0; End of AED taper/conversion period: end of week 8; End of monotherapy period: end of week 18 | 
| Change in Total Score From Baseline in MADRS in Those Subjects With a MADRS Score of ≥14 at Randomization. | The total score of MADRS is defined as the sum of all individual symptom scores, ranging from 0 to 60, higher score indicates more severe depression. Each of the 10 symptoms of depression on MADRS was measured on a scale of 0 to 6 with 0 representing the lowest severity of the symptom and 6 representing the highest severity | Week 0 to Week 18, Baseline: Day 0; End of AED taper/conversion period: end of week 8; End of monotherapy period: end of week 18 | 
| Percentage of Subjects With Increase of Body Weight >= 7% |  | 18 Week Double-blind treatment period | 
| Proportion (%) of Subjects With Normal Baseline Sodium Reaching Blood Sodium ≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L | Proportion (%) of Subjects With Normal Baseline Sodium Reaching Blood Sodium ≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L | 18 Week Double-blind treatment period | 
| Proportion (%) of Events in Each Classification of the Columbia Suicide Severity Rating Scale (C SSRS). |  | 18 Week Double-blind treatment period | 
| Standardized Seizure Frequency (SSF) by Period | Seizure frequency was evaluated by using a standardized frequency per 4 weeks (28 days). It was evaluated for five periods: baseline (Weeks -8 to -1), titration (Weeks 1 to 2), AED taper/conversion (Weeks 3 to 8), monotherapy (Weeks 9 to 18), and double-blind (Weeks 1 to 18). | Week 1 to Week 18, Double-blind: weeks 1 to 18; Baseline: weeks -8 to -1; Titration: weeks 1 to 2; AED taper/conversion: weeks 3 to 8; Monotherapy: weeks 9 to 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seizure, Epilepsy, Anticonvulsant, Historical Control, Monotherapy