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

Epilepsy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01091662
• Other study ID #: 093-046
• Status: Completed
• Phase: Phase 3
• First received: March 17, 2010
• Last updated: July 15, 2016
• Start date: June 2010
• Est. completion date: November 2012

Study information

• Verified date: July 2016
• Source: Sunovion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 172
• Est. completion date: November 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 70 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Epilepsies, Partial
• Epilepsy

Intervention

Drug:
• Eslicarbazepine acetate 1600 mg
1600 mg once per day
• Eslicarbazepine acetate 1200 mg
1200 once per day

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Sunovion

Countries where clinical trial is conducted

United States,  Bulgaria,  Czech Republic,  Serbia,  Ukraine, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Proportion (%) of Subjects With Increase of Body Weight >= 7% From Baseline		18 Week Double-blind treatment period	Yes
Secondary	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	Yes
Secondary	Proportion (%) of Events in Each Classification of the Columbia Suicide Severity Rating Scale (C SSRS).		18 Week Double-blind treatment period	Yes
Secondary	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	No