Epilepsy, Generalized Tonic-Clonic Seizures
Conditions
Keywords
Levetiracetam, epilepsy, generalized tonic-clonic
Brief summary
The purpose of this study is to evaluate the efficacy, safety and tolerability of levetiracetam treatment used as adjunctive therapy in Japanese and Chinese epilepsy patients aged ≥16 years and with uncontrolled Generalized Tonic-Clonic seizures despite treatment with 1 or 2 anti-epileptic drugs.
Interventions
DRUGLevetiracetam
Oral dose at flexible increase doses: 1000 mg/day or 2000 mg/day or 3000 mg/day, twice daily, 28 weeks
DRUGPlacebo
Matching oral placebo tablets twice daily for 28 weeks
Sponsors
UCB Japan Co. Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* An epilepsy patient with generalized tonic-clonic seizures that are classifiable according to the ILAE classification of epileptic seizures (Epilepsia, 1981) * A patient on a stable dose of 1 or 2 anti-epileptic drugs for the last 4 weeks (potassium bromide and sodium bromide for the last 12 weeks) prior to and during the combined baseline period
Exclusion criteria
* Presence of any sign (clinical or imaging procedures) suggesting a progressive brain lesion/disease, in particular, progressive disorder with epileptic seizures * Diagnosis of Lennox-Gastaut Syndrome * Confirmed focal epilepsy based on clinical signs (seizure types), with consistent electroencephalogram and magnetic resonance imagining features * A history of convulsive or non-convulsive status epilepticus while taking concomitant anti-epileptic drugs for the last 3 months prior to Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From the Combined Baseline in the Generalized Tonic-clonic Seizure Frequency Per Week Over the 28-week Treatment Period (Dose Adjustment + Evaluation Periods) | From Baseline to Week 28 | Percentage change in generalized tonic-clonic (GTC) seizure frequency per week from Combined Baseline B over the Treatment Period A is calculated using the equation: Percentage change from Baseline = ((A-B)/B)\*100. Percentage change from baseline is not defined for subjects whose baseline information is missing / unknown or equal to zero, or whose seizure frequency per week is missing / unknown. A negative value in change in generalized tonic-clonic (GTC) seizure frequency indicates a reduction of generalized tonic-clonic (GTC) seizure frequency over the 28-week treatment Period. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage Change in Generalized Tonic-clonic Seizure Frequency Per Week From the Combined Baseline Over the Evaluation Period | From Baseline to Evaluation Period (Week 12 to Week 28) | Percentage change in generalized tonic-clonic (GTC) seizure frequency per week from combined baseline B over the Evaluation Period A is calculated using the equation: Percentage change from Baseline = ((A-B)/B)\*100. Percentage change from baseline is not defined for subjects whose baseline Information is missing / unknown or equal to zero, or whose seizure frequency per week is missing / unknown. A negative value in change in generalized tonic-clonic (GTC) seizure frequency indicates a reduction of generalized tonic-clonic (GTC) seizure frequency. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline. |
| Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Treatment Period | From Baseline to Week 28 | A subject with an at least 50 % reduction in weekly generalized tonic-clonic (GTC) seizure frequency from Combined Baseline Period to the Treatment Period is considered a GTC 50 % responder. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline |
| Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Evaluation Period | From Baseline to Evaluation Period (Week 12 to Week 28) | A subject with an at least 50 % reduction in weekly generalized tonic-clonic (GTC) seizure frequency from Combined Baseline Period to the Evaluation Period is considered a GTC 50 % responder. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline |
| Generalized Tonic-clonic Seizure Freedom Over the Evaluation Period | Evaluation Period (Week 12 to Week 28) | A subject with a non-missing weekly generalized tonic-clonic (GTC) baseline seizure frequency and a weekly GTC seizure frequency of zero throughout the Evaluation Period, is considered as a GTC seizure-free subject on the Evaluation Period. |
Countries
China, Japan
Participant flow
Recruitment details
This study started to enroll subjects in Japan and China in October 2010.
Pre-assignment details
Participant Flow refers to the Randomized Set consisting of all screened subjects who signed the Informed Consent form, participated in the prospective Baseline Period and were randomized at Visit 2.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo for 28 weeks
Placebo: Matching oral placebo tablets twice daily | 125 |
| Levetiracetam Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks
Levetiracetam: Oral dose tablets, twice daily | 126 |
| Total | 251 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 4 |
| Overall Study | Lack of Efficacy | 40 | 27 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Other Reason | 2 | 5 |
| Overall Study | Protocol Violation | 6 | 5 |
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | Placebo | Levetiracetam | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 11 Participants | 10 Participants | 21 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 113 Participants | 115 Participants | 228 Participants |
| Age, Continuous | 32.8 years STANDARD_DEVIATION 12.5 | 31.5 years STANDARD_DEVIATION 11.3 | 32.2 years STANDARD_DEVIATION 11.9 |
| Region of Enrollment China | 104 participants | 104 participants | 208 participants |
| Region of Enrollment Japan | 21 participants | 22 participants | 43 participants |
| Sex: Female, Male Female | 49 Participants | 47 Participants | 96 Participants |
| Sex: Female, Male Male | 76 Participants | 79 Participants | 155 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 125 | 40 / 126 |
| serious Total, serious adverse events | 4 / 125 | 1 / 126 |
Outcome results
Primary
Percentage Change From the Combined Baseline in the Generalized Tonic-clonic Seizure Frequency Per Week Over the 28-week Treatment Period (Dose Adjustment + Evaluation Periods)
Percentage change in generalized tonic-clonic (GTC) seizure frequency per week from Combined Baseline B over the Treatment Period A is calculated using the equation: Percentage change from Baseline = ((A-B)/B)\*100. Percentage change from baseline is not defined for subjects whose baseline information is missing / unknown or equal to zero, or whose seizure frequency per week is missing / unknown. A negative value in change in generalized tonic-clonic (GTC) seizure frequency indicates a reduction of generalized tonic-clonic (GTC) seizure frequency over the 28-week treatment Period. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
Time frame: From Baseline to Week 28
Population: Full Analysis Set consisted of all subjects in the SS who had an evaluable Baseline and at least 1 post-Baseline GTC seizure count data point for the primary efficacy analysis excluding those who had seriously violated GCP. Evaluable Baseline for the primary efficacy analysis: at least 1 GTC seizure was documented for the Combined Baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From the Combined Baseline in the Generalized Tonic-clonic Seizure Frequency Per Week Over the 28-week Treatment Period (Dose Adjustment + Evaluation Periods) | -13.19 Percentage Change | Standard Deviation 55.54 |
| Levetiracetam | Percentage Change From the Combined Baseline in the Generalized Tonic-clonic Seizure Frequency Per Week Over the 28-week Treatment Period (Dose Adjustment + Evaluation Periods) | -68.22 Percentage Change | Standard Deviation 34.95 |
Comparison: The statistical hypotheses, null hypothesis (H0) and alternate hypothesis (H1), are stated below:~H0: μLEV = μPBO vs. H1: μLEV ≠ μPBO~ANCOVA on the endpoint percentage change from Combined Baseline of GTC seizures per week using treatment and country as factors (categorical predictors) and Combined Baseline GTC seizure frequency per week as a covariate (a continuous predictor) where μLEV and μPBO are adjusted means for LEV and PBO, respectively.p-value: <0.000195% CI: [-68.24, -44.02]ANCOVA
Secondary
Generalized Tonic-clonic Seizure Freedom Over the Evaluation Period
A subject with a non-missing weekly generalized tonic-clonic (GTC) baseline seizure frequency and a weekly GTC seizure frequency of zero throughout the Evaluation Period, is considered as a GTC seizure-free subject on the Evaluation Period.
Time frame: Evaluation Period (Week 12 to Week 28)
Population: Of the 226 subjects in the Full Analysis Set (FAS), 205 are included in the analysis of this Outcome Measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Generalized Tonic-clonic Seizure Freedom Over the Evaluation Period | 3 participants |
| Levetiracetam | Generalized Tonic-clonic Seizure Freedom Over the Evaluation Period | 32 participants |
Secondary
Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Evaluation Period
A subject with an at least 50 % reduction in weekly generalized tonic-clonic (GTC) seizure frequency from Combined Baseline Period to the Evaluation Period is considered a GTC 50 % responder. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
Time frame: From Baseline to Evaluation Period (Week 12 to Week 28)
Population: Of the 226 subjects in the Full Analysis Set (FAS), 205 are included in the analysis of this Outcome Measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Evaluation Period | 33 participants |
| Levetiracetam | Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Evaluation Period | 82 participants |
Secondary
Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Treatment Period
A subject with an at least 50 % reduction in weekly generalized tonic-clonic (GTC) seizure frequency from Combined Baseline Period to the Treatment Period is considered a GTC 50 % responder. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
Time frame: From Baseline to Week 28
Population: Full Analysis Set consisted of all subjects in the SS who had an evaluable Baseline and at least 1 post-Baseline GTC seizure count data point for the primary efficacy analysis excluding those who had seriously violated GCP. Evaluable Baseline for the primary efficacy analysis: at least 1 GTC seizure was documented for the Combined Baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Treatment Period | 31 participants |
| Levetiracetam | Generalized Tonic-clonic Seizures 50 % Responder Rate (the Proportion of Subjects With 50 % or More Reduction From the Combined Baseline in the Frequency of Generalized Tonic-clonic Seizures) During the Treatment Period | 91 participants |
Secondary
The Percentage Change in Generalized Tonic-clonic Seizure Frequency Per Week From the Combined Baseline Over the Evaluation Period
Percentage change in generalized tonic-clonic (GTC) seizure frequency per week from combined baseline B over the Evaluation Period A is calculated using the equation: Percentage change from Baseline = ((A-B)/B)\*100. Percentage change from baseline is not defined for subjects whose baseline Information is missing / unknown or equal to zero, or whose seizure frequency per week is missing / unknown. A negative value in change in generalized tonic-clonic (GTC) seizure frequency indicates a reduction of generalized tonic-clonic (GTC) seizure frequency. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline.
Time frame: From Baseline to Evaluation Period (Week 12 to Week 28)
Population: Of the 226 subjects in the Full Analysis Set (FAS), 205 are included in the analysis of this Outcome Measure in Evaluation Period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Percentage Change in Generalized Tonic-clonic Seizure Frequency Per Week From the Combined Baseline Over the Evaluation Period | -4.44 Percentage Change | Standard Deviation 153.82 |
| Levetiracetam | The Percentage Change in Generalized Tonic-clonic Seizure Frequency Per Week From the Combined Baseline Over the Evaluation Period | -68.27 Percentage Change | Standard Deviation 42.63 |