Safety and Tolerability of Intravenous Brivaracetam (Infusion or Bolus) as Adjunctive Antiepileptic Therapy

• ClinicalTrials.gov Identifier: NCT01405508
• Recruitment Status: Completed
• First Posted: July 29, 2011
• Results First Posted: April 13, 2016
• Last Update Posted: July 11, 2018
• Sponsor: UCB Pharma
• Information provided by (Responsible Party): UCB Pharma

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Epilepsy
• Interventions: Drug: Brivaracetam tablets; Drug: Brivaracetam bolus; Drug: Brivaracetam infusion; Other: Placebo
• Enrollment: 105

Participant Flow

Recruitment Details	This study started to recruit patients in August 2011 and concluded in July 2012. 105 subjects were randomized to 4 different treatment groups.
Pre-assignment Details	Participant Flow refers to the Randomized Set (RS).

Arm/Group Title	Placebo Tablets / Brivaracetam Bolus	Placebo Tablets / Brivaracetam Infusion	Brivaracetam (BRV) Tablets / BRV Bolus	Brivaracetam (BRV) Tablets / BRV Infusion
Arm/Group Description	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week
Period Title: Overall Study
Started	26	26	27	26
Completed	25	25	27	26
Not Completed	1	1	0	0
Reason Not Completed
AE, non-serious non-fatal	1	1	0	0

Baseline Characteristics

Arm/Group Title		Placebo Tablets / Brivaracetam Bolus	Placebo Tablets / Brivaracetam Infusion	Brivaracetam (BRV) Tablets / BRV Bolus	Brivaracetam (BRV) Tablets / BRV Infusion	Total Title
Arm/Group Description		Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	[Not Specified]
Overall Number of Baseline Participants		26	26	27	26	105
Baseline Analysis Population Description		Baseline Characetristics refer to the Safety Population consisting of all subjects who took at least 1 dose of study drug.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	26 participants	26 participants	27 participants	26 participants	105 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	26 100.0%	25 96.2%	27 100.0%	25 96.2%	103 98.1%
	>=65 years	0 0.0%	1 3.8%	0 0.0%	1 3.8%	2 1.9%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	26 participants	26 participants	27 participants	26 participants	105 participants
		40.6 (12.2)	39.5 (14.4)	42.0 (9.2)	44.4 (12.6)	41.6 (12.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	26 participants	26 participants	27 participants	26 participants	105 participants
	Female	12 46.2%	10 38.5%	17 63.0%	17 65.4%	56 53.3%
	Male	14 53.8%	16 61.5%	10 37.0%	9 34.6%	49 46.7%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With at Least One Treatment-emergent Adverse Event During the Study (Maximum 40 Days)
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 could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time Frame	40 days

Outcome Measure Data

Analysis Population Description

Safety Population consisting of all subjects who took at least 1 dose of study drug.

Arm/Group Title	Placebo Tablets / Brivaracetam Bolus	Placebo Tablets / Brivaracetam Infusion	Brivaracetam (BRV) Tablets / BRV Bolus	Brivaracetam (BRV) Tablets / BRV Infusion
Arm/Group Description:	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week
Overall Number of Participants Analyzed	26	26	27	26
Measure Type: Number; Unit of Measure: Participants
	20	19	21	20

2. Secondary Outcome

Title	Number of Subjects Who Withdrew Due to a Treatment-emergent Adverse Event During the Study (Maximum 40 Days)
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 could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time Frame	40 days

Outcome Measure Data

Analysis Population Description

Safety Population consisting of all subjects who took at least 1 dose of study drug.

Arm/Group Title	Placebo Tablets / Brivaracetam Bolus	Placebo Tablets / Brivaracetam Infusion	Brivaracetam (BRV) Tablets / BRV Bolus	Brivaracetam (BRV) Tablets / BRV Infusion
Arm/Group Description:	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week
Overall Number of Participants Analyzed	26	26	27	26
Measure Type: Number; Unit of Measure: Participants
	1	1	0	0

3. Secondary Outcome

Title	Number of Subjects With at Least One Injection-related Treatment-emergent Adverse Event (TEAE) During the Evaluation 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 could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time Frame	4.5-day Evaluation Period

Outcome Measure Data

Analysis Population Description

Safety Population consisting of all subjects who took at least 1 dose of study drug.

Arm/Group Title	Placebo Tablets / Brivaracetam Bolus	Placebo Tablets / Brivaracetam Infusion	Brivaracetam (BRV) Tablets / BRV Bolus	Brivaracetam (BRV) Tablets / BRV Infusion
Arm/Group Description:	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week	Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week
Overall Number of Participants Analyzed	26	26	27	26
Measure Type: Number; Unit of Measure: Participants
	1	3	4	3

Adverse Events

Time Frame	Adverse Events were collected from Baseline over Run-In (Day 1) and Evaluation Period (Day 8 to Day 12) to the Safety Visit or Early Discontinuation Visit (up to 54 days).
Adverse Event Reporting Description	Adverse Events refer to the Safety Population consisting of all subjects who took at least 1 dose of study drug.
Arm/Group Title	Placebo Tablets / Brivaracetam Bolus		Placebo Tablets / Brivaracetam Infusion		Brivaracetam (BRV) Tablets / BRV Bolus		Brivaracetam (BRV) Tablets / BRV Infusion
Arm/Group Description	Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week		Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week		Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week		Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In; If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week
All-Cause Mortality
	Placebo Tablets / Brivaracetam Bolus		Placebo Tablets / Brivaracetam Infusion		Brivaracetam (BRV) Tablets / BRV Bolus		Brivaracetam (BRV) Tablets / BRV Infusion
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--		--/--
Serious Adverse Events
	Placebo Tablets / Brivaracetam Bolus		Placebo Tablets / Brivaracetam Infusion		Brivaracetam (BRV) Tablets / BRV Bolus		Brivaracetam (BRV) Tablets / BRV Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0.00%)		0/26 (0.00%)		0/27 (0.00%)		0/26 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo Tablets / Brivaracetam Bolus		Placebo Tablets / Brivaracetam Infusion		Brivaracetam (BRV) Tablets / BRV Bolus		Brivaracetam (BRV) Tablets / BRV Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/26 (65.38%)		15/26 (57.69%)		15/27 (55.56%)		14/26 (53.85%)
Cardiac disorders
Postural orthostatic tachycardia syndrome * 1	2/26 (7.69%)	2	0/26 (0.00%)	0	1/27 (3.70%)	1	0/26 (0.00%)	0
Ear and labyrinth disorders
Vertigo * 1	1/26 (3.85%)	1	1/26 (3.85%)	1	2/27 (7.41%)	2	1/26 (3.85%)	1
Gastrointestinal disorders
Dyspepsia * 1	1/26 (3.85%)	1	0/26 (0.00%)	0	2/27 (7.41%)	2	0/26 (0.00%)	0
General disorders
Fatigue * 1	1/26 (3.85%)	1	2/26 (7.69%)	4	3/27 (11.11%)	4	0/26 (0.00%)	0
Infusion site pain * 1	0/26 (0.00%)	0	3/26 (11.54%)	3	2/27 (7.41%)	2	0/26 (0.00%)	0
Injection site erythema * 1	0/26 (0.00%)	0	0/26 (0.00%)	0	2/27 (7.41%)	2	0/26 (0.00%)	0
Injection site pain * 1	0/26 (0.00%)	0	0/26 (0.00%)	0	2/27 (7.41%)	2	0/26 (0.00%)	0
Nervous system disorders
Somnolence * 1	8/26 (30.77%)	8	7/26 (26.92%)	7	7/27 (25.93%)	9	9/26 (34.62%)	10
Dizziness * 1	4/26 (15.38%)	4	4/26 (15.38%)	4	3/27 (11.11%)	3	4/26 (15.38%)	4
Headache * 1	2/26 (7.69%)	2	1/26 (3.85%)	1	2/27 (7.41%)	3	2/26 (7.69%)	2
Dysgeusia * 1	2/26 (7.69%)	2	0/26 (0.00%)	0	2/27 (7.41%)	2	0/26 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough * 1	0/26 (0.00%)	0	2/26 (7.69%)	2	0/27 (0.00%)	0	0/26 (0.00%)	0
Skin and subcutaneous tissue disorders
Rash * 1	3/26 (11.54%)	3	1/26 (3.85%)	1	0/27 (0.00%)	0	0/26 (0.00%)	0
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA15.0

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 Cares
• Phone: +1 887 822 9493

• Responsible Party: UCB Pharma
• ClinicalTrials.gov Identifier: NCT01405508
• Other Study ID Numbers: N01258; 2008-004714-27 ( EudraCT Number )
• First Submitted: July 27, 2011
• First Posted: July 29, 2011
• Results First Submitted: March 14, 2016
• Results First Posted: April 13, 2016
• Last Update Posted: July 11, 2018