Brivaracetam as add-on Treatment in Adolescents and Adults Suffering From Epilepsy

Study Overview
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Brief Summary
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This study will compare the safety and efficacy of Brivaracetam at flexible dose with Placebo in subjects suffering from Epilepsy.

Official Title
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An International, Randomized, Double-blind, Parallel-group, Placebo-controlled, Flexible Dose Study: Evaluation of the Safety and Efficacy of Brivaracetam in Subjects (≥ 16 to 70 Years Old) Suffering From Localization-related or Generalized Epilepsy.

Conditions
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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 were aged from 16 to 70 years, inclusive. Subjects under 18 years of age were only included where legally permitted and ethically accepted Subjects had well-characterized localization-related Epilepsy or generalized Epilepsy according to the International League Against Epilepsy (ILAE) classification For subjects suffering from localization-related Epilepsy: subjects had at least 2 Partial-Onset Seizures (POSs) whether or not secondarily generalized per month during the 3 months preceding Visit 1 according to the ILAE classification For subjects suffering from localization-related Epilepsy: subjects had at least 4 Partial-Onset Seizures (POSs) whether or not secondarily generalized during the 4-week Baseline Period according to the ILAE classification For subjects suffering from generalized Epilepsy: subjects had at least 2 Type II-seizure days per month during the 3 months preceding Visit 1 according to the ILAE classification For subjects suffering from generalized Epilepsy: subjects had at least 4 Type II-seizure days during the 4 week Baseline Period according to the ILAE classification Subjects were uncontrolled while treated by 1 to 3 permitted concomitant Antiepileptic Drugs (AEDs). Vagal nerve stimulation was allowed and was not counted as a concomitant AED Exclusion Criteria: For subjects who suffered from localization-related Epilepsy: history or presence of Seizures occurring only in clusters (too frequently or indistinctly separated to be reliably counted) before Visit 2 or occurring only as Type IA non-motor Subjects with a history or presence of Status Epilepticus during the year preceding Visit 1 or during Baseline

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 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>Matching Placebo tablets administered twice a day | Drug: Placebo<br>* Daily oral dose of two equal intakes, morning and evening, of Placebo in a double-blinded way for the 16-week Treatment Period<br>|
| Experimental: Brivaracetam<br>A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day | Drug: Brivaracetam<br>* Daily oral dose of two equal intakes, morning and evening, Brivaracetam 20 mg/day or Brivaracetam 50 mg/day or Brivaracetam 100 mg/day or Brivaracetam 150 mg/day, in a double-blinded way for the 16-week Treatment Period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With at Least One Adverse Event During the 16-week Treatment Period | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | Week 2 to the end of the Treatment Period (Week 16) | 
| Partial Onset Seizure (Type I) Frequency Per Week Over the 16-week Treatment Period | Partial (Type I) seizures can be classified into one of the following three groups: Simple partial seizures Complex partial seizures Partial seizures evolving to generalized tonic-clonic convulsions. Partial Onset Seizure (POS) frequency per week over the Treatment Period (TP) was calculated as: (Total Type I seizures over the TP)*7/(Total number of days with no missing seizure count in the TP) | Baseline (Week 0) to the end of the Treatment Period (Week 16) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder Rate for Partial Onset Seizures (Type I) Frequency Per Week Over the 16-week Treatment Period | The responder rate was presented as the percentage of responders and non-responders. A subject is a responder, if the subject has at least 50 % reduction in Partial Onset Seizure frequency per week from Baseline to Treatment Period. Subjects with zero seizure frequency per week at Baseline were considered as non-responders. | Baseline (Week 0) to the end of Treatment Period (Week 16) | 
| Seizure Frequency (All Seizure Types) Per Week Over the 16-week Treatment Period | There are three different types of seizures: Type I: Partial seizures Type II: Generalized seizures Type III: Unclassified epileptic seizures. All seizure frequency per week over Treatment Period (TP) was calculated as: (Total number of seizures over the TP)*7/(Total number of days with no missing seizure count in the TP) | Baseline (Week 0) to the end of Treatment Period (Week 16) | 
| Percent Change From Baseline to the 16-week Treatment Period in Partial Onset Seizure (Type I) Frequency Per Week | Percent change from Baseline was calculated as percent reduction by: (weekly seizure frequency Baseline - weekly seizure frequency Treatment)*100/(weekly seizure frequency Baseline). A negative value in percent Change from Baseline indicates an improvement from Baseline. The higher the negative values for percent change in Partial Onset Seizure (POS) frequency, the higher the improvement from Baseline. | Baseline (Week 0) to end of Treatment Period (Week 16) | 
| Categorized Response From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 16-week Treatment Period | Subjects were classified in 1 of the following categories based on their percent reduction from Baseline to Treatment Period in Partial Onset Seizure (POS) frequency per week: <-25 %, -25 % to <25 %, 25 % to <50 %, 50 % to <75 %, 75 % to <100 %, and 100 %. Subjects having zero for Baseline seizure frequency per week were classified in the <-25 % category. | Baseline to 16-week Treatment Period | 
| Seizure Freedom Rate (All Seizure Types) Over the 16-week Treatment Period | Subjects were considered seizure free if their seizure counts for every day over the Treatment Period (TP) was zero and if they did not discontinue before the end of the TP. Seizure freedom rate was calculated as: (total number of seizure - free subjects in treatment group during TP)/(total number of evaluable Intent-To-Treat (ITT) subjects in treatment group) | Baseline (Week 0) to the end of Treatment Period (Week 16) | 
| Reduction of Type IC/Type I Seizure Frequency Ratio From Baseline to the 16-week Treatment Period | The type IC/Type I seizure frequency ratio is represented by the percentage of subjects having a reduction in the ratio of Type IC seizure frequency over Type IA, IB, and IC seizure frequency from Baseline to Treatment Period. | Baseline to 16-week Treatment Period | 
| Time to First Type I Seizure During the 16-week Treatment Period | Time to first Type I seizure during the 16-week Treatment Period was measured in days. | Baseline to 16-week Treatment Period | 
| Time to Fifth Type I Seizure During the 16-week Treatment Period | Time to fifth Type I seizure during the 16-week Treatment Period was measured in days. | Baseline to 16-week Treatment Period | 
| Time to Tenth Type I Seizure During Treatment Period | Time to tenth Type I seizure during the 16-week Treatment Period was measured in days. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Seizure Worry Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Daily Activities / Social Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Hospital Anxiety Score | The Hospital Anxiety and Depression Scale (HADS) was used to evaluate Anxiety and Depression. The HADS was developed as a self-administered scale to assess the presence and severity of Anxiety and Depression. It consists of 14 items that are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension was calculated with each score ranging from 0 to 21 (higher scores indicating greater problems). A negative value in change from Baseline indicates an improvement from Baseline. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Hospital Depression Score | The Hospital Anxiety and Depression Scale (HADS) was used to evaluate Anxiety and Depression.The HADS was developed as a self-administered scale to assess the presence and severity of Anxiety and Depression. It consists of 14 items that are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension was calculated with each score ranging from 0 to 21 (higher scores indicating greater problems). A negative value in change from Baseline indicates an improvement from Baseline. | Baseline to 16-week Treatment Period | 
| Patient's Global Evaluation Scale (P-GES) Evaluated at Last Visit or Early Discontinuation Visit | The Patient's Global Evaluation Scale (P-GES) is a global assessment of the disease evolution which was performed using a seven-point scale (1= Marked worsening to 7= Marked improvement) with the start of the study medication as the reference time point. The subject completed it by answering to the following: 'Overall, has there been a change in your seizures since the start of the study medication?' | Baseline to last visit or early discontinuation visit in the 16-week Treatment Period | 
| Investigator's Global Evaluation Scale (I-GES) Evaluated at Last Visit or Early Discontinuation Visit | The Investigator's Global Evaluation Scale (I-GES) is a global assessment of the disease evolution which was performed using a seven-point scale (1= Marked worsening to 7= Marked improvement) with the start of the study medication as the reference time point. The Investigator completed it by answering to the following: 'Assess the overall change in the severity of patient's illness, compared to start of study medication.' | Baseline to Last Visit or Early Discontinuation Visit in the 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Energy/Fatigue Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Emotional Well-being Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Cognitive Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Overall Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. | Baseline to 16-week Treatment Period | 
| Change From Baseline to the 16-week Treatment Period in Medication Effects Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 multi-item subscales: Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items), and a Health Status item. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. | Baseline to 16-week Treatment Period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, Brivaracetam, Partial Onset Seizures