Adjunctive Zonisamide in Primary Generalised Tonic Clonic Seizures

Epilepsy Clinical Trial

Official title:

A Double-blind, Randomised, Placebo-controlled Multi-centre Study to Assess the Efficacy and Safety of Adjunctive Zonisamide in Primary Generalised Tonic Clonic Seizures

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00692003
• Other study ID #: E2090-E044-315
• Secondary ID: Eudra ID #2007-0
• Status: Terminated
• Phase: Phase 3
• First received: June 3, 2008
• Last updated: September 11, 2012
• Start date: August 2008

Study information

• Verified date: September 2012
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: European Union: European Medicines Agency
• Study type: Interventional

Clinical Trial Summary

Zonisamide is already marketed for the treatment of partial seizures in epilepsy. This study is intended to provide evidence that zonisamide is safe and effective in the treatment of primary generalised tonic-clonic seizures. The total trial duration will be 5.5-6.5 months. After that subjects who have completed the study will be eligible to enrol 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-E044-316).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 21
• Est. primary completion date: November 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Subject is male or female and aged 6-65 years.

2. Subject has = 3 PGTCS over the two months before screening and during the eight weeks Baseline Period with at least one seizure in each one month period. PGTCS must occur in the context of Idiopathic Generalized Epilepsy (IGE) and may be accompanied by other primary generalized seizures, provided these are also consistent with a diagnosis of IGE.

3. Subject (or parent/caregiver, for subjects below the age of consent) is willing to sign an informed consent form. For subjects below the age of consent in their country, where appropriate they must 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 Antiepileptic Drugs (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 generalized epilepsy which has PGTCS (and which may be accompanied by other generalized 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 generalized epilepsy. 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 must abide by the 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.

9. Subject has a body weight = 20 kg.

Exclusion Criteria:

1. Subject has progressive or focal neurological disease (as determined by pre-existing 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 generalized tonic clonic seizures which are suspected to be secondarily generalized.

3. Subjects with cryptogenic or symptomatic generalized epilepsy.

4. Subjects with psychogenic seizures.

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

6. Subject has seizures that only occur in clustered patterns.

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

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

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

10. Subject has a history of sensitivity to sulfonamide drugs or zonisamide and its excipients.

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

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

13. Subject has abnormal screening laboratory values that were clinically significant.

14. 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.

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

16. Subject has received previous treatment with zonisamide.

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

18. 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).

19. 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.

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

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

22. Subject is not able to swallow capsules.

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

Study Design

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

Related Conditions & MeSH terms

• Epilepsy
• Seizures

Intervention

Drug:
• Zonisamide
25-400 mg capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg; >= 12 years old: 50 mg daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events) Down Titration Period (4 weeks)
• Placebo
25-400 mg Zonisamide Placebo capsules orally once daily in the evening. Maximum study duration of 28 weeks comprising: Baseline Period (Week-8/-4 to Week 0) no treatment Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg Zonisamide Placebo; >= 12 years old: 50 mg Zonisamide Placebo capsules daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events) Down Titration Period (4 weeks)

Locations

Country	Name	City	State
Australia	Strategic Health Evaluators Pty Ltd	Chatswood	New South Wales
Australia	Austin Health	Heidelburg	Victoria
Australia	St. Vincents Hospital	Melbourne
Australia	The Royal Melbourne Hospital	Melbourne	Victoria
Australia	The Prince of Wales Hospital	Randwick	New South Wales
Croatia	CH Split	Split	HR
Croatia	CH Sestre Milosrdnice University Hospital	Zagreb	HR
Croatia	UHC Zagreb	Zagreb	HR
Czech Republic	Neurologicke oddeleni	Hradec Kralove
Czech Republic	Private Neurologi Office	Kromeriz
Czech Republic	Fakultni nemocnice Olomouc	Olomouc
Czech Republic	Fakultni nemocnice s poliklinikou Ostrava	Ostrava
Czech Republic	Fakultni nemocnice Plzen	Plzen
Czech Republic	Nemocnice Na Homolce	Praha 5
Czech Republic	Centrum neurologicke pece	Rychnov nad Kneznou
Estonia	Neurodiagnostica AP OY	Tallinn
Estonia	West-Tallinn Central Hospital	Tallinn
Estonia	Tartu University Hospital	Tartu
Finland	Kuopio Epilepsy Center	Kuopio	SF
Finland	Oulu University Central Hospital	Oulu
Germany	Institut fur Diagnostik der Epilepsien	Berlin
Germany	Neurochirurgische Klinik der Universitat Freiburg	Freiburg
Germany	Interdisziplinares Epilepsiezentrum am Klinikum der Philipps-Universitat Marburg	Marburg
Germany	Neurologische Gemeinschaftspraxis	Munchen
Germany	Universitatsklinikum Ulm	Ulm
Hungary	Bethesda Hospital for Children	Budapest
Hungary	Heim Pal Hospital	Budapest
Hungary	National Institute of Psychiatry and Neurology	Budapest
Hungary	Orszagos Idegsebeszeti Tudomanyos Intezet	Budapest
Hungary	Szent Istvan Hospital	Budapest
Hungary	Bekes County Pandy Kalman Hospital	Gyula
Hungary	Bacs-Kiskun County ONK Hospital	Kecskemet
Hungary	Vas County Markusovszky Hospital	Szombathely
Hungary	Veszpem County Csolnoky F. Hospital	Veszpem
Lithuania	Kaunas Medical University Hospital	Kaunas
Lithuania	Neuromeda	Kaunas
Lithuania	Vilnius University Hospital Santariskiu klinikos	Vilnius
Poland	Niepubliczny ZOZ KENDRON	Bialystok
Poland	Wojewodzki Szpital Specjalistyczny im. M. Kopernika	Gdansk
Poland	Specjalistyczny Szpital Wieloprofilowy	Katowice
Poland	Centrum Neurologii Klinicznej	Krakow
Poland	Szpital im. M. Kopernika	Lodz
Poland	Uniwersytet Medyczny	Poznan
Romania	Centrul Medical Sana	Bucharest
Romania	Spitalul Clinic de Psihiatrie	Bucharest
Romania	Spitalul Universitar de Urgenta Bucuresti	Bucharest
Romania	Spitalul Clinic Judetean de Urgenta Cluj	Cluj-Napoca
Romania	Spitalul Clinic de Urgenta Sfanta Treime	Iasi
Romania	Spitalul Clinic Judetean de Urgenta Sf Spiridon Iasi	Iasi
Romania	Spitalul Clinic Judetean de Urgenta Tg Mures	Tg Mures
Russian Federation	GOU VPO Krasnoyarskaya State Medical Academy of Roszdrav	Krasnoyarsk
Russian Federation	FGU Moscow Research Institute of Psychiatry of Roszdrav	Moscow
Russian Federation	GOU VPO Moscow State University of Medicine and Dentistry of Roszdrav	Moscow
Russian Federation	GOU VPO Russian State Medical University of Roszdrav	Moscow
Russian Federation	GOU VPO Smolensk State Medical Academy of Roszdrav	Moscow
Russian Federation	GOU VPO Novosibirsk State Medical University of Roszdrav	Novosibirsk
Russian Federation	GOU VPO Smolensk State Medical Academy of Roszdrav	Smolensk
Russian Federation	GOU VPO Smolensk State Medical Academy of Roszdrav	Smolensk
Russian Federation	St. Petersburg State Medical Pediatric Academy	St. Petersburg
Russian Federation	GOU VPO St. Petersburg State Medical University	St.Petersburg
Russian Federation	GU St. Petersburg Research Institute of Psychoneurology	St.Petersburg
Russian Federation	Yaroslavskaya State Medical Academy	Yaroslavl
Serbia	Clinical Center of Serbia	Belgrade
Serbia	University Medical Center Zvezdara	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Serbia	Clinical Center of Nis	Nis
Ukraine	Tsentr Psihosomatychnoyi Patologiyi Dnipropetrovskoyi oblasnoyi klinichnoyi likarni imeni Mechnikova	Dniepropetrovsk
Ukraine	Derzhavna Ustanova Institut Nevrologiy	Kharkiv
Ukraine	Kyiv City Psychiatric Hospital #2, Poliklinichne Viddilenya	Kyiv
Ukraine	Miska Klinichna psihonevrologichna Tsentr Epilepsiyi	Kyiv
Ukraine	Lvivskyiy oblasnyi Protyepileptuchnyy tsentr	Lviv
Ukraine	Odesskyy Derzhavnyy Medychnyy Universitet	Odesa
Ukraine	Vinnitskyy Natsionalnyy Medychnyy Universitet	Vinnitsa

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Limited

Countries where clinical trial is conducted

Australia,  Croatia,  Czech Republic,  Estonia,  Finland,  Germany,  Hungary,  Lithuania,  Poland,  Romania,  Russian Federation,  Serbia,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Considered Responders as Assessed During the Maintenance Period	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 from baseline in Primary Generalised Tonic-Clonic Seizures (PGTCS) frequency of >= 50% (i.e. 28-day PGTC seizure frequency in the period from Week 4 to the Week 16 visit compared to Week -8/-4 to randomization at Week 0). Each participant's response to treatment was assessed on the basis of their seizure diaries. The diary was dispensed at the Screening Visit and maintained by the participant (parent/caregiver) through out the titration and maintenance treatment periods until the Early termination Visit at Week 16. Due to early termination of the study by the Sponsor, no formal analyses were conducted.	Baseline (Week -8/-4 to Week 0) and Maintenance Phase (Week 4 to Week 16)	No
Secondary	Absolute Change From Baseline in 28-day PGTC Seizure Frequency	Absolute Change from Baseline in 28-day PGTC Seizure Frequency 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.	Baseline and up to 16 weeks	No