Epilepsy, Partial Seizures
Conditions
Keywords
Keppra, Levetiracetam, Children, Epilepsy, Partial Seizures
Brief summary
Objective of the First Period: To evaluate the efficacy of Levetiracetam dry syrup at doses up to a maximum of 60 mg/kg/day or 3000 mg/day used as an adjunctive therapy in Japanese pediatric patients (4 to 16 years) with uncontrolled partial seizures despite treatment with 1 or 2 anti-epileptic drug(s).
Detailed description
Objectives of the Second Period: To provide the Levetiracetam treatment to subjects who are judged by the investigators to benefit from the long-term treatment and who are willing to continuously receive this drug. To continuously evaluate the safety of the Levetiracetam long-term administration at doses ranging from 20 mg/kg/day or 1000 mg/day to 60 mg/kg/day or 3000 mg/day in subjects who completed the First Period of this study.
Interventions
DRUGLevetiracetam
First Period: Dry syrup 50 %, 20 mg/kg/day or 1000 mg/day, 40 mg/kg/day or 2000 mg/day, 60 mg/kg/day or 3000 mg/day, twice daily administration Per Os (PO) for 14 weeks. Second Period: Dry syrup 50 % or tablets (250 mg and 500 mg strengths), 20 to 60 mg/kg/day or 1000 to 3000 mg/day, twice daily administration Per Os (PO) until indication granted.
Sponsors
UCB Japan Co. Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* The patient has partial Epilepsy and the diagnosis must be confirmed in the last 6 months * The patients must be on a stable 1 or 2 anti-epileptic drug(s) treatment during the 4 weeks prior to Baseline and must have at least 8 partial seizures during the 8-week prospective Baseline Period * Patient at the age of 4 to 16 years, and at the body weight of 11 to 82 kg
Exclusion criteria
* The patient has a treatable seizure etiology * The patient has Epilepsy secondary to a progressive cerebral disease or any other progressively neurodegenerative disease, including Rasmussen and Landau-Kleffner diseases * The patient has a history of status Epilepticus during the 3 months prior to Visit 1 * The patient has a past and present history of pseudo seizures * The patient has a current diagnosis of Lennox-Gastaut syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Partial Seizure Frequency Per Week Over the 14-weeks Treatment Period | From Baseline (Week 0-8) to the 14-weeks Treatment Period (First Period: 4 weeks Up-titration (Week 8-12) and 10 weeks Evaluation (Week 12-22)); Week 0-22 | The change in partial seizure frequency from Baseline (B) over the Treatment Period (T) is given as a percentage reduction computed as: (B values- T values) / B values x 100. Positive values in percent reduction mean that the value decreased from Baseline during the first 14-week Period. Frequency per week of partial seizures = (Total number of partial seizures in a certain Period/number of observation days in the Period) x 7. Partial seizures can be classified into: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures. |
| Incidence of Treatment-Emergent Adverse Events (TEAEs) During the Second Period (up to Three Years Until the Time of Approval Granted) | During the second Period from Visit 8 (Week 22) to the end of the Follow-up Period (up to three years until the time of approval granted) | An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with the pharmaceutical product. Incidence of treatment-emergent AEs is reported by the percentage of subjects with at least one treatment-emergent AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Partial Seizure Frequency Per Week Over the 10-weeks Evaluation Period | 10-weeks Evaluation Period (Part of the first Period: Week 12 to Week 22) | The seizure frequency per week was calculated as: Frequency per week of partial seizures = (Total number of partial seizures in the Evaluation Period/number of days for observation in the Evaluation Period) x 7. Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures. |
| Percentage of Partial Seizures 50 % Responders Over the 14-weeks Treatment Period | 14-weeks Treatment Period (First Period: 4 weeks Up-titration (Week 8-12) and 10 weeks Evaluation (Week 12-22)) | 50 % responders are those subjects which have a 50 % or more reduction in the frequency of partial seizures from Baseline to the Treatment Period. The results show the percentage of participants that are 50 % responders. Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures. |
| Percentage of Partial Seizures 50 % Responders Over the 10-weeks Evaluation Period | 10-weeks Evaluation Period (Part of the first Period: Week 12 to Week 22) | 50 % responders are those subjects which have a 50 % or more reduction in the frequency of partial seizures from Baseline to the Evaluation Period. The results show the percentage of participants that are 50 % responders. Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures. |
| Change From Baseline in Partial Seizure Frequency Per Week Over the 10-week Evaluation Period | From Baseline (Week 0-8) to the 10-weeks Evaluation Period (Part of the first Period: Week 12 to Week 22) | The change in partial seizure frequency from Baseline (B) over the Evaluation Period (E) is given as a percentage reduction computed as: (B values- E values) / B values x 100. Positive values in percent reduction mean that the value decreased from Baseline to the 10-week Evaluation Period. Frequency per week of partial seizures = (Total number of partial seizures in a certain Period/number of observation days in the Period) x 7. Partial seizures can be classified into: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures. |
| Number of Seizure-free Subjects Over the 10-weeks Evaluation Period | 10-weeks Evaluation Period (Part of the first Period: Week 12 to Week 22) | Seizure-free means not having a seizure of type I (Partial seizure). Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures. |
| Incidence of Treatment-emergent Adverse Drug Reactions (ADRs) During the Second Period (up to Three Years Until the Time of Approval Granted) | During the second Period from Visit 8 (Week 22) to the end of the Follow-up Period (up to three years until the time of approval granted) | An Adverse Drug Reaction (ADR) is an Adverse Event for which a causal relationship between the product and the occurrence is suspected. Incidence of ADRs is reported by the number of subjects with at least one ADR. |
| Change From Baseline in Partial Seizure Frequency Per Week for the Second Period (up to Three Years From Informed Consent Until the Time of Approval Granted) | From Baseline (Week 0-8) until the time of approval granted (up to three years from date of informed consent (Week 0); without 6-weeks Withdrawal Period) | The outcome was also calculated for each 3-month Period but here only the result for the total Second Evaluation Period (Second Period without following 6-weeks Withdrawal Period for withdrawers) is presented. Change in partial seizure frequency from Baseline (B) over Second Evaluation Period (E) is given as a percentage reduction computed as: (B values- E values) / B values x 100. Positive values in percent reduction show a decrease from Baseline. Frequency per week of partial seizures = (Total number of partial seizures in a certain Period/number of observation days in the Period) x 7. |
| Number of Seizure-free Subjects Over the 14-weeks Treatment Period | 14-weeks Treatment Period (First Period: 4 weeks Up-titration (Week 8-12) and 10 weeks Evaluation (Week 12-22)) | Seizure-free means not having a seizure of type I (Partial seizure). Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures. |
| Partial Seizure Frequency Per Week Over the 14-weeks Treatment Period | 14-weeks Treatment Period (First Period: 4 weeks Up-titration (Week 8-12) and 10 weeks Evaluation (Week 12-22)) | The seizure frequency per week was calculated as: Frequency per week of partial seizures = (Total number of partial seizures in the Treatment Period/number of days for observation in the Treatment Period) x 7. Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures. |
Countries
Japan
Participant flow
Recruitment details
Full Analysis Set (FAS) includes all subjects taking at least one dose of study medication. Per-Protocol Set (PPS) is a subset of the FAS, consisting of subjects without major protocol violations affecting the primary efficacy variable.
Pre-assignment details
Participant Flow refers to the Full Analysis Set. First Period started after Baseline (Week 0 to Week 8).
Participants by arm
| Arm | Count |
|---|---|
| Levetiracetam * First Period (4 weeks Up-titration and 10 weeks Evaluation): Dry syrup 50 %, 20 mg/kg/day or 1000 mg/day, 40 mg/kg/day or 2000 mg/day, 60 mg/kg/day or 3000 mg/day, twice daily administration Per Os (PO) for 14 weeks.
* Second Period: Dry syrup 50 % or tablets (250 mg and 500 mg strengths), 20 to 60 mg/kg/day or 1000 to 3000 mg/day, twice daily administration Per Os (PO) until indication granted.
* Withdrawal Period (6 weeks): Patients on the dose at 60 mg/kg/day or 3000 mg/day will be decreased to 40 mg/kg/day or 2000 mg/day for first 2 weeks and then to 20 mg/kg/day or 1000 mg/day for 2 additional weeks. For patients on the dose at 40 mg/kg/day or 2000 mg/day, the dosage will be decreased to 20 mg/kg/day or 1000 mg/day for 2 weeks and then the treatment with LEV will be stopped. | 73 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 1st Period (From Week 8 to Week 22) | Adverse Event | 4 |
| 1st Period (From Week 8 to Week 22) | Lack of Efficacy | 6 |
| 1st Period (From Week 8 to Week 22) | Withdrawal by Subject | 1 |
| 2nd Period (Week 22 to the End of Study) | Adverse Event | 3 |
| 2nd Period (Week 22 to the End of Study) | Lack of Efficacy | 9 |
| 2nd Period (Week 22 to the End of Study) | Protocol Violation | 1 |
| 2nd Period (Week 22 to the End of Study) | Withdrawal by Subject | 7 |
Baseline characteristics
| Characteristic | Levetiracetam |
|---|---|
| Age Categorical >=12 - <16 years | 29 participants |
| Age Categorical >=4 - <8 years | 22 participants |
| Age Categorical >=8 - <12 years | 22 participants |
| Age, Continuous | 10.1 years STANDARD_DEVIATION 3.4 |
| Body Mass Index (BMI) | 17.15 kilogram / meter^2 (kg/m^2) STANDARD_DEVIATION 2.99 |
| Body Weight | 32.43 kilogram (kg) STANDARD_DEVIATION 13.2 |
| Height | 134.55 centimeter (cm) STANDARD_DEVIATION 20.69 |
| Hospitalization Status No | 73 participants |
| Hospitalization Status Yes | 0 participants |
| Region of Enrollment Japan | 73 participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 66 / 73 |
| serious Total, serious adverse events | 8 / 73 |
Outcome results
Primary
Change From Baseline in Partial Seizure Frequency Per Week Over the 14-weeks Treatment Period
The change in partial seizure frequency from Baseline (B) over the Treatment Period (T) is given as a percentage reduction computed as: (B values- T values) / B values x 100. Positive values in percent reduction mean that the value decreased from Baseline during the first 14-week Period. Frequency per week of partial seizures = (Total number of partial seizures in a certain Period/number of observation days in the Period) x 7. Partial seizures can be classified into: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures.
Time frame: From Baseline (Week 0-8) to the 14-weeks Treatment Period (First Period: 4 weeks Up-titration (Week 8-12) and 10 weeks Evaluation (Week 12-22)); Week 0-22
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam | Change From Baseline in Partial Seizure Frequency Per Week Over the 14-weeks Treatment Period | 43.21 Percent reduction |
Primary
Incidence of Treatment-Emergent Adverse Events (TEAEs) During the Second Period (up to Three Years Until the Time of Approval Granted)
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with the pharmaceutical product. Incidence of treatment-emergent AEs is reported by the percentage of subjects with at least one treatment-emergent AE.
Time frame: During the second Period from Visit 8 (Week 22) to the end of the Follow-up Period (up to three years until the time of approval granted)
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam | Incidence of Treatment-Emergent Adverse Events (TEAEs) During the Second Period (up to Three Years Until the Time of Approval Granted) | 98.2 percentage of participants |
Secondary
Change From Baseline in Partial Seizure Frequency Per Week for the Second Period (up to Three Years From Informed Consent Until the Time of Approval Granted)
The outcome was also calculated for each 3-month Period but here only the result for the total Second Evaluation Period (Second Period without following 6-weeks Withdrawal Period for withdrawers) is presented. Change in partial seizure frequency from Baseline (B) over Second Evaluation Period (E) is given as a percentage reduction computed as: (B values- E values) / B values x 100. Positive values in percent reduction show a decrease from Baseline. Frequency per week of partial seizures = (Total number of partial seizures in a certain Period/number of observation days in the Period) x 7.
Time frame: From Baseline (Week 0-8) until the time of approval granted (up to three years from date of informed consent (Week 0); without 6-weeks Withdrawal Period)
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam | Change From Baseline in Partial Seizure Frequency Per Week for the Second Period (up to Three Years From Informed Consent Until the Time of Approval Granted) | 41.32 Percent reduction |
Secondary
Change From Baseline in Partial Seizure Frequency Per Week Over the 10-week Evaluation Period
The change in partial seizure frequency from Baseline (B) over the Evaluation Period (E) is given as a percentage reduction computed as: (B values- E values) / B values x 100. Positive values in percent reduction mean that the value decreased from Baseline to the 10-week Evaluation Period. Frequency per week of partial seizures = (Total number of partial seizures in a certain Period/number of observation days in the Period) x 7. Partial seizures can be classified into: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures.
Time frame: From Baseline (Week 0-8) to the 10-weeks Evaluation Period (Part of the first Period: Week 12 to Week 22)
Population: Of the 73 subjects in the FAS, 68 subjects had available data at Baseline and during the Evaluation Period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam | Change From Baseline in Partial Seizure Frequency Per Week Over the 10-week Evaluation Period | 39.02 Percent reduction |
Secondary
Incidence of Treatment-emergent Adverse Drug Reactions (ADRs) During the Second Period (up to Three Years Until the Time of Approval Granted)
An Adverse Drug Reaction (ADR) is an Adverse Event for which a causal relationship between the product and the occurrence is suspected. Incidence of ADRs is reported by the number of subjects with at least one ADR.
Time frame: During the second Period from Visit 8 (Week 22) to the end of the Follow-up Period (up to three years until the time of approval granted)
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam | Incidence of Treatment-emergent Adverse Drug Reactions (ADRs) During the Second Period (up to Three Years Until the Time of Approval Granted) | 15 participants |
Secondary
Number of Seizure-free Subjects Over the 10-weeks Evaluation Period
Seizure-free means not having a seizure of type I (Partial seizure). Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures.
Time frame: 10-weeks Evaluation Period (Part of the first Period: Week 12 to Week 22)
Population: Of the 73 subjects in the FAS, 68 subjects had available data over the Evaluation Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam | Number of Seizure-free Subjects Over the 10-weeks Evaluation Period | 3 participants |
Secondary
Number of Seizure-free Subjects Over the 14-weeks Treatment Period
Seizure-free means not having a seizure of type I (Partial seizure). Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures.
Time frame: 14-weeks Treatment Period (First Period: 4 weeks Up-titration (Week 8-12) and 10 weeks Evaluation (Week 12-22))
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam | Number of Seizure-free Subjects Over the 14-weeks Treatment Period | 2 participants |
Secondary
Partial Seizure Frequency Per Week Over the 10-weeks Evaluation Period
The seizure frequency per week was calculated as: Frequency per week of partial seizures = (Total number of partial seizures in the Evaluation Period/number of days for observation in the Evaluation Period) x 7. Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures.
Time frame: 10-weeks Evaluation Period (Part of the first Period: Week 12 to Week 22)
Population: Full Analysis Set (FAS). Only subjects having values unequal to zero over Baseline and values equal to or greater than zero over Treatment Period are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam | Partial Seizure Frequency Per Week Over the 10-weeks Evaluation Period | 3.90 Seizures per week |
Secondary
Partial Seizure Frequency Per Week Over the 14-weeks Treatment Period
The seizure frequency per week was calculated as: Frequency per week of partial seizures = (Total number of partial seizures in the Treatment Period/number of days for observation in the Treatment Period) x 7. Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures.
Time frame: 14-weeks Treatment Period (First Period: 4 weeks Up-titration (Week 8-12) and 10 weeks Evaluation (Week 12-22))
Population: Full Analysis Set (FAS). Only subjects having values unequal to zero over Baseline and values equal to or greater than zero over Treatment Period are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam | Partial Seizure Frequency Per Week Over the 14-weeks Treatment Period | 3.92 Seizures per week |
Secondary
Percentage of Partial Seizures 50 % Responders Over the 10-weeks Evaluation Period
50 % responders are those subjects which have a 50 % or more reduction in the frequency of partial seizures from Baseline to the Evaluation Period. The results show the percentage of participants that are 50 % responders. Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures.
Time frame: 10-weeks Evaluation Period (Part of the first Period: Week 12 to Week 22)
Population: Of the 73 subjects in the FAS, 68 subjects had available data over the Evaluation Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam | Percentage of Partial Seizures 50 % Responders Over the 10-weeks Evaluation Period | 38.2 percentage of participants |
Secondary
Percentage of Partial Seizures 50 % Responders Over the 14-weeks Treatment Period
50 % responders are those subjects which have a 50 % or more reduction in the frequency of partial seizures from Baseline to the Treatment Period. The results show the percentage of participants that are 50 % responders. Partial seizures can be classified into one of the following three groups: * Simple partial seizures * Complex partial seizures * Partial seizures evolving to secondarily generalized seizures.
Time frame: 14-weeks Treatment Period (First Period: 4 weeks Up-titration (Week 8-12) and 10 weeks Evaluation (Week 12-22))
Population: Full Analysis Set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam | Percentage of Partial Seizures 50 % Responders Over the 14-weeks Treatment Period | 38.4 percentage of participants |