Rufinamide Given as Adjunctive Therapy in Participants With Refractory Partial Seizures

A Double-Blind, Placebo-Controlled, Parallel-Group Study of Rufinamide Given as Adjunctive Therapy in Patients With Refractory Partial Seizures

To evaluate the effect of rufinamide on total partial seizure frequency in adolescent and adult participants (12 to 80 years, inclusive) with refractory partial onset seizures maintained on a maximum of 3 stable antiepileptic drugs (AEDs).

Study Overview

• Status: Completed
• Conditions: Epilepsy
• Intervention / Treatment: Drug: Placebo; Drug: Rufinamide

• Study Type: Interventional
• Enrollment (Actual): 356
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36693
      • University of South Alabama Medical Center
    • Northport, Alabama, United States, 35476
      • Neurology Clinic PC
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Epilepsy and Neurology
    • Tucson, Arizona, United States, 85724-5023
      • University of Arizona, Dept. of Neurology
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Clinical Trials, Inc
  • California
    • Fresno, California, United States, 93710
      • Neuro-Pain Medical Center, Inc.
    • Oceanside, California, United States, 92056
      • Neurology Center
    • San Francisco, California, United States, 94115
      • California Pacific Epilepsy
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital, Dept. of Neurology
  • Florida
    • Bradenton, Florida, United States, 34205
      • Bradenton Research Center
    • Gainesville, Florida, United States, 32611
      • University of Florida, Dept. of Neurology
    • Jacksonville, Florida, United States, 32209
      • University of Florida, The Neuroscience Institute at Shands
    • Loxahatchee Groves, Florida, United States, 33470
      • Pediatric Neurologists of Palm Beach
    • Orlando, Florida, United States, 32835
      • Nemours Children's Clinic
    • Orlando, Florida, United States
      • Pediatric Neurology - PA
    • Panama City, Florida, United States, 32405
      • Bay Medical Center
    • Tampa, Florida, United States, 33606
      • University of Southern Florida, Dept. of Neurology
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Child Neurology Associates, PC
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia, Dept. of Neurology
    • Canton, Georgia, United States, 30114
      • Medical Associates of North Georgia
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • The Queen's Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60614-3394
      • Children's Memorial Hospital, Northwest University
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Hope Children's Hospital
    • Park Ridge, Illinois, United States, 60068
      • Advocate Lutheran General Children's Hospital
    • Springfield, Illinois, United States, 62794-9643
      • Southern Illinois University Neurology and Pharmacology
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Via Christi Comprehensive Epilepsy Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0284
      • University of Kentucky, Dept. of Neurology
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins Hospital, Dept. of Neurology
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center, Dept. of Neurology
    • Hopedale, Massachusetts, United States, 01747
      • University of Massachusetts, Neurology Associates
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, Dept. of Neurology
    • Saint Paul, Minnesota, United States, 55102
      • Minnesota Epilepsy Group, PC
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Ronald Schwartz, M.D.
    • Hattiesburg, Mississippi, United States
      • Hattiesburg Clinic
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • The Comprehensive Epilepsy Care Center for Children and Adults
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University
    • Springfield, Missouri, United States, 65807
      • Saint John's Medical Research
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0001
      • Dartmouth Medical School Neuroscience Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center, Albert Einstein College of Medicine
    • Lawrence, New York, United States, 11559
      • Five Towns Neuroscience Research
    • New York, New York, United States, 10032
      • Columbia University Medical center
    • New York, New York, United States, 10016
      • New York University Medical Centre, Comprehensive Epilepsy Center
    • New York, New York, United States, 10021
      • Weill Cornell Medical Center, Comprehensive Epilepsy Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Asheville, North Carolina, United States, 28806
      • Asheville Neurology Specialists, Pa
    • Chapel Hill, North Carolina, United States, 27599-7025
      • University of North Carolina at Chapel Hill, Dept. of Neurology
    • Durham, North Carolina, United States, 27710
      • Duke Health Center at Morreene Road
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation, Dept. of Neurology
    • Columbus, Ohio, United States, 43210
      • Ohio State University
    • Toledo, Ohio, United States, 43614
      • Medical University of Ohio at Toledo, Dept. of Neurology
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Altoona, Pennsylvania, United States, 16602
      • Blair Medical Associates, Inc.
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104-4204
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4283
      • Hospital of the University of Pennsylvania, Dept. of Neurology
    • Pittsburgh, Pennsylvania, United States
      • Children's Hospital of Pittsburgh - Dept of Pediatrics
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Mid-South Physicians Group, PLLC
    • Memphis, Tennessee, United States, 38105
      • University of Tennessee Health Sciences Center, Dept. of Neurology
    • Memphis, Tennessee, United States
      • Ut Medical Group
    • Nashville, Tennessee, United States, 37203
      • Access Clinical Trials, Inc
  • Texas
    • Dallas, Texas, United States, 75230
      • Neurological Clinic of Texas, PA
    • Dallas, Texas, United States, 75390-9034
      • University Of Texas Southwestern Medical Center At Dallas
    • El Paso, Texas, United States, 79905
      • Texas Tech University Health Sciences Center, Dept. of Neuropsychiatry
    • Houston, Texas, United States
      • University of Texas - Dept of Neurology
    • Irving, Texas, United States, 75061
      • Baylor Medical Center of Irving
  • Utah
    • West Jordan, Utah, United States, 84088
      • Epilepsy and Neurodevelopment, Inc.
  • Vermont
    • Burlington, Vermont, United States, '05401
      • University of Vermont, College of Medicine, Clinical Neurophysiology Lab
    • Burlington, Vermont, United States
      • Fletcher Allen Healthcare
  • Virginia
    • Richmond, Virginia, United States, 23298-0211
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98105
      • University of Washington, Harborview Medical Center, Regional Epilepsy Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin, Dept. of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA

1. Male and female patients between 12 and 80 years of age, inclusive.
2. Diagnosis of epilepsy with partial-onset seizures with or without secondarily generalized seizures according with the International League Against Epilepsy Classification of Epileptic Seizures (1981). Diagnosis should have been established by clinical history, electroencephalogram (EEG) and computed tomography/magnetic resonance imaging (CT/MRI) of the brain performed within the last 10 years and consistent with localization-related epilepsy.
3. Non-controlled partial seizures despite having been treated with at least two different antiepileptic drugs (given concurrently or sequentially) for at least two years.
4. Patient willing to participate and written consent signed by patient or legal guardian prior to entering the study or undergoing any study procedures. If the written consent is provided by a legal guardian because the patient is unable to do so, assent of the patient must also be obtained.
5. Reliability and willingness of patients to make themselves available for the study period, and ability to record seizures and report adverse events themselves or have a caregiver who can record seizures and report adverse events.
6. Female patients of non-childbearing potential by reason of surgery, radiation, or menopause (at least one year post onset); or of childbearing potential using two approved methods of contraception (such as an intrauterine device [IUD], implant, oral contraceptive, or barrier method plus spermicide). Use of a low-dose estrogen oral contraceptive ("minipill") alone will not be permitted. Female patients of childbearing potential must have a confirmed negative serum pregnancy test at screening and a negative urine pregnancy test prior to randomization, and agree to continue to use two approved methods of contraception through the follow-up visit (Visit 8) or for 30 days after their final dose of study medication, whichever is longer.
7. At least six seizures during the prospective Baseline Phase (56 days) with no 21-day seizure-free periods. Simple partial seizures without motor signs will not be included in determining this criterion.
8. Current treatment with a maximum of three approved antiepileptic drugs, and no evidence of non-compliance with ongoing AED therapy.
9. Stable dose(s) of the same AED(s) for one month prior to screening.
10. If using a vagal nerve stimulator, it must have been implanted for at least six months prior to randomization. Stimulator parameters may not be changed for at least one month prior to screening or thereafter during the study. Magnet use will be allowed, but must be documented throughout the study. A vagal nerve stimulator will not be counted as an AED for the purpose of inclusion into the trial.

EXCLUSION CRITERIA:

1. Participation in a study involving administration of an investigational compound within one month of Visit 1 (Screening), or within five half-lives of the previous investigational compound, whichever is longer; or any prior exposure to rufinamide.
2. Presence of non-motor simple partial seizures only.
3. Presence of generalized epilepsies or seizures, such as absences, myoclonic epilepsies, Lennox-Gastaut syndrome.
4. History of status epilepticus in the past year or seizure clusters where individual seizures cannot be counted.
5. Evidence of clinically significant disease (cardiac, respiratory, gastrointestinal, hepatic, hematologic or renal disease, etc.) that in the opinion of the Investigator could affect the patient's safety or trial conduct.
6. Clinically significant ECG abnormality.
7. Patients with a diagnosis of major active psychiatric disease will be excluded from the study. However, those patients who are only taking a stable dose of either a selective serotonin reuptake inhibitor (SSRI) antidepressant drug or a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant drug for a diagnosed depressive disorder can be included as long as they have been on the SSRI or SNRI for a period of two months or longer before randomization. Other antidepressant medications will not be allowed.
8. Progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors.
9. Occurrence of psychogenic seizures in the previous year.
10. History of drug abuse and/or positive finding on urinary drug screening, other than prescribed medication
11. History of alcohol abuse in the past two years.
12. History of suicide attempt within the previous 10 years.
13. Multiple drug allergies (dermatological, hematological or organ toxicity) or more than one severe drug reaction(s).
14. Concomitant use of felbamate or use of felbamate within two months prior to Visit 1.
15. Frequent need of rescue benzodiazepines (more than once a month).
16. Patients with a known hypersensitivity to rufinamide, triazole derivatives, or to any excipients used in the formulation.
17. Concomitant use of vigabatrin. Patients who took vigabatrin in the past must be off vigabatrin for at least five months prior to Visit 1 and must not have evidence of a clinically significant abnormality in a visual perimetry test.
18. All Patients with a diagnosis of Congenital Short QT Syndrome. Patients with a family history of Congenital Short QT Syndrome may be excluded on the basis of the Investigator's clinical judgment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; For 12-day Titration Phase and 12 week Maintenance Phase, placebo tablets matching to rufinamide 400 mg oral tablets will be administered according to the same regimen scheme as described for rufinamide. For 12-day Titration Phase, 1 matching placebo tablet will be administered twice daily and increased by 1 tablet every 3 days up to maximum of 4 matching placebo tablets twice daily (placebo tablet matched to rufinamide total daily dose of 3200 mg). For the 12 week maintenance phase, 4 placebo tablets matching to rufinamide maintenance doses of 1600 mg twice daily (3200 mg total daily dose) will be administered. Similar to the dose reduction permitted in the rufinamide group, participants in placebo group will be allowed only during the Titration Phase to have the dose reduced to 3 tablets twice daily.	Drug: Placebo; For the 12-day Titration Phase, one matching placebo tablet will be administered twice daily and increased by 1 matching placebo tablet every 3 days up to maximum of 4 matching placebo tablets twice daily (placebo tablet matched to rufinamide total daily dose of 3200 mg). For the 12 week maintenance phase, 4 placebo tablets matching to rufinamide maintenance doses of 1600 mg twice daily (3200 mg total daily dose) will be administered. Similar to the dose reduction permitted in the rufinamide group, participants in placebo group will be allowed only during the Titration Phase to have the dose reduced to 3 placebo tablets twice daily.
Active Comparator: Rufinamide; For the 12-day Titration Phase, rufinamide will be administered orally in doses starting with 400 milligram (mg) twice daily and increased every 3 days in 400 mg twice daily increments up to 1600 mg twice daily (total daily dose 3200 mg). For the 12 week Maintenance Phase, maintenance doses of 1600 mg twice daily (3200 mg total daily dose) will be administered. Participants unable to tolerate the target dose (3200 mg/day) will be allowed only during the Titration Phase to have the dose reduced to 3 tablets twice daily (corresponding to a dose of 2400 mg/day in the rufinamide group).	Drug: Rufinamide; For the titration phase, Rufinamide will be administered orally in doses starting with 400 mg twice daily and increased every 3 days in 400 mg twice daily increments up to 1600 mg twice daily (total daily dose 3200 mg). For the Maintenance Phase, maintenance doses of 1600 mg twice daily (3200 mg total daily dose) will be administered. Participants unable to tolerate the target dose (3200 mg/day) will be allowed only during the Titration Phase to have the dose reduced to 3 tablets twice daily (corresponding to a dose of 2400 mg/day in the rufinamide group).; Other Names: E2080; BANZEL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Total Partial Seizure Frequency Per 28 Days During Maintenance Phase Relative to the Baseline Phase	Seizure data was collected via patient diary, which was used to record daily seizure count and type. Intent-to-treat (ITT) population: All randomized participants who had baseline Patient Seizure Diary data and had at least completed the titration period.	Baseline, Days 13 to 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With 50% or Greater Reduction in Total Partial Seizure Frequency Per 28 Days During the Maintenance Phase Relative to the Baseline Phase	Seizure data was collected via patient diary, which was used to record daily seizure count and type.	Baseline, Days 13 to 96
Log10 Transformed Total Partial Seizure Frequency Per 28 Days During the Baseline Phase and Maintenance Phase	Total partial seizure frequencies per 28 days during the double-blind Maintenance and Baseline Phases were transformed using logarithms to the base 10 (log10), because it was expected from previous studies that the results would not be normally distributed.	Days 13 to 96
Reduction From Baseline in Total Partial Seizure Frequency Rate (RRATIO) During Maintenance Phase	RRATIO= 100*(T-B)/(T+B) where T= total seizure frequency per 28 days during the Maintenance Phase, and B=total seizure frequency per 28 days during the Baseline Phase.	Baseline, Days 13 to 96

Collaborators and Investigators

• Sponsor: Eisai Inc.

Publications and helpful links

General Publications

• Panebianco M, Prabhakar H, Marson AG. Rufinamide add-on therapy for drug-resistant epilepsy. Cochrane Database Syst Rev. 2020 Nov 8;11(11):CD011772. doi: 10.1002/14651858.CD011772.pub3.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2006
• Primary Completion (Actual): May 20, 2009
• Study Completion (Actual): May 20, 2009

Study Registration Dates

• First Submitted: June 7, 2006
• First Submitted That Met QC Criteria: June 7, 2006
• First Posted (Estimate): June 8, 2006

Study Record Updates

• Last Update Posted (Actual): June 14, 2021
• Last Update Submitted That Met QC Criteria: May 20, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Rufinamide
• Other Study ID Numbers: E2080-A001-301; 2016-004944-12 (EudraCT Number)