Clinical trial NCT00477295: A Double-blind Study to Compare the Efficacy and Safety of Zonisamide and Carbamazepine as Monotherapy, in Newly Diagnosed Partial Epilepsy
Official title: A Randomized, Multi-centre, Double-blind Study, to Compare the Efficacy and Safety of Zonisamide and Carbamazepine as Monotherapy, in Newly Diagnosed Partial Epilepsy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Epilepsy
Keywords: Epilepsy
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2007-05-23
Enrollment: 583
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a two-arm, randomized, double-blind, non-inferiority study using a flexible dosing regime to allow optimal zonisamide or carbamazepine therapy for individual subjects. Assessment of eligibility will take place at the Screening Visit. The subjects will be randomized to either the carbamazepine or zonisamide arm at the Randomization Visit (T1). T1 must occur as soon as possible (and at least within 14 days) of the Screening Visit in order to optimize subject care.


Eligibility criteria: INCLUSION CRITERIA:

Subjects will be eligible for the study if they meet all of the following inclusion criteria:

1. Male or female subjects, 18 to 75 years of age inclusive.
2. Subjects with untreated, newly diagnosed epilepsy having at least two well documented, unprovoked, clinically evaluated and classified partial seizures (with or without secondary generalization) or generalized tonic-clonic seizures (without clear focal origin) within 12 months of the Screening Visit, of which at least one seizure occurred within three months of the Screening Visit (\> one seizure within a 24 hour period will be counted as one seizure).
3. Subjects will either have had no previous use of an AED, or treatment with one AED for a maximum duration of two weeks before the Randomization Visit (T1).
4. Subjects have a documented electroencephalogram (EEG) within 12 months of the Screening Visit, compatible with localization-related epilepsy (to exclude primary generalized epilepsy).
5. Subjects have a documented computed axial tomography (CAT) scan or magnetic resonance imaging (MRI) scan confirming the absence of a progressive neurological lesion within 12 months of the Screening Visit.
6. Female subjects without childbearing potential (two years post-menopausal, bilateral oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with childbearing potential must not be pregnant as confirmed by a negative pregnancy test at screening and randomization, must not be lactating and must be using a medically acceptable form of contraception, for the duration of the study and for one month following discontinuation of the study drug. Medically acceptable contraception is defined here as oral contraception pill with at least 50 micrograms ethinylestradiol per intake, contraceptive injections and implants, or intrauterine device in place for at least three months.
7. Subjects who are able and willing to follow investigational study procedures, maintain a seizure diary, and report AEs.
8. Subjects who are able and willing to give written informed consent.

EXCLUSION CRITERIA:

Subjects who meet any of the following exclusion criteria will not be eligible for the study:

1. Subjects have a history of clinical investigations, including EEG data, that are suggestive of idiopathic generalised epilepsy as defined by the International League Against Epilepsy (ILAE).
2. Subjects with a history of absence, myoclonic, clonic, tonic, or atonic seizures.
3. Subjects have a history of status epilepticus, and/or non-epileptic seizures (e.g., metabolic, pseudo-seizures).
4. Subjects have experienced seizures relating to drugs, alcohol, acute medical illness, mental retardation, or subjects with situation-related seizures.
5. Subjects have progressive encephalopathy or findings consistent with progressive CNS disease or lesion (e.g. infection, demyelination, or tumour).
6. Subjects have a history of a significant or currently uncontrolled disease that will interfere with the conduct of this study or the assessment of safety and efficacy of the study drug.
7. Subjects have been previously treated with carbamazepine or zonisamide.
8. Subjects have received an investigational drug or device in the three months prior to the Screening Visit.
9. Subjects have a known hypersensitivity to sulfonamides, dibenzazepine derivatives, or tricyclic antidepressants.
10. Subjects have a history of bone marrow depression, low platelet count or other blood dyscrasia.
11. Subjects have a history of acute intermittent porphyria.
12. Subjects have a history of renal disorder (serum creatinine level of \> 135 Ã¬mol / l (1.5 mg/dL at the Screening Visit), hepatic disorder or clinically significant abnormal liver function tests; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \>2 times the upper normal limit.
13. Subjects have a body weight of less than 40 kg.
14. Subjects have a history of progressive malignancy within the previous 5 years (excluding a history of non-metastasized and adequately treated cutaneous squamous cell carcinoma).
15. Subjects have a history of psychiatric illness or mood disorder requiring electro-convulsive or drug therapy within the previous 6 months which is considered uncontrolled; a history of suicide attempt; alcohol or drug abuse; chronic treatment with benzodiazepines or barbiturates.
16. Subjects are currently taking carbonic anhydrase inhibitors.
17. Subjects have a history of pancreatitis, nephrolithiasis or hypercalcuria, clinically significant laboratory or electro-cardiographic abnormalities, or uncontrolled hypertension.
18. Subjects are currently taking mono-amine oxidase inhibitors (MAOIs) or any other excluded medications.

Primary outcomes:
measure: Percentage of Participants Who Experienced Seizure Freedom for 26-weeks During the Maintenance Phase
timeFrame: Week 31 through Week 109
Secondary outcomes:
measure: Percentage of Participants Who Experienced Seizure Freedom for 12-months During the FDP and Maintenance Period
timeFrame: Week 5 through Week 109
measure: Analysis of Time to Drop Out Due to an Adverse Event (AE)
timeFrame: Week 1 through Week 109
measure: Analysis of Time to Drop Out Due to Lack of Efficacy
timeFrame: Week 1 through Week 109
measure: Time to 6-months Seizure Freedom
timeFrame: Week 5 through Week 83
measure: Time to 12-months Seizure Freedom
timeFrame: Week 5 through Week 83
measure: Change From Baseline in Total ABNAS Score at Maintenance Period Visit 1
timeFrame: Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)
measure: Change From Baseline in Bond and Lader VAS Mood Sub-Scores at Maintenance Period Visit 1
timeFrame: Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)
measure: Change From Baseline in QOLIE-31-P Overall Score at Maintenance Period Visit 1
timeFrame: Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)
measure: Change From Baseline in SF-36 Aggregate Mental and Physical Component Score at Maintenance Period Visit 1
timeFrame: Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)
measure: Percentage of Participants With EQ-5D Scores at Maintenance Period Visit 1
timeFrame: Week 31 through Week 83
Other outcomes:
Locations:
city: Camperdown
country: Australia
city: Clayton
country: Australia
city: Fitzroy
country: Australia
city: Flinders
country: Australia
city: Heidelberg West
country: Australia
city: Parkville
country: Australia
city: Queensland
country: Australia
city: Wellington
country: Australia
city: Aalborg
country: Denmark
city: Bethune cedex
country: France
city: Dijon
country: France
city: Paris
country: France
city: St. Etienne
country: France
city: Berlin
country: Germany
city: Bochum
country: Germany
city: Duesseldorf
country: Germany
city: Munich
country: Germany
city: Schwerin
country: Germany
city: Westerstede
country: Germany
city: Athens
country: Greece
city: Thessaloniki
country: Greece
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Gyula
country: Hungary
city: Hodmezovasarhely
country: Hungary
city: Nyregyhaza
country: Hungary
city: Zalaegerszeg-Pozva
country: Hungary
city: Bangalore
country: India
city: Hyderabad
country: India
city: Koturpuram
country: India
city: Madurai
country: India
city: New Delhi
country: India
city: Pune
country: India
city: Milan
country: Italy
city: Monza
country: Italy
city: Orbassano
country: Italy
city: Rome
country: Italy
city: Anyang
country: Korea, Republic of
city: Seol
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Wonju
country: Korea, Republic of
city: Gdansk
country: Poland
city: Katowice
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Lublin
country: Poland
city: Poznan
country: Poland
city: Sosnowiec
country: Poland
city: Szcecin
country: Poland
city: Warszawa
country: Poland
city: Kaliningrad
country: Russian Federation
city: Kazan
country: Russian Federation
city: Moscow
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Yaroslavl
country: Russian Federation
city: Belgrade
country: Serbia
city: Nis
country: Serbia
city: Novi Sad
country: Serbia
city: Subotica
country: Serbia
city: Bratislava
country: Slovakia
city: Bratslava
country: Slovakia
city: Brezno
country: Slovakia
city: Nove Zamky
country: Slovakia
city: Vranov nad Toplou
country: Slovakia
city: Zilina
country: Slovakia
city: Sandton
country: South Africa
city: Alicante
country: Spain
city: Bacelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Malaga
country: Spain
city: Oviedo
country: Spain
city: Sevilla
country: Spain
city: Goteborg
country: Sweden
city: Lund
country: Sweden
city: Changhua
country: Taiwan
city: Yong Kang
country: Taiwan
city: Bristol
country: United Kingdom
city: Liverpool
country: United Kingdom
city: Treliske
country: United Kingdom
Study officials:
affiliation: Eisai Limited
name: Joanna Segieth
role: STUDY_DIRECTOR
References:
citation: Baulac M, Brodie MJ, Patten A, Segieth J, Giorgi L. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol. 2012 Jul;11(7):579-88. doi: 10.1016/S1474-4422(12)70105-9. Epub 2012 Jun 8.