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

Epilepsy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00464269
• Other study ID #: N01253
• Secondary ID: 2006-006345-14
• Status: Completed
• Phase: Phase 3
• Start date: September 2007
• Est. completion date: January 2009

Study information

• Verified date: July 2022
• Source: UCB Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 400
• Est. completion date: January 2009
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Epilepsy
• Seizures

Intervention

Other:
• Placebo
Active Substance: Placebo Pharmaceutical Form: Film-coated tablet Concentration: 2.5 mg, 10 mg and 25 mg Route of Administration: Oral use

Drug:
• Brivaracetam 2.5 mg
Active Substance: Brivaracetam Pharmaceutical Form: Film-coated tablet Concentration: 2.5 mg Route of Administration: Oral use
• Brivaracetam 10 mg
Active Substance: Brivaracetam Pharmaceutical Form: Film-coated tablet Concentration: 10 mg Route of Administration: Oral use
• Brivaracetam 25 mg
Active Substance: Brivaracetam Pharmaceutical Form: Film-coated tablet Concentration: 25 mg Route of Administration: Oral use

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
UCB Pharma

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Mexico, 

References & Publications (14)

Asadi-Pooya AA, Sperling MR, Chung S, Klein P, Diaz A, Elmoufti S, Schiemann J, Whitesides J. Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study. Epilepsy Res. 2017 Mar;131:70-75. doi: — View Citation

Ben-Menachem E, Mameniškiene R, Quarato PP, Klein P, Gamage J, Schiemann J, Johnson ME, Whitesides J, McDonough B, Eckhardt K. Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies. Neurology. 2016 Jul 19;87(3):314-23 — View Citation

Benbadis S, Klein P, Schiemann J, Diaz A, Elmoufti S, Whitesides J. Efficacy, safety, and tolerability of brivaracetam with concomitant lamotrigine or concomitant topiramate in pooled Phase III randomized, double-blind trials: A post-hoc analysis. Epileps — View Citation

Biton V, Berkovic SF, Abou-Khalil B, Sperling MR, Johnson ME, Lu S. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia. 2014 Jan;55(1):57-66. doi: 10. — View Citation

Brandt C, Borghs S, Elmoufti S, Mueller K, Townsend R, de la Loge C. Health-related quality of life in double-blind Phase III studies of brivaracetam as adjunctive therapy of focal seizures: A pooled, post-hoc analysis. Epilepsy Behav. 2017 Apr;69:80-85. — View Citation

Brodie MJ, Fakhoury T, McDonough B, Colson AO, Stockis A, Elmoufti S, Whitesides J. Brivaracetam-induced elevation of carbamazepine epoxide levels: A post-hoc analysis from the clinical development program. Epilepsy Res. 2018 Sep;145:55-62. doi: 10.1016/j — View Citation

Brodie MJ, Whitesides J, Schiemann J, D'Souza J, Johnson ME. Tolerability, safety, and efficacy of adjunctive brivaracetam for focal seizures in older patients: A pooled analysis from three phase III studies. Epilepsy Res. 2016 Nov;127:114-118. doi: 10.10 — View Citation

Klein P, Johnson ME, Schiemann J, Whitesides J. Time to onset of sustained =50% responder status in patients with focal (partial-onset) seizures in three phase III studies of adjunctive brivaracetam treatment. Epilepsia. 2017 Feb;58(2):e21-e25. doi: 10.11 — View Citation

Klein P, Laloyaux C, Elmoufti S, Gasalla T, Martin MS. Time course of 75%-100% efficacy response of adjunctive brivaracetam. Acta Neurol Scand. 2020 Aug;142(2):175-180. doi: 10.1111/ane.13287. Epub 2020 Jun 9. — View Citation

Moseley BD, Dimova S, Elmoufti S, Laloyaux C, Asadi-Pooya AA. Long-term efficacy and tolerability of adjunctive brivaracetam in adults with focal to bilateral tonic-clonic (secondary generalized) seizures: Post hoc pooled analysis. Epilepsy Res. 2021 Oct; — View Citation

Moseley BD, Sperling MR, Asadi-Pooya AA, Diaz A, Elmouft S, Schiemann J, Whitesides J. Efficacy, safety, and tolerability of adjunctive brivaracetam for secondarily generalized tonic-clonic seizures: Pooled results from three Phase III studies. Epilepsy R — View Citation

Mukuria C, Young T, Keetharuth A, Borghs S, Brazier J. Sensitivity and responsiveness of the EQ-5D-3L in patients with uncontrolled focal seizures: an analysis of Phase III trials of adjunctive brivaracetam. Qual Life Res. 2017 Mar;26(3):749-759. doi: 10. — View Citation

Ryvlin P, Dimova S, Elmoufti S, Floricel F, Laloyaux C, Nondonfaz X, Biton V. Tolerability and efficacy of adjunctive brivaracetam in adults with focal seizures by concomitant antiseizure medication use: Pooled results from three phase 3 trials. Epilepsia — View Citation

Toledo M, Whitesides J, Schiemann J, Johnson ME, Eckhardt K, McDonough B, Borghs S, Kwan P. Safety, tolerability, and seizure control during long-term treatment with adjunctive brivaracetam for partial-onset seizures. Epilepsia. 2016 Jul;57(7):1139-51. do — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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