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

Epilepsy Clinical Trial

Official title:

A Multi-center, 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: NCT00490035
• Other study ID #: N01252
• Secondary ID: 2006-006344-59
• Status: Completed
• Phase: Phase 3
• Start date: September 2007
• Est. completion date: February 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: 399
• Est. completion date: February 2009
• Est. primary completion date: February 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 70 Years

Eligibility

Inclusion Criteria:

• Subjects were from 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
• 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 drugs (AEDs). Vagal nerve stimulation 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
Daily oral dose of two equal intakes, morning and evening, of Placebo in a double-blinded way for the 12-week Treatment Period

Drug:
• Brivaracetam
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
• Brivaracetam
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.
• Brivaracetam
Daily oral dose of two equal intakes, morning and evening, of Brivaracetam 100 mg /day in a double-blinded way for the 12-week Treatment Period.

Locations

Country	Name	City	State
Belgium	13	Gent
Belgium	19	La Louviere
Belgium	12	Liege
Belgium	10	Saint-Vith
Finland	44	Kuopio
Finland	41	Oulu
Finland	42	Seinajoki
Finland	43	Tampere
France	60	Angers Cedex 9
France	56	Bethune
France	62	Bron
France	57	Dijon
France	53	Lille
France	52	Montpellier Cedex
France	64	Nancy
France	54	Paris
France	51	Rennes
France	61	Roanne
France	55	Strasbourg
Germany	76	Bad Berka
Germany	73	Berlin
Germany	79	Bernau
Germany	78	Bielefeld
Germany	74	Freiburg
Germany	75	Kehl-Kork
Germany	77	Mainz
Germany	70	Munchen
Germany	72	Radeberg
Germany	71	Ulm
Hungary	94	Budapest
Hungary	90	Debrecen
Hungary	92	Pecs
India	256	Bangalore
India	257	Bangalore
India	253	Hyderabad
India	258	Jaipur
India	255	Kolkata
India	250	Lucknow
India	259	Mumbai
India	270	Pune
India	251	Pune Maharashtra
Italy	104	Bologna
Italy	105	Foggia
Italy	101	Perugia
Italy	103	Roma
Italy	107	Roma
Netherlands	124	Breda
Netherlands	125	Den Haag
Netherlands	122	Zwolle
Poland	142	Bialystok
Poland	143	Gdansk
Poland	153	Grodzisk Mazowiecki
Poland	147	Katowice
Poland	151	Katowice
Poland	141	Kielce
Poland	150	Krakow
Poland	148	Lodz
Poland	144	Lublin
Poland	152	Poznan
Poland	146	Szczecin
Poland	145	Warsaw
Poland	140	Warszawa
Poland	149	Warszawa
Spain	187	Alcorcon
Spain	181	Barcelona
Spain	182	Madrid
Spain	184	San Sebastian
Spain	183	Vigo
Spain	185	Zaragoza
Switzerland	201	Biel
Switzerland	205	Geneve
Switzerland	203	St Gallen
Switzerland	202	Tschugg
Switzerland	204	Zürich
United Kingdom	223	Liverpool
United Kingdom	224	Middlesborough

Sponsors (1)

Lead Sponsor	Collaborator
UCB Pharma SA

Countries where clinical trial is conducted

Belgium,  Finland,  France,  Germany,  Hungary,  India,  Italy,  Netherlands,  Poland,  Spain,  Switzerland,  United Kingdom, 

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

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

Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia. 2014 Jan;55(1):47-56. doi: 10.1111/epi.12432. Epub 2013 — 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 Secondarily Generalized Seizures.	From Baseline to 12-week Treatment Period
Secondary	Responder Rate for Partial Onset Seizures (Type I) Frequency Per Week Over the 12-week Treatment Period	Responders are those subjects with at least 50 % reduction from Baseline to Treatment Period in Partial Onset Seizure frequency per week.; The Responder Rate for Partial Onset Seizures (Type I) is the proportion of subjects who have a >= 50 % reduction in seizure frequency per week from Baseline.	From 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 types of Epilepsy: Partial Epilepsies (Type I), Generalized Epilepsies (Type II) and uncertain classification of Epilepsies (Type III).	From 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	The percent change from Baseline was computed as: Weekly Seizure Frequency (Treatment) - Weekly Seizure Frequency (Baseline) / Weekly Seizure Frequency (Baseline) * 100. Negative values indicate a reduction from Baseline with higher negative values showing higher reduction.	From 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	The categories are: <= 25 %; - 25 % to < 25 %; 25 % to < 50 %; 50 % to < 75 %; 75 % to < 100 %; 100 %	From 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 entire Treatment Period was zero and if they completed the Treatment Period.	From Baseline to 12-week Treatment Period
Secondary	Time to First Type I Seizure During the 12-week Treatment Period	The time to first Type I Seizure during the 12-week Treatment Period was measured in days.	From Baseline to 12-week Treatment Period
Secondary	Time to Fifth Type I Seizure During the 12-week Treatment Period	The time to Fifth Type I Seizure during the 12-week Treatment Period was measured in days.	From Baseline to 12-week Treatment Period
Secondary	Time to Tenth Type I Seizure During the 12-week Treatment Period	The time to tenth Type I Seizure during the 12-week Treatment Period was measured in days.	From 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.	From 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 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 Seizure Worry 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 Daily Activities/Social 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 Hospital Anxiety Score	The Hospital Anxiety and Depression Scale (HADS) was used to evaluate anxiety and depression simultaneously. The HADS was developed as a self-administered scale that has been designed to assess the presence and severity of both 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 and higher scores indicating higher depression / anxiety. Negative values in Change from Baseline indicate a decrease of HADS from Baseline to Treatment Period.	From 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 simultaneously. The HADS was developed as a self-administered scale that has been designed to assess the presence and severity of both 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 and higher scores indicating higher depression / anxiety. Negative values in Change from Baseline indicate a decrease of HADS from Baseline to Treatment Period.	From Baseline to 12-week Treatment Period
Secondary	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 not mentally impaired had to complete it by answering the following question: "Overall, has there been a change in your seizures since the start of the study medication?"	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 reference time point. The Investigator was to complete it by answering the following question: "Assess the Overall change in the severity of patient's illness, compared to start of study medication."	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