Double-blind, Randomized Study Evaluating the Efficacy and Safety of Brivaracetam in Adults With Partial Onset Seizures

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of Brivaracetam to support the submission file in the indication of adjunctive treatment in adolescents and adults with partial onset seizures.

Official Title
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An International, Double-blind, Parallel-group, Placebo-controlled, Randomized Study: Evaluation of the Efficacy and Safety of Brivaracetam in Subjects (>= 16 to 70 Years Old) With Partial Onset Seizures

Conditions
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Epilepsy

Intervention / Treatment
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* Other: Placebo
* Drug: Brivaracetam 2.5 mg
* Drug: Brivaracetam 10 mg
* Drug: Brivaracetam 25 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects were 16 to 70 years, both inclusive. Subjects under 18 years of age were only included where legally permitted and ethically accepted Subjects with well-characterized focal epilepsy or epileptic syndrome according to the International League Against Epilepsy (ILAE) classification Subjects had a history of partial onset seizures (POS) whether or not secondarily generalized (Type I seizures according to the ILAE classification) Subjects had at least 2 POS whether or not secondarily generalized per month during the 3 months preceding Visit 1 (V1) Subjects had at least 8 POS whether or not secondarily generalized during the 8-Week Baseline Period Subjects were uncontrolled while treated by 1 to 2 permitted concomitant antiepileptic drug(s) (AEDs). Vagal nerve stimulation (VNS) was allowed and was not counted as a concomitant AED Exclusion Criteria: History or presence of seizures occurring only in clusters (too frequently or indistinctly separated to be reliably counted) before Visit 3 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. Daily oral dose of two equal intakes, morning and evening, of Placebo in a double-blinded way for the 12-week Treatment Period. | Other: Placebo<br>* Active Substance: Placebo Pharmaceutical Form: Film-coated tablet Concentration: 2.5 mg, 10 mg and 25 mg Route of Administration: Oral use<br>|
| Experimental: Brivaracetam 5 mg/day<br>Brivaracetam 5 mg/day, 2.5 mg administered twice a day. Daily oral dose of two equal intakes, morning and evening, of Brivaracetam 5 mg /day in a double-blinded way for the 12-week Treatment Period. | Drug: Brivaracetam 2.5 mg<br>* Active Substance: Brivaracetam Pharmaceutical Form: Film-coated tablet Concentration: 2.5 mg Route of Administration: Oral use<br>|
| Experimental: BRV 20mg/day<br>Brivaracetam 20 mg/day, 10 mg administered twice a day. Daily oral dose of two equal intakes, morning and evening, of Brivaracetam 20 mg /day in a double-blinded way for the 12-week Treatment Period. | Drug: Brivaracetam 10 mg<br>* Active Substance: Brivaracetam Pharmaceutical Form: Film-coated tablet Concentration: 10 mg Route of Administration: Oral use<br>|
| Experimental: BRV 50mg/day<br>Brivaracetam 50 mg/day, 25 mg administered twice a day. Daily oral dose of two equal intakes, morning and evening, of Brivaracetam 50 mg /day, in a double-blinded way for the 12-week Treatment Period. | Drug: Brivaracetam 25 mg<br>* Active Substance: Brivaracetam Pharmaceutical Form: Film-coated tablet Concentration: 25 mg Route of Administration: Oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Partial Onset Seizure (Type I) Frequency Per Week Over the 12-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 to 12-week Treatment Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder Rate for Partial Onset Seizure (Type I) Frequency Per Week Over the 12-week Treatment Period | The responder rate was presented as the number 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 to 12-week Treatment Period | 
| All Seizure Frequency (Type I+II+III) Per Week Over the 12-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 to 12-week Treatment Period | 
| Percent Change From Baseline to the 12-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). The higher the values for percent change in Partial Onset Seizure (POS) frequency, the higher the improvement from Baseline. | Baseline to 12-week Treatment Period | 
| Categorized Percentage Change From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 12-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 12-week Treatment Period | 
| Seizure Freedom Rate (All Seizure Types) Over the 12-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 to 12-week Treatment Period | 
| Time to First Type I Seizure During the 12-week Treatment Period | The time to first Partial Onset Seizure (POS) in the Treatment Period is defined as the time between beginning of the Treatment Period and the date of occurrence of first Type I seizure. Subjects withdrawing during the Treatment Period before having a first Type I seizure were considered as having a first Type I seizure on the last day of their Treatment Period. | Baseline to 12-week Treatment Period | 
| Time to Fifth Type I Seizure During the 12-week Treatment Period | The time to fifth Partial Onset Seizure (POS) in the Treatment Period is defined as the time between beginning of the Treatment Period and the date of occurrence of fifth Type I seizure. Subjects withdrawing during the Treatment Period before having a fifth Type I seizure were considered as having a fifth Type I seizure on the last day of their Treatment Period. | Baseline to 12-week Treatment Period | 
| Time to Tenth Type I Seizure During the 12-week Treatment Period | The time to tenth Partial Onset Seizure (POS) in the Treatment Period is defined as the time between beginning of the Treatment Period and the date of occurrence of tenth Type I seizure. Subjects withdrawing during the Treatment Period before having a tenth Type I seizure were considered as having a tenth Type I seizure on the last day of their Treatment Period. | Baseline to 12-week Treatment Period | 
| Reduction of Type IC/Type I Seizure Frequency Ratio From Baseline to the 12- 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 12-week Treatment Period | 
| Change From Baseline to the 12-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 seven multi-items 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 social function (5 items) - and a health status item. The subscale scores, the total score and the health status item score range from 0 to 100 and higher scores indicating better function. | Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-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 seven multi-items 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 social function (5 items) - and a health status item. The subscale scores, the total score and the health status item score range from 0 to 100 and higher scores indicating better function. | Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-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 seven multi-items 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 social function (5 items) - and a health status item. The subscale scores, the total score and the health status item score range from 0 to 100 and higher scores indicating better function. | Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-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 both anxiety and depression simultaneously. 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 and higher scores indicating higher depression / anxiety. A negative value in change from Baseline shows an improvement in HADS from Baseline. | Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-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 both anxiety and depression simultaneously. 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 and higher scores indicating higher depression / anxiety. A negative value in change from Baseline shows an improvement in HADS from Baseline. | Baseline to 12-week Treatment Period | 
| Patient's Global Evaluation Scale (P-GES) Evaluated at Last Visit or Early Discontinuation Visit | 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 12-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 12-week Treatment Period | 
| Change From Baseline to the 12-week Treatment Period in Energy/Fatigue Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven 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. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline. | From Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-week Treatment Period in Emotional Well-Being Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven 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. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline. | From Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-week Treatment Period in Cognitive Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven 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. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline. | From Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-week Treatment Period in Medication Effects Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven 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. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline. | From Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-week Treatment Period in Overall Quality of Life Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven 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. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline. | From Baseline to 12-week Treatment Period | 
| Change From Baseline to the 12-week Treatment Period in Health Status of Life Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) Score | The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven 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. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline. | From Baseline to 12-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, Adolescents & Adults