Epilepsy
Conditions
Keywords
Keppra XR, conversion to monotherapy, partial seizures
Brief summary
The primary objective of this study is to assess the efficacy of two doses of Keppra XR compared with a historical control as the placebo, in the monotherapy treatment of partial onset seizures.
Interventions
DRUGKeppra XR
Administered as two 500 mg tablets (1000 mg) and two placebo tablets once daily for 18 weeks
Sponsors
UCB Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects 12 to 75 years of age. * Subjects must have inadequately controlled partial onset epilepsy. * Subjects must be experiencing 2 to 40 seizures per 4-week period while being maintained on one or two standard AED(s)
Exclusion criteria
* A history of status epilepticus in the 6 months preceding randomization. * Significant medical, psychiatric or neurological illness. * Intake of benzodiazepines on more than an occasional basis * History of previous treatment with levetiracetam or sensitivity to levetiracetam.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Cumulative Exit Rate at 112 Days After the Beginning of the Previous Antiepileptic Drug (AED) Tapering Phase | 112 days | Cumulative exit rate at day 112, based on the duration between start date of previous AED tapering to the earliest date exit criterion was met; calculated using Kaplan Meier Methods. Subjects prematurely discontinued for reasons unrelated to exit criteria were censored as of last dose of study drug. Subjects who completed without meeting exit criteria were censored at Day 112. Exit criteria include increase in seizure frequency, severity, duration, status epilepticus, or new generalized seizure. Upper 95% 2-sided confidence limit for exit rate is compared to the historical control rate: 0.678. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Cumulative Rate of Exit Events, Which Include Discontinuation Due to Exit Criteria, Withdrawal Due to Adverse Events (AE) and Withdrawal Due to Lack of Efficacy, at 112 Days After the Beginning of Previous Antiepileptic Drug (AED) Tapering Phase | 112 days | The cumulative exit event rate at Day 112 was calculated using Kaplan Meier methods. The exit event rate estimate was based on the duration between the start date of previous AED tapering to the earliest date an exit event occured. Subjects who prematurely discontinued for reasons unrelated to exit criteria, adverse event, or lack of efficacy were censored as of the last dose of study medication. Subjects who completed the study without having an exit event were censored as of Day 112. |
| The Cumulative Rate of Exit Events Due to Any Reasons at 112 Days After the Beginning of Previous Antiepileptic Drug (AED) Tapering Phase | 112 days | The cumulative exit event rate at Day 112 was calculated using Kaplan Meier methods. The exit event rate estimate was based on the duration between the start date of previous AED tapering to the earliest date an exit event occured. Subjects who completed the study without having an exit event were censored as of Day 112. |
| The Cumulative Exit Rate at 112 Days for the Keppra XR 1000 mg Group After the Beginning of the Previous Antiepileptic Drug (AED) Tapering Phase | 112 days | Keppra XR 1000 mg arm was not intended for inferential analysis (planned 3 to 1 randomization, Keppra XR 2000 mg: 1000 mg). The Exit Rate was based on the duration between the start date of previous AED tapering to the earliest date an exit crterion was met. Subjects who prematurely discontinued for reasons unrelated to exit criteria were censored as of the last dose of study medication. Subjects who completed the study without meeting an exit criterion were censored as of Day 112. |
Countries
Mexico, Poland, Russia, United States
Participant flow
Recruitment details
The Efficacy (EFF) population is defined as all subjects in the Intent to Treat (ITT) population who enter into the Previous Antiepileptic (AED) Discontinuation (D/C) Phase. The Per Protocol (PP) population consists of all subjects in the EFF population who have no important protocol deviations related to efficacy.
Pre-assignment details
Subjects are to be randomized into treatment with either Keppra XR 2000 mg/day or Keppra XR 1000 mg/day in a 3:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Keppra XR 1000 mg/Day 1000 mg/day once daily for 18 weeks (administered as two Keppra XR tablets and two placebo tablets once daily) | 57 |
| Keppra XR 2000 mg/Day 2000 mg/day once daily for 18 weeks (administered as four Keppra XR tablets once daily) | 171 |
| Total | 228 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Other: Error determining exit criteria | 1 | 0 |
| Overall Study | Other: No contact for extended period | 0 | 1 |
| Overall Study | Other: Patient non-compliant | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 14 |
| Overall Study | Withdrawal of consent | 1 | 5 |
Baseline characteristics
| Characteristic | Keppra XR 1000 mg/Day | Keppra XR 2000 mg/Day | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 11 Participants | 31 Participants | 42 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 43 Participants | 140 Participants | 183 Participants |
| Age, Continuous | 33.48 years STANDARD_DEVIATION 16.32 | 34.31 years STANDARD_DEVIATION 13.69 | 34.11 years STANDARD_DEVIATION 14.36 |
| Region of Enrollment Mexico | 17 participants | 43 participants | 60 participants |
| Region of Enrollment Poland | 16 participants | 51 participants | 67 participants |
| Region of Enrollment Russian Federation | 16 participants | 48 participants | 64 participants |
| Region of Enrollment United States | 8 participants | 29 participants | 37 participants |
| Sex: Female, Male Female | 33 Participants | 99 Participants | 132 Participants |
| Sex: Female, Male Male | 24 Participants | 72 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 57 | 87 / 171 |
| serious Total, serious adverse events | 2 / 57 | 12 / 171 |
Outcome results
Primary
The Cumulative Exit Rate at 112 Days After the Beginning of the Previous Antiepileptic Drug (AED) Tapering Phase
Cumulative exit rate at day 112, based on the duration between start date of previous AED tapering to the earliest date exit criterion was met; calculated using Kaplan Meier Methods. Subjects prematurely discontinued for reasons unrelated to exit criteria were censored as of last dose of study drug. Subjects who completed without meeting exit criteria were censored at Day 112. Exit criteria include increase in seizure frequency, severity, duration, status epilepticus, or new generalized seizure. Upper 95% 2-sided confidence limit for exit rate is compared to the historical control rate: 0.678.
Time frame: 112 days
Population: Of the 171 (Keppra 2000 mg) subjects randomized, 158 subjects entered the Previous Antiepileptic Drug Tapering Phase and were included in the Efficacy Population. Primary Efficacy analysis was conducted for the Keppra XR 2000 mg/day group only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Keppra XR 2000 mg/Day | The Cumulative Exit Rate at 112 Days After the Beginning of the Previous Antiepileptic Drug (AED) Tapering Phase | 0.375 proportion of subjects |
Secondary
The Cumulative Exit Rate at 112 Days for the Keppra XR 1000 mg Group After the Beginning of the Previous Antiepileptic Drug (AED) Tapering Phase
Keppra XR 1000 mg arm was not intended for inferential analysis (planned 3 to 1 randomization, Keppra XR 2000 mg: 1000 mg). The Exit Rate was based on the duration between the start date of previous AED tapering to the earliest date an exit crterion was met. Subjects who prematurely discontinued for reasons unrelated to exit criteria were censored as of the last dose of study medication. Subjects who completed the study without meeting an exit criterion were censored as of Day 112.
Time frame: 112 days
Population: Of the 57 (Keppra 1000 mg) subjects randomized, 54 subjects entered the Previous Antiepileptic Drug Tapering Phase and were included in the Efficacy Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Keppra XR 1000 mg/Day | The Cumulative Exit Rate at 112 Days for the Keppra XR 1000 mg Group After the Beginning of the Previous Antiepileptic Drug (AED) Tapering Phase | 0.334 proportion of subjects |
Secondary
The Cumulative Rate of Exit Events Due to Any Reasons at 112 Days After the Beginning of Previous Antiepileptic Drug (AED) Tapering Phase
The cumulative exit event rate at Day 112 was calculated using Kaplan Meier methods. The exit event rate estimate was based on the duration between the start date of previous AED tapering to the earliest date an exit event occured. Subjects who completed the study without having an exit event were censored as of Day 112.
Time frame: 112 days
Population: Of the 171 (Keppra 2000 mg) subjects randomized, 158 subjects entered the Previous Antiepileptic Drug Tapering Phase and were included in the Efficacy Population. Evaluated for Keppra XR 2000 mg/day only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Keppra XR 2000 mg/Day | The Cumulative Rate of Exit Events Due to Any Reasons at 112 Days After the Beginning of Previous Antiepileptic Drug (AED) Tapering Phase | 0.475 proportion of subjects |
Secondary
The Cumulative Rate of Exit Events, Which Include Discontinuation Due to Exit Criteria, Withdrawal Due to Adverse Events (AE) and Withdrawal Due to Lack of Efficacy, at 112 Days After the Beginning of Previous Antiepileptic Drug (AED) Tapering Phase
The cumulative exit event rate at Day 112 was calculated using Kaplan Meier methods. The exit event rate estimate was based on the duration between the start date of previous AED tapering to the earliest date an exit event occured. Subjects who prematurely discontinued for reasons unrelated to exit criteria, adverse event, or lack of efficacy were censored as of the last dose of study medication. Subjects who completed the study without having an exit event were censored as of Day 112.
Time frame: 112 days
Population: Of the 171 (Keppra 2000 mg) subjects randomized, 158 subjects entered the Previous Antiepileptic Drug Tapering Phase and were included in the Efficacy Population. Evaluated for Keppra XR 2000 mg/day only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Keppra XR 2000 mg/Day | The Cumulative Rate of Exit Events, Which Include Discontinuation Due to Exit Criteria, Withdrawal Due to Adverse Events (AE) and Withdrawal Due to Lack of Efficacy, at 112 Days After the Beginning of Previous Antiepileptic Drug (AED) Tapering Phase | 0.385 proportion of subjects |