Evaluating the Efficacy and Safety of Zonisamide in the Treatment of Partial Seizures

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00327717
• Collaborator: (none)
• Enrollment: 240
• Locations: 8
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 30
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

The objectives of this trial are to evaluate the safety and efficacy of Zonisamide as adjunctive therapy in medically refractory patients receiving other antiepileptic drugs (AEDs).

Condition or Disease	Intervention/Treatment	Phase
Partial Seizures	Drug: Zonisamide; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 240 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Placebo-controlled, Double-blind Study to Evaluate the Efficacy and Safety of Zonisamide in the Treatment of Partial Seizures
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zonisamide 100 mg tablet	Drug: Zonisamide; Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.; Other Names: Zonegran
Placebo Comparator: Placebo	Drug: Placebo; Patients in placebo group were titrated with placebo in the same way as in zonisamide group.

Outcome Measures

Primary Outcome Measures

1. Median Percent Change From Baseline in All Partial Seizure Frequency (Complex Partial Seizures (CP)+ Simple Partial Seizures (SP) + Secondary Generalization Seizures (SGS)) During the Fixed-dose Phase [Baseline and 16 weeks]

   The median percent change in seizure frequency of all partial seizures (CP+SP+SGS) from baseline during the fixed-dose phase.

Secondary Outcome Measures

1. The Mean Percent Change From Baseline in Complex Partial (CP) Seizure Frequency [Baseline and 16 weeks]

   The Mean Percent Change in seizure frequency of CP from baseline during the fixed-dose phase.

2. The Mean Percent Change From Baseline in Simple Partial (SP) Seizure Frequency [Baseline and 16 weeks]

   The Mean percent change in seizure frequency of SP from baseline during the fixed-dose phase.

3. The Mean Percent Change From Baseline in Partial Seizures With Secondary Generalization (SGS) [Baseline and 16 weeks]

   The mean percent change in seizure frequency of SGS from baseline during the fixed-dose phase.

4. Responder Rate [Baseline and 16 weeks]

   Responder rate is defined as percentage of participants with >=50% reduction in seizure frequency from baseline.

5. Mean Number of Seizure Free Days [12 weeks]

   Mean number of seizure free days per 28 day period during fixed dose phase

6. Mean Percentage of Change in Seizure Free Days [16 weeks]

7. Mean Time to First Seizure (Days) [16 weeks]

   Mean time to first seizure during fixed dose phase

8. Percentage of Seizure-free Participants During Fixed-dose Phase [16 weeks]

   Percentage of seizure-free participants during fixed-dose phase

9. Drop - Out Rate [16 weeks]

   Number of Participants who dropped out of the study. In the Study drop-out rate is defined as number of participants.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

According to the International League Against Epilepsy (ILAE) classification of seizure type (1981) and international classification of epilepsies and epileptic syndromes (ILAE, 1989), definite diagnosis of partial seizures (with or without secondary generalized seizures) refractory to current anti epilepsy drug (AED) therapy.

Inclusion criteria:

1. Adult male or female, 16 to 70 years old;

2. Classified according to the ILAE classification of seizure type (1981) and international classification of epilepsy and epileptic syndromes (ILAE, 1989) into partial seizures (with or without secondary generalized seizures);

3. Based on the retrospective subject diary, at least 4 partial seizures per month ( 4 weeks ) within 12 weeks prior to entry;

4. No more than 8 secondary generalized tonic, clonic, or tonic-clonic seizures per month within 12 weeks prior to entry;

5. Antiepileptic therapy including at least 1-2 concomitant AEDs and were on a stable dose(s) of the same AEDs for the 3 months prior to enrollment;

6. Had performed electro encephalogram (EEG) within 6 months prior to entry, and computer tomography (CT) or magnetic resonance imaging (MRI) examination to mainly exclude space-occupying disease;

7. Was able to count seizure frequencies;

8. Women with child bearing potential, were not to be pregnant or nursing, and must have agreed to practice during the study a reliable form of contraception (oral contraceptive, condom, intrauterine device or diaphragm).

9. Signed written informed consent and agreed to comply with the protocol.

Exclusion criteria:

1. History or evidence of a progressive central nervous system (CNS) disease;

2. Nonepileptic seizures and pseudoepileptic seizures;

3. Severe mental retardation or unstable psychical status;

4. Clinically significant cardiac, hepatic, renal, or hematological disease, uncontrolled hypertension (systolic blood pressure (SBP) ≥150 and/or diastolic blood pressure (DBP) ≥100mmHg), Symptomatic ischemic heart disease, cerebral infarction or atherosclerosis obliterans;

5. History of malignant neoplastic disease;

6. Any condition that might interfere the pharmacokinetics (absorption, distribution, and/or excretion) of drugs, such as liver or kidney dysfunction, hypoproteinemia;

7. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or history of hemolytic anemia or acute intermittent porphyria.

8. History of kidney stone;

9. History of alcohol or drug abuse within 2 years;

10. Sensitivity to sulfonamide medications or history of severe drug allergy;

11. Administration of monoamine oxidase inhibitor (MAOI), antidepressants or antipsychotic a psycho-tropic within 14 days prior to entry;

12. History of status epileptics in the past years or seizure clusters where individual seizures cannot be counted ;

13. History of zonisamide administration;

14. History of acetazolamide administration to treat epilepsy within 2 months prior to entry;

15. Joined the clinical trial of other AEDs within 30 days prior to entry;

16. Pregnant women or women in lactation;

17. Abnormal clinical laboratory values with clinical significance judged by investigators (for example, if abnormal hepatic function is caused by concurrent other AEDs, the abnormal value within 2 times of normal could be acceptable);

18. Inability of subject to return for scheduled visits or to comply with any other aspect of the protocol.

19. Subjects who, in the opinion of the investigator, were poor medical candidates or pose any other risk for therapy with an investigational drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Peking University First Hospital	Beijing	Beijing	China	100034
2	Peking Union Hospital	Beijing	Beijing	China	100053
3	Peking Union Medical College Hospital	Beijing	Beijing	China	100730
4	The First Affiliated Hospital of Chongqing Medical University	Chongqing	Chongqing	China	400016
5	Shanghai Changzheng Hospital	Shanghai	Shanghai	China	200003
6	Shanghai Hua-shan Hospital	Shanghai	Shanghai	China	200040
7	XiÆan Xijing Hospital	XiÆan	Shanxi	China	710032
8	Chengdu Huaxi Hospital	Chengdu	Sichuan	China	610041

Sponsors and Collaborators

• Eisai Inc.

Investigators

• Study Director: Di Hong, Eisai China Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT00327717
• Other Study ID Numbers: E2090-AS086-311
• First Posted: May 18, 2006
• Last Update Posted: Aug 15, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by Eisai Inc.: Epilepsy; Partial seizures
• Additional relevant MeSH terms: Seizures; Zonisamide

Study Results

Participant Flow

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Period Title: Overall Study
STARTED	120	120
COMPLETED	111	106
NOT COMPLETED	9	14

Baseline Characteristics

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo	Total
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.	Total of all reporting groups
Overall Participants	111	106	217
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.72 (12.18)	30.69 (11.59)	31.73 (11.89)
Sex: Female, Male (Count of Participants)
Female	54 48.6%	43 40.6%	97 44.7%
Male	57 51.4%	63 59.4%	120 55.3%
Race/Ethnicity, Customized (participants) [Number]
Asian	120 108.1%	97 91.5%	217 100%
Region of Enrollment (participants) [Number]
China	111 100%	106 100%	217 100%

Outcome Measures

1. Primary Outcome

Title	Median Percent Change From Baseline in All Partial Seizure Frequency (Complex Partial Seizures (CP)+ Simple Partial Seizures (SP) + Secondary Generalization Seizures (SGS)) During the Fixed-dose Phase
Description	The median percent change in seizure frequency of all partial seizures (CP+SP+SGS) from baseline during the fixed-dose phase.
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS)

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	111	106
Median (Full Range) [Percent Change]	-48.42 (73.83)	-26.58 (157.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	The Mean Percent Change From Baseline in Complex Partial (CP) Seizure Frequency
Description	The Mean Percent Change in seizure frequency of CP from baseline during the fixed-dose phase.
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

FAS population. Complex partial seizure patients

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	69	69
Mean (Standard Deviation) [Percent Change]	-31.65 (87.28)	-25.21 (68.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.253
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	The Mean Percent Change From Baseline in Simple Partial (SP) Seizure Frequency
Description	The Mean percent change in seizure frequency of SP from baseline during the fixed-dose phase.
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

FAS Population. Simple partial seizure patients

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	29	25
Mean (Standard Deviation) [Percent Change]	-49.14 (62.06)	56.03 (318.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.211
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	The Mean Percent Change From Baseline in Partial Seizures With Secondary Generalization (SGS)
Description	The mean percent change in seizure frequency of SGS from baseline during the fixed-dose phase.
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

FAS Population. Secondary generalization patients

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	36	42
Mean (Standard Deviation) [Percent Change]	-53.2 (54.81)	-4.08 (178.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.516
	Comments
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Responder Rate
Description	Responder rate is defined as percentage of participants with >=50% reduction in seizure frequency from baseline.
Time Frame	Baseline and 16 weeks

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	111	106
Number [Percentage of Participants]	48.6 43.8%	34.9 32.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments
	Method	X^2 test
	Comments

6. Secondary Outcome

Title	Mean Number of Seizure Free Days
Description	Mean number of seizure free days per 28 day period during fixed dose phase
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	111	106
Mean (Standard Deviation) [Days]	22.31 (6.14)	21.43 (7.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.090
	Comments
	Method	X^2 test
	Comments

7. Secondary Outcome

Title	Mean Percentage of Change in Seizure Free Days
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	111	106
Mean (Standard Deviation) [Percent Change]	79.69 (21.93)	76.52 (25.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.090
	Comments
	Method	X^2 test
	Comments

8. Secondary Outcome

Title	Mean Time to First Seizure (Days)
Description	Mean time to first seizure during fixed dose phase
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	111	106
Mean (Standard Deviation) [Days]	22.31 (6.14)	21.43 (7.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.162
	Comments
	Method	X^2 test
	Comments

9. Secondary Outcome

Title	Percentage of Seizure-free Participants During Fixed-dose Phase
Description	Percentage of seizure-free participants during fixed-dose phase
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	111	106
Number [Percentage of Participants]	1.8 1.6%	2.8 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zonisamide 100 mg Tablet, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.678
	Comments
	Method	X^2 test
	Comments

10. Secondary Outcome

Title	Drop - Out Rate
Description	Number of Participants who dropped out of the study. In the Study drop-out rate is defined as number of participants.
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Zonisamide 100 mg Tablet	Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.	Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Measure Participants	111	106
Number [Number of Participants]	4 3.6%	6 5.7%

Adverse Events

Adverse Event Reporting Description	Placebo group has 2 fewer subjects - consent withdrawn 1 and lost to follow up 1.
Arm/Group Title	Zonisamide 100 mg Tablet		Placebo
Arm/Group Description	Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.		Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
All Cause Mortality
	Zonisamide 100 mg Tablet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zonisamide 100 mg Tablet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/120 (0%)		0/118 (0%)
Other (Not Including Serious) Adverse Events
	Zonisamide 100 mg Tablet		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	95/120 (79.2%)		75/118 (63.6%)
Gastrointestinal disorders
nausea	13/120 (10.8%)	14	7/118 (5.9%)	7
Abdominal distention	6/120 (5%)	6	1/118 (0.8%)	1
Investigations
White blood cell count decreased	10/120 (8.3%)	10	4/118 (3.4%)	4
Platelet count decreased	7/120 (5.8%)	7	4/118 (3.4%)	4
Weight decreased	6/120 (5%)	6	4/118 (3.4%)	4
Metabolism and nutrition disorders
anorexia	22/120 (18.3%)	22	6/118 (5.1%)	7
Nervous system disorders
Headache	13/120 (10.8%)	16	6/118 (5.1%)	8
Dizziness	12/120 (10%)	15	13/118 (11%)	16
Memory impairment	8/120 (6.7%)	8	1/118 (0.8%)	1
Psychiatric disorders
somnolence	15/120 (12.5%)	18	17/118 (14.4%)	18
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	13/120 (10.8%)	17	17/118 (14.4%)	22

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.