Epilepsy
Conditions
Keywords
Epilepsy, Brivaracetam, Partial Onset Seizures, Adjunctive treatment
Brief summary
This study will evaluate the efficacy and safety of brivaracetam at doses of 100 and 200mg/day compared to placebo as adjunctive treatment in adult focal epilepsy subjects with partial onset seizures not fully controlled despite current treatment with 1 or 2 concomitant antiepileptic drugs.
Interventions
DRUGPlacebo
Daily oral dose of two equal intakes of placebo in a double-blinded way for the 12-week treatment period
DRUGBrivaracetam
Daily oral dose of two equal intakes of Brivaracetam 100 mg/ day in a double-blinded way for the 12-week treatment period
DRUGAntiepileptic drugs with market authorization available per country
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
16 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Well-characterized focal epilepsy/epileptic syndrome according to the 1989 International League Against Epilepsy (ILAE) classification * Presence of an EEG reading compatible with the clinical diagnosis of focal epilepsy within the last 5 years * Presence of a brain MRI/computed tomography (CT) scan performed within the last 2 years * Subjects having at least 8 Type I seizures \[POS; focal seizures (according to the 1981 ILAE classification)\] during the 8-week Baseline Period with at least 2 Type I seizures during each 4-week interval of the Baseline Period * Subjects having at least 2 partial onset seizures whether or not secondarily generalized per month during the 3 months preceding V1 * Subjects being uncontrolled while treated by 1 or 2 permitted concomitant AED(s). Vagal Nerve Stimulation (VNS) is allowed and will be counted as a concomitant AED * Permitted concomitant AED(s) and VNS being stable and at optimal dosage for the subject from at least 1 month (3 months for phenobarbital, phenytoin, and primidone) before V1 and expected to be kept stable during the Baseline and Treatment Period. Benzodiazepine taken more than once a week (for any indication) will be considered as a concomitant AED
Exclusion criteria
* Subject previously randomized within this study or any other prior study with BRV as a dosing arm * Seizure type IA (1981 ILAE classification) nonmotor as only seizure type. * Subject is currently treated with LEV or has taken LEV within 90 days prior to V1 * Subject has any medical or psychiatric condition, obvious cognitive impairment or mental retardation that, in the opinion of the Investigator, could jeopardize or would compromise the subject's ability to participate in this study * Subjects whose seizures could not be reliably counted on a regular basis due to their fast and repetitive occurrence (clusters or flurries) * Subject has history or presence of status epilepticus during the year preceding V1 or during Baseline * Subject has history or presence of known psychogenic nonepileptic seizures * Subject on felbamate with less than 18 months exposure before V1 * Subject currently on vigabatrin. Subject with history of vigabatrin use but either no visual fields examination report available including standard static (Humphrey or Octopus) or kinetic perimetry (Goldman) or results of these examinations are abnormal * Subject taking any drug with possible central nervous system (CNS) effects except if stable from at least 1 month before V1 and expected to be kept stable during the Treatment Period * Subject has history of cerebrovascular accident, including transient ischemic attack, in the last 6 months * Subject is suffering from severe cardiovascular disease or peripheral vascular disease * Subject has a lifetime history of suicide attempt or has suicidal ideation in the past 6 months * Subject has ongoing psychiatric disease other than mild controlled disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Reduction Over Placebo for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | 12 week Treatment Period | Primary endpoint: United States of America (FDA) |
| 50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | Baseline to 12 week Treatment Period | Primary Endpoint: European Regulatory Authorities A responder is a participant who experienced a 50% or greater reduction in partial onset seizure (Type I) frequency over the Treatment Period standardized to a 28-day duration. |
Secondary
| Measure | Time frame |
|---|---|
| Percent Change in Partial Onset Seizure (Type I) Frequency From the Baseline to the Treatment Period | Baseline to 12 week Treatment Period |
| Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | 12 week Treatment Period |
| All Seizure Frequency (Type I + II + III) During the 12-week Treatment Period | 12 week Treatment Period |
| Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | Baseline to 12 week Treatment Period |
| Time to the First Type I Seizure During the Treatment Period | 12 week Treatment Period |
| Time to the Fifth Type I Seizure During the Treatment Period | 12 week Treatment Period |
| Time to the Tenth Type I Seizure During the Treatment Period | 12 week Treatment Period |
Countries
Austria, Belgium, Brazil, Bulgaria, Canada, Czechia, Estonia, Finland, France, Germany, Hong Kong, Hungary, India, Italy, Japan, Latvia, Lithuania, Mexico, Netherlands, Poland, Puerto Rico, Russia, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Recruitment for the N01358 study began in December 2010. The study concluded in May 2014.
Pre-assignment details
The Participant Flow and Baseline Demographics data is taken from the Randomized Set (RS). The RS consists of all subjects who were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo tablets administered twice daily | 263 |
| Brivaracetam 100 mg/Day Brivaracetam 50 mg administered twice daily | 254 |
| Brivaracetam 200 mg/Day Brivaracetam 100 mg administered twice daily | 251 |
| Total Title | 768 |
| Total | 1,536 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | AE, non-serious non-fatal | 9 | 15 | 13 |
| Overall Study | AE, serious fatal | 0 | 0 | 2 |
| Overall Study | Erroneously Randomized | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 3 |
| Overall Study | Non Compliance | 2 | 0 | 0 |
| Overall Study | Patient Randomized by Mistake | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 3 | 1 |
| Overall Study | Randomized in Error | 0 | 0 | 1 |
| Overall Study | SAE, non-fatal | 1 | 5 | 1 |
| Overall Study | SAE, non-fatal+AE, non-serious non-fatal | 0 | 1 | 1 |
| Overall Study | Screen Failure | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 4 |
Baseline characteristics
| Characteristic | Placebo | Brivaracetam 100 mg/Day | Brivaracetam 200 mg/Day | Total Title |
|---|---|---|---|---|
| Age, Continuous | 39.8 years STANDARD_DEVIATION 12.8 | 39.0 years STANDARD_DEVIATION 13.4 | 39.7 years STANDARD_DEVIATION 12.8 | 39.5 years STANDARD_DEVIATION 13 |
| BMI | 26.6 kg/m^2 STANDARD_DEVIATION 5.7 | 26.7 kg/m^2 STANDARD_DEVIATION 5.6 | 26.4 kg/m^2 STANDARD_DEVIATION 6 | 26.6 kg/m^2 STANDARD_DEVIATION 5.8 |
| Height | 168.4 centimeters STANDARD_DEVIATION 10 | 166.6 centimeters STANDARD_DEVIATION 9.8 | 168.7 centimeters STANDARD_DEVIATION 9.9 | 167.9 centimeters STANDARD_DEVIATION 9.9 |
| Racial Group American Indian or Alaska Native | 10 participants | 8 participants | 11 participants | 29 participants |
| Racial Group Asian | 32 participants | 32 participants | 29 participants | 93 participants |
| Racial Group Black or African American | 11 participants | 8 participants | 7 participants | 26 participants |
| Racial Group Missing | 3 participants | 2 participants | 3 participants | 8 participants |
| Racial Group Other | 17 participants | 21 participants | 18 participants | 56 participants |
| Racial Group White | 190 participants | 183 participants | 183 participants | 556 participants |
| Sex: Female, Male Female | 128 Participants | 152 Participants | 117 Participants | 397 Participants |
| Sex: Female, Male Male | 135 Participants | 102 Participants | 134 Participants | 371 Participants |
| Weight | 76.1 kilograms STANDARD_DEVIATION 19.9 | 74.1 kilograms STANDARD_DEVIATION 16.8 | 75.5 kilograms STANDARD_DEVIATION 19 | 75.2 kilograms STANDARD_DEVIATION 18.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 61 / 261 | 96 / 253 | 97 / 250 |
| serious Total, serious adverse events | 9 / 261 | 8 / 253 | 8 / 250 |
Outcome results
Primary
50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration
Primary Endpoint: European Regulatory Authorities A responder is a participant who experienced a 50% or greater reduction in partial onset seizure (Type I) frequency over the Treatment Period standardized to a 28-day duration.
Time frame: Baseline to 12 week Treatment Period
Population: Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brivaracetam 100 mg/Day | 50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | Responders | 21.6 Percentage of subjects |
| Brivaracetam 100 mg/Day | 50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | Non-Responders | 78.4 Percentage of subjects |
| Brivaracetam 200 mg/Day | 50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | Responders | 38.9 Percentage of subjects |
| Brivaracetam 200 mg/Day | 50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | Non-Responders | 61.1 Percentage of subjects |
| Placebo | 50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | Non-Responders | 62.2 Percentage of subjects |
| Placebo | 50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | Responders | 37.8 Percentage of subjects |
p-value: <0.00195% CI: [1.6, 3.6]Regression, Logistic
p-value: <0.00195% CI: [1.5, 3.3]Regression, Logistic
Primary
Percent Reduction Over Placebo for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration
Primary endpoint: United States of America (FDA)
Time frame: 12 week Treatment Period
Population: Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam 100 mg/Day | Percent Reduction Over Placebo for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | 22.8 Percentage of reduction |
| Brivaracetam 200 mg/Day | Percent Reduction Over Placebo for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | 23.2 Percentage of reduction |
| Placebo | Percent Reduction Over Placebo for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration | 0 Percentage of reduction |
p-value: <0.00195% CI: [13.3, 31.2]ANCOVA
p-value: <0.00195% CI: [13.8, 31.6]ANCOVA
Secondary
All Seizure Frequency (Type I + II + III) During the 12-week Treatment Period
Time frame: 12 week Treatment Period
Population: Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brivaracetam 100 mg/Day | All Seizure Frequency (Type I + II + III) During the 12-week Treatment Period | 8.7 number of seizures/ 28-day |
| Brivaracetam 200 mg/Day | All Seizure Frequency (Type I + II + III) During the 12-week Treatment Period | 6.3 number of seizures/ 28-day |
| Placebo | All Seizure Frequency (Type I + II + III) During the 12-week Treatment Period | 5.8 number of seizures/ 28-day |
Secondary
Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period
Time frame: Baseline to 12 week Treatment Period
Population: Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brivaracetam 100 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | <-25 % | 16.6 percentage of subjects |
| Brivaracetam 100 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | -25 % to <25 % | 40.5 percentage of subjects |
| Brivaracetam 100 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 25 % to <50 % | 21.2 percentage of subjects |
| Brivaracetam 100 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 50 % to <75 % | 13.9 percentage of subjects |
| Brivaracetam 100 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 75 % to <100 % | 6.9 percentage of subjects |
| Brivaracetam 100 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 100 % | 0.8 percentage of subjects |
| Brivaracetam 200 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 100 % | 6.0 percentage of subjects |
| Brivaracetam 200 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | <-25 % | 14.3 percentage of subjects |
| Brivaracetam 200 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 50 % to <75 % | 19.0 percentage of subjects |
| Brivaracetam 200 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 75 % to <100 % | 13.9 percentage of subjects |
| Brivaracetam 200 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | -25 % to <25 % | 28.6 percentage of subjects |
| Brivaracetam 200 mg/Day | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 25 % to <50 % | 18.3 percentage of subjects |
| Placebo | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | -25 % to <25 % | 29.3 percentage of subjects |
| Placebo | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 25 % to <50 % | 22.1 percentage of subjects |
| Placebo | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 100 % | 6.0 percentage of subjects |
| Placebo | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 50 % to <75 % | 18.1 percentage of subjects |
| Placebo | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | <-25 % | 10.8 percentage of subjects |
| Placebo | Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period | 75 % to <100 % | 13.7 percentage of subjects |
Secondary
Percent Change in Partial Onset Seizure (Type I) Frequency From the Baseline to the Treatment Period
Time frame: Baseline to 12 week Treatment Period
Population: Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brivaracetam 100 mg/Day | Percent Change in Partial Onset Seizure (Type I) Frequency From the Baseline to the Treatment Period | 17.6 percentage of change |
| Brivaracetam 200 mg/Day | Percent Change in Partial Onset Seizure (Type I) Frequency From the Baseline to the Treatment Period | 37.2 percentage of change |
| Placebo | Percent Change in Partial Onset Seizure (Type I) Frequency From the Baseline to the Treatment Period | 35.6 percentage of change |
p-value: <0.00195% CI: [7.6, 24.2]Wilcoxon (Mann-Whitney)
p-value: <0.00195% CI: [10.4, 26.4]Wilcoxon (Mann-Whitney)
Secondary
Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period
Time frame: 12 week Treatment Period
Population: Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brivaracetam 100 mg/Day | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | No seizures but discontinued | 0.4 percentage of subjects |
| Brivaracetam 100 mg/Day | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | Seizure free | 0.8 percentage of subjects |
| Brivaracetam 100 mg/Day | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | Not seizure free | 98.8 percentage of subjects |
| Brivaracetam 200 mg/Day | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | No seizures but discontinued | 1.2 percentage of subjects |
| Brivaracetam 200 mg/Day | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | Seizure free | 5.2 percentage of subjects |
| Brivaracetam 200 mg/Day | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | Not seizure free | 93.7 percentage of subjects |
| Placebo | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | Seizure free | 4.0 percentage of subjects |
| Placebo | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | Not seizure free | 94.8 percentage of subjects |
| Placebo | Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period | No seizures but discontinued | 1.2 percentage of subjects |
Secondary
Time to the Fifth Type I Seizure During the Treatment Period
Time frame: 12 week Treatment Period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brivaracetam 100 mg/Day | Time to the Fifth Type I Seizure During the Treatment Period | 16 days |
| Brivaracetam 200 mg/Day | Time to the Fifth Type I Seizure During the Treatment Period | 21 days |
| Placebo | Time to the Fifth Type I Seizure During the Treatment Period | 23 days |
p-value: <0.00195% CI: [0.53, 0.8]Semi-parametric hazards regression model
p-value: <0.00195% CI: [0.47, 0.71]Semi-parametric hazards regression model
Secondary
Time to the First Type I Seizure During the Treatment Period
Time frame: 12 week Treatment Period
Population: Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brivaracetam 100 mg/Day | Time to the First Type I Seizure During the Treatment Period | 3 days |
| Brivaracetam 200 mg/Day | Time to the First Type I Seizure During the Treatment Period | 5 days |
| Placebo | Time to the First Type I Seizure During the Treatment Period | 6 days |
p-value: <0.00195% CI: [0.56, 0.82]Semi-parametric hazards regression model
p-value: <0.00195% CI: [0.54, 0.79]Semi-parametric hazards regression model
Secondary
Time to the Tenth Type I Seizure During the Treatment Period
Time frame: 12 week Treatment Period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brivaracetam 100 mg/Day | Time to the Tenth Type I Seizure During the Treatment Period | 32 days |
| Brivaracetam 200 mg/Day | Time to the Tenth Type I Seizure During the Treatment Period | 37 days |
| Placebo | Time to the Tenth Type I Seizure During the Treatment Period | 43 days |
p-value: 0.00995% CI: [0.6, 0.93]Semi-parametric hazards regression model
p-value: <0.00195% CI: [0.55, 0.85]Semi-parametric hazards regression model