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

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

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.

Study Overview

• Status: Completed
• Conditions: Epilepsy
• Intervention / Treatment: Drug: Eslicarbazepine acetate 1600 mg; Drug: Eslicarbazepine acetate 1200 mg

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.

• Study Type: Interventional
• Enrollment (Actual): 172
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
    • Multirprofile Hospital for Active Treatment "Pulse," AD, town of Blagoevgrad
  • Pleven, Bulgaria, 5800
    • University Multiprofile Hospital for Active Treatment "Dr. Georgi Stranski," EAD, town of Pleven
  • Sofia, Bulgaria, 1202
    • Second Multiprofile Hospital for Active Treatment - Sofia, AD, city of Sofia Neurology Department
  • Varna, Bulgaria, 9000
    • Diagnostic and Consultative Center "Equita" EOOD, town of Varna
• Czech Republic
  • Chocen
    • Smetanova, Chocen, Czech Republic, 56501
      • Policlinic Chocen, Private Neurology
  • Pocernicka
    • Praha, Pocernicka, Czech Republic, 1427 16
  • Praha
    • Kolejni, Praha, Czech Republic, 160 00
      • Neurologicka ordinance
  • Praugue
    • Rychnov nad Kneznou, Praugue, Czech Republic, 516 01
      • CTC Rycnov nad Kneznou
  • Tiebovice
    • Ostrava, Tiebovice, Czech Republic, 72200
      • Cerebrovaskularni poradna s.r.o.
  • Zin
    • Koterova, Zin, Czech Republic, 760 01
      • Poradna pro epilepsie
• Serbia
  • Belgrade, Serbia, 11000
    • Clinic of Neurology, Clinical Center of Serbia
  • Belgrade
    • Palmoticeva, Belgrade, Serbia, 11000
      • Institute of Mental Health, Department of epilepsy and clinical neurophysiology
• Ukraine
  • Dnipropetrovsk, Ukraine, 49005
    • 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
  • Donetsk, Ukraine, 83008
    • Communal Medical and Preventive Treatment Institution "Regional Clincal Psychiatric Hospital" Donetsk National Medical University
  • Kharkiv, Ukraine, 61068
    • State Institution "Institute of neurology, psychiatry and narcology of AMS of Ukraine" Department of cerebrovascular patology
  • Kharkov, Ukraine, 61018
    • State Treatment and Prevention Institution
  • Kharkov, Ukraine, 61153
    • State Institution "Institute of the Health Care of Children & Adolescents of Academy of Medical Sciences of Ukraine" Dept of Psychiatry
  • Kiev, Ukraine, 01030
    • State Institution Railway Clinical Hospital #1 of Kiev Railway Station of DTGO South Western Railroad Psycho-neurological Department
  • Lviv, Ukraine, 79021
    • Communal Institution "Lviv Regional Clinical Psychiatric Hospital" Department #20, Lviv National Medical University, named after Danylo
  • Odessa, Ukraine, 65006
    • Communal Institution "Odessa Regional Clinical Psych Hospital #1" Department of Day Care
  • Poltava, Ukraine, 36003
    • Poltava Regional Clinical Psychiatric Hospital named O.F. Maltsev
  • Simferopol, Ukraine, 95006
    • Crimean Republic Institution "Clinical Psychiatric Hospital #1"
  • Vinnytsia, Ukraine, 21005
    • 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
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Sciences Center
  • Arkansas
    • Conway, Arkansas, United States, 72034
      • Arkansas Neurology
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Bakersfield, California, United States, 93301
      • Kern County Neurological Medical Group, INC.
    • Fresno, California, United States, 93710
      • Neuro-Pain Medical Center
    • Los Angeles, California, United States, 90073
      • West Los Angeles VA Medical Center
    • Ventura, California, United States, 93003
      • Neurosearch II Inc.
  • Colorado
    • Englewood, Colorado, United States, 80113
      • Specialty Nuerology, PC
  • Florida
    • Hialeah, Florida, United States, 33012
      • Palm Springs Research Institute, Inc
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Miami, Florida, United States, 33165
      • Pharma Care Research LLC
    • Panama City, Florida, United States, 32405
      • Bay Neurological Institute
    • Venice, Florida, United States, 34292
      • Loveland Scientific Resources Inc.
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Josephson Wallack Munshower Neurology PC
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Department of Neurology
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Louisiana State University Health Science Center - Shreveport
  • Maryland
    • Baltimore, Maryland, United States, 21209
      • The Sandra and Malcom Berman Brain & Spine Institute
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Detroit Medical Center
  • Minnesota
    • Golden Valley, Minnesota, United States, 55422
      • Minneappolis Clinic of Neurology
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Northeast Regional Epilepsy Group
    • Newark, New Jersey, United States, 07103
      • UMDNJ DOC 8th Floor 8100
    • Princeton, New Jersey, United States, 08540
      • Global Medical Institutes, LLC
    • Toms River, New Jersey, United States, 08755
      • Shore Neurology, PA
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Orchard Park, New York, United States, 14127
      • Dent Neurologic Institute
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Department of Neurology
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina Neurology
  • Ohio
    • Canton, Ohio, United States, 44718
      • Ohio Clinical Research Partners, LLC
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Tulsa Clinical Research LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University School of Medicine
  • Texas
    • Austin, Texas, United States, 78754
      • Community Clinical Research Inc.
    • Brownwood, Texas, United States, 76801
      • Brownwood Regional Medical Center
    • Dallas, Texas, United States, 75214
      • MD
    • DeSoto, Texas, United States, 75115
      • Vital Clinical Research
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Milwaukee, Wisconsin, United States, 53215
      • Regional Epilepsy Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Eslicarbazepine acetate 1600 mg; 1600 mg once per day
EXPERIMENTAL: 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.	Drug: Eslicarbazepine acetate 1200 mg; 1200 once per day

What is the study measuring?

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 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	From beginning of Week 3 to end of Week 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion (%) 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.	Week 9 through 18
Percentage of Subjects Seizure-free During the Last 4 Weeks on Eslicarbazepine Acetate Monotherapy.	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.	Week 15 through 18
Completion Rate (% of Subjects Completing the 18 Weeks of Double-blind Treatment).	Subjects completing the study were determined as subjects who completed the 18 weeks of double-blind treatment.	18 weeks
Completion Rate During the 10 Weeks of Monotherapy (% of Subjects Entering the Monotherapy Period Who Complete).	Monotherapy completion rate was defined as the proportion (%) of subjects entering the monotherapy period who completed the 10 weeks of monotherapy treatment.	Week 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).	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
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 1-18; baseline: weeks -8 to -1; Titration: weeks 1-2; AED taper/conversion; weeks 3-8; monotherapy weeks 9-18
Proportion (%) of Subjects Reaching Each Exit Criteria	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	Week 1 to Week 18, (beginning of week 1 to end of 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 in Montgomery-Asberg Depression Rating Scale (MADRS),From Baseline .	The total score of MADRS is defined as the sum of all individual item scores. From 0-60, high score indicates more severe	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 of MADRS From Baseline in Those Subjects With a MADRS Score of ≥14 at Randomization.	The total score of MADRS is defined as the sum of all individual item scores. From 0-60, higher score indicates more severe	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
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.	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 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).	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

Collaborators and Investigators

• Sponsor: Sunovion
• Investigators: Study Director: CNS Medical Dirctor, Sunovion

Publications and helpful links

General Publications

• Jacobson MP, Pazdera L, Bhatia P, Grinnell T, Cheng H, Blum D; study 046 team. Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study. BMC Neurol. 2015 Mar 28;15:46. doi: 10.1186/s12883-015-0305-5.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (ACTUAL): November 1, 2012
• Study Completion (ACTUAL): November 1, 2012

Study Registration Dates

• First Submitted: March 17, 2010
• First Submitted That Met QC Criteria: March 22, 2010
• First Posted (ESTIMATE): March 24, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): October 24, 2016
• Last Update Submitted That Met QC Criteria: September 13, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Epilepsy; Seizures; Monotherapy; Anticonvulsant; Historical control
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Epilepsies, Partial; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Eslicarbazepine acetate
• Other Study ID Numbers: 093-046