Trial Outcomes & Findings for Assessing The Long-Term Safety And To Explore The Long-Term Efficacy Of Zonisamide As Monotherapy In Newly Diagnosed Partial Seizures (NCT NCT00848549)

Last Updated: 2015-12-24

Results Overview

The retention rate is defined as the percentage of subjects remaining on the study at each visit, starting from the first dose of study drug in the extension phase.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

295 participants

Primary outcome timeframe

At 3, 6, 9, 12, 15, 18, 21, 24, and 27 months

Results posted on

2015-12-24

Participant Flow

E2090-E044-314 is a double-blind extension of E2090-E044-310 (NCT00477295) "base study." Assessment of eligibility took place at the Study Entry Visit (SEV), which was the same day as their final visit of Study 310. Subjects remained on the same investigational product as they were randomized to in Study 310 until unblinding of that study.

Participant milestones

Participant milestones
Measure	Zonisamide Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.
E2090-E044-310 (Base Study) Disposition STARTED	282	301
E2090-E044-310 (Base Study) Disposition COMPLETED	161	192
E2090-E044-310 (Base Study) Disposition NOT COMPLETED	121	109
E2090-E044-310 (Base Study) Transition STARTED	161	192
E2090-E044-310 (Base Study) Transition COMPLETED	137	158
E2090-E044-310 (Base Study) Transition NOT COMPLETED	24	34
E2090-E044-314 (Extension Study) STARTED	137	158
E2090-E044-314 (Extension Study) COMPLETED	120	134
E2090-E044-314 (Extension Study) NOT COMPLETED	17	24

Reasons for withdrawal

Reasons for withdrawal
Measure	Zonisamide Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.
E2090-E044-310 (Base Study) Disposition Adverse Event	31	35
E2090-E044-310 (Base Study) Disposition Withdrawal by Subject	35	24
E2090-E044-310 (Base Study) Disposition Lack of Efficacy	23	23
E2090-E044-310 (Base Study) Disposition Protocol Violation	3	8
E2090-E044-310 (Base Study) Disposition Physician Decision	4	5
E2090-E044-310 (Base Study) Disposition Lost to Follow-up	21	11
E2090-E044-310 (Base Study) Disposition Other	4	3
E2090-E044-310 (Base Study) Transition Chose not to enter 314 Extension study	24	34
E2090-E044-314 (Extension Study) Adverse Event	2	1
E2090-E044-314 (Extension Study) Protocol Violation	1	2
E2090-E044-314 (Extension Study) Withdrawal by Subject	8	12
E2090-E044-314 (Extension Study) Lack of Efficacy	1	1
E2090-E044-314 (Extension Study) Physician Decision	0	2
E2090-E044-314 (Extension Study) Other	5	6

Baseline Characteristics

Assessing The Long-Term Safety And To Explore The Long-Term Efficacy Of Zonisamide As Monotherapy In Newly Diagnosed Partial Seizures

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zonisamide n=282 Participants Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine n=301 Participants Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Total n=583 Participants Total of all reporting groups
Age, Continuous Base Study 310 (NCT00477295, n=583)	37.1 years STANDARD_DEVIATION 16.33 • n=5 Participants	35.6 years STANDARD_DEVIATION 15.50 • n=7 Participants	36.35 years STANDARD_DEVIATION 15.92 • n=5 Participants
Age, Continuous Extension Study 314 (NCT00848549, n=295)	37.8 years STANDARD_DEVIATION 16.13 • n=5 Participants	34.4 years STANDARD_DEVIATION 14.93 • n=7 Participants	36.1 years STANDARD_DEVIATION 15.53 • n=5 Participants
Sex/Gender, Customized Female (Base Study 310, NCT00477295)	107 participants n=5 Participants	128 participants n=7 Participants	235 participants n=5 Participants
Sex/Gender, Customized Male (Base Study 310, NCT00477295)	174 participants n=5 Participants	172 participants n=7 Participants	346 participants n=5 Participants
Sex/Gender, Customized Female (Extension Study 314, NCT00848549)	57 participants n=5 Participants	59 participants n=7 Participants	116 participants n=5 Participants
Sex/Gender, Customized Male (Extension Study 314, NCT00848549)	80 participants n=5 Participants	99 participants n=7 Participants	179 participants n=5 Participants

PRIMARY outcome

Timeframe: At 3, 6, 9, 12, 15, 18, 21, 24, and 27 months

Population: The Intent-to-Treat (ITT) Population is defined as all subjects who received at least one dose of investigational product(IP)

The retention rate is defined as the percentage of subjects remaining on the study at each visit, starting from the first dose of study drug in the extension phase.

Outcome measures

Outcome measures
Measure	Zonisamide n=137 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine n=158 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.
Percentage of Participants Remaining in the Study at Each Visit 3 months	95.6 Percentage of Participants Interval 92.2 to 99.1	93.7 Percentage of Participants Interval 89.8 to 97.5
Percentage of Participants Remaining in the Study at Each Visit 6 months	87.6 Percentage of Participants Interval 82.0 to 93.2	84.2 Percentage of Participants Interval 78.4 to 89.9
Percentage of Participants Remaining in the Study at Each Visit 9 months	76.6 Percentage of Participants Interval 69.5 to 83.8	75.3 Percentage of Participants Interval 68.5 to 82.1
Percentage of Participants Remaining in the Study at Each Visit 12 months	58.4 Percentage of Participants Interval 50.1 to 66.7	61.4 Percentage of Participants Interval 53.7 to 69.0
Percentage of Participants Remaining in the Study at Each Visit 15 months	38.7 Percentage of Participants Interval 30.5 to 46.9	43.7 Percentage of Participants Interval 35.9 to 51.5
Percentage of Participants Remaining in the Study at Each Visit 18 months	27.7 Percentage of Participants Interval 20.2 to 35.3	27.8 Percentage of Participants Interval 20.8 to 34.9
Percentage of Participants Remaining in the Study at Each Visit 21 months	13.1 Percentage of Participants Interval 7.4 to 18.8	12.7 Percentage of Participants Interval 7.4 to 17.9
Percentage of Participants Remaining in the Study at Each Visit 24 months	5.8 Percentage of Participants Interval 1.9 to 9.8	2.5 Percentage of Participants Interval 0.1 to 5.0
Percentage of Participants Remaining in the Study at Each Visit 27 months	1.5 Percentage of Participants Interval 0.0 to 3.5	0.6 Percentage of Participants Interval 0.0 to 1.9

SECONDARY outcome

Timeframe: Week 1 to Week 109 (in core study) and Month 1 to Month 27 (in extension study)

Population: 310 ITT Population (combined ITT Population from basecore study and extension phase). 24 participants were discontinued in each arm due to lack of efficacy; these were the participants that were evaluated in this outcome.

Lack of efficacy was if the subject had poor seizure control (defined as experiencing a seizure despite being on the maximum dose for = 2 weeks). The subject could withdraw at any time due to lack of efficacy.

Outcome measures

Outcome measures
Measure	Zonisamide n=24 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine n=24 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.
Time to Drop-out Due to Lack of Efficacy	297.9 Days Standard Deviation 170.03	289.0 Days Standard Deviation 108.93

SECONDARY outcome

Timeframe: Week 1 to Week 109 (in base study) and Month 1 to Month 27 (in extension study)

Population: 310 ITT Population (33 participants were discontinued in the Zonisamide arm and 35 were discontinued in the Carbamazepine arm; these were the participants evaluated for this outcome)

Adverse events in study subjects included any change in the subject's condition. This includes symptoms, physical findings, or clinical syndromes. All AEs that occurred after signing of informed consent through the last visit and for 15 days following study drug discontinuation were captured on the AE Case Report Form (CRF).

Outcome measures

Outcome measures
Measure	Zonisamide n=33 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine n=35 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.
Time to Drop-out Due to Adverse Event (AE)	131.9 Days Standard Deviation 166.90	97.2 Days Standard Deviation 114.47

SECONDARY outcome

Timeframe: Week 5 to Week 109 (in base study) and Month 1 to Month 27 (in extension phase)

Population: 310 ITT Population

The number of participants that have remained seizure free for at least a 24 month consecutive period from the start of the Flexible Dosing Period (FDP: the period following the Titration Period and leading into the Maintenance Period) in the base study through the treatment period of this study. Seizure freedom was defined as the absence of all seizure regardless of seizure type.

Outcome measures

Outcome measures
Measure	Zonisamide n=281 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine n=300 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.
Percentage of Participants That Are Seizure Free for at Least 24 Month Consecutive Period in the Base Study and Extension Phase	32.3 Percentage of Participants Interval 26.5 to 38.0	35.2 Percentage of Participants Interval 29.5 to 40.9

SECONDARY outcome

Timeframe: Weeks 0, 26, 52, 78 and 117

Population: ITT Population

The QOLIE-31-P is a 31-item questionnaire evaluating a participant's QOL perception in 7 domains: seizure worry,emotional well being,energy/fatigue, cognitive functioning, medication effects, social functioning,overall QOL. The overall score is derived by weighing and then summing the 7 domain scores. Precoded numeric values for some domains are such that a higher number reflects a more favorable health state; others are such that a higher number reflects a less favorable state. Precoded values are converted to 0-100 point scores; higher converted scores always reflect better QOL.

Outcome measures

Outcome measures
Measure	Zonisamide n=137 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine n=158 Participants Subjects received the same study drug to which they had been randomized in the base study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.
Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit Week 0	4.697 Score on a scale Standard Deviation 16.254	7.101 Score on a scale Standard Deviation 13.781
Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit Week 26	6.101 Score on a scale Standard Deviation 16.566	10.956 Score on a scale Standard Deviation 14.940
Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit Week 52	8.602 Score on a scale Standard Deviation 14.326	11.687 Score on a scale Standard Deviation 13.653
Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit Week 78	4.287 Score on a scale Standard Deviation 15.566	1.902 Score on a scale Standard Deviation 13.495
Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit Week 117	-0.292 Score on a scale Standard Deviation 17.332	15.849 Score on a scale Standard Deviation 12.302

Adverse Events

Zonisamide (Extension Study 314, NCT00848549)

Serious events: 7 serious events

Other events: 12 other events

Deaths: 0 deaths

Carbamazepine (Extension Study 314, NCT00848549)

Serious events: 7 serious events

Other events: 10 other events

Deaths: 0 deaths

Zonisamide (Base Study 310, NCT00477295)

Serious events: 15 serious events

Other events: 72 other events

Deaths: 0 deaths

Carbamazepine (Base Study 310, NCT00477295)

Serious events: 17 serious events

Other events: 69 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Zonisamide (Extension Study 314, NCT00848549) n=137 participants at risk Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Carbamazepine (Extension Study 314, NCT00848549) n=158 participants at risk Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range.	Zonisamide (Base Study 310, NCT00477295) n=281 participants at risk 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.	Carbamazepine (Base Study 310, NCT00477295) n=300 participants at risk 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.
Investigations Weight Decreased	5.8% 8/137 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	0.00% 0/158 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	6.8% 19/281 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	0.00% 0/300 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.
Nervous system disorders Headache	4.4% 6/137 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	6.3% 10/158 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	10.3% 29/281 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	12.3% 37/300 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.
Nervous system disorders Somnolence	0.00% 0/137 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	0.00% 0/158 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	6.0% 17/281 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	7.7% 23/300 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.
Nervous system disorders Dizziness	0.00% 0/137 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	0.00% 0/158 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	3.9% 11/281 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	7.7% 23/300 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/137 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	0.00% 0/158 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	7.8% 22/281 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.	1.7% 5/300 • From the time the subject signed the informed consent form through the Final Visit/Early Termination Visit and for 15 days following study drug discontinuation. Adverse events were assessed at clinical visits based on the subject's diary, vitals, weight, physical examination, neurological exam, and laboratory evaluations.

Additional Information

Eisai Inc.

Eisai Call Center

Phone: 888-422-4743

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place