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

• ClinicalTrials.gov Identifier: NCT00504881
• Recruitment Status: Completed
• First Posted: July 20, 2007
• Results First Posted: March 17, 2017
• Last Update Posted: April 3, 2018
• Sponsor: UCB Pharma SA
• Information provided by (Responsible Party): UCB Pharma ( UCB Pharma SA )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Epilepsy
• Interventions: Drug: Placebo; Drug: Brivaracetam
• Enrollment: 480

Participant Flow

Recruitment Details	This multicenter study was conducted in 15 countries. It started in October 2007 and concluded in December 2008.
Pre-assignment Details	The Participant Flow refers to the Randomized Set (RS).

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description	Matching Placebo tablets administered twice a day	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
Period Title: Overall Study
Started	121	359
Completed	111	323
Not Completed	10	36
Reason Not Completed
Lack of Efficacy	1	5
Lost to Follow-up	0	2
Withdrawal by Subject	1	4
Non-Compliance	1	0
No Birth Control	0	1
Safety Visit not performed	0	1
AE, serious fatal	0	1
SAE, non-fatal	2	6
AE, non-serious non-fatal	4	14
SAE,non-fatal+AE,non-serious non-fatal	0	2
AE of unknown type	1	0

Baseline Characteristics

Arm/Group Title		Placebo	Brivaracetam	Total Title
Arm/Group Description		Matching Placebo tablets administered twice a day	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	[Not Specified]
Overall Number of Baseline Participants		121	359	480
Baseline Analysis Population Description		Baseline characteristics refer to the Randomized Set (RS).
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	121 participants	359 participants	480 participants
	<=18 years	3 2.5%	5 1.4%	8 1.7%
	Between 18 and 65 years	116 95.9%	352 98.1%	468 97.5%
	>=65 years	2 1.7%	2 0.6%	4 0.8%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	121 participants	359 participants	480 participants
		36.5 (11.5)	35.6 (11.5)	35.85 (11.52)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	121 participants	359 participants	480 participants
	Female	52 43.0%	178 49.6%	230 47.9%
	Male	69 57.0%	181 50.4%	250 52.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects With at Least One Adverse Event During the 16-week Treatment Period
Description	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.
Time Frame	Week 2 to the end of the Treatment Period (Week 16)

Outcome Measure Data

Analysis Population Description

The Safety Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	121	359
Measure Type: Number; Unit of Measure: percentage of participants
	66.1	66.6

2. Primary Outcome

Title	Partial Onset Seizure (Type I) Frequency Per Week Over the 16-week Treatment Period
Description	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)
Time Frame	Baseline (Week 0) to the end of the Treatment Period (Week 16)

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Median (Inter-Quartile Range); Unit of Measure: seizures per week
	1.86; (1.00 to 3.98)	1.74; (0.86 to 4.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Brivaracetam
	Comments	ANCOVA on log-transformed partial seizure frequency per week over the treatment period, with log-transformed baseline seizure frequency per week as covariate, and including terms for treatment and stratification factors.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.125
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent Reduction over Placebo
	Estimated Value	7.3
	Confidence Interval	(2-Sided) 95%; -2.2 to 15.9
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Responder Rate for Partial Onset Seizures (Type I) Frequency Per Week Over the 16-week Treatment Period
Description	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.
Time Frame	Baseline (Week 0) to the end of Treatment Period (Week 16)

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Measure Type: Number; Unit of Measure: percentage of participants
Responders	16.7	30.3
Non-Responders	83.3	69.7

4. Secondary Outcome

Title	Seizure Frequency (All Seizure Types) Per Week Over the 16-week Treatment Period
Description	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)
Time Frame	Baseline (Week 0) to the end of Treatment Period (Week 16)

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Median (Inter-Quartile Range); Unit of Measure: number of seizures per week
	1.87; (1.00 to 4.59)	1.74; (0.86 to 4.04)

5. Secondary Outcome

Title	Percent Change From Baseline to the 16-week Treatment Period in Partial Onset Seizure (Type I) Frequency Per Week
Description	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.
Time Frame	Baseline (Week 0) to end of Treatment Period (Week 16)

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Median (Inter-Quartile Range); Unit of Measure: percent change
	-18.93; (-39.05 to -7.83)	-26.92; (-55.98 to 11.44)

6. Secondary Outcome

Title	Categorized Response From Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the 16-week Treatment Period
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Measure Type: Number; Unit of Measure: percentage of participants
<- 25 %	14.8	18.3
-25 % to < 25 %	44.4	29.1
25 % to < 50 %	24.1	22.3
50 % to < 75 %	13.9	17.0
75 % to < 100 %	2.8	11.8
100 %	0	1.5

7. Secondary Outcome

Title	Seizure Freedom Rate (All Seizure Types) Over the 16-week Treatment Period
Description	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)
Time Frame	Baseline (Week 0) to the end of Treatment Period (Week 16)

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Measure Type: Number; Unit of Measure: percentage of participants
Seizure-free	0	1.5
No Seizure but non-completer	0	0
Not Seizure free	100.0	98.5

8. Secondary Outcome

Title	Reduction of Type IC/Type I Seizure Frequency Ratio From Baseline to the 16-week Treatment Period
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

The Intention-to-treat (ITT) population was defined as all randomized subjects who received at least 1 dose of study medication.

Type IC Population consists of those subjects with at least one Type IC seizure during the Baseline period.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day Placebo: Daily oral dose of two equal intakes, morning and evening, of Placebo in a double-blinded way for the 16-week Treatment Period	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 Brivaracetam: 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
Overall Number of Participants Analyzed	35	94
Measure Type: Number; Unit of Measure: percentage of participants
	54.3	47.9

9. Secondary Outcome

Title	Time to First Type I Seizure During the 16-week Treatment Period
Description	Time to first Type I seizure during the 16-week Treatment Period was measured in days.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Median (95% Confidence Interval); Unit of Measure: days
	3; (2 to 4)	4; (4 to 5)

10. Secondary Outcome

Title	Time to Fifth Type I Seizure During the 16-week Treatment Period
Description	Time to fifth Type I seizure during the 16-week Treatment Period was measured in days.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Median (95% Confidence Interval); Unit of Measure: days
	14; (11 to 19)	18; (16 to 21)

11. Secondary Outcome

Title	Time to Tenth Type I Seizure During Treatment Period
Description	Time to tenth Type I seizure during the 16-week Treatment Period was measured in days.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	323
Median (95% Confidence Interval); Unit of Measure: days
	36; (23 to 44)	38; (31 to 43)

12. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	98	284
Mean (Standard Deviation); Unit of Measure: units on a scale
	3.04 (12.58)	4.22 (13.73)

13. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	99	291
Mean (Standard Deviation); Unit of Measure: units on a scale
	4.66 (23.23)	10.29 (21.99)

14. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	99	290
Mean (Standard Deviation); Unit of Measure: units on a scale
	5.61 (21.87)	2.66 (23.48)

15. Secondary Outcome

Title	Change From Baseline to the 16-week Treatment Period in Hospital Anxiety Score
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the HADS. Only subjects having values at baseline ans at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	97	286
Mean (Standard Deviation); Unit of Measure: units on a scale
	-0.57 (3.35)	-0.85 (3.62)

16. Secondary Outcome

Title	Change From Baseline to the 16-week Treatment Period in Hospital Depression Score
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the HADS. Only subjects having values at baseline ans at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	97	285
Mean (Standard Deviation); Unit of Measure: units on a scale
	0.30 (3.08)	-0.41 (3.54)

17. Secondary Outcome

Title	Patient's Global Evaluation Scale (P-GES) Evaluated at Last Visit or Early Discontinuation Visit
Description	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?'
Time Frame	Baseline to last visit or early discontinuation visit in the 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Evaluable subjects are subjects who completed the GES at last treatment period visit.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	99	282
Mean (Standard Deviation); Unit of Measure: units on a scale
	4.73 (1.37)	5.07 (1.36)

18. Secondary Outcome

Title	Investigator's Global Evaluation Scale (I-GES) Evaluated at Last Visit or Early Discontinuation Visit
Description	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.'
Time Frame	Baseline to Last Visit or Early Discontinuation Visit in the 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Evaluable subjects are subjects for whom the GES was completed by the investigator at last treatment period visit.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	108	319
Mean (Standard Deviation); Unit of Measure: units on a scale
	4.79 (1.14)	5.00 (1.22)

19. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	99	286
Mean (Standard Deviation); Unit of Measure: units on a scale
	2.98 (18.00)	3.34 (19.06)

20. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	99	287
Mean (Standard Deviation); Unit of Measure: units on a scale
	1.97 (19.29)	2.84 (18.07)

21. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	99	290
Mean (Standard Deviation); Unit of Measure: units on a scale
	2.28 (19.88)	5.51 (18.55)

22. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	98	291
Mean (Standard Deviation); Unit of Measure: units on a scale
	-0.48 (17.40)	4.08 (19.23)

23. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to 16-week Treatment Period

Outcome Measure Data

Analysis Population Description

Localization-related epilepsy Intent-To-Treat (ITT) Population (POS). The ITT Population was defined as all randomized subjects who received at least 1 dose of study medication.

Only subjects who are not mentally impaired were to complete the QOLIE-31-P. Only subjects having values at baseline and at the considered visit are included.

Arm/Group Title	Placebo	Brivaracetam
Arm/Group Description:	Matching Placebo tablets administered twice a day	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
Overall Number of Participants Analyzed	99	290
Mean (Standard Deviation); Unit of Measure: units on a scale
	2.83 (27.21)	-0.24 (25.84)

Adverse Events

Time Frame	Adverse Events (AEs) were collected up to 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20).
Adverse Event Reporting Description	Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
Arm/Group Title	Placebo		Brivaracetam
Arm/Group Description	Matching Placebo tablets administered twice a day		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
All-Cause Mortality
	Placebo		Brivaracetam
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Placebo		Brivaracetam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/121 (7.44%)		20/359 (5.57%)
Blood and lymphatic system disorders
Neutropenia * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Cardiac disorders
Myocardial ischaemia * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Ear and labyrinth disorders
Vertigo * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Gastrointestinal disorders
Abdominal pain * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
General disorders
Chest pain * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Drowning * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Fatigue * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Infections and infestations
Hepatitis B * 1	1/121 (0.83%)	1	0/359 (0.00%)	0
Pyelonephritis acute * 1	1/121 (0.83%)	1	0/359 (0.00%)	0
Injury, poisoning and procedural complications
Drug toxity * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Overdose * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Ankle fracture * 1	1/121 (0.83%)	1	0/359 (0.00%)	0
Burns second degree * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Face injury * 1	1/121 (0.83%)	1	0/359 (0.00%)	0
Fall * 1	1/121 (0.83%)	1	0/359 (0.00%)	0
Head injury * 1	1/121 (0.83%)	1	0/359 (0.00%)	0
Skin laceration * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Spinal fracture * 1	1/121 (0.83%)	1	0/359 (0.00%)	0
Metabolism and nutrition disorders
Diabetis mellitus inadequate control * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Nervous system disorders
Headache * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Tremor * 1	1/121 (0.83%)	1	0/359 (0.00%)	0
Dizziness * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Postictal state * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
Convulsion * 1	1/121 (0.83%)	1	7/359 (1.95%)	9
Status epilepticus * 1	0/121 (0.00%)	0	1/359 (0.28%)	3
Pregnancy, puerperium and perinatal conditions
Pregnancy * 1	0/121 (0.00%)	0	2/359 (0.56%)	2
Psychiatric disorders
Depression * 1	1/121 (0.83%)	1	1/359 (0.28%)	1
Psychotic disorder * 1	0/121 (0.00%)	0	1/359 (0.28%)	1
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 9.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Brivaracetam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/121 (33.06%)		139/359 (38.72%)
Gastrointestinal disorders
Nausea * 1	11/121 (9.09%)	14	20/359 (5.57%)	26
General disorders
Fatigue * 1	5/121 (4.13%)	5	27/359 (7.52%)	31
Infections and infestations
Nasopharyngitis * 1	8/121 (6.61%)	10	14/359 (3.90%)	16
Musculoskeletal and connective tissue disorders
Back pain * 1	8/121 (6.61%)	9	11/359 (3.06%)	11
Nervous system disorders
Dizziness * 1	7/121 (5.79%)	9	31/359 (8.64%)	36
Headache * 1	24/121 (19.83%)	45	52/359 (14.48%)	79
Somnolence * 1	5/121 (4.13%)	7	40/359 (11.14%)	47
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 9.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: UCB (Study Director)
• Organization: UCB Clinical Trial Call Center
• Phone: +1 877 822 9493

Publications of Results:

Kwan P, Trinka E, Van Paesschen W, Rektor I, Johnson ME, Lu S. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia. 2014 Jan;55(1):38-46. doi: 10.1111/epi.12391. Epub 2013 Oct 3.

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: 10.1007/s11136-016-1483-3. Epub 2016 Dec 21.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bresnahan R, Panebianco M, Marson AG. Brivaracetam add-on therapy for drug-resistant epilepsy. Cochrane Database Syst Rev. 2022 Mar 14;3(3):CD011501. doi: 10.1002/14651858.CD011501.pub3.

Ben-Menachem E, Baulac M, Hong SB, Cleveland JM, Reichel C, Schulz AL, Wagener G, Brandt C. Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease: An open-label, long-term follow-up trial. Epilepsy Res. 2021 Feb;170:106526. doi: 10.1016/j.eplepsyres.2020.106526. Epub 2020 Dec 4.

• Responsible Party: UCB Pharma ( UCB Pharma SA )
• ClinicalTrials.gov Identifier: NCT00504881
• Other Study ID Numbers: N01254; 2006-006346-34 ( EudraCT Number )
• First Submitted: July 19, 2007
• First Posted: July 20, 2007
• Results First Submitted: March 14, 2016
• Results First Posted: March 17, 2017
• Last Update Posted: April 3, 2018