Epilepsy, Partial Onset Seizures
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy of Levetiracetam (LEV) used as monotherapy, with efficacy measured as 6-month seizure freedom at the last evaluated dose in the LEV 1000 mg/day to 2000 mg/day group, in newly or recently diagnosed epilepsy subjects.
Interventions
* Active Substance: Levetiracetam * Pharmaceutical Form: Film-coated tablet * Concentration: LEV 250 mg, LEV 500 mg * Frequency: Twice daily * Route of Administration: Oral use
Sponsors
UCB Japan Co. Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is male or female and aged ≥ 16 years at Visit 1 * Subjects with newly or recently diagnosed Epilepsy having experienced unprovoked Partial Seizures (IA, IB, IC), that are classifiable according to the International League Against Epilepsy (ILAE) classification of Epileptic Seizures * Subjects with at least 2 unprovoked seizures separated by a minimum of 48 hours in the year prior to Visit 1, of which, at least 1 unprovoked seizure occurred in the 3 months prior to Visit 1 * Minimum body weight of 40 kg at Visit 1
Exclusion criteria
* Subject has a history or presence of seizure types other than partial (IA, IB, IC) * Subject has an experience of any type of brain surgery in the consecutive 2 years prior to Visit 1 * Subject has a history or presence of known Pseudo-Seizures * Subject has been treated for Epilepsy with any Antiepileptic Drug (AED) within the 6 months prior to Visit 1. However, acute and sub-acute seizure treatments are accepted for a maximum use of 2 weeks, if the treatments are stopped for the week prior to Visit 1 * Subject has a known clinically significant acute or chronic illness, such as but not restricted to: cardiac, renal, hepatic dysfunction, endocrinological, or psychiatric illness, and that may impair reliable participation in the study or necessitate the use of medication not allowed by the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group Who Are Seizure Free for 26 Consecutive Weeks of Treatment During the Evaluation Period | From the end of the 1-week Stabilization Period over the 26-weeks Evaluation Period | A subject was considered seizure free, if no seizure occurred during the 6 consecutive months (26 weeks) in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: * A documented seizure during 6 consecutive months of the Evaluation Analysis Period * Subject discontinued the study prematurely during the Evaluation Analysis Period * Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects in the Levetiracetam (LEV) 3000 mg/Day Group Who Are Seizure Free for 26 Consecutive Weeks of Treatment During the Evaluation Period | From the end of the 1-week Stabilization Period over the 26-weeks Evaluation Period | A subject was considered seizure free, if no seizure occurred during the 6 consecutive months (26 weeks) in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: * A documented seizure during 6 consecutive months of the Evaluation Analysis Period * Subject discontinued the study prematurely during the Evaluation Analysis Period * Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period. |
| Percentage of Subjects in the Levetiracetam (LEV) 3000 mg/Day Group Who Are Seizure Free for 52 Consecutive Weeks of Treatment During the Evaluation Period and the Maintenance Period | From entry in the 26-weeks Evaluation Period to the end of the 26-weeks Maintenance Period | Subjects who complete the 26-weeks Evaluation Period without having a seizure will continue receiving LEV 3000 mg/day during the 26-weeks Maintenance Period unless a seizure occurs. |
| Time to First Seizure at the Last Evaluated Dose in Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group | During Evaluation, Maintenance and Safety Follow Up Period after 1-week Stabilization Period, assessed up to 1 year | Time was measured from first day of last evaluated dose. Seizures during Stabilization were not considered. The Median time to first seizure will be estimated from the Kaplan-Meier curve. |
| Percentage of Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group Who Are Seizure Free for 52 Consecutive Weeks of Treatment During the Evaluation Period and the Maintenance Period | From entry in the 26-weeks Evaluation Period to the end of the 26-weeks Maintenance Period | Subjects who complete the 26-weeks Evaluation Period without having a seizure will continue receiving the same dose of LEV as in the Evaluation Period during the 26-weeks Maintenance Period unless a seizure occurs. |
| Time to First Seizure in Subjects in the Levetiracetam (LEV) 3000 mg/Day Group | During Evaluation, Maintenance and Safety Follow Up Period after 1-week Stabilization Period, assessed up to 1 year | Time was measured from first day of last evaluated dose. Seizures during Stabilization were not considered. The Median time to first seizure will be estimated from the Kaplan-Meier curve. |
| Time to Withdrawal in Subjects in the Levetiracetam (LEV) 3000 mg/Day Group | During 1-week Stabilization Period, Evaluation, Maintenance and Safety Follow Up Period, assessed up to 1 year | Median time to withdrawal will be estimated from the Kaplan-Meier curve. |
| Time to Withdrawal at the Last Evaluated Dose in Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group | During 1-week Stabilization Period, Evaluation, Maintenance and Safety Follow Up Period, assessed up to 1 year | Median time to withdrawal will be estimated from the Kaplan-Meier curve. |
Countries
Japan
Participant flow
Recruitment details
This multicenter study started to enroll subjects in December 2011 in order to end up with 27 centers with enrolled subjects in Japan.
Pre-assignment details
Participant Flow refers to the Randomized Set (RS). RS consists of all subjects who were randomized to the study groups.
Participants by arm
| Arm | Count |
|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group * Formulation: Tablet
* Strength: LEV 250 mg, LEV 500 mg
* Dosage: First study dose is 1000 mg/day and if a seizure occurs, the dose will be increased to 2000 mg/day. Max dose in the Follow Up Period is 3000 mg/day.
* Frequency: Twice daily | 61 |
| Levetiracetam 3000 mg/Day Group * Formulation: Tablet
* Strength: LEV 250 mg, LEV 500 mg
* Dosage: 1000 mg/day for first two weeks, then 2000 mg/day for two weeks then 3000 mg/day by the end of the trial.
* Frequency: Twice daily | 10 |
| Total Title | 71 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | AE, non-serious non-fatal | 3 | 1 |
| Overall Study | Lack of Efficacy | 4 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other Reason | 2 | 0 |
| Overall Study | SAE, non-fatal | 2 | 0 |
| Overall Study | SAE,non-fatal+AE,non-serious non-fatal | 1 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 3 |
Baseline characteristics
| Characteristic | Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Total Title | Levetiracetam 3000 mg/Day Group |
|---|---|---|---|
| Age, Categorical <=18 years | 10 Participants | 11 Participants | 1 Participants |
| Age, Categorical >=65 years | 6 Participants | 7 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 53 Participants | 8 Participants |
| Age, Continuous | 36.5 years STANDARD_DEVIATION 18 | 36.5 years STANDARD_DEVIATION 17.9 | 37.0 years STANDARD_DEVIATION 18.6 |
| Height | 161.96 centimeter (cm) STANDARD_DEVIATION 8.77 | 162.54 centimeter (cm) STANDARD_DEVIATION 9.02 | 166.07 centimeter (cm) STANDARD_DEVIATION 10.21 |
| Region of Enrollment Japan | 61 participants | 71 participants | 10 participants |
| Sex: Female, Male Female | 34 Participants | 38 Participants | 4 Participants |
| Sex: Female, Male Male | 27 Participants | 33 Participants | 6 Participants |
| Weight | 58.98 kilogram (kg) STANDARD_DEVIATION 12.3 | 59.48 kilogram (kg) STANDARD_DEVIATION 12.67 | 62.58 kilogram (kg) STANDARD_DEVIATION 15.11 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 58 / 61 | 10 / 10 |
| serious Total, serious adverse events | 8 / 61 | 2 / 10 |
Outcome results
Primary
Percentage of Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group Who Are Seizure Free for 26 Consecutive Weeks of Treatment During the Evaluation Period
A subject was considered seizure free, if no seizure occurred during the 6 consecutive months (26 weeks) in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: * A documented seizure during 6 consecutive months of the Evaluation Analysis Period * Subject discontinued the study prematurely during the Evaluation Analysis Period * Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period.
Time frame: From the end of the 1-week Stabilization Period over the 26-weeks Evaluation Period
Population: Data for the primary outcome measure refer to the Full Analysis Set (FAS). FAS includes all subjects in the Safety Set who had at least 1 treatment day in the Evaluation Period. This means that subjects in LEV 1000 to 2000 mg/day group had to have at least 1 treatment day in the Evaluation Period on their final evaluated dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Percentage of Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group Who Are Seizure Free for 26 Consecutive Weeks of Treatment During the Evaluation Period | 73.8 percentage of participants |
Comparison: The primary efficacy variable was to be calculated as the proportion p=n/N of subjects (n) staying seizure free for 6 months out of the total number of subjects (N). For this proportion p, an exact 2-sided 95% confidence interval (CI) was computed based on the F distribution.~The hypothesis H0: p=0.4 was to be formally rejected in favor of H1: p\>0.4, if the lower confidence limit for p was greater than 0.4.95% CI: [60.9, 84.2]
Secondary
Percentage of Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group Who Are Seizure Free for 52 Consecutive Weeks of Treatment During the Evaluation Period and the Maintenance Period
Subjects who complete the 26-weeks Evaluation Period without having a seizure will continue receiving the same dose of LEV as in the Evaluation Period during the 26-weeks Maintenance Period unless a seizure occurs.
Time frame: From entry in the 26-weeks Evaluation Period to the end of the 26-weeks Maintenance Period
Population: Data for this secondary outcome measure refer to the Full Analysis Set (FAS). FAS includes all subjects in the Safety Set who had at least 1 treatment day in the Evaluation Period. This means that subjects in LEV 1000 to 2000 mg/day group had to have at least 1 treatment day in the Evaluation Period on their final evaluated dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Percentage of Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group Who Are Seizure Free for 52 Consecutive Weeks of Treatment During the Evaluation Period and the Maintenance Period | 59.0 percentage of participants |
Secondary
Percentage of Subjects in the Levetiracetam (LEV) 3000 mg/Day Group Who Are Seizure Free for 26 Consecutive Weeks of Treatment During the Evaluation Period
A subject was considered seizure free, if no seizure occurred during the 6 consecutive months (26 weeks) in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: * A documented seizure during 6 consecutive months of the Evaluation Analysis Period * Subject discontinued the study prematurely during the Evaluation Analysis Period * Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period.
Time frame: From the end of the 1-week Stabilization Period over the 26-weeks Evaluation Period
Population: Data for this secondary outcome measure refer to the Full Analysis Set (FAS). FAS includes all subjects in the Safety Set who had at least 1 treatment day in the Evaluation Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Percentage of Subjects in the Levetiracetam (LEV) 3000 mg/Day Group Who Are Seizure Free for 26 Consecutive Weeks of Treatment During the Evaluation Period | 22.2 percentage of participants |
Secondary
Percentage of Subjects in the Levetiracetam (LEV) 3000 mg/Day Group Who Are Seizure Free for 52 Consecutive Weeks of Treatment During the Evaluation Period and the Maintenance Period
Subjects who complete the 26-weeks Evaluation Period without having a seizure will continue receiving LEV 3000 mg/day during the 26-weeks Maintenance Period unless a seizure occurs.
Time frame: From entry in the 26-weeks Evaluation Period to the end of the 26-weeks Maintenance Period
Population: Data for this secondary outcome measure refer to the Full Analysis Set (FAS). FAS includes all subjects in the Safety Set who had at least 1 treatment day in the Evaluation Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Percentage of Subjects in the Levetiracetam (LEV) 3000 mg/Day Group Who Are Seizure Free for 52 Consecutive Weeks of Treatment During the Evaluation Period and the Maintenance Period | 11.1 percentage of participants |
Secondary
Time to First Seizure at the Last Evaluated Dose in Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group
Time was measured from first day of last evaluated dose. Seizures during Stabilization were not considered. The Median time to first seizure will be estimated from the Kaplan-Meier curve.
Time frame: During Evaluation, Maintenance and Safety Follow Up Period after 1-week Stabilization Period, assessed up to 1 year
Population: Data for this secondary outcome measure refer to the Full Analysis Set (FAS). FAS includes all subjects in the Safety Set who had at least 1 treatment day in the Evaluation Period. This means that subjects in LEV 1000 to 2000 mg/day group had to have at least 1 treatment day in the Evaluation Period on their final evaluated dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Time to First Seizure at the Last Evaluated Dose in Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group | NA days |
Secondary
Time to First Seizure in Subjects in the Levetiracetam (LEV) 3000 mg/Day Group
Time was measured from first day of last evaluated dose. Seizures during Stabilization were not considered. The Median time to first seizure will be estimated from the Kaplan-Meier curve.
Time frame: During Evaluation, Maintenance and Safety Follow Up Period after 1-week Stabilization Period, assessed up to 1 year
Population: Data for this secondary outcome measure refer to the Full Analysis Set (FAS). FAS includes all subjects in the Safety Set who had at least 1 treatment day in the Evaluation Period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Time to First Seizure in Subjects in the Levetiracetam (LEV) 3000 mg/Day Group | 106 days |
Secondary
Time to Withdrawal at the Last Evaluated Dose in Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group
Median time to withdrawal will be estimated from the Kaplan-Meier curve.
Time frame: During 1-week Stabilization Period, Evaluation, Maintenance and Safety Follow Up Period, assessed up to 1 year
Population: Data for this secondary outcome measure refer to the Full Analysis Set (FAS). FAS includes all subjects in the Safety Set who had at least 1 treatment day in the Evaluation Period. This means that subjects in LEV 1000 to 2000 mg/day group had to have at least 1 treatment day in the Evaluation Period on their final evaluated dose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Time to Withdrawal at the Last Evaluated Dose in Subjects in the Levetiracetam (LEV) 1000 mg/Day to 2000 mg/Day Group | NA days |
Secondary
Time to Withdrawal in Subjects in the Levetiracetam (LEV) 3000 mg/Day Group
Median time to withdrawal will be estimated from the Kaplan-Meier curve.
Time frame: During 1-week Stabilization Period, Evaluation, Maintenance and Safety Follow Up Period, assessed up to 1 year
Population: Data for this secondary outcome measure refer to the Full Analysis Set (FAS). FAS includes all subjects in the Safety Set who had at least 1 treatment day in the Evaluation Period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Levetiracetam 1000 mg/Day to 2000 mg/Day Group | Time to Withdrawal in Subjects in the Levetiracetam (LEV) 3000 mg/Day Group | 91 days |