A Study to Evaluate the Efficacy and Safety of Brivaracetam in Study Participants (>=16 to 80 Years of Age) With Epilepsy

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy of brivaracetam (BRV) compared to placebo (PBO) as adjunctive treatment in subjects (>=16 to 80 years of age) with partial seizures with or without secondary generalization despite current treatment with 1 or 2 concomitant antiepileptic drugs (AEDs) and to assess the safety and tolerability of BRV in subjects >= 16 years to 80 years of age.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study to Evaluate the Efficacy and Safety of Adjunctive Brivaracetam in Subjects (>=16 to 80 Years of Age) With Partial Seizures With or Without Secondary Generalization

Conditions
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Partial Seizures With or Without Secondary Generalization, Epilepsy

Intervention / Treatment
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* Drug: Placebo
* Drug: Brivaracetam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects (male or female) from 16 to 80 years of age at Visit 1, both inclusive Female subjects with childbearing potential are eligible if they use a medically accepted contraceptive method Subjects having at least 8 partial seizures (according to the 1981 ILAE classification) during the 8-Week Baseline Period with at least 2 partial seizures during each 4-week interval of the Baseline Period Subjects having at least 2 partial seizures whether or not secondary generalization per month during the 3 months preceding Visit 1 Subjects uncontrolled while treated by 1 or 2 permitted concomitant antiepileptic drug [AED](s). Vagal Nerve Stimulation (VNS) is allowed and will be counted as a concomitant AED Exclusion Criteria: Subject has history or presence of status epilepticus during the year preceding Visit 1 or during Baseline Subject is currently treated with levetiracetam Subject has taken levetiracetam within 90 days prior to Visit 1

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>12 weeks Treatment Period: Subjects will receive Placebo 4 weeks Down-Titration Period: Subjects will receive Placebo | Drug: Placebo<br>* Pharmaceutical form: Film-coated tablets Route of administration: Oral use<br>|
| Experimental: BRV 50 mg/day<br>12 weeks Treatment Period: Subjects will receive BRV 50 mg/day - Subjects entering into the Long term follow up (LTFU) study or managed access program (MAP): 2 weeks Transition Period: Subjects will receive BRV 50 mg/day followed by LTFU or MAP: Subjects will receive BRV 100 mg/day - Subjects not entering into the LTFU study or MAP: 4 weeks Down-Titration Period: Subjects will receive BRV 25 mg/day for 1 week followed by Placebo for 3 weeks, followed by a Study Drug-Free Period | Drug: Placebo<br>* Pharmaceutical form: Film-coated tablets Route of administration: Oral use<br>Drug: Brivaracetam<br>* Pharmaceutical form: Film-coated tablets Concentration: 25 mg tablets and 50 mg tablets Route of administration: Oral use<br>* Other names: Briviact;|
| Experimental: BRV 200 mg/day<br>12 weeks Treatment Period: Subjects will receive BRV 200 mg/day - Subjects entering into the Long term follow up (LTFU) study or managed access program (MAP): 2 weeks Transition Period: Subjects will receive BRV 150 mg/day followed by LTFU or MAP: Subjects will receive BRV 100 mg/day - Subjects not entering into the LTFU study or MAP: 4 weeks Down-Titration Period: Subjects will receive BRV 150 mg/day for 1 week followed by BRV 100 mg/day for 1 week, followed by BRV 50 mg/day for 1 week, followed by BRV 25 mg/day for 1 week followed by a Study Drug-Free Period | Drug: Placebo<br>* Pharmaceutical form: Film-coated tablets Route of administration: Oral use<br>Drug: Brivaracetam<br>* Pharmaceutical form: Film-coated tablets Concentration: 25 mg tablets and 50 mg tablets Route of administration: Oral use<br>* Other names: Briviact;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. Treatment-Emergent AEs were defined as AEs which had onset on or after the first dose of IMP. As per planned analysis, safety data for all study periods was combined excluding Open-Label Temporary period. | From start of the Treatment Period (Week 0) until Safety Visit (up to Week 18); only for OLTP- From last visit of Transition Period to beginning of MAP (up to 4 Years 10 Months) | 
| Percentage of Participants With Treatment-Emergent AEs (TEAEs) Leading to Study Withdrawal | An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. Treatment-Emergent AEs were defined as AEs which had onset on or after the first dose of IMP. As per planned analysis, safety data for all study periods was combined excluding Open-Label Temporary period. | From start of the Treatment Period (Week 0) until Safety Visit (up to Week 18); only for OLTP- From last visit of Transition Period to beginning of MAP (up to 4 Years 10 Months) | 
| Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | Serious Adverse event (SAE) was defined as any events which: • results in death, • is life-threatening threatening (note that this did not include a reaction that might have caused death had it occurred in a more severe form.), •results in significant or persistent disability/incapacity, • results in a congenital anomaly/birth defect (including that occurring in a fetus), • results in Important medical event that, based upon appropriate medical judgment, may jeopardize the participant and might require medical or surgical intervention to prevent 1 of the other outcomes listed here, and • results in initial inpatient hospitalization or prolongation of hospitalization. As per planned analysis, safety data for all study periods was combined excluding Open-Label Temporary period. | From start of the Treatment Period (Week 0) until Safety Visit (up to Week 18); only for OLTP- From last visit of Transition Period to beginning of MAP (up to 4 Years 10 Months) | 
| Partial Seizure Frequency Per 28 Days During the 12-week Treatment Period | According to International League Against Epilepsy (ILAE) classification (1981), seizures were classified as type IA (IA1, IA2, IA3, and IA4), IB, IC, II (IIA, IIB, IIC, IID, IIE, and IIF) or III. 28 day adjusted seizure frequency for partial seizures (seizure types IA+IB+IC) was calculated for treatment period by dividing the number of partial seizures by the number of days for which the DRC was completed for treatment period and multiplying the resulting value by 28. | From Baseline to 12-week Treatment Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 50% Responder Rate Based on Percent Change in Partial Seizure Frequency Per 28 Days From Baseline to the 12-week Treatment Period | Responders were those participants with at least 50% reduction from Baseline to the 12-week Treatment Period in partial seizure frequency per 28 days. 50% Responder rate was calculated for treatment period by dividing the number of 50% responders by the number of participants in the analysis set and multiplying the resulting value by 100. | From Baseline to 12-week Treatment Period | 
| Percent Change in Partial Seizure Frequency Per 28 Days From Baseline to the 12-week Treatment Period | Percent change from Baseline to the Treatment Period in partial seizure frequency was calculated by subtracting 28-day adjusted Treatment Period partial seizure frequency from 28-day adjusted Baseline Period partial seizure frequency, and multiplying the resulting quantity by 100 and dividing by the Baseline Period 28-day adjusted partial seizure frequency. A negative value in percent change from Baseline indicates a decrease in partial seizure frequency from Baseline to the Treatment Period. | From Baseline to 12-week Treatment Period | 
| Percentage of Participants With Categorized Percent Change in Partial Seizure Frequency Per 28 Days From Baseline to the 12-week Treatment Period | The percentage of participants within each of the following categories of percent change in partial seizure frequency from Baseline to the Treatment Period were summarized for each treatment group: 100%, 75% to less than 100%, 50% to less than 75%, 25% to less than 50%, -25% to less than 25%, and less than -25%. Percent change from Baseline to the Treatment Period in partial seizure frequency was calculated by subtracting 28-day adjusted Treatment Period partial seizure frequency from 28-day adjusted Baseline Period partial seizure frequency and multiplying the resulting quantity by 100 and dividing by the Baseline Period 28-day adjusted partial seizure frequency. | From Baseline to 12-week Treatment Period | 
| All Seizure Frequency (Partial, Generalized, and Unclassified Epileptic Seizures) Per 28 Days During the 12-week Treatment Period | There were three types of epileptic seizures: Partial epileptic seizures (Type I), Generalized epileptic seizures (Type II) and unclassified epileptic seizures (Type III). 28 day adjusted seizure frequency for all seizure types was calculated for treatment period by dividing the number of targeted seizures by the number of days for which the DRC was completed for treatment period and multiplying the resulting value by 28. | During the 12-week Treatment Period | 
| Percentage of Participants Who Are Seizure Free (Partial, All Epileptic Seizures) During the 12-week Treatment Period | Participants were defined as seizure free, if they did not have missing diary days and no reported seizures during the Treatment Period. | During the 12-week Treatment Period | 
| Time to 1st Partial Seizure During the 12-week Treatment Period | The evaluation of time to 1st partial seizure was based on the relative day of occurrence of the 1st partial seizure during the Treatment Period. | During the 12-week Treatment Period | 
| Time to 5th Partial Seizure During the 12-week Treatment Period | The evaluation of time to 5th partial seizure was based on the relative day of occurrence of the 5th partial seizure during the Treatment Period. | During the 12-week Treatment Period | 
| Time to 10th Partial Seizure During the 12-week Treatment Period | The evaluation of time to 10th partial seizure was based on the relative day of occurrence of the 10th partial seizure during the Treatment Period. | During the 12-week Treatment Period | 
| Brivaracetam Plasma Concentration | Blood samples were collected at indicated time points to determine the brivaracetam plasma concentration. Participants of arm 'BRV 200 mg/day' received BRV 200 mg/day until Week 12 only and 150 mg/day during the Transition Period at Week 14. Therefore, the data is reported according to the dosage information at specified time point. As per planned analysis, one blood sample was collected for BRV plasma levels during each dosing interval between 0 to 4 hours, 4 to 8 hours, and 8 to 12 hours postdose. | Plasma samples were collected at >0-4hours, >4-8hours, >8hours in weeks 2, 4, 8, 12, and 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, Partial seizures with or without secondary generalization, Brivaracetam, Briviact