Efficacy and Safety of Adjunctive Zonisamide in Myoclonic Seizures Associated With Idiopathic Generalised Epilepsy

Sponsor
Eisai Limited (Industry)
Overall Status
Terminated
CT.gov ID
NCT00693017
Collaborator
(none)
10
72
2
0.1

Study Details

Study Description

Brief Summary

This study is intended to provide evidence that zonisamide is safe and effective in the treatment of myoclonic seizures. The total planned trial duration will be 6.5 months. After that, subjects who have completed the study will be eligible to enroll in an open-label extension study until zonisamide is marketed for this indication or further development in this indication stops. This extension study will be described in a separate protocol (E2090-E044-318).

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
10 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Double-blind, Randomised, Placebo-controlled, Multi-centre Study to Assess the Efficacy and Safety of Adjunctive Zonisamide in Myoclonic Seizures Associated With Idiopathic Generalised Epilepsy
Study Start Date :
Jun 1, 2008
Actual Primary Completion Date :
Nov 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Zonisamide

Drug: Zonisamide
50-400 mg capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks)
Other Names:
  • Zonegran
  • Placebo Comparator: Placebo

    Drug: Placebo
    50-400 mg Zonisamide Placebo capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks)

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants Considered Responders as Assessed During the Maintenance Period [Baseline (Week -8 to Week 0) and Maintenance Period (Week 4 to Week 16)]

      The number of participants who were considered responders during the 12 week Maintenance Period (Week 4 to Week 16). A responder was defined as a participant with a decrease >= 50% from baseline in the number of days with myoclonic seizures per 28 days (i.e. 28-day myoclonic seizure frequency in Period from Week 4 to the Week 16 visit compared to Week -8 to randomization at Week 0 [Screening/ Baseline Period]). Occurrence of seizures was documented in a seizure diary. The diary was dispensed at the Screening Visit and maintained by the participant (parent/caregiver) and reviewed at each following visit. The diary was completed daily. All seizures except myoclonic seizures were counted individually in the the diary. Due to early termination of the study by the Sponsor, no formal analyses were conducted.

    Secondary Outcome Measures

    1. Percentage Change From Baseline in the Monthly Number of Days With Myoclonic Seizures [Baseline and up to 16 weeks]

      Percentage Change from Baseline in the monthly number of days with myoclonic seizures was assessed both for the Maintenance Period alone (Week 4 to Week 16) and for the entire double-blind treatment period (Week 0 to Week 16). Due to early termination of the study by the Sponsor, no formal analyses were conducted.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Subject is male or female and aged 12-65 years.

    2. Subject has at least eight days with at least one myoclonic seizure over the two months Baseline Period. Myoclonic seizures must occur in the context of IGE and may be accompanied by other primary generalized seizures, provided these are also consistent with a diagnosis of Idiopathic Generalized Epilepsy (IGE).

    3. Subject (or parent/caregiver, for subjects below the age of consent) is willing to sign an informed consent form. Subjects below the age of consent in their country, must where appropriate be willing to give informed (written or verbal) assent. Subjects from the age specified in local regulations will be required to sign an appropriate informed consent form.

    4. Subject is taking a stable regimen of one or two other AEDs for at least two weeks prior to Visit 1 (start of the Baseline Period).

    5. Subject has a clinical diagnosis of any type of idiopathic generalised epilepsy (IGE) which has myoclonic seizures (and which may be accompanied by other generalised seizure types), according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures (1981) and the ILAE Classification of Epilepsies and Epileptic Syndromes (1989). Diagnosis should have been established by clinical history, electroencephalogram (EEG) and computed tomography/magnetic resonance imaging (CT/MRI) of the brain consistent with idiopathic generalised epilepsy. A CT/MRI scan should have been performed within five years of the screening visit or, if not available from this period, should be performed in the Baseline Period.

    6. EEG should have been performed within one year of the screening visit or, if not available from this period, should be performed in the Baseline Period.

    7. Female subjects are pre-menarchal, or if of childbearing potential, are not pregnant or lactating, or are post-menopausal.

    8. Female subjects of childbearing potential ≥ 18 years must abide by one of the following medically acceptable contraceptive measures: oral contraception pill, contraceptive injections, implants or patches, intrauterine device in place for at least three months or vasectomised partner or abstinence throughout the study. Subjects <18 years and of childbearing potential must be either abstinent or willing to use one of the medically appropriate forms of contraception for the duration of the study.

    Exclusion Criteria:
    1. Subject has progressive or focal neurological disease (as determined by preexisting brain imaging such as CT or MRI performed maximally five years before the screening visit), or clinically significant organic disease.

    2. Subject has a history of, or results of clinical investigations (including EEG data) that are suggestive of, partial seizures as defined by the ILAE, including generalised tonic clonic seizures which are suspected to be secondarily generalised.

    3. Subjects with cryptogenic or symptomatic generalised epilepsy.

    4. Subjects with psychogenic seizures.

    5. Subject has a history of convulsive status epilepticus within a year of screening while complying with AEDs.

    6. Subject has a history of renal calculi or renal insufficiency (above the upper normal limits of creatinine).

    7. Subject has a known diagnosis of human immunodeficiency virus (HIV) or hepatitis B or

    1. Subject has a predisposing condition that might interfere with absorption, distribution, or excretion of zonisamide.

    2. Subject has a history of sensitivity to sulfonamide drugs or to zonisamide or any of its excipients.

    3. Subject has a recent history of excessive alcohol use or drug abuse.

    4. Subject has a history of suicide attempt in the five years before the screening visit.

    5. Subject has abnormal screening laboratory values that are clinically significant.

    6. Subject has a history of demonstrated non-compliance with treatment, or the subject or parent/caregiver can be reasonably expected not to be compliant with study procedures or to complete the study.

    7. Subject has participated in a study of an investigational drug or device within 30 days prior to screening.

    8. Subject has received previous treatment with zonisamide.

    9. Subject is treated with ketogenic diet or vagus nerve stimulator.

    10. Subject has a history of necessary treatment with rescue benzodiazepines which is foreseen to continue during the study. Rescue benzodiazepines will not be allowed in this study (stable dosing with a benzodiazepine as (one of the) baseline anti-epileptic drug(s) is allowed).

    11. Concomitant use of acetazolamide, carbonic anhydrase inhibitors such as topiramate and drugs with anticholinergic activity.

    12. Current psychosis or moderate to severe depression, or use of anti-psychotic drugs, MAOIs, tricyclic antidepressants, benzodiazepine or barbiturate treatment for disorders other than epilepsy, and stimulants (amphetamine derivatives) within 28 days before the screening visit.

    13. Concomitant use of felbamate or use of felbamate within two months prior to Visit 1.

    14. Subject is unable to swallow capsules.

    15. Subject is not in general good health as determined by medical history, physical exam and screening laboratory results.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Strategic Health Evaluators Pty Ltd Chatswood New South Wales Australia 2067
    2 The Prince of Wales Hospital Randwick New South Wales Australia 2031
    3 Austin Health Heidelburg Victoria Australia 3084
    4 The Royal Melbourne Hospital Melbourne Victoria Australia 3050
    5 CH Split Split HR Croatia 10000
    6 CH Sestre Milosrdnice University Hospita Zagreb HR Croatia 10000
    7 UHC Zagreb Zagreb HR Croatia 10000
    8 Neurologicke oddeleni Kralove Czech Republic 500 03
    9 Private Neurologi Office Kromeriz Czech Republic 767 01
    10 Fakultni nemocnice Olomouc Olomouc Czech Republic 775 20
    11 Fakultni nemocnice s poliklinikou Ostrava Ostrava Czech Republic 708 52
    12 Fakultni nemocnice Plzen Plzen Czech Republic 305 99
    13 Nemocnice Na Homolce Praha 5 Czech Republic 150 30
    14 Centrum neurologicke pece Rychnov nad Kneznou Czech Republic 516 01
    15 West-Tallinn Central Hospital Tallinn Estonia 10611
    16 Neurodiagnostica AP OY Tallinn Estonia 11312
    17 Tartu University Hospital Tartu Estonia 51014
    18 Kuopio Epilepsy Center Kuopio Finland SF-70211
    19 Oulu University Central Hospital Oulu Finland 90220
    20 Institut fur Diagnostik der Epilepsien (IDE) gGmbH Epilepsie-Zentrum Berlin- Brandenburg. Berlin Germany 10365
    21 Neurochirurgische Klinik der Universitat Freiburg Freiburg Germany 79106
    22 Interdisziplinares Epilepsiezentrum am Klinikum der Philipps-Universitat Marburg Marburg Germany 35039
    23 Neurologische Gemeinschaftspraxis Munchen Germany 80333
    24 Universitatsklinikum Ulm Ulm Germany 89081
    25 National Institute of Psychiatry and Neurology Budapest Hungary 1021
    26 Heim Pal Hospital Budapest Hungary 1089
    27 Szent Istvan Hospital Budapest Hungary 1091
    28 Orszagos Idegsebeszeti Tudomanyos Intezet Budapest Hungary 1145
    29 Bethesda Hospital for Children Budapest Hungary 1146
    30 Bekes County Pandy Kalman Hospital Gyula Hungary 5703
    31 Bacs-Kiskun County ONK Hospital Kecskemet Hungary 6000
    32 Vas County Markusovszky Hospital Szombathely Hungary 9400
    33 Veszprem County Csolnoky F. Hospital Veszprem Hungary 8200
    34 Kaunas Medical University Hospital Kaunas Lithuania 50009
    35 Neuromeda Kaunas Lithuania 50185
    36 Vilnius University Hospital Santariskiu klinikos Vilnius Lithuania 8861
    37 Niepubliczny ZOZ Kendron Bialystok Poland 15-420
    38 Wojewozki Szpital Specjalistyczny im. M. Kopernika Gdansk Poland 80-803
    39 Specjalistyczny Szpital Wieloprofilowy Katowice Poland 40-635
    40 Centrum Neurologii Klinicznej Krakow Poland 31-530
    41 Szpital im. M. Kopernika Lodz Poland 93-513
    42 Uniwersytet Medyczny Poznan Poland 60-355
    43 Centrul Medical Sana Bucharest Romania 011025
    44 Spitalul Clinic de Psihiatrie "Prof. Dr. Alexandru Obregia" Bucharest Romania 041914
    45 Spitalul Universitar de Urgenta Bucuresti Bucharest Romania 050098
    46 Spitalul Clinic Judetean de Urgenta Cluj Cluj-Napoca Romania 400006
    47 Spitalul Clinic Judetean de Urgenta "Sf Spiridon" Iasi Lasi Romania 700111
    48 Spitalul Clinic de Urgenta "Sfanta Treime" Lasi Romania 700309
    49 Spitalul Clinic Judetean de Urgenta Tg Mures Tg Mures Romania 540136
    50 GOU VPO Krasnoyarskaya State Medical Academy of Roszdrav Krasnoyarsk Russian Federation 660022
    51 FGU Moscow Research Institute of Psychiatry of Roszdrav Moscow Russian Federation 107076
    52 GOU VPO Russian State Medical University of Roszdrav Moscow Russian Federation 117997
    53 GUZ of Moscow City Clinical Hospital #1 n.a. N.I.Pirogov Moscow Russian Federation 119049
    54 GOU VPO Moscow State University of Medicine and Dentistry of Roszdra Moscow Russian Federation 127473
    55 GOU VPO Novosibirsk State Medical University of Roszdrav Novosibirsk Russian Federation 630091
    56 GOU VPO Smolensk State Medical Academy of Roszdrav Smolensk Russian Federation 214018
    57 GOU VPO Smolensk State Medical Academy of Roszdrav Smolensk Russian Federation 214019
    58 GU St. Petersburg Research Institute of Psychoneurology Bekhtereva of Roszdrav St. Petersburg Russian Federation 192019
    59 St. Petersburg State Medical Pediatric Academy St. Petersburg Russian Federation 194100
    60 GOU VPO St. Petersburg State Medical University St. Petersburg Russian Federation 197022
    61 Yaroslavskaya State Medical Academy Yaroslavl Russian Federation 150000
    62 Clinical Center of Serbia Belgrade Serbia 11000
    63 University Medical Center Zvezdara Belgrade Serbia 11000
    64 Clinical center Kragujevac Kragujevac Serbia 34000
    65 Clinical Center of NIS Nis Serbia 18000
    66 Tsentr Psihosomatychnoyi Patologiyi Dnipropetrovskoyi oblasnoyi klinichnoyi likarni imeni Mechnikova Dnipropetrovsk Ukraine 49005
    67 Derzhavna Ustanova Institut Nevrologiy Kharkiv Ukraine 61068
    68 Kyiv City Psychiatric Hospital #2, Poliklinichne Viddilenya Kyiv Ukraine 2660
    69 Miska Klinichna psihonevrologichna Kyiv Ukraine 3080
    70 Lvivskyiy oblasnyi Protyepileptuchnyy tsentr Lviv Ukraine 7910
    71 Odesskyy Derzhavnyy Medychnyy Universitet Odesa Ukraine 65006
    72 Vinnitskyy Natsionalnyy Medychnyy Universitet Vinnitsa Ukraine 21005

    Sponsors and Collaborators

    • Eisai Limited

    Investigators

    • Study Director: Rob van Maanen, M.D., Eisai Limited

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Eisai Limited
    ClinicalTrials.gov Identifier:
    NCT00693017
    Other Study ID Numbers:
    • E2090-E044-317
    • 2007-003556-10
    First Posted:
    Jun 6, 2008
    Last Update Posted:
    Dec 24, 2015
    Last Verified:
    Nov 1, 2015

    Study Results

    Participant Flow

    Recruitment Details This study was recruited at three study centers (1 in Australia and 2 in Hungary). A further 39 study centers in Europe and Australia were initiated. A total of 12 study sites in the following countries were not initiated; (2 in Finland), (3 in Czech Republic), and (7 in Ukraine) during the period of 04 June 2008 to 05 January 2009.
    Pre-assignment Detail 10 participants were screened for eligibility and six participants did not continue after the Screening Visit due to the Sponsor's decision to terminate the study. 4 participants were enrolled and treated during the study.
    Arm/Group Title Zonisamide Placebo
    Arm/Group Description 50-400 mg capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks) 50-400 mg Zonisamide Placebo capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks)
    Period Title: Overall Study
    STARTED 2 2
    COMPLETED 0 0
    NOT COMPLETED 2 2

    Baseline Characteristics

    Arm/Group Title Zonisamide Placebo Total
    Arm/Group Description 50-400 mg capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks) 50-400 mg Zonisamide Placebo capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks) Total of all reporting groups
    Overall Participants 2 2 4
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    24.0
    (16.97)
    33.5
    (23.33)
    28.8
    (17.54)
    Sex: Female, Male (Count of Participants)
    Female
    1
    50%
    1
    50%
    2
    50%
    Male
    1
    50%
    1
    50%
    2
    50%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants Considered Responders as Assessed During the Maintenance Period
    Description The number of participants who were considered responders during the 12 week Maintenance Period (Week 4 to Week 16). A responder was defined as a participant with a decrease >= 50% from baseline in the number of days with myoclonic seizures per 28 days (i.e. 28-day myoclonic seizure frequency in Period from Week 4 to the Week 16 visit compared to Week -8 to randomization at Week 0 [Screening/ Baseline Period]). Occurrence of seizures was documented in a seizure diary. The diary was dispensed at the Screening Visit and maintained by the participant (parent/caregiver) and reviewed at each following visit. The diary was completed daily. All seizures except myoclonic seizures were counted individually in the the diary. Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    Time Frame Baseline (Week -8 to Week 0) and Maintenance Period (Week 4 to Week 16)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Zonisamide Placebo
    Arm/Group Description 50-400 mg capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks) 50-400 mg Zonisamide Placebo capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks)
    Measure Participants 0 0
    2. Secondary Outcome
    Title Percentage Change From Baseline in the Monthly Number of Days With Myoclonic Seizures
    Description Percentage Change from Baseline in the monthly number of days with myoclonic seizures was assessed both for the Maintenance Period alone (Week 4 to Week 16) and for the entire double-blind treatment period (Week 0 to Week 16). Due to early termination of the study by the Sponsor, no formal analyses were conducted.
    Time Frame Baseline and up to 16 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Zonisamide Placebo
    Arm/Group Description 50-400 mg capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks) 50-400 mg Zonisamide Placebo capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks)
    Measure Participants 0 0

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Zonisamide Placebo
    Arm/Group Description 50-400 mg capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks) 50-400 mg Zonisamide Placebo capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks)
    All Cause Mortality
    Zonisamide Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Zonisamide Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/2 (0%) 1/2 (50%)
    General disorders
    Sudden unexplained death in epilepsy 0/2 (0%) 1/2 (50%)
    Other (Not Including Serious) Adverse Events
    Zonisamide Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/2 (100%) 2/2 (100%)
    Eye disorders
    Vision blurred 1/2 (50%) 1/2 (50%)
    Gastrointestinal disorders
    Vomiting 1/2 (50%) 0/2 (0%)
    Nervous system disorders
    Dizziness 1/2 (50%) 0/2 (0%)
    Headache 0/2 (0%) 1/2 (50%)
    Somnolence 1/2 (50%) 0/2 (0%)
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic 0/2 (0%) 1/2 (50%)

    Limitations/Caveats

    Due to early termination of the study by the Sponsor. No formal analyses were conducted.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Antonio Laurenza, MD, Executive Director
    Organization Eisai Inc
    Phone 1 201 949-4157
    Email antonio_laurenza@eisai.com
    Responsible Party:
    Eisai Limited
    ClinicalTrials.gov Identifier:
    NCT00693017
    Other Study ID Numbers:
    • E2090-E044-317
    • 2007-003556-10
    First Posted:
    Jun 6, 2008
    Last Update Posted:
    Dec 24, 2015
    Last Verified:
    Nov 1, 2015