Clinical trial NCT00988429: Efficacy and Safety of Eslicarbazepine Acetate (BIA 2-093) as Adjunctive Therapy for Refractory Partial Seizures
Official title: Efficacy and Safety of Eslicarbazepine Acetate (BIA 2-093) as Adjunctive Therapy for Refractory Partial Seizures in a Double-blind, Randomised, Placebo-controlled, Parallel-group, Multicentre Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Partial Epilepsy
Keywords: Refractory
partial
epilepsy
efficacy
eslicarbazepine
safety
Lead sponsor: Bial - Portela C S.A.
Sponsor class: INDUSTRY
Collaborators: name: Sumitomo Pharma America, Inc.
First posted: 2009-10-02
Enrollment: 653
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 exclusion criteria.
25. Inadequate completion of the study diary.
26. Any other condition or circumstance that, in the opinion of the Investigator, may compromise the patient's ability to comply with the study protocol.

Primary outcomes:
measure: Seizure Frequency Over the 12-week Maintenance Period.
timeFrame: 12-week maintenance period (Week 3 to week 14)
Secondary outcomes:
measure: Proportion of Responders
timeFrame: Baseline (Week-8 through Week -1) and Maintenance period (Week 3 to week 14)
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama Department of Neurology
state: Alabama
city: Northport
country: United States
facility: Neurology Clinic, P.C.
state: Alabama
city: Phoenix
country: United States
facility: 21st Century Neurology - Division of Xenoscience, Inc.
state: Arizona
city: Phoenix
country: United States
facility: Barrow Neurological Institute / St. Joseph's Hospital and Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Phoenix Neurological Associates/Clinical Research Advantage
state: Arizona
city: Sun City
country: United States
facility: ANI Research, PC
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Health Sciences Center
state: Arizona
city: Conway
country: United States
facility: Arkansas Neurology
state: Arkansas
city: Little Rock
country: United States
facility: Clinical Trials Inc.
state: Arkansas
city: Bakersfield
country: United States
facility: Kern County Neurological Medical Group, INC.
state: California
city: Fresno
country: United States
facility: Neuro-Pain Medical Center, Inc.
state: California
city: Loma Linda
country: United States
facility: Loma Linda University
state: California
city: Long Beach
country: United States
facility: Collaborative Neuroscience Network, INC
state: California
city: Murrieta
country: United States
facility: Viking Clinical Research Center
state: California
city: San Francisco
country: United States
facility: Bright Minds Institute
state: California
city: San Jose
country: United States
facility: Milestone Clinical Research
state: California
city: Ventura
country: United States
facility: Neurosearch II, Inc.
state: California
city: Aurora
country: United States
facility: University of Colorado Health Sciences
state: Colorado
city: Denver
country: United States
facility: Denver Health
state: Colorado
city: Bradenton
country: United States
facility: Bradenton Research Center
state: Florida
city: Gainesville
country: United States
facility: Optima Neurological Services, LLC
state: Florida
city: Gainesville
country: United States
facility: University of Florida Department of Neurology
state: Florida
city: Gulf Breeze
country: United States
facility: NW FL Clinical Research Group, LLC
state: Florida
city: Hialeah
country: United States
facility: Palm Springs Research Institute
state: Florida
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Pharmax Research Clinic
state: Florida
city: Miami
country: United States
facility: Advanced Pharma CR, LLC
state: Florida
city: Miami
country: United States
facility: University of Miami - Miller School of Medicine Department of Neurology
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Miami
country: United States
facility: Neuroscience Consultants
state: Florida
city: Miami
country: United States
facility: Kendall South Medical Center, Inc.
state: Florida
city: Port Charlotte
country: United States
facility: Medsol Clinical Research Center
state: Florida
city: Sarasota
country: United States
facility: Lovelace Scientific Resources
state: Florida
city: Tampa
country: United States
facility: University of South Florida - Department of Neurology
state: Florida
city: Tampa
country: United States
facility: Pediatric Epilepsy & Neurology Specialists, PA
state: Florida
city: Venice
country: United States
facility: Lovelace Scientific Resources
state: Florida
city: Wellington
country: United States
facility: Palm Beach Clinical Research Network, LLC.
state: Florida
city: Rome
country: United States
facility: Harbin Clinic
state: Georgia
city: Boise
country: United States
facility: Consultants in Epilepsy and Neurology, PPLC
state: Idaho
city: Springfield
country: United States
facility: Southern Ilinois University School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Josephson Wallack Munshower Neurology P.C.
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic, PC
state: Iowa
city: Des Moines
country: United States
facility: Broadlawns Medical Center
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: LSUHSC Epilepsy Center
state: Louisiana
city: New Orleans
country: United States
facility: Louisiana Research Associates, Inc.
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy and Sleep Centre
state: Maryland
city: Boston
country: United States
facility: MGH Epilepsy Service Massachusetts, General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University/Detroit Medical Center
state: Michigan
city: Golden Valley
country: United States
facility: Minneapolis Clinic of Neurology, Ltd
state: Minnesota
city: Saint Paul
country: United States
facility: Minnesota Epilepsy Group, P.A.
state: Minnesota
city: Flowood
country: United States
facility: Precise Research Centers
state: Mississippi
city: Chesterfield
country: United States
facility: The Comprehensive Epilepsy Care Centre for Chidren and Adults
state: Missouri
city: Camden
country: United States
facility: The Cooper Health System
state: New Jersey
city: Gibbsboro
country: United States
facility: Clinical Research Centre of New Jersey
state: New Jersey
city: Hackensack
country: United States
facility: Northeast Regional Epilepsy Group
state: New Jersey
city: New Brunswick
country: United States
facility: UMDNJ-Robert Wood Johnson Medical School
state: New Jersey
city: Paterson
country: United States
facility: St. Joseph Regional Medical Center
state: New Jersey
city: Toms River
country: United States
facility: Shore Neurology, PA
state: New Jersey
city: Albany
country: United States
facility: Albany Medical College - Neurosciences Institute
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Cedarhurst
country: United States
facility: Five Towns Neuroscience Research
state: New York
city: Liverpool
country: United States
facility: Neurological Care of CNY
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: NYU Comprehensive Epilepsy Centre
state: New York
city: New York
country: United States
facility: Wiell Cornell Medical Centre Epilepsy Centre
state: New York
city: Orchard Park
country: United States
facility: Dent Neurologic Institute
state: New York
city: Rochester
country: United States
facility: Strong Epilepsy Center - University of Rochester Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: The Neurological Institute, P.A.
state: North Carolina
city: Hickory
country: United States
facility: PMG Research of Hickory, LLC
state: North Carolina
city: Wilmington
country: United States
facility: Wilmington Medical Research
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Medical Centre
state: Ohio
city: Dayton
country: United States
facility: Neurology Specialists, Inc
state: Ohio
city: Toledo
country: United States
facility: University of Toledo - Health Science Campus
state: Ohio
city: Oklahoma City
country: United States
facility: Lynn Health Science Institute
state: Oklahoma
city: Tulsa
country: United States
facility: Tulsa Clinical Reserch
state: Oklahoma
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Comprehensive Epilepsy Center - Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University School of Medicine - Department of Neurology
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Childrens Hospital of Pittsburg of UPMC - Division of Child Neurology
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Brownwood
country: United States
facility: Private Practice of Dr. Edwin Green
state: Texas
city: Dallas
country: United States
facility: Texas Neurology, PA
state: Texas
city: Dallas
country: United States
facility: Neurology Consultants of Dallas, P.A.
state: Texas
city: Dallas
country: United States
facility: Neurological Clinic of Texas
state: Texas
city: Dallas
country: United States
facility: UTSWMC Department of Neurology, Division of Epilepsy Research
state: Texas
city: DeSoto
country: United States
facility: Medistat Clinical Research
state: Texas
city: DeSoto
country: United States
facility: Nemmar Clinical Resources
state: Texas
city: Houston
country: United States
facility: Houston Neurology and Sleep Center
state: Texas
city: San Antonio
country: United States
facility: Innovative Clinical Trials
state: Texas
city: San Antonio
country: United States
facility: Road Runner Research
state: Texas
city: Temple
country: United States
facility: Scott and White Memorial Hospital Sherwood and Brindley Foundation
state: Texas
city: Salt Lake City
country: United States
facility: Wasatch Clinical Research
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia - Comprehensive Epilepsy Program
state: Virginia
city: Norfolk
country: United States
facility: Sentara Medical Group, Neurology Specialists Sentara Heart Hospital
state: Virginia
city: Bellevue
country: United States
facility: Neurological Associates of Washington/Clinical Trials of America, Inc
state: Washington
city: Renton
country: United States
facility: Ranier Clinical Research Center
state: Washington
city: Seattle
country: United States
facility: University Washington Regional Epilepsy Center Harborview
state: Washington
city: Tacoma
country: United States
facility: MultiCare Adult Neurology
state: Washington
city: Madison
country: United States
facility: Dean & St. Mary's Outpatient Center Neurological Institute and Spine Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Regional Epilepsy Centre of Aurora Healthcare- St. Luke's Medical Centre
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin - Department of Neurology
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Hospital Privado de la comunidad de Mar de Plata
city: Buenos Aires
country: Argentina
facility: CEMIC
city: Buenos Aires
country: Argentina
facility: Centro Neurológico de Tratamiento y Rehabilitación
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Capital Federal
country: Argentina
facility: Hospital Ramos Mejía
city: Capital Federal
country: Argentina
facility: Hospital Británico
city: Capital Federal
country: Argentina
facility: Fleni
city: Capital Federal
country: Argentina
facility: Instituto Médico Especializado (IME)
city: Cordoba
country: Argentina
facility: Hospital Privado - Centro Médico de Córdoba S.A.
city: Cordoba
country: Argentina
facility: Centro de Neurologia y Neurorehabilitacion
city: Ottignies
country: Belgium
facility: Centre Neurologique William Lennox
city: Ottignies
country: Belgium
facility: Clinique Saint-Pierre
city: Wilrijk
country: Belgium
facility: AZ. Sint-Augustinus
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericórdia de Belo Horizonte
city: Campinas
country: Brazil
facility: Hospital das Clínicas - UNICAMP
city: Curitiba
country: Brazil
facility: Instituto de Neurologia de Curitiba
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Hospital São Lucas - PUCRS
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clinicas da FMRP
city: Santo André
country: Brazil
facility: Faculdade de Medicina do ABC
city: Sao Paulo
country: Brazil
facility: Hospital São Paulo - UNIFESP
city: São Paulo
country: Brazil
facility: Irmandade da Santa Casa de Misericórdia de São Paulo
city: São Paulo
country: Brazil
facility: Hospital Brigadeiro
city: Calgary
country: Canada
facility: University of Calgary Clinical Neurosciences
state: Alberta
city: Vancouver
country: Canada
facility: BC Children's Hospital
state: British Columbia
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Nikosia
country: Cyprus
facility: The Cyprus Institute of Neurology
city: Bordeaux
country: France
facility: CENTRE HOSPITALIER PELLEGRIN, CHU de BORDEAUX
city: Bron
country: France
facility: Hopital Femme-Mere-Enfant, Hospices Civils de Lyon
city: Lille
country: France
facility: Hopital Roger Salengro, Chru de Lille
city: Montpellier
country: France
facility: Hopital Gui de Chauliac, Chu de Montpellier
city: Nancy
country: France
facility: Hopital Central, Chu de Nancy
city: Paris
country: France
facility: Centre Hospitalier Sainte-Anne
city: Rennes
country: France
facility: Hopital Pontchaillou, Chru de Rennes
city: Strasbourg
country: France
facility: Hopital Civil, Chru de Strasbourg
city: Berlin
country: Germany
facility: Epilepsie-Zentrum Berlin Brandenburg am Evangelischen Krankenhaus Königin Elisabeth Herzberge
city: Berlin
country: Germany
facility: Charite, Universitätsmedizin Berlin, CVK
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Munich
country: Germany
facility: Klinik für Neurologie, Klinische Neurophysiologie und Stroke Unit
city: Regensburg
country: Germany
facility: Klinik und Poliklinik für Neurologie der Universität Regensburg im Bezirksklinikum
city: Athens
country: Greece
facility: Evangelismos General Hospital
city: Thessaloniki
country: Greece
facility: Agios Loukas (St. Luke's) Hospital
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki "Papanikolaou"
city: Foggia
country: Italy
facility: Azienda Ospedaliero, Universitaria "Ospedali Riuniti", Clinica della Malattie del Sistema Nervoso, Università di Foggia
city: Messina
country: Italy
facility: A.O.U Policlinico di Messina
city: Napoli
country: Italy
facility: Università degli Studi di Napoli Policlinico Federico II
city: Novara
country: Italy
facility: Azienda Ospedaliero - Universitaria Maggiore della Carità
city: Pavia
country: Italy
facility: Istituto Neurologico Casimiro Mondino
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore Policlinico "A. Gemelli"
city: Torino
country: Italy
facility: Azienda Universitatia Ospedaliera San Giovanni Battista
city: Kraków
country: Poland
facility: Centrum Neurologii Klinicznej
city: Lodz
country: Poland
facility: NZOZ Polimedica
city: Lublin
country: Poland
facility: Wojewódzki Szpital Specjalistyczny w Lublinie Oddzial Neurologii
city: Olsztyn
country: Poland
facility: Wojewódzki Szpital Specjalistyczny w Olsztynie, Oddzial Neurologii
city: Poznan
country: Poland
facility: NZOZ "NEURO - KARD,"Ilkowski I Partnerzy Spólka, Partnerska Lekarzy
city: Warszawa
country: Poland
facility: Instytut Psychiatrii i Neurologii, II Klinika Neurologiczna
Study officials:
References:
citation: Andermann E, Rosenfeld W, Penovich P, Rogin J, Cendes F, Carreno M, Ramsay RE, Ben-Menachem E, Gama H, Rocha F, Soares-da-Silva P, Tosiello R, Blum D, Grinnell T. Comparative analysis of the safety and tolerability of eslicarbazepine acetate in older (>/=60 years) and younger (18-59 years) adults. Epilepsy Res. 2021 Jan;169:106478. doi: 10.1016/j.eplepsyres.2020.106478. Epub 2020 Oct 10.
citation: Cramer JA, Colman S, Anastassopoulos KP, Grinnell T, Mehta D, Williams GR. Associations between seizure severity change and patient characteristics, changes in seizure frequency, and health-related quality of life in patients with focal seizures treated with adjunctive eslicarbazepine acetate: Post hoc analyses of clinical trial results. Epilepsy Behav. 2020 Nov;112:107312. doi: 10.1016/j.yebeh.2020.107312. Epub 2020 Aug 12.