A Double-blind Study to Compare the Efficacy and Safety of Zonisamide and Carbamazepine as Monotherapy, in Newly Diagnosed Partial Epilepsy

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00477295
• Collaborator: (none)
• Enrollment: 583
• Locations: 80
• Arms: 2
• Duration (Months): 44.1
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: Zonisamide; Drug: Carbamazepine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 583 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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 Start Date: May 1, 2007
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Zonisamide	Drug: Zonisamide; Week 1 and 2 either 100mg zonisamide or 200 mg carbamazepine Week 3 and 4 either 200mg zonisamide or 4800 mg carbamazepine Week 5 and 6 either 300mg zonisamide or 600 mg carbamazepine; this dose then to be maintained unless a subject has a seizure more than two weeks post a dose increase.; Other Names: Zonegran
Active Comparator: Carbamazepine	Drug: Carbamazepine; Week 1 and 2 either 100mg zonisamide or 200 mg carbamazepine Week 3 and 4 either 200mg zonisamide or 4800 mg carbamazepine Week 5 and 6 either 300mg zonisamide or 600 mg carbamazepine; this dose then to be maintained unless a subject has a seizure more than two weeks post a dose increase.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Experienced Seizure Freedom for 26-weeks During the Maintenance Phase [Week 31 through Week 109]

   A subject achieved a 26-week seizure-free period if they were free of all seizures, regardless of seizure type, for 26 weeks while receiving the same dose. The occurrence of seizures was documented in the seizure diary, which was maintained by the subject and reviewed at each following visit.

Secondary Outcome Measures

1. Percentage of Participants Who Experienced Seizure Freedom for 12-months During the FDP and Maintenance Period [Week 5 through Week 109]

   A subject achieved a 12-month seizure-free period if they were free of all seizures, regardless of seizure type, for 12 months while receiving the same dose. The occurrence of seizures was documented in the seizure diary, which was maintained by the subject and reviewed at each following visit.

2. Analysis of Time to Drop Out Due to an Adverse Event (AE) [Week 1 through Week 109]

   An AE is defined as any untoward medical occurrence in a subject and does not necessarily have a causal relationship with the medicinal product. Adverse events were identified by: any unfavorable or unintended sign, symptom or disease temporarily associated with the use of a medicinal product; any new disease or exacerbation of an existing disease; any deterioration in nonprotocol-required measurements of laboratory values or other clinical test; and recurrence of an intermittent medical condition not present at Baseline.

3. Analysis of Time to Drop Out Due to Lack of Efficacy [Week 1 through Week 109]

   Lack of efficacy was evaluated by the subject and on the basis of whether zonisamide and carbamazepine gave the subject at least a 26-week seizure free rate. The subject could withdraw at any time due to lack of efficacy.

4. Time to 6-months Seizure Freedom [Week 5 through Week 83]

   A subject achieved a 6-months seizure-free period if they were free of all seizures, regardless of seizure type, for 6-months while receiving the same dose. The occurrence of seizures was documented in the seizure diary, which was maintained by the subject and reviewed at each following visit.

5. Time to 12-months Seizure Freedom [Week 5 through Week 83]

   A subject achieved a 12-month seizure-free period if they were free of all seizures, regardless of seizure type, for 12-months while receiving the same dose. The occurrence of seizures was documented in the seizure diary, which was maintained by the subject and reviewed at each following visit.

6. Change From Baseline in Total ABNAS Score at Maintenance Period Visit 1 [Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)]

   The Aldenkamp-Baker Neuropsychological Assessment Scale(ABNAS) is a subject based questionnaire to measure subjective perceived drug-related cognitive impairments. The ABNAS measured seven critical domains of cognition(tiredness/fatigue,hyperexcitability, slowing(mental and motor),memory impairment,attention disorders,impairment of motor coordination, and language disorders). The total score ranged from 0 to 72, with a higher score reflecting a high level of problems.

7. Change From Baseline in Bond and Lader VAS Mood Sub-Scores at Maintenance Period Visit 1 [Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)]

   The Bond-Lader Visual Analogue Scale (VAS) is made up of 16 pairs of alternative descriptors of mood and attention at either end of a 10 cm line. Subjects were asked to rate their feelings at the time of assessment by indicating the point on the line which best represent their mood. Each item was scored by measuring the position relative to the left hand end of the line and levels of anxiety, sedation, and dysphoria were then calculated from the combined scores of selected items. The scores ranged from 0 to 100, with a high score reflecting a high level of anxiety, sedation or dysphoria.

8. Change From Baseline in QOLIE-31-P Overall Score at Maintenance Period Visit 1 [Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)]

   The Quality of Life in Epilepsy - Problems(QOLIE-31-P) was completed by the patient and contained 30 items covering seven subscales(seizure worry, overall Quality of Life (QOL),emotional well-being,energy-fatigue, cognition,medication effects and social function) and one item covering health status. It also included seven items addressing overall distress related to each subscale, an item addressing the relative importance of each subscale topic, and an item addressing perception of overall change in QOL at the end of the study. A high score reflects a good QOL. The following scale range is a sample of 1 of the 7 of the subscales: 10 (Best possible quality of life) - 0 (Worst possible quality of life); Rand Corporation QOLIE-31 Scoring Manual was used. The QOLIE-31 overall score is calculated by summing the product of each scale score times its weight and summing overall all scales.

9. Change From Baseline in SF-36 Aggregate Mental and Physical Component Score at Maintenance Period Visit 1 [Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)]

   The Short Form 36 Health and Well-Being Questionnaire (SF-36) is a 36-item generic health related QOL instrument covering the following domains: physical functioning, role-physical,bodily pain, general health, social functioning,role-emotional, mental health, and vitality. It yields a profile of eight scores, one for each domain, and physical and mental health summary measures. Each domain is described by a score ranging from 0 to 100, for a range of total possible scoes of 0-400 for physical and 0-400 for mental. An increase represents an improvement, whereas a decrease reflects a worsening.

10. Percentage of Participants With EQ-5D Scores at Maintenance Period Visit 1 [Week 31 through Week 83]

    The European Quality of Life Group 5-Dimension Self-Report Questionnaire (EQ-5D) is a preference based generic health related quality of life (HRQoL) instrument which classifies health states across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain has three levels, they are (1) no problems, (2) some problems, (3) extreme problems. The percentages shown are calculated from the number of subjects at that visit with non-missing data for that score.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 ìmol / 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Camperdown		Australia
2		Clayton		Australia
3		Fitzroy		Australia
4		Flinders		Australia
5		Heidelberg West		Australia
6		Parkville		Australia
7		Queensland		Australia
8		Wellington		Australia
9		Aalborg		Denmark
10		Bethune cedex		France
11		Dijon		France
12		Paris		France
13		St. Etienne		France
14		Berlin		Germany
15		Bochum		Germany
16		Duesseldorf		Germany
17		Munich		Germany
18		Schwerin		Germany
19		Westerstede		Germany
20		Athens		Greece
21		Thessaloniki		Greece
22		Budapest		Hungary
23		Debrecen		Hungary
24		Gyula		Hungary
25		Hodmezovasarhely		Hungary
26		Nyregyhaza		Hungary
27		Zalaegerszeg-Pozva		Hungary
28		Bangalore		India
29		Hyderabad		India
30		Koturpuram		India
31		Madurai		India
32		New Delhi		India
33		Pune		India
34		Milan		Italy
35		Monza		Italy
36		Orbassano		Italy
37		Rome		Italy
38		Anyang		Korea, Republic of
39		Seol		Korea, Republic of
40		Seoul		Korea, Republic of
41		Wonju		Korea, Republic of
42		Gdansk		Poland
43		Katowice		Poland
44		Krakow		Poland
45		Lodz		Poland
46		Lublin		Poland
47		Poznan		Poland
48		Sosnowiec		Poland
49		Szcecin		Poland
50		Warszawa		Poland
51		Kaliningrad		Russian Federation
52		Kazan		Russian Federation
53		Moscow		Russian Federation
54		Saint Petersburg		Russian Federation
55		Yaroslavl		Russian Federation
56		Belgrade		Serbia
57		Nis		Serbia
58		Novi Sad		Serbia
59		Subotica		Serbia
60		Bratislava		Slovakia
61		Bratslava		Slovakia
62		Brezno		Slovakia
63		Nove Zamky		Slovakia
64		Vranov nad Toplou		Slovakia
65		Zilina		Slovakia
66		Sandton		South Africa
67		Alicante		Spain
68		Bacelona		Spain
69		Barcelona		Spain
70		Madrid		Spain
71		Malaga		Spain
72		Oviedo		Spain
73		Sevilla		Spain
74		Goteborg		Sweden
75		Lund		Sweden
76		Changhua		Taiwan
77		Yong Kang		Taiwan
78		Bristol		United Kingdom
79		Liverpool		United Kingdom
80		Treliske		United Kingdom

Sponsors and Collaborators

• Eisai Inc.

Investigators

• Study Director: Joanna Segieth, Eisai Limited

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT00477295
• Other Study ID Numbers: E2090-E044-310; 2006-000156-40
• First Posted: May 23, 2007
• Last Update Posted: Dec 24, 2015
• Last Verified: Nov 1, 2015

• Keywords provided by Eisai Inc.: Epilepsy
• Additional relevant MeSH terms: Epilepsy; Epilepsies, Partial; Carbamazepine; Zonisamide

Study Results

Participant Flow

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Period Title: Overall Study
STARTED	282	301
COMPLETED	161	192
NOT COMPLETED	121	109

Baseline Characteristics

Arm/Group Title	Zonisamide	Carbamazepine	Total
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP(the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	Total of all reporting groups
Overall Participants	281	300	581
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.1 (16.33)	35.6 (15.50)	36.4 (15.91)
Sex: Female, Male (Count of Participants)
Female	107 38.1%	128 42.7%	235 40.4%
Male	174 61.9%	172 57.3%	346 59.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Experienced Seizure Freedom for 26-weeks During the Maintenance Phase
Description	A subject achieved a 26-week seizure-free period if they were free of all seizures, regardless of seizure type, for 26 weeks while receiving the same dose. The occurrence of seizures was documented in the seizure diary, which was maintained by the subject and reviewed at each following visit.
Time Frame	Week 31 through Week 109

Outcome Measure Data

Analysis Population Description

Per Protocol Population: All randomized subjects who received at least one dose of study medication and who had no major protocol violations.

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP(the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	223	233
Number [Percentage of Participants]	79.4 28.3%	83.7 27.9%

2. Secondary Outcome

Title	Percentage of Participants Who Experienced Seizure Freedom for 12-months During the FDP and Maintenance Period
Description	A subject achieved a 12-month seizure-free period if they were free of all seizures, regardless of seizure type, for 12 months while receiving the same dose. The occurrence of seizures was documented in the seizure diary, which was maintained by the subject and reviewed at each following visit.
Time Frame	Week 5 through Week 109

Outcome Measure Data

Analysis Population Description

Per Protocol Population. N=number of subjects with evaluable data.

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP(the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	216	229
Number [Percentage of participants]	67.6 24.1%	74.7 24.9%

3. Secondary Outcome

Title	Analysis of Time to Drop Out Due to an Adverse Event (AE)
Description	An AE is defined as any untoward medical occurrence in a subject and does not necessarily have a causal relationship with the medicinal product. Adverse events were identified by: any unfavorable or unintended sign, symptom or disease temporarily associated with the use of a medicinal product; any new disease or exacerbation of an existing disease; any deterioration in nonprotocol-required measurements of laboratory values or other clinical test; and recurrence of an intermittent medical condition not present at Baseline.
Time Frame	Week 1 through Week 109

Outcome Measure Data

Analysis Population Description

Per Protocol Population

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	223	233
Median (Standard Error) [Median Days]	NA (NA)	NA (NA)

4. Secondary Outcome

Title	Analysis of Time to Drop Out Due to Lack of Efficacy
Description	Lack of efficacy was evaluated by the subject and on the basis of whether zonisamide and carbamazepine gave the subject at least a 26-week seizure free rate. The subject could withdraw at any time due to lack of efficacy.
Time Frame	Week 1 through Week 109

Outcome Measure Data

Analysis Population Description

Per Protocol Population

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	223	233
Median (Standard Error) [Median Days]	722 (NA)	NA (NA)

5. Secondary Outcome

Title	Time to 6-months Seizure Freedom
Description	A subject achieved a 6-months seizure-free period if they were free of all seizures, regardless of seizure type, for 6-months while receiving the same dose. The occurrence of seizures was documented in the seizure diary, which was maintained by the subject and reviewed at each following visit.
Time Frame	Week 5 through Week 83

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population - randomized subjects who received at least one dose of study medication.

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	281	300
Mean (Standard Deviation) [Days]	222.7 (49.78)	220.4 (46.31)

6. Secondary Outcome

Title	Time to 12-months Seizure Freedom
Description	A subject achieved a 12-month seizure-free period if they were free of all seizures, regardless of seizure type, for 12-months while receiving the same dose. The occurrence of seizures was documented in the seizure diary, which was maintained by the subject and reviewed at each following visit.
Time Frame	Week 5 through Week 83

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	281	300
Mean (Standard Deviation) [Days]	399.3 (55.03)	395.6 (42.19)

7. Secondary Outcome

Title	Change From Baseline in Total ABNAS Score at Maintenance Period Visit 1
Description	The Aldenkamp-Baker Neuropsychological Assessment Scale(ABNAS) is a subject based questionnaire to measure subjective perceived drug-related cognitive impairments. The ABNAS measured seven critical domains of cognition(tiredness/fatigue,hyperexcitability, slowing(mental and motor),memory impairment,attention disorders,impairment of motor coordination, and language disorders). The total score ranged from 0 to 72, with a higher score reflecting a high level of problems.
Time Frame	Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population: All randomized subjects who received at least one dose of study medication. This was measured using Observed Case (OC).

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	281	300
Mean (Standard Deviation) [Scores on a Scale]	1.6 (15.43)	-0.1 (12.71)

8. Secondary Outcome

Title	Change From Baseline in Bond and Lader VAS Mood Sub-Scores at Maintenance Period Visit 1
Description	The Bond-Lader Visual Analogue Scale (VAS) is made up of 16 pairs of alternative descriptors of mood and attention at either end of a 10 cm line. Subjects were asked to rate their feelings at the time of assessment by indicating the point on the line which best represent their mood. Each item was scored by measuring the position relative to the left hand end of the line and levels of anxiety, sedation, and dysphoria were then calculated from the combined scores of selected items. The scores ranged from 0 to 100, with a high score reflecting a high level of anxiety, sedation or dysphoria.
Time Frame	Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population. This was measured using Observed Case (OC).

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	281	300
Anxiety	-2.036 (23.6120)	-1.993 (26.1087)
Sedation	-0.475 (21.7476)	-1.362 (18.0103)
Dysphoria	-1.930 (21.7585)	-3.833 (19.7824)

9. Secondary Outcome

Title	Change From Baseline in QOLIE-31-P Overall Score at Maintenance Period Visit 1
Description	The Quality of Life in Epilepsy - Problems(QOLIE-31-P) was completed by the patient and contained 30 items covering seven subscales(seizure worry, overall Quality of Life (QOL),emotional well-being,energy-fatigue, cognition,medication effects and social function) and one item covering health status. It also included seven items addressing overall distress related to each subscale, an item addressing the relative importance of each subscale topic, and an item addressing perception of overall change in QOL at the end of the study. A high score reflects a good QOL. The following scale range is a sample of 1 of the 7 of the subscales: 10 (Best possible quality of life) - 0 (Worst possible quality of life); Rand Corporation QOLIE-31 Scoring Manual was used. The QOLIE-31 overall score is calculated by summing the product of each scale score times its weight and summing overall all scales.
Time Frame	Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population. This was measured using Observed Case (OC).

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	281	300
Mean (Standard Deviation) [Scores on a Scale]	4.474 (15.2838)	6.090 (13.2861)

10. Secondary Outcome

Title	Change From Baseline in SF-36 Aggregate Mental and Physical Component Score at Maintenance Period Visit 1
Description	The Short Form 36 Health and Well-Being Questionnaire (SF-36) is a 36-item generic health related QOL instrument covering the following domains: physical functioning, role-physical,bodily pain, general health, social functioning,role-emotional, mental health, and vitality. It yields a profile of eight scores, one for each domain, and physical and mental health summary measures. Each domain is described by a score ranging from 0 to 100, for a range of total possible scoes of 0-400 for physical and 0-400 for mental. An increase represents an improvement, whereas a decrease reflects a worsening.
Time Frame	Baseline and Maintenance Period Visit 1 (Week 31 to Week 83)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population. This was measured using Observed Case (OC).

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	281	300
Aggregate Mental Component Score	1.027 (10.9124)	2.495 (10.5310)
Aggregate Physical Component Score	1.895 (7.6287)	2.041 (6.2613)

11. Secondary Outcome

Title	Percentage of Participants With EQ-5D Scores at Maintenance Period Visit 1
Description	The European Quality of Life Group 5-Dimension Self-Report Questionnaire (EQ-5D) is a preference based generic health related quality of life (HRQoL) instrument which classifies health states across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain has three levels, they are (1) no problems, (2) some problems, (3) extreme problems. The percentages shown are calculated from the number of subjects at that visit with non-missing data for that score.
Time Frame	Week 31 through Week 83

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population. This was measured using Observed Case (OC). The percentages shown are calculated from the number of subjects at that visit with non-missing data for that score (n=174,196).

Arm/Group Title	Zonisamide	Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.	The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
Measure Participants	174	196
Mobility: No problems	90.8 32.3%	86.7 28.9%
Mobility: Some problems	8.7 3.1%	12.9 4.3%
Mobility: Confined to Bed	0.5 0.2%	0.5 0.2%
Self-Care:No problems	96.7 34.4%	97.6 32.5%
Self-Care: Some problems	2.7 1%	2.4 0.8%
Self-Care: Unable to wash or dress	0.5 0.2%	0.0 0%
Usual Activities: No problems	89.1 31.7%	84.8 28.3%
Usual Activities: Some problems	9.8 3.5%	15.2 5.1%
Usual Activities: Unable to perform	1.1 0.4%	0.0 0%
Pain/Discomfort: None	75.5 26.9%	73.2 24.4%
Pain/Discomfort: Moderate	22.3 7.9%	25.4 8.5%
Pain/Discomfort: Extreme	2.2 0.8%	1.4 0.5%
Anxiety/Depression: None	64.3 22.9%	62.9 21%
Anxiety/Depression: Moderate	31.3 11.1%	34.8 11.6%
Anxiety/Depression: Extreme	4.4 1.6%	2.4 0.8%

Adverse Events

Time Frame	A Treatment-Emergent Adverse Event (TEAE) is an Adverse Event (AE) with a start date on or after Day 1 and within 15 days of last dose, including AEs with missing start dates, for up to 116 weeks.
Adverse Event Reporting Description	For each AE category, a subject with two or more adverse events in that category is only counted once.
Arm/Group Title	Zonisamide		Carbamazepine
Arm/Group Description	The starting dose in this arm was zonisamide 100mg daily. The dose during the Titration Period (4 weeks) ranged from 100 to 200mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 300 to 500mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.		The starting dose in this arm was carbamazepine 200mg daily. The dose during the Titration Period (4 weeks) ranged from 200 to 400mg daily. During the Flexible Dosing Period (FDP), the subjects were given doses ranging from 600 to 1200mg daily or if they could not tolerate that dose, were allowed one down-titration or were withdrawn. If the subjects remained seizure-free for 26 weeks by the end of FDP (the subject was allowed 3 chances to achieve this), they entered the Maintenance Period (26 weeks), where they remained on the same dose they were taking at the end of the FDP.
All Cause Mortality
	Zonisamide		Carbamazepine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zonisamide		Carbamazepine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/281 (5.3%)		17/300 (5.7%)
Cardiac disorders
Bradycardia	0/281 (0%)		1/300 (0.3%)
Myocardial infarction	1/281 (0.4%)		0/300 (0%)
Ear and labyrinth disorders
Vertigo	1/281 (0.4%)		0/300 (0%)
Gastrointestinal disorders
Gastric ulcer	0/281 (0%)		1/300 (0.3%)
General disorders
Death	1/281 (0.4%)		0/300 (0%)
Pyrexia	1/281 (0.4%)		0/300 (0%)
Hepatobiliary disorders
Cholelithiasis	0/281 (0%)		1/300 (0.3%)
Infections and infestations
Appendicitis	1/281 (0.4%)		0/300 (0%)
Chronic sinusitis	0/281 (0%)		1/300 (0.3%)
Sinusitis bacterial	0/281 (0%)		1/300 (0.3%)
Typhoid fever	1/281 (0.4%)		0/300 (0%)
Injury, poisoning and procedural complications
Facial bones fracture	0/281 (0%)		2/300 (0.7%)
Femur fracture	0/281 (0%)		1/300 (0.3%)
Head injury	0/281 (0%)		1/300 (0.3%)
Humerus fracture	0/281 (0%)		1/300 (0.3%)
Joint dislocation	1/281 (0.4%)		0/300 (0%)
Muscle strain	0/281 (0%)		1/300 (0.3%)
Radius fracture	0/281 (0%)		1/300 (0.3%)
Skull fracture	0/281 (0%)		1/300 (0.3%)
Investigations
Hepatic enzyme increased	0/281 (0%)		1/300 (0.3%)
Metabolism and nutrition disorders
Hypokalemia	1/281 (0.4%)		0/300 (0%)
Musculoskeletal and connective tissue disorders
Bone pain	1/281 (0.4%)		0/300 (0%)
Musculoskeletal pain	0/281 (0%)		1/300 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm	1/281 (0.4%)		0/300 (0%)
Prostate cancer	0/281 (0%)		1/300 (0.3%)
Nervous system disorders
Partial seizures with secondary generalization	0/281 (0%)		4/300 (1.3%)
Complex partial seizures	1/281 (0.4%)		0/300 (0%)
Convulsion	1/281 (0.4%)		0/300 (0%)
Epilepsy	0/281 (0%)		1/300 (0.3%)
Ischemic stroke	0/281 (0%)		1/300 (0.3%)
Partial seizures	1/281 (0.4%)		0/300 (0%)
Subarachnoid hemorrahage	0/281 (0%)		1/300 (0.3%)
Psychiatric disorders
Acute psychosis	1/281 (0.4%)		0/300 (0%)
Suicidal ideation	0/281 (0%)		1/300 (0.3%)
Suicide attempt	0/281 (0%)		1/300 (0.3%)
Respiratory, thoracic and mediastinal disorders
Nasal septum deviation	0/281 (0%)		1/300 (0.3%)
Respiratory disorder	1/281 (0.4%)		0/300 (0%)
Rhinitis hypertrophic	0/281 (0%)		1/300 (0.3%)
Skin and subcutaneous tissue disorders
Rash	0/281 (0%)		2/300 (0.7%)
Purpura	1/281 (0.4%)		0/300 (0%)
Vascular disorders
Hypotension	0/281 (0%)		1/300 (0.3%)
Other (Not Including Serious) Adverse Events
	Zonisamide		Carbamazepine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/281 (25.6%)		69/300 (23%)
Investigations
weight decreased	19/281 (6.8%)		0/300 (0%)
Metabolism and nutrition disorders
decreased appetite	22/281 (7.8%)		5/300 (1.7%)
Nervous system disorders
headache	29/281 (10.3%)		37/300 (12.3%)
somnolence	17/281 (6%)		23/300 (7.7%)
dizziness	11/281 (3.9%)		23/300 (7.7%)

Limitations/Caveats

[Not Specified]

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.