Efficacy and Safety of Eslicarbazepine Acetate as Adjunctive Therapy for Refractory Partial Epilepsy

• ClinicalTrials.gov Identifier: NCT00957372
• Recruitment Status: Completed
• First Posted: August 12, 2009
• Results First Posted: August 5, 2013
• Last Update Posted: July 2, 2014
• Sponsor: Bial - Portela C S.A.
• Information provided by (Responsible Party): Bial - Portela C S.A.

Tracking Information

• First Submitted Date: August 10, 2009
• First Posted Date: August 12, 2009
• Results First Submitted Date: March 26, 2013
• Results First Posted Date: August 5, 2013
• Last Update Posted Date: July 2, 2014
• Study Start Date: December 2004
• Actual Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 1, 2013)

• Seizure Frequency [ Time Frame: 12 weeks ]
  The primary efficacy endpoint is the natural log transformation of the seizure frequency per 4 weeks. The primary efficacy analysis was based on results for the ITT population during the 12-week maintenance period. Seizure frequency was compared between each active treatment group and the placebo group using an ANCOVA model with treatment as a factor and seizure frequency as a covariate
• PART II: Nº of Treatment-Emergent Adverse Events (TEAE) [ Time Frame: 1-year ]
  The primary objective for Part II of the study was to evaluate the safety and tolerability of eslicarbazepine acetate (ESL, BIA 2-093) at doses titrated to an efficacy or safety endpoint over a 1-year open-label period. Safety assessments were based primarily on AEs (Number of participants with at least one treatment-emergent adverse events are reported); assessment of AEs was based on treatment relatedness, action taken on study drug, outcome, and causality.

• Original Primary Outcome Measures (submitted: August 11, 2009): seizure frequency over the 12-week maintenance period, standardized to a 'frequency per 4 weeks' [ Time Frame: 12 weeks ]
• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (submitted: August 11, 2009)

• proportion of responders (i.e., patients with a ≥ 50% reduction in seizure frequency during the 12-week maintenance period compared with the 8-week baseline period) [ Time Frame: 12 weeks ]
• seizure frequency per week for each week of the baseline, titration, and maintenance periods [ Time Frame: 12 weeks ]
• distribution of seizure reduction (< 50%, 50-75%, or > 75% seizure reduction) [ Time Frame: 12 weeks ]
• proportion of seizure-free patients (100% seizure reduction) [ Time Frame: 12 weeks ]
• proportion of patients with a ≥ 25% exacerbation in seizure frequency compared to baseline [ Time Frame: 12 weeks ]
• seizure frequency by seizure type [ Time Frame: 12 weeks ]
• incidence of adverse events [ Time Frame: 1 year ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Eslicarbazepine Acetate as Adjunctive Therapy for Refractory Partial Epilepsy
• Official Title: Efficacy and Safety of BIA 2-093 as Adjunctive Therapy for Refractory Partial Seizures in a Double-blind, Randomized, Placebo-controlled, Parallel-group, Multicenter Clinical Trial
• Brief Summary: The primary objective was to evaluate the efficacy of eslicarbazepine acetate (ESL) administered once daily at 1200 mg or 800 mg, compared with placebo as adjunctive therapy in patients with refractory partial epilepsy over a 12-week maintenance period.

Detailed Description

This was a phase III, 2-part multicenter study. Part I was an 26-week parallel-group, randomized, placebo-controlled design consisting of an 8 week baseline period, a 2 week double-blinded titration period, 12 week maintenance period, and a 4 week tapering-off period. After completing the baseline period, patients were randomized in a 1:1:1 ratio to 1 of the 2 ESL daily dose levels (1200 or 800 mg) or placebo.

Part II was a 1-year open-label extension for patients who had completed Part I. Starting at 800 mg/day, the dosage could be titrated at 400 mg intervals down to a minimum of 400 mg/day or up to a maximum of 1200 mg/day. Patients who completed Part II could participate in a study extension and continue treatment with ESL until marketing authorization is obtained or clinical development is discontinued, with visits scheduled at the discretion of the investigator but at least every 6 months.

Results from Part I & II were presented in two separate reports.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Partial Epilepsy

Intervention

• Drug: eslicarbazepine acetate
  oral tablet, 800 mg or 1200 mg once daily
  Other Name: Zebinix
• Drug: placebo (Part I)
  once daily placebo comparator
• Drug: ESL - Open-label Extension (Part II)
  Part II was a 1-year open-label extension for patients who had completed Part I. Starting at 800 mg/day, the dosage could be titrated at 400 mg intervals down to a minimum of 400 mg/day or up to a maximum of 1200 mg/day

Study Arms

• Experimental: ESL 800 mg daily (Part I)
  ESL 800mg daily
  Intervention: Drug: eslicarbazepine acetate
• Experimental: ESL 1200 mg daily (Part I)
  ESL 1200mg daily
  Intervention: Drug: eslicarbazepine acetate
• Placebo Comparator: placebo (Part I)
  placebo
  Intervention: Drug: placebo (Part I)
• Experimental: ESL - Open-label Extension (Part II)
  All patients were treated with only ESL during Part II.
  Intervention: Drug: ESL - Open-label Extension (Part II)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 30, 2009): 253
• Original Actual Enrollment (submitted: August 11, 2009): 258
• Actual Study Completion Date: June 2008
• Actual Primary Completion Date: June 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• written informed consent signed by patient
• aged 18 years or more
• documented diagnosis of simple or complex partial seizures with or without secondary generalisation since at least 12 months prior to screening
• at least 4 partial seizures in each 4 week period during the last 8 weeks prior to screening, currently treated with 1 or 2 AEDs (any except oxcarbazepine and felbamate), in a stable dose regimen during at least 2 months prior to screening (patients using vigabatrin should have been on this medication for at least 1 year with no deficit in visual field identified)
• excepting epilepsy, patient is judged to be in general good health based on medical history, physical examination and laboratory tests
• post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation; in case of woman of childbearing potential, patient must present a serum beta-hCG test consistent with a non-gravid state and agree to remain abstinent or use reliable contraception (oral contraception should be combined with a barrier method)

Exclusion Criteria:

• only simple partial seizures with no motor symptomatology (classified as A2-4 according to the International Classification of Epileptic Seizures) that are not video-EEG documented
• primarily generalised epilepsy
• known rapid progressive neurological disorder; history of status epilepticus or cluster seizures (i.e., 3 or more seizures within 30 minutes) within the 3 months prior to screening
• seizures of psychogenic origin within the last 2 years
• history of schizophrenia or suicide attempt
• currently on or with exposure to felbamate or oxcarbazepine more within one month of screening
• using benzodiazepines on more than on an occasional basis (except when used chronically as AED)
• previous use of ESL or participation in a clinical study with ESL
• known hypersensitivity to carbamazepine, oxcarbazepine or chemically related substances
• history of abuse of alcohol, drugs or medications within the last 2 years
• uncontrolled cardiac, renal, hepatic, endocrine, gastrointestinal, metabolic, haematological or oncology disorder
• second or third-degree atrioventricular blockade not corrected with a pacemaker
• relevant clinical laboratory abnormalities

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Portugal
• Removed Location Countries: Spain

Administrative Information

• NCT Number: NCT00957372
• Other Study ID Numbers: BIA-2093-303
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Bial - Portela C S.A.
• Study Sponsor: Bial - Portela C S.A.
• Collaborators: Not Provided

Investigators

• Principal Investigator: Antonio Gil-Nagel, MD; Hospital Ruber Internacional La Masó 38, Mirasierra 28034 Madrid, Spain
• Principal Investigator: Jose Lopes-Lima, MD; Hospital Santo António Largo Prof. Abel Salazar, 4099-001 Porto, Portugal

• PRS Account: Bial - Portela C S.A.
• Verification Date: June 2014