Epilepsy
Conditions
Keywords
Epilepsy, Keppra® XR, Levetiracetam XR, Extended release
Brief summary
This is a safety and efficacy study of Keppra® extended release formulation - XR in patients with epilepsy.
Interventions
DRUGKeppra® extended release formulation - XR
500mg extended release oral tablet, 2 tablets once daily
DRUGPlacebo
oral tablets, 2 tablets once daily
Sponsors
UCB Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with a confirmed diagnosis of refractory epilepsy * Patients must be receiving a stable dose of 1 - 3 concomitant Anti-Epileptic Drugs (AED) * Female patients without childbearing potential. Female patients with childbearing potential are eligible if they use a medically accepted non-hormonal contraceptive method
Exclusion criteria
* Seizures occurring in clusters * Status epilepticus within 3 months of Visit 1 * History of non-epileptic seizures * Known allergic reaction or intolerance to pyrrolidine derivatives and/or excipients * Pregnant or lactating women. Any woman with childbearing potential who is not using a medically accepted, non-hormonal method of birth control
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Partial Onset Seizure (POS) Frequency Per Week - Intention-To-Treat (ITT) Population | Treatment period (12 weeks) | Number of POS over the treatment period standardized to 1 week period. |
| Partial Onset Seizure (POS) Frequency Per Week - Per Protocol (PP) Population | Treatment Period (12 weeks) | Number of POS over the treatment period standardized to 1 week period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| POS Seizure Frequency Per Week Over Baseline and Treatment Period | Baseline Period (8 weeks) - Treatment Period (12 weeks) | — |
| All (Type I+II+III) Seizures Frequency Per Week | Treatment period (12 weeks) | Number of All type Seizures over the treatment period standardized to 1 week period (Type I -Partial Onset Seizures, Type II - Generalized Seizures, Type III - Unclassified Epileptic Seizures) |
| 50% Response in Weekly POS Frequency | Treatment period (12 weeks) | A subject is considered as a 50% responder in POS if he/she has a \>= 50% decrease from Baseline in the POS frequency/week over Treatment period. |
| Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | over the treatment period (12 weeks) | The response is classified according to the percent reduction from baseline in the POS frequency per week over the Treatment Period of 12 weeks duration. |
Countries
Brazil, Finland, India, Mexico, Russia, South Africa, Ukraine
Participant flow
Recruitment details
The N01235 study began recruitment in August 2006 with study completion occurring in May 2007.
Pre-assignment details
Baseline and Participant Flow data consists of the Intent-to-Treat (ITT) analysis group. The ITT group consists of all randomized subjects.
Participants by arm
| Arm | Count |
|---|---|
| Keppra® Keppra® extended release formulation (XR) | 79 |
| Placebo placebo | 79 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | no blood sampling possible | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal of Consent | 2 | 1 |
Baseline characteristics
| Characteristic | Keppra® | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 33.97 years STANDARD_DEVIATION 13.41 | 32.38 years STANDARD_DEVIATION 12.6 | 33.17 years STANDARD_DEVIATION 13 |
| Region of Enrollment Brazil | 1 participants | 0 participants | 1.0 participants |
| Region of Enrollment Finland | 2 participants | 2 participants | 4.0 participants |
| Region of Enrollment India | 25 participants | 26 participants | 51.0 participants |
| Region of Enrollment Mexico | 15 participants | 16 participants | 31.0 participants |
| Region of Enrollment Russian Federation | 19 participants | 19 participants | 38.0 participants |
| Region of Enrollment South Africa | 4 participants | 4 participants | 8.0 participants |
| Region of Enrollment Ukraine | 13 participants | 12 participants | 25.0 participants |
| Sex: Female, Male Female | 27 Participants | 32 Participants | 59 Participants |
| Sex: Female, Male Male | 52 Participants | 47 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 77 | 21 / 79 |
| serious Total, serious adverse events | 6 / 77 | 2 / 79 |
Outcome results
Primary
Partial Onset Seizure (POS) Frequency Per Week - Intention-To-Treat (ITT) Population
Number of POS over the treatment period standardized to 1 week period.
Time frame: Treatment period (12 weeks)
Population: Intention-to-treat (ITT) (Analyses were performed on subjects from the ITT with non-missing information during baseline and treatment period.)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Keppra® | Partial Onset Seizure (POS) Frequency Per Week - Intention-To-Treat (ITT) Population | 0.912 seizures per week (log-transformed data) | Standard Error 0.053 |
| Placebo | Partial Onset Seizure (POS) Frequency Per Week - Intention-To-Treat (ITT) Population | 1.067 seizures per week (log-transformed data) | Standard Error 0.052 |
p-value: 0.03895% CI: [0.009, 0.301]ANCOVA
Comparison: Treatment difference was assessed through the percent reduction in POS freq/week of Keppra over Placebo by back transformation of the results of the ANCOVA on log data95% CI: [0.9, 26]Transf. of ANCOVA results on log data
Primary
Partial Onset Seizure (POS) Frequency Per Week - Per Protocol (PP) Population
Number of POS over the treatment period standardized to 1 week period
Time frame: Treatment Period (12 weeks)
Population: Per Protocol (PP) Population (Analyses were performed on subjects from the PP Population with non-missing information during both baseline and treatment period)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Keppra® | Partial Onset Seizure (POS) Frequency Per Week - Per Protocol (PP) Population | 0.914 seizures per week (log-transformed data) | Standard Error 0.049 |
| Placebo | Partial Onset Seizure (POS) Frequency Per Week - Per Protocol (PP) Population | 1.119 seizures per week (log-transformed data) | Standard Error 0.048 |
p-value: 0.00395% CI: [0.07, 0.341]ANCOVA
Comparison: Treatment difference was assessed through the percent reduction in POS frequency per week of Keppra over Placebo by back transformation of the results of the ANCOVA on log data95% CI: [6.7, 28.9]Transf. of ANCOVA results on log data
Secondary
50% Response in Weekly POS Frequency
A subject is considered as a 50% responder in POS if he/she has a \>= 50% decrease from Baseline in the POS frequency/week over Treatment period.
Time frame: Treatment period (12 weeks)
Population: ITT Based on the number of evaluable patients. A patient is considered as evaluable for the response status if he has seizure information in at least one of the periods (baseline or treatment period)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Keppra® | 50% Response in Weekly POS Frequency | Response | 34 Participants |
| Keppra® | 50% Response in Weekly POS Frequency | Non-Response | 45 Participants |
| Placebo | 50% Response in Weekly POS Frequency | Response | 23 Participants |
| Placebo | 50% Response in Weekly POS Frequency | Non-Response | 56 Participants |
p-value: 0.0795% CI: [0.95, 3.55]Regression, Logistic
Secondary
All (Type I+II+III) Seizures Frequency Per Week
Number of All type Seizures over the treatment period standardized to 1 week period (Type I -Partial Onset Seizures, Type II - Generalized Seizures, Type III - Unclassified Epileptic Seizures)
Time frame: Treatment period (12 weeks)
Population: ITT (Analyses were performed on subjects from the ITT with non-missing information during baseline and treatment period.)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Keppra® | All (Type I+II+III) Seizures Frequency Per Week | 0.928 seizures per week (log-transformed data) | Standard Error 0.053 |
| Placebo | All (Type I+II+III) Seizures Frequency Per Week | 1.086 seizures per week (log-transformed data) | Standard Error 0.052 |
p-value: 0.03495% CI: [0.012, 0.305]ANCOVA
Comparison: Treatment difference was assessed through the percent reduction in POS frequency per week of Keppra over Placebo by back transformation of the results of the ANCOVA on log data95% CI: [1.2, 26.3]Transf. of ANCOVA results on log data
Secondary
POS Seizure Frequency Per Week Over Baseline and Treatment Period
Time frame: Baseline Period (8 weeks) - Treatment Period (12 weeks)
Population: ITT Population - no imputation techniques used for missing data (number of subjects with non-missing data for Baseline = ITT Population and for Treatment period = 75 patients for levetiracetam and 78 patients for PBO) Clusters of type I count are included in the count of Type I seizures
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Keppra® | POS Seizure Frequency Per Week Over Baseline and Treatment Period | Baseline POS frequency per week | 1.80 seizures per week |
| Keppra® | POS Seizure Frequency Per Week Over Baseline and Treatment Period | Treatment POS frequency per week | 0.99 seizures per week |
| Placebo | POS Seizure Frequency Per Week Over Baseline and Treatment Period | Baseline POS frequency per week | 2.11 seizures per week |
| Placebo | POS Seizure Frequency Per Week Over Baseline and Treatment Period | Treatment POS frequency per week | 1.36 seizures per week |
Secondary
Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks
The response is classified according to the percent reduction from baseline in the POS frequency per week over the Treatment Period of 12 weeks duration.
Time frame: over the treatment period (12 weeks)
Population: ITT Based on the number of evaluable patients. A patient is considered as evaluable for the response status if he has seizure information in at least one of the periods (baseline or treatment period).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Keppra® | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | -25% - <25% | 14 Participants |
| Keppra® | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | 75% - <100% | 11 Participants |
| Keppra® | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | 25% - <75% | 35 Participants |
| Keppra® | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | 100% | 8 Participants |
| Keppra® | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | < -25% | 11 Participants |
| Placebo | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | 100% | 2 Participants |
| Placebo | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | < -25% | 13 Participants |
| Placebo | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | -25% - <25% | 23 Participants |
| Placebo | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | 25% - <75% | 34 Participants |
| Placebo | Response in Weekly POS Frequency (Categorized Into 6 Categories According to Reduction) Over the Treatment Period of 12 Weeks | 75% - <100% | 7 Participants |
p-value: 0.033Mantel Haenszel