BRITE: Brivaracetam Efficacy and Safety Study in Subjects With Partial Onset Seizures

• Sponsor: UCB Pharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01261325
• Collaborator: (none)
• Enrollment: 768
• Locations: 207
• Arms: 3
• Duration (Months): 41
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of brivaracetam at doses of 100 and 200mg/day compared to placebo as adjunctive treatment in adult focal epilepsy subjects with partial onset seizures not fully controlled despite current treatment with 1 or 2 concomitant antiepileptic drugs.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: Placebo; Drug: Brivaracetam; Drug: Brivaracetam; Drug: Antiepileptic drugs with market authorization available per country	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 768 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study to Evaluate the Efficacy and Safety of Brivaracetam in Subjects (≥16 to 80 Years Old) With Partial Onset Seizures
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching placebo tablets administered twice daily	Drug: Placebo; Daily oral dose of two equal intakes of placebo in a double-blinded way for the 12-week treatment period; Drug: Antiepileptic drugs with market authorization available per country
Experimental: Brivaracetam 100 mg/ day Brivaracetam 50 mg/ day administered twice daily.	Drug: Brivaracetam; Daily oral dose of two equal intakes of Brivaracetam 100 mg/ day in a double-blinded way for the 12-week treatment period; Drug: Antiepileptic drugs with market authorization available per country
Experimental: Brivaracetam 200 mg/ day Brivaracetam 100 mg/ day administered twice daily	Drug: Brivaracetam; Daily oral dose of two equal intakes of Brivaracetam 200 mg/ day in a double-blinded way for the 12-week treatment period.; Drug: Antiepileptic drugs with market authorization available per country

Outcome Measures

Primary Outcome Measures

1. Percent Reduction Over Placebo for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration [12 week Treatment Period]

   Primary endpoint: United States of America (FDA)

2. 50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration [Baseline to 12 week Treatment Period]

   Primary Endpoint: European Regulatory Authorities A responder is a participant who experienced a 50% or greater reduction in partial onset seizure (Type I) frequency over the Treatment Period standardized to a 28-day duration.

Secondary Outcome Measures

1. Percent Change in Partial Onset Seizure (Type I) Frequency From the Baseline to the Treatment Period [Baseline to 12 week Treatment Period]

2. Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period [Baseline to 12 week Treatment Period]

3. Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period [12 week Treatment Period]

4. All Seizure Frequency (Type I + II + III) During the 12-week Treatment Period [12 week Treatment Period]

5. Time to the First Type I Seizure During the Treatment Period [12 week Treatment Period]

6. Time to the Fifth Type I Seizure During the Treatment Period [12 week Treatment Period]

7. Time to the Tenth Type I Seizure During the Treatment Period [12 week Treatment Period]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Well-characterized focal epilepsy/epileptic syndrome according to the 1989 International League Against Epilepsy (ILAE) classification

• Presence of an EEG reading compatible with the clinical diagnosis of focal epilepsy within the last 5 years

• Presence of a brain MRI/computed tomography (CT) scan performed within the last 2 years

• Subjects having at least 8 Type I seizures [POS; focal seizures (according to the 1981 ILAE classification)] during the 8-week Baseline Period with at least 2 Type I seizures during each 4-week interval of the Baseline Period

• Subjects having at least 2 partial onset seizures whether or not secondarily generalized per month during the 3 months preceding V1

• Subjects being uncontrolled while treated by 1 or 2 permitted concomitant AED(s). Vagal Nerve Stimulation (VNS) is allowed and will be counted as a concomitant AED

• Permitted concomitant AED(s) and VNS being stable and at optimal dosage for the subject from at least 1 month (3 months for phenobarbital, phenytoin, and primidone) before V1 and expected to be kept stable during the Baseline and Treatment Period. Benzodiazepine taken more than once a week (for any indication) will be considered as a concomitant AED

Exclusion Criteria:

• Subject previously randomized within this study or any other prior study with BRV as a dosing arm

• Seizure type IA (1981 ILAE classification) nonmotor as only seizure type.

• Subject is currently treated with LEV or has taken LEV within 90 days prior to V1

• Subject has any medical or psychiatric condition, obvious cognitive impairment or mental retardation that, in the opinion of the Investigator, could jeopardize or would compromise the subject's ability to participate in this study

• Subjects whose seizures could not be reliably counted on a regular basis due to their fast and repetitive occurrence (clusters or flurries)

• Subject has history or presence of status epilepticus during the year preceding V1 or during Baseline

• Subject has history or presence of known psychogenic nonepileptic seizures

• Subject on felbamate with less than 18 months exposure before V1

• Subject currently on vigabatrin. Subject with history of vigabatrin use but either no visual fields examination report available including standard static (Humphrey or Octopus) or kinetic perimetry (Goldman) or results of these examinations are abnormal

• Subject taking any drug with possible central nervous system (CNS) effects except if stable from at least 1 month before V1 and expected to be kept stable during the Treatment Period

• Subject has history of cerebrovascular accident, including transient ischemic attack, in the last 6 months

• Subject is suffering from severe cardiovascular disease or peripheral vascular disease

• Subject has a lifetime history of suicide attempt or has suicidal ideation in the past 6 months

• Subject has ongoing psychiatric disease other than mild controlled disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	001	Phoenix	Arizona	United States
2	013	Phoenix	Arizona	United States
3	006	Tucson	Arizona	United States
4	775	Little Rock	Arkansas	United States
5	045	Sacramento	California	United States
6	025	San Francisco	California	United States
7	060	Aurora	Colorado	United States
8	085	Colorado Springs	Colorado	United States
9	071	Miami	Florida	United States
10	110	Miami	Florida	United States
11	073	Naples	Florida	United States
12	090	Ocala	Florida	United States
13	027	Orlando	Florida	United States
14	064	Port Charlotte	Florida	United States
15	044	Sarasota	Florida	United States
16	023	Atlanta	Georgia	United States
17	063	Atlanta	Georgia	United States
18	062	Columbus	Georgia	United States
19	048	Rome	Georgia	United States
20	039	Boise	Idaho	United States
21	005	Peoria	Illinois	United States
22	017	Winfield	Illinois	United States
23	020	Ames	Iowa	United States
24	069	Iowa City	Iowa	United States
25	780	Lexington	Kentucky	United States
26	092	Hammond	Louisiana	United States
27	008	Bethesda	Maryland	United States
28	068	Waldorf	Maryland	United States
29	055	East Lansing	Michigan	United States
30	009	Golden Valley	Minnesota	United States
31	051	Missoula	Montana	United States
32	032	Lebanon	New Hampshire	United States
33	042	Hamilton	New Jersey	United States
34	058	Voorhees	New Jersey	United States
35	095	Kingston	New York	United States
36	022	New York	New York	United States
37	099	New York	New York	United States
38	098	Poughkeepsie	New York	United States
39	010	Asheville	North Carolina	United States
40	003	Durham	North Carolina	United States
41	096	Canton	Ohio	United States
42	034	Cleveland	Ohio	United States
43	070	Columbus	Ohio	United States
44	002	Toledo	Ohio	United States
45	043	Oklahoma City	Oklahoma	United States
46	091	Oklahoma City	Oklahoma	United States
47	054	Tulsa	Oklahoma	United States
48	015	Philadelphia	Pennsylvania	United States
49	028	Charleston	South Carolina	United States
50	021	Port Royal	South Carolina	United States
51	050	Arlington	Texas	United States
52	061	Austin	Texas	United States
53	011	Dallas	Texas	United States
54	035	Dallas	Texas	United States
55	049	Houston	Texas	United States
56	036	Charlottesville	Virginia	United States
57	033	Seattle	Washington	United States
58	056	Spokane	Washington	United States
59	052	Madison	Wisconsin	United States
60	057	Milwaukee	Wisconsin	United States
61	089	Casper	Wyoming	United States
62	202	Innsbruck		Austria
63	201	Linz		Austria
64	200	Wien		Austria
65	203	Wien		Austria
66	226	Hechteleksel		Belgium
67	227	Leuven		Belgium
68	228	Liege		Belgium
69	104	Belo Horizonte		Brazil
70	100	Florianopolis		Brazil
71	103	Riberao Preto		Brazil
72	101	Sao Paulo		Brazil
73	294	Blagoevrad		Bulgaria
74	286	Sofiya		Bulgaria
75	287	Sofiya		Bulgaria
76	075	Calgary	Alberta	Canada
77	078	London	Ontario	Canada
78	076	Toronto	Ontario	Canada
79	077	Greenfield Park	Quebec	Canada
80	079	Montreal	Quebec	Canada
81	080	Saskatoon	Saskatchewan	Canada
82	916	Kromeriz		Czechia
83	913	Ostrava Poruba		Czechia
84	251	Ostrava		Czechia
85	256	Ostrava		Czechia
86	252	Praha 1		Czechia
87	253	Praha 4		Czechia
88	250	Zlin		Czechia
89	650	Tallinn		Estonia
90	652	Tallinn		Estonia
91	653	Tallinn		Estonia
92	651	Tartu		Estonia
93	275	Kuopio		Finland
94	278	Oulu		Finland
95	276	Tampere		Finland
96	277	Turku		Finland
97	301	Bethune		France
98	308	Marseille		France
99	305	Montpellier		France
100	329	Berlin		Germany
101	326	Bernau		Germany
102	332	Bielefeld		Germany
103	902	Erlangen		Germany
104	331	Goettingen		Germany
105	904	Kehl-Kork		Germany
106	327	Kiel		Germany
107	900	Marburg		Germany
108	335	Muenchen		Germany
109	334	Osnabruck		Germany
110	330	Ravensburg		Germany
111	328	Ulm		Germany
112	701	Hong Kong		Hong Kong
113	700	Shatin		Hong Kong
114	410	Budapest		Hungary
115	411	Budapest		Hungary
116	412	Budapest		Hungary
117	414	Debrecen		Hungary
118	413	Kecskemet		Hungary
119	727	Hyderabad	Andhra Pradesh	India
120	731	Nashik	Maharashtra	India
121	725	Mumbai	Maharastra	India
122	728	Mumbai	Maharastra	India
123	726	Bangalore		India
124	729	Madurai		India
125	377	Monserrato	Cagliari	Italy
126	378	Bari		Italy
127	380	Firenze		Italy
128	379	Milano		Italy
129	386	Napoli		Italy
130	376	Perugia		Italy
131	375	Pisa		Italy
132	383	Pozzilli		Italy
133	384	Reggio Calabria		Italy
134	382	Torino		Italy
135	855	Hiroshima		Japan
136	852	Itami-city		Japan
137	850	Osaka		Japan
138	851	Shizuoka		Japan
139	854	Yokohama-City		Japan
140	753	Busan		Korea, Republic of
141	752	Gwangju		Korea, Republic of
142	750	Seoul		Korea, Republic of
143	751	Seoul		Korea, Republic of
144	754	Seoul		Korea, Republic of
145	627	Daugapils		Latvia
146	629	Jekabpils		Latvia
147	626	Riga		Latvia
148	628	Riga		Latvia
149	625	Valmiera		Latvia
150	425	Alytus		Lithuania
151	427	Kaunas		Lithuania
152	426	Vilnius		Lithuania
153	126	Guadalajara	Jalisco	Mexico
154	128	Guadalajara	Jalisco	Mexico
155	129	Aguascalientes		Mexico
156	127	Culiacan		Mexico
157	125	Distrito Federal		Mexico
158	130	Mexico D.F.		Mexico
159	401	Heemstede		Netherlands
160	400	Heeze		Netherlands
161	403	Zwolle		Netherlands
162	475	Bialystok		Poland
163	485	Gdansk		Poland
164	791	Gdansk		Poland
165	478	Katowice		Poland
166	480	Katowice		Poland
167	481	Katowice		Poland
168	476	Krakow		Poland
169	793	Krakow		Poland
170	483	Lublin		Poland
171	477	Poznan		Poland
172	479	Poznan		Poland
173	482	Poznan		Poland
174	488	Warszawa		Poland
175	038	San Juan		Puerto Rico
176	501	Kazan		Russian Federation
177	506	Kazan		Russian Federation
178	502	Moscow		Russian Federation
179	503	Moscow		Russian Federation
180	505	Moscow		Russian Federation
181	509	Nizhny Novgorod		Russian Federation
182	508	Smolensk		Russian Federation
183	536	Badalona		Spain
184	528	Barcelona		Spain
185	529	Barcelona		Spain
186	535	Barcelona		Spain
187	540	Barcelona		Spain
188	539	San Sebastian		Spain
189	532	Santiago de Compostela		Spain
190	527	Valencia		Spain
191	537	Valencia		Spain
192	526	Valladolid		Spain
193	551	Goteborg		Sweden
194	552	Linkoping		Sweden
195	550	Stockholm		Sweden
196	806	Kaohsiung City		Taiwan
197	801	Taichung		Taiwan
198	800	Tainan		Taiwan
199	803	Taoyuan Hsien		Taiwan
200	603	Birmingham		United Kingdom
201	606	Cardiff		United Kingdom
202	601	Cornwall		United Kingdom
203	600	London		United Kingdom
204	605	Middlesborough		United Kingdom
205	607	Newcastle		United Kingdom
206	608	Salford		United Kingdom
207	602	Swansea		United Kingdom

Sponsors and Collaborators

• UCB Pharma

Investigators

• Study Director: UCB Clinical Trial Call Center, [phone] (UCB)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Product Information
• FDA Safety Alerts and Recalls

Publications

None provided.

• Responsible Party: UCB Pharma
• ClinicalTrials.gov Identifier: NCT01261325
• Other Study ID Numbers: N01358; 2010-019361-28
• First Posted: Dec 16, 2010
• Last Update Posted: Jul 22, 2022
• Last Verified: Jul 1, 2022

• Keywords provided by UCB Pharma: Epilepsy; Brivaracetam; Partial Onset Seizures; Adjunctive treatment
• Additional relevant MeSH terms: Epilepsy; Seizures; Brivaracetam; Anticonvulsants

Study Results

Participant Flow

Recruitment Details	Recruitment for the N01358 study began in December 2010. The study concluded in May 2014.
Pre-assignment Detail	The Participant Flow and Baseline Demographics data is taken from the Randomized Set (RS). The RS consists of all subjects who were randomized.

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Period Title: Overall Study
STARTED	263	254	251
COMPLETED	246	225	225
NOT COMPLETED	17	29	26

Baseline Characteristics

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day	Total Title
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Overall Participants	263	254	251	768
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.8 (12.8)	39.0 (13.4)	39.7 (12.8)	39.5 (13.0)
Sex: Female, Male (Count of Participants)
Female	128 48.7%	152 59.8%	117 46.6%	397 51.7%
Male	135 51.3%	102 40.2%	134 53.4%	371 48.3%
Weight (kilograms) [Median (Standard Deviation) ]
Median (Standard Deviation) [kilograms]	76.1 (19.9)	74.1 (16.8)	75.5 (19.0)	75.2 (18.6)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	168.4 (10.0)	166.6 (9.8)	168.7 (9.9)	167.9 (9.9)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.6 (5.7)	26.7 (5.6)	26.4 (6.0)	26.6 (5.8)
Racial Group (participants) [Number]
American Indian or Alaska Native	10 3.8%	8 3.1%	11 4.4%	29 3.8%
Asian	32 12.2%	32 12.6%	29 11.6%	93 12.1%
Black or African American	11 4.2%	8 3.1%	7 2.8%	26 3.4%
White	190 72.2%	183 72%	183 72.9%	556 72.4%
Other	17 6.5%	21 8.3%	18 7.2%	56 7.3%
Missing	3 1.1%	2 0.8%	3 1.2%	8 1%

Outcome Measures

1. Primary Outcome

Title	Percent Reduction Over Placebo for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration
Description	Primary endpoint: United States of America (FDA)
Time Frame	12 week Treatment Period

Outcome Measure Data

Analysis Population Description

Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.

Arm/Group Title	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day	Placebo
Arm/Group Description	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily	Matching placebo tablets administered twice daily
Measure Participants	252	249	259
Number [Percentage of reduction]	22.8	23.2	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Type I error rate of 0.05 based on a Hochberg multiple comparison procedure would be considered statistically significant" or similar, as accurate and appropriate.
	Method	ANCOVA
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Percent reduction over PBO
	Estimated Value	22.8
	Confidence Interval	(2-Sided) 95%; 13.3 to 31.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 200 mg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant with control of Type I error rate based on a Hochberg multiple comparison procedure.
	Method	ANCOVA
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Percent reduction over PBO
	Estimated Value	23.2
	Confidence Interval	(2-Sided) 95%; 13.8 to 31.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	50% Responder Rate for Partial Onset Seizure (Type I) Frequency Over the Treatment Period Standardized to a 28-day Duration
Description	Primary Endpoint: European Regulatory Authorities A responder is a participant who experienced a 50% or greater reduction in partial onset seizure (Type I) frequency over the Treatment Period standardized to a 28-day duration.
Time Frame	Baseline to 12 week Treatment Period

Outcome Measure Data

Analysis Population Description

Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Measure Participants	259	252	249
Responders	21.6	38.9	37.8
Non-Responders	78.4	61.1	62.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Brivaracetam 200 mg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant with control of Type I error rate based on a Hochberg multiple comparison procedure.
	Method	Regression, Logistic
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Odds ratio (BRV versus PBO)
	Estimated Value	2.39
	Confidence Interval	(2-Sided) 95%; 1.6 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant with control of Type I error rate based on a Hochberg multiple comparison procedure.
	Method	Regression, Logistic
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Odds ratio (BRV versus PBO)
	Estimated Value	2.19
	Confidence Interval	(2-Sided) 95%; 1.5 to 3.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percent Change in Partial Onset Seizure (Type I) Frequency From the Baseline to the Treatment Period
Time Frame	Baseline to 12 week Treatment Period

Outcome Measure Data

Analysis Population Description

Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Measure Participants	259	252	249
Median (Inter-Quartile Range) [percentage of change]	17.6	37.2	35.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Brivaracetam 200 mg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant at a nominal 0.050 significance level.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median difference vs placebo
	Estimated Value	15.8
	Confidence Interval	(2-Sided) 95%; 7.6 to 24.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hodges-Lehmann non-parametric effect estimates and corresponding two-sided 95% confidence intervals are provided above.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant at a nominal 0.050 significance level.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median difference vs placebo
	Estimated Value	18.1
	Confidence Interval	(2-Sided) 95%; 10.4 to 26.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hodges-Lehmann non-parametric effect estimates and corresponding two-sided 95% confidence intervals are provided above.

4. Secondary Outcome

Title	Categorized Percent Reduction Form Baseline in Seizure Frequency for Partial Onset Seizure (Type I) Over the Treatment Period
Time Frame	Baseline to 12 week Treatment Period

Outcome Measure Data

Analysis Population Description

Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Measure Participants	259	252	249
<-25 %	16.6	14.3	10.8
-25 % to <25 %	40.5	28.6	29.3
25 % to <50 %	21.2	18.3	22.1
50 % to <75 %	13.9	19.0	18.1
75 % to <100 %	6.9	13.9	13.7
100 %	0.8	6.0	6.0

5. Secondary Outcome

Title	Seizure Freedom Rate (All Seizure Types) During the 12-week Treatment Period
Time Frame	12 week Treatment Period

Outcome Measure Data

Analysis Population Description

Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Measure Participants	259	252	249
Seizure free	0.8	5.2	4.0
No seizures but discontinued	0.4	1.2	1.2
Not seizure free	98.8	93.7	94.8

6. Secondary Outcome

Title	All Seizure Frequency (Type I + II + III) During the 12-week Treatment Period
Time Frame	12 week Treatment Period

Outcome Measure Data

Analysis Population Description

Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Measure Participants	259	252	249
Median (Inter-Quartile Range) [number of seizures/ 28-day]	8.7	6.3	5.8

7. Secondary Outcome

Title	Time to the First Type I Seizure During the Treatment Period
Time Frame	12 week Treatment Period

Outcome Measure Data

Analysis Population Description

Analysis population consists of the Intent-to-Treat (ITT) Population, which is all randomized subjects who received at least 1 dose of study medication and have at least 1 post-Baseline seizure diary.

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Measure Participants	259	252	249
Median (95% Confidence Interval) [days]	3	5	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Brivaracetam 200 mg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant at a nominal 0.050 significance level.
	Method	Semi-parametric hazards regression model
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.56 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Brivaracetam versus Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant at a nominal 0.050 significance level.
	Method	Semi-parametric hazards regression model
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.54 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Brivaracetam versus Placebo.

8. Secondary Outcome

Title	Time to the Fifth Type I Seizure During the Treatment Period
Time Frame	12 week Treatment Period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Measure Participants	259	252	249
Median (95% Confidence Interval) [days]	16	21	23

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Brivaracetam 200 mg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant at a nominal 0.050 significance level.
	Method	Semi-parametric hazards regression model
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Brivaracetam versus Placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant at a nominal 0.050 significance level.
	Method	Semi-parametric hazards regression model
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.47 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio is Brivaracetam versus Placebo.

9. Secondary Outcome

Title	Time to the Tenth Type I Seizure During the Treatment Period
Time Frame	12 week Treatment Period

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Brivaracetam 100 mg/Day	Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily	Brivaracetam 50 mg administered twice daily	Brivaracetam 100 mg administered twice daily
Measure Participants	259	252	249
Median (95% Confidence Interval) [days]	32	37	43

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Brivaracetam 200 mg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	Statistically significant at a nominal 0.050 significance level.
	Method	Semi-parametric hazards regression model
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Brivaracetam 100 mg/Day, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant at a nominal 0.050 significance level.
	Method	Semi-parametric hazards regression model
	Comments	Effects of treatment, country, combination of LEV status and number of previous AEDs, and log-transformed baseline seizure frequency are in the model.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.55 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment-emergent Adverse Events (TEAE) were collected during the study up to week 18
Adverse Event Reporting Description	TEAEs are comprised of the Safety Population, which consists of all randomized subjects who receive at least 1 dose of study medication. The Non-serious Adverse Events section represents a >= 5% threshold of subjects experiencing Non-serious TEAEs in any treatment group and not the total population.
Arm/Group Title	Placebo		Brivaracetam 100 mg/Day		Brivaracetam 200 mg/Day
Arm/Group Description	Matching placebo tablets administered twice daily		Brivaracetam 50 mg administered twice daily		Brivaracetam 100 mg administered twice daily
All Cause Mortality
	Placebo		Brivaracetam 100 mg/Day		Brivaracetam 200 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Brivaracetam 100 mg/Day		Brivaracetam 200 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/261 (3.4%)		8/253 (3.2%)		8/250 (3.2%)
Cardiac disorders
Acute myocardial infarction	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Coronary artery stenosis	1/261 (0.4%)	1	0/253 (0%)	0	0/250 (0%)	0
General disorders
Death	0/261 (0%)	0	0/253 (0%)	0	1/250 (0.4%)	1
Sudden unexplained death in epilepsy	0/261 (0%)	0	0/253 (0%)	0	1/250 (0.4%)	1
Infections and infestations
Localised infection	0/261 (0%)	0	0/253 (0%)	0	1/250 (0.4%)	1
Meningitis viral	1/261 (0.4%)	1	0/253 (0%)	0	0/250 (0%)	0
Pneumonia	1/231 (0.4%)	1	0/253 (0%)	0	0/250 (0%)	0
Injury, poisoning and procedural complications
Fall	0/261 (0%)	0	1/253 (0.4%)	1	2/250 (0.8%)	2
Craniocerebral injury	0/261 (0%)	0	0/253 (0%)	0	1/250 (0.4%)	1
Humerus fracture	0/261 (0%)	0	0/253 (0%)	0	1/250 (0.4%)	1
Rib fracture	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Traumatic renal injury	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Clavicle fracture	1/261 (0.4%)	1	0/253 (0%)	0	0/250 (0%)	0
Joint dislocation	1/261 (0.4%)	1	0/253 (0%)	0	0/250 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Thymoma	1/261 (0.4%)	1	0/253 (0%)	0	0/250 (0%)	0
Nervous system disorders
Grand mal convulsion	1/261 (0.4%)	1	0/253 (0%)	0	1/250 (0.4%)	1
Seizure cluster	0/261 (0%)	0	0/253 (0%)	0	1/250 (0.4%)	1
Status epilepticus	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Epilepsy	1/261 (0.4%)	1	0/253 (0%)	0	0/250 (0%)	0
Postictal state	1/261 (0.4%)	1	0/253 (0%)	0	0/250 (0%)	0
Psychiatric disorders
Adjustment disorder	0/261 (0%)	0	1/253 (0.4%)	1	1/250 (0.4%)	1
Agitation	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Conversion disorder	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Epileptic psychosis	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Psychotic disorder	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Vascular disorders
Haematoma	0/261 (0%)	0	1/253 (0.4%)	1	0/250 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Brivaracetam 100 mg/Day		Brivaracetam 200 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/261 (23.4%)		96/253 (37.9%)		97/250 (38.8%)
General disorders
Fatigue	10/261 (3.8%)	10	19/253 (7.5%)	19	29/250 (11.6%)	32
Infections and infestations
Urinary tract infection	8/261 (3.1%)	8	13/253 (5.1%)	13	2/250 (0.8%)	2
Nervous system disorders
Somnolence	20/261 (7.7%)	20	49/253 (19.4%)	53	42/250 (16.8%)	43
Dizziness	13/261 (5%)	14	26/253 (10.3%)	27	36/250 (14.4%)	38
Headache	22/261 (8.4%)	30	17/253 (6.7%)	18	20/250 (8%)	21

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

UCB has > 60 but <= 180 days to review results communications prior to public release and may delete information that is confidential and compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that the results shall be published regardless of outcome.