Partial Seizures
Conditions
Brief summary
The purpose of this study is to assess the long-term safety and efficacy of zonisamide used as an adjunctive treatment in pediatric subjects treated with 1 or 2 other anti-epileptic drugs (AEDs).
Detailed description
Those subjects who completed the double-blind study (E2090-E044-312) will be invited to participate in this extension study. The study consists of two main parts: Transition Period (double-blind) and Open Label Period. The study will start with the Transition Period during which subjects already on zonisamide will continue on the same dose of zonisamide and those who were taking placebo will be up-titrated to an appropriate dose of zonisamide. After all subjects have completed the Transition Period, the study will become open-label with every subject on the study receiving zonisamide. The study medication will be taken once daily in the evening. For those subjects previously in the placebo group, dosing with zonisamide will start with a dose of approximately 1 mg/kg. In order that the blind is maintained from the previous study, these subjects will initially continue taking the same number of placebo capsules as they were taking in the Maintenance Period of the E2090-E044-312 study until the up- titration is completed. Those subjects previously in the zonisamide arm will continue on the same dose which they received during the Maintenance Period of the E2090-E044-312 study. In order that the blind is maintained, they will also take placebo capsules in order to mirror the up- titration dose regimen of the subjects previously randomized to receive placebo in the E2090-E044-312 study. All subjects will stop taking placebo capsules after the Transition Period is complete. The duration of the Transition Period depends on the dose the subject appeared to have received when completing the core study E2090-E044-312. For those who completed on 8 mg/kg, the Transition Period will last 7 weeks. For those on 6 mg/kg, the Transition Period will last 5 weeks. However, during the double-blind Transition Period, some subjects may experience adverse events (AEs). If this should occur, the subject may be down titrated to one level above the minimal dose. The overall duration of the study will be up to 59 weeks. The overall duration of the Transition Period may thus be as short as 2 weeks or prolonged to as many as 11 weeks. The Open Label Period will continue for up to a maximum of 59 weeks (approximately 15 months). At the end of the study, Eisai will continue to supply zonisamide as part of this open-label extension protocol until the marketing authorisation of zonisamide for this indication or further development in this indication is stopped. In countries where no marketing authorisation will be applied for, Eisai has a compassionate use policy which can be applied for, if required.
Interventions
DRUGZonisamide
Transition Period from Study E2090-E044-312: Placebo Open-Label Period: 1 to 8 mg/kg orally per day for approximately 59 weeks.
Sponsors
Eisai Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Subject has completed the double-blind study E2090-E044-312. 2. Parent/caregiver is willing to sign an informed consent where the subject is under the age of consent. 3. Subject is male or female aged 6 to 18 years who is willing to give informed (written or verbal) assent, if applicable. If mandated by local regulations, subjects of relevant age will be required to sign an appropriate informed consent. 4. Subject is in general good health as determined by medical history, physical exam and screening laboratory results.
Exclusion criteria
1. Subject has a body weight \< 20 kg. 2. Subject has developed a history of renal calculi or renal insufficiency (creatinine level \> 135 µmol/l (1.5 mg/dl). 3. Subject has a known diagnosis of human immunodeficiency virus (HIV) or hepatitis B or C. 4. Subject has a history of sensitivity to sulfonamide drugs or zonisamide and its excipients. 5. Female subject of 10 years of age or greater, or of child bearing potential (i.e. started menses) and is not taking or prepared to take a medically acceptable form of contraception (i.e. oral contraceptive pill, surgical sterilization, an implant or injected form of contraception, or intrauterine device), or who is not prepared to abstain from sexual activity for the duration of the study and for one month after the last administration of study medication. NOTE: Should a female subject become of child bearing potential during the study, they must be reconsented in order to given consent to undergo pregnancy testing and either confirm abstinence or receive a medically appropriate form of contraception. 6. Subject has a recent history of excessive alcohol use or drug abuse. 7. Subject has a history of suicide attempt. 8. Subject has a clinically significant organic disease. 9. Subject has a history of demonstrated non-compliance with treatment or subject or parent/legal guardian can be reasonably expected not to be compliant with study procedures or to complete the study. 10. Frequent need of rescue benzodiazepines (one or more times a month). 11. Concomitant use of acetazolamide, carbonic anhydrase inhibitors such as topiramate, furosemide and drugs with anticholinergic activity. 12. Concomitant use of felbamate or use of felbamate within 2 months prior to Visit 1 of the E2090-E044-312 study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Week 1 through Week 59 | Treatment Emergent Adverse Event (TEAE) is defined as an Adverse Event with a start date on or after Day 1 and within 15 days of last dose. For each event, each participant experiencing an event is only counted once even if they had multiple episodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Decrease From Baseline in 28-day Seizure Frequency of =50%(Responder) in the Open Label Period | Baseline through Week 59 | A participant with a decrease from baseline in seizure frequency of =50 % was considered a responder. Participants'parent or guardian maintained a seizure diary recording the date,number, and type of seizures the subject had. The primary analysis assessed the percent of responders from baseline in the Open Label Visit Period. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed. |
| Median Change From Study 312 Baseline in the 28-day Seizure Frequency During the Open Label Period | Baseline of study 312 (Week -8 to Week 0) to Week 59 of study 313 | Participants' parent or guardian maintained a seizure diary recording the date, number, and type of seizures the subject had. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed from baseline of study 312 through the Open Label Visit Period. |
| Median Percent Change From Study 312 Baseline in the 28-day Seizure Frequency During the Open Label Period | Baseline of study 312 (Week -8 to Week 0) to Week 59 of study 313 | Participants' parent or guardian maintained a seizure diary recording the date, number, and type of seizures the subject had. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed from baseline of study 312 through the Open Label Visit Period. Percentage change = 100% x (seizure frequency at period - seizure frequency at Study 312 baseline)/seizure frequency at Study 312 baseline. |
Countries
Italy
Participant flow
Recruitment details
Subjects who completed E2090-E044-312 (NCT00566254)Study 312 core study were invited to participate in this extension study.
Participants by arm
| Arm | Count |
|---|---|
| Zonisamide(Placebo During Core Study) Participants previously receiving placebo in Study 312, started dosing with zonisamide with a dose of 1 mg/kg/day and titrated upwards with weekly dose increases until a dose of 8 mg/kg/day was reached at the end of the Transition Period (weeks 2 -11). Downtitration was allowed between the limits of 1 to 8 mg/kg/day during Transition Period. Subsequently, a 45-57 week Open-label period followed. Placebo dosing ceased in Open-label Period. | 72 |
| Zonisamide (Zonisamide During Core Study) Participants previously receiving zonisamide in Study 312 continued taking the same dose of study drug (8 mg/kg/day),supplemented with an increasing number of placebo capsules to mirror the up-titration regimen being followed by those previously receiving placebo.Down-titration was allowed between the limits of 1 to 8 mg/kg/day during Transition Period.Subsequently, a 45-57 week Open-label period followed. | 72 |
| Total | 144 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Lack of Efficacy | 14 | 13 |
| Overall Study | Other | 1 | 3 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 2 |
Baseline characteristics
| Characteristic | Zonisamide(Placebo During Core Study) | Zonisamide (Zonisamide During Core Study) | Total |
|---|---|---|---|
| Age, Customized 12-18 Years | 38 Participants | 39 Participants | 77 Participants |
| Age, Customized 6-11 Years | 34 Participants | 33 Participants | 67 Participants |
| Sex: Female, Male Female | 32 Participants | 41 Participants | 73 Participants |
| Sex: Female, Male Male | 40 Participants | 31 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 18 / 72 | 25 / 72 |
| serious Total, serious adverse events | 3 / 72 | 7 / 72 |
Outcome results
Primary
Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency
Treatment Emergent Adverse Event (TEAE) is defined as an Adverse Event with a start date on or after Day 1 and within 15 days of last dose. For each event, each participant experiencing an event is only counted once even if they had multiple episodes.
Time frame: Week 1 through Week 59
Population: Safety Population (all subjects who entered the study and received at least one dose of study drug)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zonisamide (Placebo During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Respiratory tract infection | 2 Participants |
| Zonisamide (Placebo During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Headache | 4 Participants |
| Zonisamide (Placebo During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Weight decreased | 6 Participants |
| Zonisamide (Placebo During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Abdominal pain | 1 Participants |
| Zonisamide (Placebo During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Decreased Appetite | 5 Participants |
| Zonisamide (Placebo During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Bronchitis | 4 Participants |
| Zonisamide (Placebo During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Nasopharyngitis | 6 Participants |
| Zonisamide (Zonisamide During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Decreased Appetite | 4 Participants |
| Zonisamide (Zonisamide During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Nasopharyngitis | 9 Participants |
| Zonisamide (Zonisamide During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Respiratory tract infection | 4 Participants |
| Zonisamide (Zonisamide During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Abdominal pain | 4 Participants |
| Zonisamide (Zonisamide During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Headache | 7 Participants |
| Zonisamide (Zonisamide During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Bronchitis | 3 Participants |
| Zonisamide (Zonisamide During Core Study) | Treatment Emergent Non-Serious Adverse Events With Greater Than 5% Frequency | Weight decreased | 6 Participants |
Secondary
Median Change From Study 312 Baseline in the 28-day Seizure Frequency During the Open Label Period
Participants' parent or guardian maintained a seizure diary recording the date, number, and type of seizures the subject had. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed from baseline of study 312 through the Open Label Visit Period.
Time frame: Baseline of study 312 (Week -8 to Week 0) to Week 59 of study 313
Population: Safety Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zonisamide (Placebo During Core Study) | Median Change From Study 312 Baseline in the 28-day Seizure Frequency During the Open Label Period | -3.8 Seizures |
| Zonisamide (Zonisamide During Core Study) | Median Change From Study 312 Baseline in the 28-day Seizure Frequency During the Open Label Period | -4.7 Seizures |
Secondary
Median Percent Change From Study 312 Baseline in the 28-day Seizure Frequency During the Open Label Period
Participants' parent or guardian maintained a seizure diary recording the date, number, and type of seizures the subject had. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed from baseline of study 312 through the Open Label Visit Period. Percentage change = 100% x (seizure frequency at period - seizure frequency at Study 312 baseline)/seizure frequency at Study 312 baseline.
Time frame: Baseline of study 312 (Week -8 to Week 0) to Week 59 of study 313
Population: Safety Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zonisamide (Placebo During Core Study) | Median Percent Change From Study 312 Baseline in the 28-day Seizure Frequency During the Open Label Period | -64.6 Percentage Change |
| Zonisamide (Zonisamide During Core Study) | Median Percent Change From Study 312 Baseline in the 28-day Seizure Frequency During the Open Label Period | -67.9 Percentage Change |
Secondary
Percentage of Participants With a Decrease From Baseline in 28-day Seizure Frequency of =50%(Responder) in the Open Label Period
A participant with a decrease from baseline in seizure frequency of =50 % was considered a responder. Participants'parent or guardian maintained a seizure diary recording the date,number, and type of seizures the subject had. The primary analysis assessed the percent of responders from baseline in the Open Label Visit Period. Seizure frequency of simple partial, complex partial, and partial seizures with secondary generalization were assessed.
Time frame: Baseline through Week 59
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zonisamide (Placebo During Core Study) | Percentage of Participants With a Decrease From Baseline in 28-day Seizure Frequency of =50%(Responder) in the Open Label Period | 55.6 Percentage of Participants |
| Zonisamide (Zonisamide During Core Study) | Percentage of Participants With a Decrease From Baseline in 28-day Seizure Frequency of =50%(Responder) in the Open Label Period | 56.9 Percentage of Participants |