Safety & Efficacy of Eslicarbazepine Monotherapy in Sub.w/Partial Epilepsy Not Well Controlled by Current Antiepileptic

Phase 3

Completed

Conditions: Epilepsy

Interventions: Drug: Eslicarbazepine acetate 1600 mg
Drug: Eslicarbazepine acetate 1200 mg

Registration Number: NCT01091662

Lead Sponsor: Sumitomo Pharma America, Inc.

Brief Summary: 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: 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 titration period, 6-week taper or conversion period, and a 10-week monotherapy period. 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 172

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)
- Medical history of seizures;
- Absence of confounding factors (pseudoseizures, syncope);
- 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 structural abnormality (eg, tumor or malformation)
≥ 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:
- Non-childbearing potential (ie, physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal);
- 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
Medical exclusion criteria: known renal insufficiency (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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
eslicarbazepine acetate 1600 mg	Eslicarbazepine acetate 1600 mg	Subjects randomized to 1600 mg QD of eslicarbazepine acetate will titrate from 600 mg QD(Day 0) to 1200 mg once a day(Week 2) to 1600 mg QD (Weeks 3-18) and may taper down from 1600 mg to 800 mg QD 3 days after the Week 18 visit.
eslicarbazepine acetate 1200 mg	Eslicarbazepine acetate 1200 mg	Subjects randomized to 1200 mg QD eslicarbazepine acetate will titrate from 400 mg QD (Day0) to 800 mg QDweek2) to 1200 mg QD(weeks 3-18) and may taper down from 1200 mg to 600 mg QD 3 days after the Week 18 visit. Subjects may continue in an open-label extension study with a starting dose of 1200 mg QD, or taper off their previous antiepileptic drugs during weeks 2-8.

Primary Outcome Measures

Name	Time	Method
Cumulative 112-day Exit Rate as Estimated by Kaplan-Meier Method	From beginning of Week 3 to end of Week 18	Cumulative exit rate was defined as the proportion of subjects meeting at least one of the following five exit criteria over a 16-week study period (from start of AED taper/con. period (Wk 3) to end of double blind monotherapy period (Wk 18)).1.One episode of status epilepticus.2.One secondary gen. partial seizure (in subjects who did not have gen.seizures during 6 mo. 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 week 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 week baseline period. If the highest number of seizures in any consecutive 2 day period during the 8 week 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

Secondary Outcome Measures

Name	Time	Method
Percentage of Subjects Seizure-free During the Last 4 Weeks on Eslicarbazepine Acetate Monotherapy.	Week 15 through 18	Percentage of participants that were Seizure-free 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.
Completion Rate (% of Subjects Completing the 18 Weeks of Double-blind Treatment).	18 weeks	Subjects completing the study were determined as subjects who completed the 18 weeks of double-blind treatment.
Time on Eslicarbazepine Acetate Monotherapy.	Week 8 to Week 18	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.
Responder Rate (Proportion [%] of Subjects With a ≥50% Reduction of Seizure Frequency From Baseline).	Week 0 to Week 18, Double-blind weeks 1-18; baseline: weeks -8 to -1; Titration: weeks 1-2; AED taper/conversion; weeks 3-8; monotherapy weeks 9-18	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.
Proportion (%) of Subjects Reaching Each Exit Criteria	Week 1 to Week 18, (beginning of week 1 to end of week 18)	The proportion (%) of subjects reaching each of the 5 exit criteria-1.One episode of status epilepticus.2.One secondary gen. partial seizure (in subjects who did not have gen.seizures during 6 mo. 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 week 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 week baseline period. If the highest number of seizures in any consecutive 2 day period during the 8 week 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
Change in Total Score From Baseline in 31-Item Quality of Life in Epilepsy (QOLIE-31).	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	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.
Proportion (%) of Subjects That Are Seizure-free During the 10-week Double-blind Monotherapy Treatment Period.	Week 9 through 18	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.
Proportion (%) of Subjects With Increase of Body Weight >= 7% From Baseline	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.	Week 0 to Week 18	Proportion (%) of Subjects With Normal Baseline Sodium Reaching Blood Sodium ≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L
Proportion (%) of Events in Each Classification of the Columbia Suicide Severity Rating Scale (C SSRS).	18 Week Double-blind treatment period
Completion Rate During the 10 Weeks of Monotherapy (% of Subjects Entering the Monotherapy Period Who Complete).	Week 8 through 18	Monotherapy completion rate was defined as the proportion (%) of subjects entering the monotherapy period who completed the 10 weeks of monotherapy treatment.
Change in Total Score of MADRS From Baseline in Those Subjects With a MADRS Score of ≥14 at Randomization.	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	The total score of MADRS is defined as the sum of all individual item scores. From 0-60, higher score indicates more severe
Change in Seizure Frequency From Baseline.	18 weeks, Double-blind:weeks 1-18; Baseline: weeks -8to -1; titration: weeks 1 to 2; AED taper/conversion: weeks 3 to 8; monotherapy; weeks 9 to 18	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).
Change in Total Score in Montgomery-Asberg Depression Rating Scale (MADRS),From Baseline .	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	The total score of MADRS is defined as the sum of all individual item scores. From 0-60, high score indicates more severe
Standardized Seizure Frequency (SSF) by Period	Double-blind: week to 18; Baseline: weeks -8 to -1; titration: weeks 1 to 2; AED taper/conversion weeks 3 to 8; monotherapy: weeks 9 to 18	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).

Trial Locations

Locations (61): West Los Angeles VA Medical Center
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Los Angeles, California, United States
Drexel University College of Medicine
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Philadelphia, Pennsylvania, United States
The Sandra and Malcom Berman Brain & Spine Institute
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Baltimore, Maryland, United States
University Hospitals Case Medical Center
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Cleveland, Ohio, United States
Neurologicka ordinance
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Kolejni, Praha, Czech Republic
Josephson Wallack Munshower Neurology PC
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Indianapolis, Indiana, United States
Regional Epilepsy Center
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Milwaukee, Wisconsin, United States
Arkansas Neurology
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Conway, Arkansas, United States
Neuro-Pain Medical Center
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Fresno, California, United States
Wayne State University/Detroit Medical Center
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Detroit, Michigan, United States
Northeast Regional Epilepsy Group
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Hackensack, New Jersey, United States
SUNY Upstate Medical University Department of Neurology
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Syracuse, New York, United States
Minneappolis Clinic of Neurology
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Golden Valley, Minnesota, United States
Vital Clinical Research
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DeSoto, Texas, United States
University Multiprofile Hospital for Active Treatment "Dr. Georgi Stranski," EAD, town of Pleven
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Pleven, Bulgaria
Marshfield Clinic
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Marshfield, Wisconsin, United States
Policlinic Chocen, private neurology
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Smetanova, Chocen, Czech Republic
Cerebrovaskularni poradna s.r.o.
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Ostrava, Tiebovice, Czech Republic
Poradna pro epilepsie
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Koterova, Zin, Czech Republic
Communal Medical and Preventive Treatment Institution "Regional Clincal Psychiatric Hospital" Donetsk National Medical University
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Donetsk, Ukraine
Communal Institution "Lviv Regional Clinical Psychiatric Hospital" Department #20, Lviv National Medical University, named after Danylo
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Lviv, Ukraine
State Institution "Institute of neurology, psychiatry and narcology of AMS of Ukraine" Department of cerebrovascular patology
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Kharkiv, Ukraine
Clinic of Neurology, Clinical Center of Serbia
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Belgrade, Serbia
State Treatment and Prevention Institution
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Kharkov, Ukraine
State Institution "Institute of the Health Care of Children & Adolescents of Academy of Medical Sciences of Ukraine" Dept of Psychiatry
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Kharkov, Ukraine
Communal Institution "Odessa Regional Clinical Psych Hospital #1" Department of Day Care
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Odessa, Ukraine
Poltava Regional Clinical Psychiatric Hospital named O.F. Maltsev
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Poltava, Ukraine
Crimean Republic Institution "Clinical Psychiatric Hospital #1"
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Simferopol, Ukraine
Palm Springs Research Institute, Inc
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Hialeah, Florida, United States
Pharma Care Research LLC
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Miami, Florida, United States
UMDNJ DOC 8th Floor 8100
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Newark, New Jersey, United States
East Carolina Neurology
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Greenville, North Carolina, United States
Louisiana State University Health Science Center - Shreveport
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Shreveport, Louisiana, United States
University of Arkansas for Medical Sciences
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Little Rock, Arkansas, United States
University of Arizona Health Sciences Center
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Tucson, Arizona, United States
Kern County Neurological Medical Group, INC.
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Bakersfield, California, United States
Neurosearch II Inc.
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Ventura, California, United States
Specialty Nuerology, PC
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Englewood, Colorado, United States
Miami Children's Hospital
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Miami, Florida, United States
Bay Neurological Institute
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Panama City, Florida, United States
Loveland Scientific Resources Inc.
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Venice, Florida, United States
Lahey Clinic
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Burlington, Massachusetts, United States
Shore Neurology, PA
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Toms River, New Jersey, United States
Global Medical Institutes, LLC
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Princeton, New Jersey, United States
Temple University School of Medicine
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Philadelphia, Pennsylvania, United States
Dent Neurologic Institute
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Orchard Park, New York, United States
Ohio Clinical Research Partners, LLC
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Canton, Ohio, United States
Tulsa Clinical Research LLC
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Tulsa, Oklahoma, United States
Brownwood Regional Medical Center
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Brownwood, Texas, United States
MD
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Dallas, Texas, United States
Multirprofile Hospital for Active Treatment "Pulse," AD, town of Blagoevgrad
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Blagoevgrad, Bulgaria
Second Multiprofile Hospital for Active Treatment - Sofia, AD, city of Sofia Neurology Department
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Sofia, Bulgaria
Diagnostic and Consultative Center "Equita" EOOD, town of Varna
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Varna, Bulgaria
Institute of Mental Health, Department of epilepsy and clinical neurophysiology
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Palmoticeva, Belgrade, Serbia
Communal Institution "Vinnytsia Regional Psycho-Neurological Hospital named after O.I. Yuschenko, Vinnytsia National Medical University named after M.I. Pirogov, Dispensary department, Department of Psychiatry and Addictology
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Vinnytsia, Ukraine
State Institution Railway Clinical Hospital #1 of Kiev Railway Station of DTGO South Western Railroad Psycho-neurological Department
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Kiev, Ukraine
CTC Rycnov nad Kneznou
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Rychnov nad Kneznou, Praugue, Czech Republic
Communal Institution "Dnipropetrovsk Regional Clinical Hospital named after l.l. Mechnikov" Regional Center of psychosomatic disorders, Psychoneurology department for patients with psychosomatic disorders and borderline condtions
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Dnipropetrovsk, Ukraine
University of Kentucky Department of Neurology
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Lexington, Kentucky, United States
Community Clinical Research Inc.
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Austin, Texas, United States
Montefiore Medical Center
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Bronx, New York, United States