Conditions: Epilepsy
Keywords: Epilepsy Brivaracetam Epilepsy Monitoring Unit Increased seizure activity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of intravenous brivaracetam (BRV) compared to intravenous lorazepam (LZP) in subjects with epilepsy undergoing Epilepsy Monitoring Unit (EMU) evaluation who experience seizures that require prompt treatment.

Detailed description:

Arms:
arm 1: Two 5 ml vials of brivaracetam administered intravenously over a 2-minute period arm 2: Four 5 ml vials of brivaracetam administered intravenously over a 4-minute period arm 3: Lorazepam bolus is to be injected based on information from the patient leaflet/package insert. The rate of injection should not exceed 2.0 mg/min. The LZP dose will be determined according to the Investigator's clinical judgment.

Interventions: intervention 1: Brivaracetam intervention 2: Lorazepam
Intervention descriptions: intervention 1: * Pharmaceutical Form: Solution for infusion
* Concentration: 10 mg/ml
* Route of Administration: intravenous intervention 2: * Pharmaceutical Form: Solution for injection
* Route of Administration: intravenous

Protocol document:
Prot_000.pdf: 
UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 1 of 66
PROTOCOL EP0087
A MULTICENTER, OPEN-LABEL, RANDOMIZED, 
PARALLEL-GROUP, ACTIVE-CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF BRIVARACETAM 
ADMINISTERED INTRAVENOUSLY AS TREATMENT FOR 
INCREASED SEIZURE ACTIVITY IN AN EPILEPSY 
MONITORING UNIT SETTING
PHASE 2
IND Number: 103908
Sponsor:
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
BELGIUM
Protocol/Amendment number
Date
Type of 
amendment
Final Protocol
28 Jul 2016
Not applicable
Protocol Amendment 1
2626 May 2017 May 
2017
Substantial
Confidential Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 2 of 66
STUDY CONTACT INFORMATION
Sponsor
UCB Biopharma SPRL
Allée de la Recherche 60
1070 Brussels
BELGIUM
Sponsor Study Physician
Name:
Address:
UCB Pharma GmbH
Alfred-Nobel-Str. 10
40789 Monheim
Germany
Phone:
+
Clinical Project Manager
Name:
Address:
UCB Biosciences, Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617 USA
Phone:
+
Clinical Trial Biostatistician
Name:
Address:
UCB Biosciences, Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617 USA
Phone:
+
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 3 of 66
Clinical Monitoring Contract Research Organization 
Name:
Pharmaceutical Research Associates, Inc.
Address:
4130 Parklake Avenue, Suite 400
Raleigh, NC 27612
Phone:
+1 919 786 8200
Fax:
+1 919 786 8201
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 4 of 66
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
USA: +1 800 880 6949
or +1 866 890 3175
Email
Global: DS_ICT@ucb.com 
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or v


UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 5 of 66
TABLE OF CONTENTS
LIST OF ABBREVIATIONS....................................................................................................9
1
SUMMARY.....................................................................................................................11
2
INTRODUCTION ...........................................................................................................11
3
STUDY OBJECTIVES....................................................................................................12
4
STUDY VARIABLES.....................................................................................................12
4.1 Efficacy variables.............................................................................................................12
4.1.1
Primary efficacy variable.....................................................................................12
4.1.2
Secondary efficacy variables ...............................................................................12
4.1.3
Other efficacy variables.......................................................................................13
4.2 Safety variables................................................................................................................13
4.2.1
Adverse events.....................................................................................................13
4.3 Pharmacokinetic variable.................................................................................................13
5
STUDY DESIGN.............................................................................................................13
5.1 Study description .............................................................................................................13
5.1.1
Study duration per subject ...................................................................................14
5.1.2
Planned number of subjects and sites ..................................................................14
5.1.3
Anticipated regions and countries .......................................................................14
5.2 Schedule of study assessments.........................................................................................14
5.3 Schematic diagram...........................................................................................................18
5.4 Rationale for study design and selection of dose.............................................................19
6
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................19
6.1 Inclusion criteria ..............................................................................................................19
6.2 Exclusion criteria .............................................................................................................19
6.3 Withdrawal criteria ..........................................................................................................21
7
STUDY TREATMENT(S) ..............................................................................................21
7.1 Description of investigational medicinal product(s)........................................................21
7.2 Treatment(s) to be administered ......................................................................................21
7.3 Packaging.........................................................................................................................22
7.4 Labeling ...........................................................................................................................22
7.5 Handling and storage requirements..................................................................................22
7.6 Drug accountability..........................................................................................................22
7.7 Procedures for monitoring subject compliance................................................................22
7.8 Concomitant medication(s)/treatment(s)..........................................................................23
7.8.1
Permitted concomitant treatments (medications and therapies) ..........................23
7.8.2
Prohibited concomitant treatments (medications and therapies).........................23
7.8.3
Rescue medication...............................................................................................23
7.9 Blinding............................................................................................................................23
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
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7.10 Randomization and numbering of subjects......................................................................23
8
STUDY PROCEDURES BY VISIT ...............................................................................23
8.1 Day -28 to Day -1/Screening ...........................................................................................23
8.2 Day 1 (Treatment Period) ................................................................................................24
8.3 Safety Follow-Up Period .................................................................................................25
9
ASSESSMENT OF EFFICACY......................................................................................26
10
ASSESSMENT OF PHARMACOKINETIC VARIABLES...........................................26
11
BIOMARKER ASSAY REFINEMENT .........................................................................26
12
ASSESSMENT OF SAFETY..........................................................................................26
12.1 Adverse events.................................................................................................................26
12.1.1
Definitions ...........................................................................................................26
12.1.1.1
Adverse event............................................................................................26
12.1.1.2
Serious adverse event ................................................................................27
12.1.1.3
Adverse events of special interest .............................................................28
12.1.2
Procedures for reporting and recording adverse events.......................................28
12.1.2.1
Description of adverse events....................................................................29
12.1.2.2
Rule for repetition of an adverse event......................................................29
12.1.2.3
Additional procedures for reporting serious adverse events .....................29
12.1.3
Follow up of adverse events ................................................................................30
12.1.4
Pregnancy ............................................................................................................30
12.1.5
Suspected transmission of an infectious agent via a medicinal product..............31
12.1.6
Overdose of investigational medicinal product ...................................................31
12.1.7
Safety signal detection.........................................................................................31
12.2 Laboratory measurements................................................................................................31
12.3 Other safety measurements..............................................................................................32
12.3.1
ECG .....................................................................................................................32
12.3.2
Vital signs ............................................................................................................33
12.3.3
Body weight and height.......................................................................................33
12.3.4
Physical examination...........................................................................................33
12.3.5
Neurological examination....................................................................................33
12.3.6
Oxygen saturation................................................................................................33
12.3.7
Self-Administered Gerocognitive Examination ..................................................33
13
STUDY MANAGEMENT AND ADMINISTRATION.................................................34
13.1 Adherence to protocol......................................................................................................34
13.2 Monitoring .......................................................................................................................34
13.2.1
Definition of source data .....................................................................................34
13.2.2
Source data verification .......................................................................................35
13.3 Data handling...................................................................................................................35
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 7 of 66
13.3.1
Case Report form completion..............................................................................35
13.3.2
Database entry and reconciliation........................................................................35
13.3.3
Subject Screening and Enrollment log/Subject Identification Code list..............35
13.4 Termination of the study..................................................................................................36
13.5 Archiving and data retention............................................................................................36
13.6 Audit and inspection ........................................................................................................36
13.7 Good Clinical Practice .....................................................................................................36
14
STATISTICS ...................................................................................................................37
14.1 Definition of analysis sets................................................................................................37
14.2 General statistical considerations.....................................................................................37
14.3 Planned efficacy analyses ................................................................................................37
14.3.1
Analysis of the primary efficacy variable............................................................37
14.3.2
Other efficacy analyses........................................................................................37
14.4 Planned safety and other analyses....................................................................................38
14.4.1
Safety analyses.....................................................................................................38
14.5 Planned interim analysis and data monitoring.................................................................38
14.6 Determination of sample size...........................................................................................38
15
ETHICS AND REGULATORY REQUIREMENTS......................................................38
15.1 Informed consent .............................................................................................................38
15.2 Subject identification cards..............................................................................................39
15.3 Institutional Review Boards and Independent Ethics Committees..................................39
15.4 Subject privacy.................................................................................................................40
15.5 Protocol amendments.......................................................................................................40
16
FINANCE, INSURANCE, AND PUBLICATION.........................................................40
17
REFERENCES ................................................................................................................40
18
APPENDICES .................................................................................................................41
18.1 Self-Administered Gerocognitive Examination...............................................................41
18.2 Protocol Amendment 1 ....................................................................................................61
19
DECLARATION AND SIGNATURE OF INVESTIGATOR .......................................65
20
SPONSOR DECLARATION ..........................................................................................66
LIST OF TABLES
Table 5‒1:
Schedule of study assessments.........................................................................15
Table 12‒1:
Anticipated serious adverse events for the epilepsy population......................28
Table 12‒2:
Laboratory measurements................................................................................32
Table 18‒1:
Summary of changes in EP0087 Protocol Amendment 1................................61
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 8 of 66
LIST OF FIGURES
Figure 5‒1:
Schematic diagram...........................................................................................18
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 9 of 66
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARS
acute repetitive seizure
AST
aspartate aminotransferase
BRV
brivaracetam
CDMS
clinical data management system
CPM
Clinical Project Manager
CPMP
Committee for Proprietary Medicinal Products
CRO
contract research organization
DBP
diastolic blood pressure
ECG
electrocardiogram
eCRF
electronic Case Report form
EMU
Epilepsy Monitoring Unit
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
interactive response technology
ITT 
intent-to-treat
iv
intravenous
LEV
levetiracetam
LZP
lorazepam
PET
positron emission tomography
PK
pharmacokinetic
PR
pulse rate
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Clinical Study Protocol
Brivaracetam
EP0087
Confidential
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PP
per protocol
PS
Patient Safety
RR
respiratory rate
SAE
serious adverse event
SAGE
Self-Administered Gerocognitive Examination
SBP
systolic blood pressure
SFU
Safety Follow-Up
SOP
Standard Operating Procedure
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
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26 May 2017
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Brivaracetam
EP0087
Confidential
Page 11 of 66
1
SUMMARY
EP0087 is an open-label, randomized, parallel-group, active-controlled study to assess the 
efficacy and safety of brivaracetam (BRV) administered intravenously as treatment for increased 
seizure activity in an epilepsy monitoring unit (EMU) setting. The primary objective is to assess 
the efficacy of intravenous (iv) BRV compared to iv lorazepam (LZP) in subjects with epilepsy 
undergoing EMU evaluation who experience seizures that require prompt treatment.
Subjects will be 18 to 70 years of age, will have an established diagnosis of epilepsy, and will be 
admitted to an institution’s EMU for seizure characterization or noninvasive presurgical 
evaluation. Upon admission to the EMU (after screening), the subject will be randomly assigned 
(1:1:1) to receive a single iv dose of BRV 100mg, BRV 200mg, or LZP. 
The primary efficacy variable is time to next seizure per clinical observation with EEG 
confirmation or rescue medication. The secondary efficacy variables are proportion of subjects 
seizure-free per clinical observation at 6 hours, 8 hours, and 12 hours after the end of study drug 
administration, and proportion of subjects who receive rescue medication during the 6 hours, 
8 hours, and 12 hours after the end of study drug administration.
The other efficacy variable is time until seizure is resolved without additional intervention per 
clinical observation for those actively seizing at the end of study drug administration.  
The pharmacokinetic variable is plasma concentration of BRV.
Safety variables are adverse events (AEs), assessment of cognitive impairment, vital signs, 
oxygen saturation, electrocardiogram (ECG), and occurrence of status epilepticus.
Study drug administration will begin when the Investigator or designee determines by clinical 
observation and electroencephalogram (EEG) that a seizure requiring intervention (ie, qualifying 
seizure) has started. The subject’s seizure activity, by clinical observation and EEG, will be 
assessed over the next 12 hours following the end of study drug administration. In addition, the 
subject’s cognitive impairment, vital signs, oxygen saturation, and ECG will be measured at 
specified time points. If the subject’s seizure activity does not stop after administration of study 
drug or seizure activity recurs, the subject may receive rescue medication at the Investigator’s 
discretion. Approximately 60 subjects will be enrolled in order to have 45 subjects (15 subjects 
per group) qualifying for primary analysis at up to 20 sites.
2
INTRODUCTION
Acute repetitive seizures (ARS), defined as recurrent seizures within 24 hours with recovery 
between seizures, are commonly treated with either benzodiazepines, a longer-acting AED, or a 
combination of both (Lowe et al, 2000). Early effective treatment suppresses seizure activity in 
order to prevent the detrimental effects of acute seizure exacerbation which may evolve into 
prolonged seizures or status epilepticus, resulting in lasting morphological and functional brain 
damage (Bergen, 2006). Benzodiazepines are effective at stopping seizure activity quickly but 
may be rapidly redistributed or have a short duration of action which may lead to a nonsustained 
clinical effect. In addition, benzodiazepines may cause respiratory depression and sedation, 
potentially leading to further complications.
The administration of longer acting AEDs may prevent recurrent seizures, improve outcomes, 
and reduce health-care costs by reducing hospitalizations. Brivaracetam, approved in 2016 by the 
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Brivaracetam
EP0087
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Food and Drug Administration (FDA) for adjunctive treatment of partial-onset seizures in adults, 
has a half-life of 9 hours. Evidence of efficacy of BRV in generalized seizures was shown for a 
subset of subjects with generalized epilepsy in a well-controlled, flexible-dose study (N01254). 
Positron emission tomography (PET) data from rhesus monkeys indicate that BRV penetrates the 
brain within minutes after iv administration (Mercier et al, 2015). In addition, data from a study 
conducted in patients with photoparoxysmal epilepsy (N01069) indicate that BRV produced an 
early and lasting effect in that model, with seizure activity suppressed at the earliest observed 
time point (0.5 hours). Taken together, BRV’s profile suggests that it may act as fast as a 
benzodiazepine, protect against or prolong time to next seizure, and be better tolerated than a 
benzodiazepine with regards to sedation, cognitive impairment, and respiratory depression. 
Intravenous BRV will be administered to subjects who have periods of increased epileptic 
seizure activity while being evaluated in an EMU. This population is comprised of subjects being 
intensively evaluated for partial-onset, generalized-onset, or mixed seizure disorders. These 
subjects are usually taking AEDs chronically and during the course of EMU evaluation the dose 
of 1 or more concomitant AEDs may be reduced. A subset of the EMU subjects will develop 
increased frequency of seizures which require treatment, usually with a benzodiazepine. Such 
study participants will be randomized to treatment with 1 of 2 doses of BRV or LZP, a 
benzodiazepine frequently used as rescue medication in the EMU setting. This study is intended 
to provide proof of concept. The efficacy results from this study will be used to aid selection of 
the optimal dose to evaluate in a future study in patients with ARS in the home setting. 
UCB is collaborating with Evogen, Inc, for further development of EvoScoreTM START, 
Evogen’s new proteomics-based blood test designed to accurately distinguish epileptic seizures 
from other events. Subjects in this study will be asked to provide blood samples for assay 
refinement.
3
STUDY OBJECTIVES
The primary objective is to assess the efficacy of iv BRV compared to iv LZP in subjects with 
epilepsy undergoing EMU evaluation who experience seizures that require prompt treatment.
The secondary objective is to compare the safety and tolerability of iv BRV and iv LZP in 
subjects with epilepsy undergoing EMU evaluation who experience seizures that require prompt 
treatment.
4
STUDY VARIABLES
4.1
Efficacy variables
4.1.1
Primary efficacy variable
The primary efficacy variable is time to next seizure (per clinical observation with EEG 
confirmation) or rescue medication. 
4.1.2
Secondary efficacy variables

Time to next seizure (per clinical observation) or rescue medication

Proportion of subjects seizure-free per clinical observation at 6 hours, 8 hours, and 12 hours 
after the end of study drug administration
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Brivaracetam
EP0087
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
Proportion of subjects who receive rescue medication during the 6 hours, 8 hours, and 
12 hours after the end of study drug administration
4.1.3
Other efficacy variables

Time until seizure is resolved without additional intervention per clinical observation (only 
for those actively seizing at the end of study drug administration)
4.2
Safety variables
4.2.1
Adverse events

Assessment of cognitive impairment 

Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate [PR], 
and respiratory rate [RR]) 

Oxygen saturation (measured by pulse oximetry) 

ECG

Occurrence of status epilepticus
4.3
Pharmacokinetic variable

plasma concentration of BRV at 1 hour and 5 hours after the end of BRV study drug 
administration
5
STUDY DESIGN
5.1
Study description
Subjects admitted to an institution’s EMU for seizure characterization or noninvasive presurgical 
evaluation will be enrolled in this study. Upon admission to the EMU and after screening, the 
subject will be randomly assigned (1:1:1) to receive a single iv dose of BRV 100mg, BRV 
200mg, or LZP. The number of subjects using levetiracitam (LEV) as concomitant AED will be 
limited to 25% of the total number of subjects who receive study drug.
Study drug administration will begin when the Investigator or designee determines by clinical 
observation and EEG that a seizure requiring intervention (ie, qualifying seizure) has started. 
Study drug administration will begin within 30 minutes of the qualifying seizure. A qualifying 
seizure is defined as any one of the following circumstances, requiring intervention in the 
opinion of the Investigator:

≥3 seizures per 24 hours

≥2 seizures in 6 hours 

Any generalized tonic-clonic seizure requiring intervention, as determined by the 
Investigator
The subject’s seizure activity by clinical observation will be assessed over the next 12 hours 
following the end of study drug administration.  The dose and regimen of concomitant AEDs 
should remain stable after study drug administration during the Treatment Period unless the 
subject needs rescue medication.  In addition, the subject’s cognitive impairment, vital signs, 
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 14 of 66
oxygen saturation, and ECG will be measured at specified time points. Blood samples will be 
obtained at specified time points. 
If the subject is seizure-free for the 12 hours following the end of study drug administration, the 
Treatment Period is concluded and other AEDs may be administered at the Investigator’s 
discretion.  The subject is then in the Safety Follow-up (SFU) Period, which lasts until 24 hours 
after the end of study drug administration. 
If the subject’s seizure activity does not stop after administration of study drug or seizure activity 
recurs, the subject may receive rescue medication (not from study drug supplies) at the 
Investigator’s discretion. At the time of rescue medication administration, the Treatment Period 
is concluded, the subject is in the SFU Period, and subject may be subsequently treated with 
AEDs at the discretion of the Investigator.
5.1.1
Study duration per subject
The total duration of the study will be up to 4.5 weeks, inclusive of the Screening Period.
Screening Period: up to 28 days for consenting, planning EMU stay, randomization, and 
inpatient EMU time prior to the seizure qualifying for study drug administration.
Treatment Period: beginning at start of study drug administration up to 12 hours following the 
end of study drug administration. 
Safety Follow-Up Period: 24 hours following the end of study drug administration.
The end of the study is defined as the date of the last visit of the last subject in the study.
5.1.2
Planned number of subjects and sites
Approximately 60 subjects will be enrolled in order to have 45 subjects (15 subjects per group) 
qualifying for primary analysis at up to 20 sites. Additional subjects may also be enrolled at the 
discretion of the Sponsor if subjects are replaced.
5.1.3
Anticipated regions and countries
This study will be conducted in the US.
5.2
Schedule of study assessments
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 15 of 66
Table 5‒1:
Schedule of study assessments
Assessments
Screening Period
(Day -28 to Day -1; includes consenting, 
planning EMU stay, randomization, 
inpatient EMU time prior to the seizure 
qualifying for study drug administration)
Treatment Period
(Day 1; start of study drug 
administration to 12h after 
end of study drug 
administration or until 
seizure or rescue 
medication)
Safety Follow-Up 
(24h after end of study drug 
administration)a
Visit  1
Visit 2
Visit 3
Screening
Prior to 
randomization
Informed consent
X
Inclusion/exclusion criteria
X
X
X
Medical historyb
X
X
Concomitant medications
X
X
X
X
Demographic data
X
Brief physical examination, including 
weight and height
X
Xc
Xd
Brief neurological examination
X
Xc
Xd
Laboratory assessment 
Xe
X
Withdrawal criteria
X
X
Cognitive impairment (SAGE)
X
Xf
Oxygen saturation 
X
Xg
Xg
Vital signs (SBP, DBP, PR, RR) 
X
Xg
Xg
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X
Xh
X
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 16 of 66
Table 5‒1:
Schedule of study assessments
Assessments
Screening Period
(Day -28 to Day -1; includes consenting, 
planning EMU stay, randomization, 
inpatient EMU time prior to the seizure 
qualifying for study drug administration)
Treatment Period
(Day 1; start of study drug 
administration to 12h after 
end of study drug 
administration or until 
seizure or rescue 
medication)
Safety Follow-Up 
(24h after end of study drug 
administration)a
Visit  1
Visit 2
Visit 3
Screening
Prior to 
randomization
Adverse events
X
X
X
X
Randomization to study drug groupi
X
Seizure activity record per clinical 
observation and EMU’s EEG data capture
X
X
X
Study drug administrationj
X
Blood sample collection
Xl
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 17 of 66
Table 5‒1:
Schedule of study assessments
Assessments
Screening Period
(Day -28 to Day -1; includes consenting, 
planning EMU stay, randomization, 
inpatient EMU time prior to the seizure 
qualifying for study drug administration)
Treatment Period
(Day 1; start of study drug 
administration to 12h after 
end of study drug 
administration or until 
seizure or rescue 
medication)
Safety Follow-Up 
(24h after end of study drug 
administration)a
Visit  1
Visit 2
Visit 3
Screening
Prior to 
randomization
BRV=brivaracetam; DBP=diastolic blood pressure; ECG=electrocardiogram; EEG=electroencephalogram; EMU=Epilepsy Monitoring Unit; 
iv=intravenous; PR=pulse rate; RR=respiratory rate; SAGE=Self-Administered Gerocognitive Examination; SBP=systolic blood pressure; SFU=Safety 
Follow-Up
a Safety Follow-Up assessments to be performed at least 24h after study drug administration. 
b Medical history including psychiatric and substance abuse history. 
c If the Screening physical and neurological examinations were performed within 7 days of Treatment Period, do not repeat. 
d If any clinically significant abnormality observed after study drug administration, then perform at SFU. 
e If subject has had laboratory assessments performed within the past 14 days, do not repeat. 
f Assessment performed at Screening (Form 1), and at 1h (Form 2), 2h (Form 3), and 3h (Form 4) after the end of study drug administration. If study 
drug administration occurs for a nocturnal seizure and subject is asleep, assessment should not be performed.
g Assessments performed at the following time points: predose, end of bolus, 5min (±3min), 15min (±5min), 30min (±10min), 1h, 2h, and 4h (±15min) 
after end of bolus, unless seizure or rescue medication occurs that ends the Treatment Period. If clinically significant abnormality is observed in the final 
assessment of the Treatment Period, continue to monitor every 4h until resolution or end of SFU Period. 
h Assessments will be performed within 60min after the start of study drug administration, and a 5min continuous ECG will be performed beginning 
with the bolus start and stopping 2 to 5min after the end of the bolus.
i    Occurs after eligibility criteria have been confirmed.
j    Subject must have a qualifying seizure (see Section 5.1).
k If abnormalities are noted, a 12-lead ECG may be administered for further assessment.
l Blood draws at 1h (±15min), 5h (±30min), 12h (±1h) and 24h (±3h) after end of study drug administration.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 18 of 66
5.3
Schematic diagram
Figure 5‒1: Schematic diagram
BRV=brivaracetam; EMU=Epilepsy Monitoring Unit; IMP=investigational medicinal product; LZP=lorazepam
Screening Period: up to 28 days for consenting, planning EMU stay, randomization after screening at the EMU admission, inpatient EMU time prior to the 
seizure qualifying for study drug administration.
Treatment Period: beginning at start of study drug administration when the subject has a qualifying seizure (see Section 5.1) and lasts up to 12 hours after the end 
of study drug administration or until a seizure occurs or rescue medication is given
Qualifying Seizure
IMP Dose:

IV BRV 100mg x 2 minutes

IV BRV 200mg x 4 minutes

IV LZP administered per site protocol
12h post-IMP dose
- or -
Time rescue med 
administered
Visit 1
(upon EMU 
admission)
EMU 
Admission
+ Rand
Visit 1
(pre-EMU 
admission)
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(Day -28 to EMU Qualifying Seizure)
Treatment Period
(Start of IMP dose to 12h post-IMP dose –
or-- time rescue med administered)
Safety Follow-up Period
(Completion of Treatment Period to 
24h post-IMP dose)
24h post-IMP 
dose
Visit 2
Pre-EMU Admission
EMU Observation
Visit 3
(before EMU 
discharge)
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 19 of 66
5.4
Rationale for study design and selection of dose
Intravenous BRV will be administered to subjects who have periods of increased epileptic 
seizure activity while being evaluated in an EMU. This population is comprised of subjects being 
intensively evaluated for partial-onset, generalized-onset, or mixed seizure disorders. These 
subjects are usually taking AEDs chronically, and during the course of EMU evaluation, the dose 
of 1 or more concomitant AEDs may be reduced. A subset of the EMU subjects will develop 
increased frequency of seizures which require treatment, usually with a benzodiazepine. Such 
study participants will be randomized to treatment with BRV 100mg, BRV 200mg, or LZP, a 
benzodiazepine frequently used as rescue medication in the EMU setting. 
As noted in the approved US product information, chronic administration of BRV (25mg to 
100mg twice daily) provides no additional benefit when added to LEV in adult patients with 
partial onset seizures.  However, it is unknown whether patients taking a stable dose of LEV or 
down-titrating LEV who experience seizures that require prompt treatment might benefit from 
acute administration of a higher dose of BRV (100mg or 200mg). Learning the outcome of these 
possible scenarios in the controlled environment of an EMU may be beneficial for clinicians.
The doses of BRV selected were based on the total daily doses in the US label and EU Summary 
of Product Characteristics, and modeling of plasma concentrations resulting from single iv doses 
up to 200mg. In addition, data on BRV in patients with generalized seizures were considered 
from the Phase 3 study N01254.
The safety and tolerability of iv administration of BRV 100mg bid has been evaluated in a 
Phase 3 study (N01258) in patients with epilepsy. Treatment with iv BRV (both bolus and 
infusion: 100mg bid) was well-tolerated. 
6
SELECTION AND WITHDRAWAL OF SUBJECTS
6.1
Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met:
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
Informed Consent form is signed and dated by the subject or by the parent(s) or legal 
representative. 
2. Subject/legal representative is considered reliable and capable of adhering to the protocol, 
visit schedule, or medication intake according to the judgment of the Investigator.
3. Subject is male or female, 18 to 70 years of age, inclusive. 
4. Subject has an established diagnosis of epilepsy.
5. Subject has been admitted to the institution’s EMU for seizure characterization or 
noninvasive presurgical evaluation or such admission is planned within 21 days of Screening.
6.2
Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria is met:
1. Subject has previously participated in this study and was treated with study drug. Re-screen 
is permitted.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 20 of 66
2. Subject has participated in another study of an investigational medicinal product (IMP) or a 
medical device within the previous 30 days of EMU admission or is currently participating in 
another study of an IMP or a medical device. 
3. Subject has taken BRV in the 21 days prior to EMU admission.
a) Subject has taken LEV in the 21 days prior to EMU admission after the LEV enrollment 
cap is met (see Section 5.1)
4. History or presence of status epilepticus during the 6 months prior to EMU admission.
5. Subject has a medical or psychiatric condition that in the opinion of the Investigator could 
jeopardize or would compromise the subject’s ability to participate in this study (eg, major 
surgery within the 2 weeks prior to screening).
6. Subject has >2x upper limit of normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or 
>ULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert’s syndrome). If subject has 
elevations only in total bilirubin that are >ULN and <1.5xULN, fractionate bilirubin to 
identify possible undiagnosed Gilbert’s syndrome (ie, direct bilirubin <35%).
For randomized subjects with a baseline result >ULN for ALT, AST, ALP, or total bilirubin, 
a baseline diagnosis and/or the cause of any clinically meaningful elevation must be 
understood and recorded in the Case Report form (CRF).
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at screening, 
repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically 
relevant increase. In case of a clinically relevant increase, inclusion of the subject must be 
discussed with the Medical Monitor.
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening.
7. Subject has chronic liver disease.
8. Subject has hypersensitivity to BRV or any of its excipients.
9. Subject has a history of alcohol or drug abuse during the 6 months prior to EMU admission.
10. Subject with a history of psychogenic seizures.
11. Subject is a pregnant or lactating female.
12. Subject has a history of a significant AE due to a benzodiazepine in the opinion of the 
Investigator.
13. Subject has respiratory failure (or is at risk for respiratory failure), untreated sleep apnea, or 
other severe cardiorespiratory disease with New York Heart Association Class III or IV 
functional status, or requires supplemental oxygen.
14. Subject has acute narrow-angle glaucoma or myasthenia gravis.
15. Subject is receiving benzodiazepine treatment (defined as an average of ≥4 administrations 
per week) that started less than 28 days prior to EMU admission.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 21 of 66
16. Subject has a known allergic reaction or intolerance to benzodiazepines or benzodiazepine 
excipients.
6.3
Withdrawal criteria
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
Subjects should be withdrawn from the study if any of the following events occur:
1. Subject develops an illness or complication that would interfere with his/her continued 
participation. This includes the initiation of a sedative medication that may interfere with the 
safety evaluations, such as sedative antipsychotics, opioids, or H1 antihistamines.
2. Investigator determines there is need to discontinue the study drug and administer a different 
treatment (eg, seizures are increasing in frequency or duration).
3. Any situation where, in the opinion of the Investigator, continued participation in the study 
would not be in the best interest of the subject.
4. Subject is noncompliant with the study procedures or medications in the opinion of the 
Investigator.
5. Subject withdraws his/her consent.
6. The sponsor or a regulatory agency requests withdrawal of the subject.
Investigators should attempt to obtain information on subjects in the case of withdrawal or 
discontinuation. All results of these evaluations and observations, together with a narrative 
description of the reason(s) for removing the subject, must be recorded in the source documents. 
The electronic Case Report form (eCRF) must document the primary reason for withdrawal or 
discontinuation.
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance.
7
STUDY TREATMENT(S)
7.1
Description of investigational medicinal product(s)
During the Screening Period, upon EMU admission and after screening assessments are  
completed, subjects will be randomly assigned (1:1:1) to receive a single iv dose of BRV 100mg, 
BRV 200mg, or LZP.
7.2
Treatment(s) to be administered
Brivaracetam bolus, the contents of two 5mL vials (=100mg [10mL] of BRV) will be 
administered iv over approximately a 2-minute period.
Brivaracetam bolus, the contents of four 5mL vials (=200mg [20mL] of BRV) will be 
administered iv over approxinately a 4-minute period.
Lorazepam bolus is to be injected based on information from the patient leaflet/package insert. 
The rate of injection should not exceed 2.0mg/min. The LZP dose will be determined according 
to the Investigator’s clinical judgment.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 22 of 66
7.3
Packaging
Brivaracetam will be contained in 5mL vials containing 50mg (5mL) of BRV.
7.4
Labeling
Clinical drug supplies will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice (GMP) and will include any locally required statements. If necessary, labels will be 
translated into the local language.
7.5
Handling and storage requirements
The Investigator (or designee) is responsible for the safe and proper storage of IMP at the site. 
Investigational medicinal product stored by the Investigator is to be kept in a secured area with 
limited access according to the storage conditions mentioned on the label.
Appropriate storage conditions must be ensured either by controlling the temperature (eg, room, 
refrigeration unit) or by completion of a temperature log in accordance with local requirements 
on a regular basis (eg, once a week), showing actual and minimum/maximum temperatures 
reached over the time interval.
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual.
7.6
Drug accountability
A Drug Accountability form will be used to record IMP dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any IMP lost, damaged (due to breakage or wastage), not used, partially used, disposed of at the 
study site, or returned to the sponsor or designee must also be recorded on the appropriate forms. 
All supplies and pharmacy documentation must be made available throughout the study for UCB 
(or designee) to review.
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned or destroyed.
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee.
The Investigator must ensure that the IMP is used only in accordance with the protocol.
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired IMP must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB SOPs or returned to UCB (or 
designee). Investigational medicinal product intended for the study cannot be used for any other 
purpose than that described in this protocol.
7.7
Procedures for monitoring subject compliance
All drug administrations will be done under supervision of the Investigator or his designee. 
Compliance will be monitored by drug accountability. Drug accountability must be recorded on 
the Drug Accountability form.
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 23 of 66
7.8
Concomitant medication(s)/treatment(s)
For any treatment other than the investigational product, including over-the-counter products, an 
accurate record must be kept in the clinic chart (source documentation) and in the eCRF. This 
record should include the name of the drug (preferably the brand name), the dose, the date(s) of 
administration, and the indication for use.
7.8.1
Permitted concomitant treatments (medications and therapies)
Concomitant medications per the EMU’s standard of care are permitted during the study. If 
receiving Concomitant AEDs, treatment should be kept stable after IMP administration during 
the Treatment Period unless the patient needs rescue medication. Concomitant AEDs can be 
administered at the Investigator's discretion after the Treatment Period ends (12 hours after study 
drug administration). 
7.8.2
Prohibited concomitant treatments (medications and therapies)
Central nervous system depressants, unless at a stable dose, should be avoided during the study; 
however, their use is allowed based on the Investigator’s clinical judgment. 
7.8.3
Rescue medication
Rescue medication will be administered as necessary per the EMU’s standard of care. If a subject 
is to stay in the EMU for further seizure characterization following administration of rescue 
medication, that subject may remain in the study awaiting a qualifying seizure. This scenario 
requires consultation with the Medical Monitor.
7.9
Blinding
This is an open-label study.
7.10
Randomization and numbering of subjects
A 1:1:1 central randomization stratified for LEV use will be used in the trial to ensure overall 
balance across the different treatment groups (LZP, BRV 100 mg, BRV 200 mg). To enroll a 
subject (Visit 1), the Investigator or designee will contact the interactive response technology 
(IRT) and provide brief details about the subject to be enrolled. Each subject will receive a 
5-digit number assigned at screening that serves as the subject identifier throughout the study. 
The subject number will be required in all communication between the Investigator or designee 
and the IRT regarding a particular subject. Subject numbers and kit numbers will be tracked via 
the IRT. 
To randomize a subject, the Investigator or designee will contact the IRT and provide brief 
details about the subject to be randomized. The IRT will automatically inform the Investigator or 
designee of the subject’s randomization number. The IRT will allocate kit numbers to the subject 
based on the subject number during the course of the study. The randomization number must be 
incorporated into the eCRF.
8
STUDY PROCEDURES BY VISIT 
8.1
Day -28 to Day -1/Screening 
Prior to any study activities, subject or legal representative will be asked to read and sign an
Informed Consent form that has been approved by an IRB/IEC and which complies with
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 24 of 66
regulatory requirements. Subject or legal representative will be given adequate time to consider 
any information concerning the study, given to them by the Investigator or designee.
As part of the informed consent procedure, subject or legal representative will be given the 
opportunity to ask the Investigator any questions regarding potential risks and benefits of 
participation in the study.

Obtain signed and dated written Informed Consent by subject/legal representative

Inclusion/exclusion criteria

Medical history, including psychiatric and substance abuse history

Concomitant medications

Demographic data

Brief physical examination, including weight and height

Brief neurological examination

Adverse events
The following assessments will be performed prior to randomization:

Inclusion/exclusion criteria

Medical history, including psychiatric and substance abuse history

Concomitant medications

Adverse events

Cognitive impairment (Self-Administered Gerocognitive Examination [SAGE]) (Form 1)

Laboratory assessment 

Withdrawal criteria

Oxygen saturation 

Vital signs (SBP, DBP, HR, RR) 

ECG

Seizure activity record per clinical observation and EMU’s EEG data capture
Once the assessments above are performed, the subject may be randomized.
8.2
Day 1 (Treatment Period)
The Treatment Period begins when the subject has a qualifying seizure (see Section 5.1) and 
study drug is administered and lasts up to 12 hours after the end of study drug administration or 
until a seizure occurs or rescue medication is given. The following procedures will be performed:

Confirm inclusion/exclusion criteria

Concomitant medications
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 25 of 66

Brief physical examination, including height and weight, if not performed within 7 days of 
Day 1

Brief neurological examination if not performed within 7 days of Day 1

Withdrawal criteria

Cognitive impairment (SAGE) at 1 hour (Form 2), 2 hours (Form 3), and 3 hours (Form 4) 
after the end of study drug administration

Oxygen saturation at predose, end of bolus, 5 (±3) minutes, 15 (±5) minutes, 30 (±10) 
minutes, 1 hour, 2 hours, and 4 hours (±15 minutes) after end of bolus, unless seizure or 
rescue medication occurs that ends the Treatment Period

Vital signs (SBP, DBP, PR, RR) at predose, end of bolus, 5 (±3) minutes, 15 (±5) minutes, 
30 (±10) minutes, 1 hour, 2 hours, and 4 hours (±15 minutes) after end of bolus, unless 
seizure or rescue medication occurs that ends the Treatment Period

ECG within 60min after the start of study drug administration. A 5-minute continuous ECG 
monitoring will be performed beginning with the start of the iv bolus and stopping 2 to 5 
minutes after the end of the iv bolus

Adverse events

Study drug administration 

Seizure activity record per clinical observation and EMU’s EEG data capture

Blood sample collection at 1 hour (±15 minutes, 5 hours (±30 minutes), and 12 (±1) hours 
after the end of study drug administration 
8.3
Safety Follow-Up Period 
The SFU Period is the 24 hours after study drug administration. The following procedures will 
be performed: 

Concomitant medications

Brief physical examination to be performed if any clinically significant abnormality observed 
after study drug administration

Brief neurological examination to be performed if any clinically significant abnormality 
observed after study drug administration

Oxygen saturation if clinically significant abnormality observed in the last assessment of the 
Treatment Period and not resolved at end of Treatment Period  

Vital signs (SBP, DBP, PR, RR) if clinically significant abnormality observed in the last 
assessment of the Treatment Period and not resolved at end of Treatment Period  

ECG

Adverse events

Seizure activity record per clinical observation and EMU’s EEG data capture
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 26 of 66

Blood sample collection at 1 hour (±15 minutes), 5 hours (±30 minutes), 12 (±1) hours, and 
24 (±3) hours after the end of study drug administration 
9
ASSESSMENT OF EFFICACY
Efficacy will be assessed by time to next seizure per clinical observation and EEG or rescue 
medication. 
10
ASSESSMENT OF PHARMACOKINETIC VARIABLES
Plasma samples for assessment of BRV concentrations will be collected at 1 hour and 5 hours 
after study drug administration for subjects who received BRV.  
The central laboratory will provide the Investigator with sampling supplies (labels, needles, 
tubes, and vials) and an instruction manual explaining how to process and ship blood samples.
Bioavailability analysis will be conducted by UCB. 
11
BIOMARKER ASSAY REFINEMENT
Blood samples for epilepsy protein biomarker assay refinement will be collected at up to 4 time 
points after study drug administration: 1h (±15 minutes), 5h (±30 minutes), 12 (±1) hours, and 24 
(±3) hours after the end of study drug administration. 
Subject refusal of biomarker sample blood draws will not be considered a protocol deviation.
Plasma samples for the biomarker assay refinement will be sent to Evogen.26 May 2017
12
ASSESSMENT OF SAFETY
12.1
Adverse events
12.1.1
Definitions
12.1.1.1
Adverse event
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that 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.
In order to ensure complete safety data collection, all AEs occurring during the study (ie, after 
the signing of the Informed Consent form), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no IMP was taken but specific 
study procedures were conducted. This includes all AEs not present prior to the initial visit and 
all AEs that recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the IMP is being studied should be 
recorded as AEs only if their nature changes considerably or their frequency or intensity 
increases in a clinically significant manner as compared to the clinical profile known to the 
Investigator from the subject’s history or the Baseline Period.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 27 of 66
12.1.1.2
Serious adverse event
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria:

Death

Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred in 
a more severe form.)

Significant or persistent disability/incapacity

Congenital anomaly/birth defect (including that occurring in a fetus)

Important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the definition of serious
(Important medical events may include, but are not limited to, potential Hy’s Law [see 
Section 12.1.1.3], allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.)

Initial inpatient hospitalization or prolongation of hospitalization
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization criteria. 
However, emergency room visits that do not result in admission to the hospital would not 
qualify for this criteria and, instead, should be evaluated for 1 of the other criteria in the 
definition of serious [eg, life-threatening adverse experience, important medical event].
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or manifested 
in an unusual or uncharacteristic manner] do not qualify for reporting. For example, if a 
subject has a condition recorded on his/her medical history and later has a preplanned surgery 
for this condition, it is not appropriate to record the surgery or hospitalization as an SAE, 
since there is no AE upon which to assess the serious criteria. Please note that, if the 
pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, 
this would then qualify as an AE and, if necessary, the seriousness of the event would need to 
be determined.)
12.1.1.2.1
Anticipated serious adverse events
The following list of Anticipated SAEs has been identified, as these events are anticipated to 
occur in the population studied in this protocol at some frequency that is independent of drug 
exposure.
This list does not change the Investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 12.1.2.3.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 28 of 66
Table 12‒1: Anticipated serious adverse events for the epilepsy population
MedDRA SOC
MedDRA PT
Congenital, familial and genetic disorders
Teratogenicity
General disorders and administrative site conditions
Sudden unexplained death in epilepsy
Nervous system disorders
Convulsiona
Status epilepticus
Pregnancy, puerperium and perinatal disorders
Abortion spontaneous
Psychiatric disorders
Psychotic behavior
Abnormal behavior
Anxiety
Sleep disorder
MedDRA=Medical Dictionary for Regulatory Activities; PT=preferred term; SOC=system organ class
a Convulsion if consistent with the seizure type known for the subject.
12.1.1.3
Adverse events of special interest
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. For this study, the AEs of special interest include: 

Autoimmune nephritis

Nephritis

Nephritis allergic

Tubulointerstitial nephritis

Tubulointerstitial nephritis and uveitis syndrome

Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the biochemical 
abnormality, must ALWAYS be reported to UCB as an AE of special interest (ie, without 
waiting for any additional etiologic investigations to have been concluded). In the event of 
this occurring, permission to contact the subject’s primary healthcare professional would be 
sought to ensure further investigation and follow up.
Adverse events of special interest should be reported to the SAE fax and email using the SAE 
form. However, if not considered an SAE, no seriousness criterion should be indicated.
12.1.2
Procedures for reporting and recording adverse events
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example:
“Did you notice anything unusual about your health (since your last visit)?”
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 29 of 66
In addition, the Investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study.
12.1.2.1
Description of adverse events
When recording an AE, the Investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own words 
on his/her own records (eg, diary card) and the corresponding medical terminology should be 
clarified in the source documentation.
Details for completion of the Adverse Event eCRF (including judgment of relationship to IMP) 
are described in the eCRF Completion Guidelines.
12.1.2.2
Rule for repetition of an adverse event
An increase in the intensity of an AE should lead to the repetition of the AE being reported with:

The outcome date of the first AE that is not related to the natural course of the disease being 
the same as the start date of the repeated AE, and the outcome of “worsening”

The AE verbatim term being the same for the first and repeated AE, so that the repeated AE 
can be easily identified as the worsening of the first one
12.1.2.3
Additional procedures for reporting serious adverse events
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information by 
the site (see contact information for SAE reporting listed in the Serious Adverse Event Reporting 
section at the front of the protocol). The Investigator must forward to UCB (or its representative) 
a duly completed “Investigator SAE Report Form for Development Drug” (SAE Report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered into 
the global safety database.
An Investigator SAE report form will be provided to the Investigator. The Investigator SAE 
Report form must be completed in English. 
It is important for the Investigator, when completing the SAE Report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This insight 
from the Investigator is very important for UCB to consider in assessing the safety of the IMP 
and in determining whether the SAE requires reporting to the regulatory authorities in an 
expedited manner.
Additional information (eg, autopsy or laboratory reports) received by the Investigator must be 
provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE Report form.
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the IMP), up to 
30 days from the end of the study for each subject, and to also inform participating subjects of 
the need to inform the Investigator of any SAE within this period. Serious AEs that the 
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 30 of 66
Investigator thinks may be associated with the IMP must be reported to UCB regardless of the 
time between the event and the end of the study.
Upon receipt of the SAE Report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the IB.
12.1.3
Follow up of adverse events
An AE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest, except for cases of 
Hy’s Law which have been identified prior to treatment initiation, where the follow up for the 
subject is transferred to the primary healthcare professional.   
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the Investigator no longer deems that it is 
clinically significant, or until the subject is lost to follow up. If no follow up is provided, the 
Investigator must provide a justification. The follow up will usually be continued for 30 days 
after the subject has discontinued his/her IMP.
Information on SAEs obtained after clinical database lock will be captured through the Patient 
Safety (PS) database without limitation of time.
12.1.4
Pregnancy
If an Investigator is notified that a subject has become pregnant after the first intake of any IMP, 
the Investigator must immediately notify UCB’s PS department by providing the completed 
Pregnancy Report and Outcome form (for contact details see Serious Adverse Event reporting 
information at the beginning of this protocol). The subject should be withdrawn from the study 
as soon as pregnancy is known (by positive pregnancy test), and the following should be 
completed:

Safety Follow-Up assessments should be conducted 24 hours after the subject has 
discontinued her IMP.
The Investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to the 
Investigator. The progression of the pregnancy and the eventual birth (if applicable) must be 
followed up using the Pregnancy Report and Outcome form in which the Investigator has to 
report on the health of the mother and of the child. Every reasonable attempt should be made to 
follow the health of the child for 30 days after birth for any significant medical issues. In certain 
circumstances, UCB may request that follow up is continued for a period longer than 30 days. If 
the subject is lost to follow up and/or refuses to give information, written documentation of 
attempts to contact the subject needs to be provided by the Investigator and filed at the site. 
UCB’s PS department is the primary contact for any questions related to the data collection for 
the pregnancy, eventual birth, and follow up.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the 
Investigator or designee is asked to contact the subject to request consent of the partner via the 
Partner Pregnancy Consent form that has been approved by the responsible IRB/IEC and should 
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be available in the Investigator site file. In case of questions about the consent process, the 
Investigator may contact the UCB/contract research organization (CRO) contract monitor for the 
study. The Investigator will complete the Pregnancy Report and Outcome form and send it to 
UCB’s PS department (for contact details see Serious Adverse Event reporting information at the 
beginning of this protocol) only after the partner has agreed that additional information can be 
captured and has provided the signed Partner Pregnancy Consent form. UCB’s PS department is 
also the primary contact for any questions related to the data collection for the partner pregnancy, 
eventual birth, and follow up.
A pregnancy becomes a serious adverse event (SAE) in the following circumstances: 
miscarriage, abortion (elective or spontaneous), unintended pregnancy after hormonal 
contraceptive failure (if the hormonal contraceptive was correctly used), ectopic pregnancy, fetal 
demise, or any congenital anomaly/birth defect of the baby. Those SAEs must be additionally 
reported using the Investigator SAE Report form.
12.1.5
Suspected transmission of an infectious agent via a medicinal 
product
For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal 
product should be considered as an SAE; such cases must be reported immediately, recorded in 
the AE module of the eCRF, and followed as any other SAE. Any organism, virus, or infectious 
particle (eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
12.1.6
Overdose of investigational medicinal product
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the eCRF. Any SAE or nonserious AE associated with excessive dosing must be 
followed as any other SAE or nonserious AE. These events are only considered AEs or SAEs if 
there are associated clinical signs and symptoms or if the act of taking the excess medicine itself 
is an AE or SAE (eg, suicide attempt).
12.1.7
Safety signal detection
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that Investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible.
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the PS representative.
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the course 
of the study.
12.2
Laboratory measurements
The following laboratory parameters will be measured:
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26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 32 of 66
Table 12‒2: Laboratory measurements
Hematology
Chemistry
Basophils
Calcium
Eosinophils
Chloride
Lymphocytes
Creatinine
Atypical lymphocytes
Magnesium
Monocytes
Potassium
Neutrophils
Sodium
Hematocrit
Glucose
Hemoglobin
BUN
MCH
AST
MCHC
ALP
MCV
ALT
Platelet count
GGT
RBC count
Total bilirubin
WBC count
LDH
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; GGT=gamma-glutamyltransferase; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood cell; 
WBC=white blood cell
All laboratory assessments are to be performed locally. Data from the local laboratory will not be 
recorded on the eCRF but will be available upon request to evaluate any SAE due to abnormal 
laboratory values. Laboratory assessments performed within the past 14 days should not be 
repeated. Pregnancy testing (minimally by urine dipstick) is conducted locally at the time of 
admission to the EMU or before randomization.
12.3
Other safety measurements
12.3.1
ECG
An ECG will be performed at Screening upon admission to the EMU and within 60min after the 
start of study drug administration. A 5-minute continuous ECG will be performed beginning with 
the start of the iv bolus and stopping 2 to 5 minutes after the end of the iv bolus. An ECG will 
also be performed at SFU. The Investigator will determine whether the results of the ECG are 
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Clinical Study Protocol
Brivaracetam
EP0087
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Page 33 of 66
normal or abnormal and assess the clinical significance of any abnormalities. If significant 
abnormalities are noted during ECG monitoring, a 12-lead ECG should be recorded in order to 
capture and document these abnormalities. If available, the original ECG tracing will be signed 
or initialed and dated by the Investigator and retained as part of the source data. Copies of all 
ECG tracings will be retrieved for all subjects presenting treatment-emergent clinically 
significant abnormalities during the study.
12.3.2
Vital signs
Vital signs (SBP, DBP, PR, and RR) after 5 minutes rest will be measured upon EMU admission, 
and on Day 1 at predose, end of bolus, 5 (±3) minutes, 15 (±5) minutes, 30 (±10) minutes, 1 
hour, 2 hours, and 4 hours (±15 minutes) after the end of bolus, unless seizure or rescue 
medication occurs that ends the Treatment Period. If a clinically significant abnormality is 
observed in the final assessment of the Treatment Period, vital signs will continue to be 
monitored every 4 hours until resolution or the end of the SFU Period.
12.3.3
Body weight and height
Body weight (subject wearing light clothing without shoes and rounded to the nearest kilogram) 
and height will be measured upon preadmission to the EMU only. 
12.3.4
Physical examination
A brief/targeted physical examination will be performed at preadmission. If the physical 
examination at Screening was not performed within 7 days of Day 1, the physical examination 
will be repeated on Day 1. If any clinically significant abnormality is observed after study drug 
administration, then the physical examination will be performed at SFU. Clinically significant 
new or worsened abnormalities will have to be reported as AEs.
12.3.5
Neurological examination
A brief/targeted neurological examination will be performed at preadmission. If the neurological 
examination at Screening was not performed within 7 days of Day 1, the neurological 
examination will be repeated on Day 1. If any clinically significant abnormality is observed after 
study drug administration, then the neurological examination will be performed at SFU. 
Clinically significant new or worsened abnormalities will have to be reported as AEs.
12.3.6
Oxygen saturation
Oxygen saturation will be measured upon EMU admission, and on Day 1 at predose, end of 
bolus, 5 (±3) minutes, 15 (±5) minutes, 30 (±10) minutes, 1 hour, 2 hours, and 4 hours (±15 
minutes), unless seizure or rescue medication occurs that ends the Treatment Period. If a 
clinically significant abnormality is observed in the final assessment of the Treatment Period, 
oxygen saturation will continue to be monitored every 4 hours until resolution or the end of the 
SFU Period.
12.3.7
Self-Administered Gerocognitive Examination
The SAGE consists of a 22-point evaluation and is a handwritten self-test of memory developed 
to facilitate the screening of mild cognitive impairment and early dementia. The SAGE will be 
completed by the subject at Screening (Form 1) and at 1 hour (Form 2), 2 hours (Form 3), and 
3 hours (Form 4) after the end of study drug administration. A subject is allowed 20 minutes to 
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Brivaracetam
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complete the SAGE. If study drug administration occurs near the subject’s normal sleep cycle 
and the subject is asleep, the SAGE does not need to be performed (let the subject sleep). 
13
STUDY MANAGEMENT AND ADMINISTRATION 
13.1
Adherence to protocol
The Investigator should not deviate from the protocol. However, the Investigator should take any 
measure necessary in deviation from or not defined by the protocol in order to protect clinical 
study subjects from any immediate hazard to their health and safety. In this case, this action 
should be taken immediately, without prior notification of the regulatory authority, IRB/IEC, or 
sponsor.
After implementation of such measure, the Investigator must notify the Clinical Project Manager 
(CPM) of the sponsor within 24 hours and follow any local regulatory requirements.
13.2
Monitoring
UCB (or designee) will monitor the study to meet the sponsor’s monitoring Standard Operating 
Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, and to ensure 
that study initiation, conduct, and closure are adequate. Monitoring of the study may be 
delegated by UCB to a CRO or a contract monitor.
The Investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
missing information. The Investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s).
The Investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study participant). 
Monitoring visits will provide UCB (or designee) with the opportunity to evaluate the progress 
of the study, verify the accuracy and completeness of eCRFs, ensure that all protocol 
requirements, applicable authorities regulations, and Investigator’s obligations are being 
fulfilled, and resolve any inconsistencies in the study records.
13.2.1
Definition of source data 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, or quality of life 
questionnaires, for example. Source documents should be kept in a secure, limited access area.
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the subject’s source documents. The 
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Brivaracetam
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Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent.
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee).
13.2.2
Source data verification
Source data verification ensures accuracy and credibility of the data obtained. During monitoring 
visits, reported data are reviewed with regard to being accurate, complete, and verifiable from 
source documents (eg, subject files, recordings from automated instruments, tracings [ECG], 
x-ray films, laboratory notes). All data reported on the eCRF should be supported by source 
documents, unless otherwise specified in Section 13.2.1.
13.3
Data handling
13.3.1
Case Report form completion
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
electronic eCRFs and in all required reports.
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change.
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator.
The Investigator should maintain a list of personnel authorized to enter data into the eCRF.
Detailed instructions will be provided in the eCRF Completion Guidelines.
13.3.2
Database entry and reconciliation
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning checks 
will be used in addition to manual review to check for discrepancies and to ensure consistency of 
the data. This study will be performed using remote data capture. The data are entered into the 
eCRFs once and are subsequently verified.
An electronic audit trail system will be maintained within the CDMS to track all data changes in 
the database once the data have been saved initially into the system or electronically loaded. 
Regular backups of the electronic data will be performed.
13.3.3
Subject Screening and Enrollment log/Subject Identification Code list
The subject’s screening and enrollment will be recorded in the Subject Screening and Enrollment 
Log.
The Investigator will keep a Subject Identification Code list. This list remains with the 
Investigator and is used for unambiguous identification of each subject.
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation.
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Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 36 of 66
13.4
Termination of the study
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at a 
single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity.
If the study is prematurely terminated or suspended, UCB (or its representative) will inform the 
Investigators/institutions and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the Investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of all 
unused IMP and other material in accordance with UCB procedures for the study.
13.5
Archiving and data retention
The Investigator will maintain adequate records for the study, including eCRFs, medical records, 
laboratory results, Informed Consent documents, drug dispensing and disposition records, safety 
reports, information regarding participants who discontinued, and other pertinent data.
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IMP. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirement(s) or by an 
agreement with UCB (CPMP/ICH/135/95, 2002 [Section 4.9.5]). The Investigator will contact 
UCB for authorization prior to the destruction of any study records or in the event of accidental 
loss or destruction of any study records. The Investigator will also notify UCB should he/she 
relocate or move the study-related files to a location other than that specified in the sponsor’s 
trial master file.
13.6
Audit and inspection
The Investigator will permit study-related audits mandated by UCB, after reasonable notice, and 
inspections by domestic or foreign regulatory authorities.
The main purposes of an audit or inspection are to confirm that the rights and well-being of the 
subjects enrolled have been protected, that enrolled subjects (ie, signing consent and undergoing 
study procedures) are appropriate for the study, and that all data relevant for the evaluation of the 
IMP have been processed and reported in compliance with the planned arrangements, the 
protocol, investigational site, and IRB/IEC SOPs, ICH GCP, and applicable regulatory 
requirements.
The Investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the Investigator will immediately 
inform UCB (or designee).
13.7
Good Clinical Practice
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
Investigator, institution, institution staff, or designees of the sponsor will lead to prompt action 
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UCB
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Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 37 of 66
by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study.
14
STATISTICS
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan.
14.1
Definition of analysis sets
The Randomized Set (RS) will consist of all subjects who are randomized.
The Intent-to-Treat (ITT) Set will consist of all randomized subjects who receive the study drug.
The Per-Protocol (PP) Set will consist of all subjects in the ITT Set who did not have any 
important protocol deviations determined to impact the interpretation of the primary efficacy 
analysis.
All efficacy and safety analyses will be carried out using the ITT Set. Selected supportive 
efficacy analyses will be carried out using the PP Set.
14.2
General statistical considerations
Descriptive statistics, such as the mean, standard deviation (SD), median, 25th percentile, 
75th percentile, minimum value, and maximum value for quantitative variables, and counts and 
percentages for categorical variables, will be provided. Key supporting data will be provided in 
data listings. All statistical testing will be carried out at a 2-sided 0.05 significance level unless 
otherwise indicated.
Statistical outliers are defined as values that are discordant with other values and are clinically 
implausible. Exclusion of outliers from an analysis requires thorough justification based on 
statistical and clinical grounds. In such cases, unless otherwise specified, the analysis will be run 
both with and without the values. Any outliers will be reviewed during data review.
14.3
Planned efficacy analyses
14.3.1
Analysis of the primary efficacy variable
Time to next seizure (per clinical observation with EEG confirmation) or rescue medication, 
representing treatment failure, from the end of study drug administration to 12 hours after the 
end of study drug administration will be compared between each BRV arm and LZP using 
survival analysis methods; if the sample size is sufficient, a subgroup analysis using strata may 
be performed.
14.3.2
Other efficacy analyses
Time to next seizure (per clinical observation) or rescue medication from the end of study drug 
administration to 12 hours after the end of study drug administration will be compared between 
each BRV arm and LZP using survival analysis methods.
Seizure freedom rates at 6 hours, 8 hours, and 12 hours after the end of study drug administration 
will be compared between each BRV arm and LZP using Fisher’s Exact Test.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 38 of 66
Proportion of subjects who receive rescue medication during 6 hours, 8 hours, and 12 hours after 
study drug administration will be compared between each BRV arm and LZP using Fisher’s 
Exact Test.
Time until seizure is resolved without additional intervention per clinical observation (only for 
those actively seizing at end of study drug administration) will be compared between each BRV 
arm and LZP using survival analysis methods.
14.4
Planned safety and other analyses
14.4.1
Safety analyses
Treatment-emergent adverse events (TEAEs) are defined as AEs which have onset on or after the 
time of initiation of the iv administration of study drug. The incidence of TEAEs, TEAEs leading 
to permanent discontinuation of study drug, and treatment-emergent serious adverse events will 
be summarized over the entire study.
Quantitative safety parameters will be summarized descriptively by time point. Categorical 
safety summaries will provide the number and percentage of subjects within each summarized 
category.
Observed values and changes from baseline (pre-dose) in vital signs, ECGs, and oxygen 
saturation will be summarized using continuous descriptive statistics.
Assessment of cognitive impairment will be summarized.
Progression to status epilepticus will be summarized.
14.5
Planned interim analysis and data monitoring
No interim analyses are planned for this study.
14.6
Determination of sample size
The study is intended to demonstrate proof of concept. The sample size is not based on statistical 
calculation. Approximately 45 subjects (approximately 15 subjects per treatment group) will 
receive the study medication and qualify for the primary analysis. 
15
ETHICS AND REGULATORY REQUIREMENTS
15.1
Informed consent
Subject’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki.
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the subject in both oral and written form by the Investigator (or 
designee). Each subject will have the opportunity to discuss the study and its alternatives with 
the Investigator.
Prior to participation in the study, the Informed Consent form should be signed and personally 
dated by the subject, or his/her legal representative, and by the person who conducted the 
informed consent discussion (Investigator or designee). The subject or his/her legal 
representative must receive a copy of the signed and dated Informed Consent form. As part of 
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 39 of 66
the consent process, each subject must consent to direct access to his/her medical records for 
study-related monitoring, auditing, IRB/IEC review, and regulatory inspection.
If the Informed Consent form is amended during the study, the Investigator (or the sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent form by the IRB/IEC and use of the amended form.
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form.
The subject may withdraw his/her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she has signed the Informed Consent form. An eCRF 
must not be started, nor may any study-specific procedure be performed for a given subject, 
without having obtained his/her written consent to participate in the study.
15.2
Subject identification cards
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the subject. 
The Investigator will fill in the subject identifying information and medical emergency contact 
information. The Investigator will instruct the subject to keep the card with him/her at all times.
15.3
Institutional Review Boards and Independent Ethics 
Committees
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki.
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed 
Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study to 
the IRB/IEC for its review and approval.
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol.
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol deviations, 
to eliminate immediate hazards to subjects.
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. For 
minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed.
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 40 of 66
requirements), at intervals appropriate to the degree of subject risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion.
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification.
15.4
Subject privacy
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number 
assigned at Screening.
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
subject’s primary medical records that directly concerns this study (including, but not limited to, 
laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports for deaths 
occurring during the study).
15.5
Protocol amendments
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective.
Significant changes to the protocol will only be made as an amendment to the protocol and must 
be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to being 
implemented.
16
FINANCE, INSURANCE, AND PUBLICATION
Insurance coverage will be handled according to local requirements.
Finance, insurance, and publication rights are addressed in the Investigator and/or CRO 
agreements, as applicable.
17
REFERENCES
Bergen DC. Do seizures harm the brain? Epilepsy Curr. 2006;6:117-8.
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002.
Mercier J, Deo AK, Holden D, et al. Brivaracetam achieves SV2A occupancy in the brain faster 
than levetiracetam. Epilepsy Curr. 2015;15(Suppl S1):323. Abstract 2.332.
Lowe MN, Palmer KJ, Wilde MI. Management of acute repetitive seizures: defining the role of 
rectal diazepam gel. Dis Manage Health Outcomes. 2000;8(6):355-68.  
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 61 of 66
18.2
Protocol Amendment 1
The purpose of Amendment 1 was to clarify assessments and procedures, such as ECG, vital 
signs, reporting of adverse events of special interest, and the SAGE. In addition, qualifying 
seizures were further defined, the study contact information was updated, and allowance was 
made for enrollment of some subjects taking LEV. Amendment 1 also includes blood sampling 
at up to 4 time points after study drug administration; 2 time points for BRV bioavailability 
analysis and epilepsy biomarker assay development, as well as 2 more optional blood samples 
for assay refinement.
The major specific changes are detailed in Table 18‒1. Some minor text changes or deletions to 
improve readability are not summarized.
Table 18‒1: Summary of changes in EP0087 Protocol Amendment 1
Protocol 
section(s) 
impacted
Summary of previous 
protocol text
Summary of revised 
protocol text
Rationale
Study contact 
information
Sponsor Study Physician: 
Clinical Trial 
Biostatistician: 
Sponsor Study Physician: 
Clinical Trial 
Biostatistician: 
 
Change in study personnel
Sections 1, 4.2, 
5.1, 8.1, 8.2, 8.3, 
10.3.1, 12.4.1, 
and Table 5-1 
A 12-lead ECG was
required for routine 
screening and safety 
assessments
The EMU standard ECG 
is sufficient for routine 
screening and safety 
assessments. A 12-lead 
ECG may be used for 
further evaluation of 
abnormal ECG results.
A 1- or 3-channel ECG is 
standard of care in the 
EMU setting, and either 
will provide adequate 
monitoring of safety with 
the injections. A 12-lead 
ECG will still be used if 
abnormalities are 
observed.
Table 5-1
None
Added blood sample 
collection 
PK and assay refinement 
variables added to 
protocol.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 62 of 66
Protocol 
section(s) 
impacted
Summary of previous 
protocol text
Summary of revised 
protocol text
Rationale
Section 5.1
Timing of study drug 
administration relative to 
the qualifying seizure; 
clarification of the 
qualifying seizure 
definition, timing of re-
introduction of AEDs
The study drug 
administration will begin 
within 30 minutes of the 
qualifying seizure, which 
is defined as any one of 
the following: ≥3 seizures 
per 24 hours; ≥2 seizures 
in 6 hours; any 
generalized tonic-clonic 
seizure requiring 
intervention, as 
determined by the 
Investigator. If rescue 
medication is 
administered, AEDs can 
be re-introduced once the 
subject is in the SFU 
Period.
Clarification
Section 5.4
Gives rationale for study 
design and selection of 
dose
Addition of language 
justifying concomitant 
LEV in some subjects.
As noted in the approved 
US product information, 
chronic administration of 
BRV (25mg to 100mg 
twice daily) provides no 
additional benefit when 
added to LEV in adult 
patients with partial onset 
seizures.  However, it is 
unknown whether patients 
taking a stable dose of 
LEV or down-titrating 
LEV who experience 
seizures that require 
prompt treatment might 
benefit from acute 
administration of a higher 
dose of BRV (100mg or 
200mg). Learning the 
outcome of these possible 
scenarios in the controlled 
environment of an EMU 
may be beneficial for 
clinicians.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 63 of 66
Protocol 
section(s) 
impacted
Summary of previous 
protocol text
Summary of revised 
protocol text
Rationale
Section 6.2
Exclusion Criterion 3: 
Subject has taken BRV or 
LEV in the 21 days prior 
to EMU admission
Exclusion Criterion 3: 
Subject has taken BRV or 
LEV in the 21 days prior 
to EMU admission
As noted in the approved 
US product information, 
chronic administration of 
BRV (25mg to 100mg 
twice daily) provides no 
additional benefit when 
added to LEV in adult 
patients with partial onset 
seizures.  However, it is 
unknown whether patients 
taking a stable dose of 
LEV or down-titrating 
LEV who experience 
seizures that require 
prompt treatment might 
benefit from acute 
administration of a higher 
dose of BRV (100mg or 
200mg). Learning the 
outcome of these possible 
scenarios in the controlled 
environment of an EMU 
may be beneficial for 
clinicians.
Section 7.8.1
Describes permitted
concomitant treatments
Addition of language: 
Concomitant AEDs can be 
re-introduced after the 
Treatment Period ends (12 
hours after study drug 
administration). 
Clarification on when 
concomitant AEDs can be 
given once subjects end 
treatment with study drug
Section 7.8.3
Defines rescue medication 
usage
Addition of language: If a 
subject is to remain in the 
EMU for further seizure 
characterization following 
administration of rescue 
medication, that subject 
may remain in the study 
awaiting a qualifying 
seizure. This scenario 
requires consultation with 
the Medical Monitor.
Allows for a subject to 
remain in the study after 
rescue medication is given 
and before study drug has 
been administered.
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 64 of 66
Protocol 
section(s) 
impacted
Summary of previous 
protocol text
Summary of revised 
protocol text
Rationale
Section 8.2
Outlines procedures 
performed during the 
Treatment Period
Added blood sample 
collection
Describes when blood 
samples are collected
Section 8.3
Outlines procedures 
performed during the 
Safety Follow-up Period
Added blood sample 
collection
Describes when blood 
samples are collected
Section 10
None
Added pharmacokinetic 
variable description
Describes new variable
Section 11
None
Added biomarker assay 
refinement
Describes assay 
refinement
Section 12.1.1.3
Defines AEOIs for this 
study
Addition of instructions 
for reporting an AESI.
Instructions
Section 12.2
Gives details on collection 
of laboratory 
measurements
Addition of language: 
Pregnancy testing 
(minimally by urine 
dipstick) is conducted 
locally at the time of 
admission to the EMU or 
before randomization.
Clarification that 
pregnancy testing must be 
done in the EMU upon 
admission or before 
randomization
Section 12.3.2
Describes procedures for 
collecting vital signs
Addition of time window 
around when vital signs 
are collected
Allows a small amount of 
flexibility in timing of 
vital signs collection so as
not to risk protocol 
violation
Section 12.3.7
Describes procedures for 
administering the SAGE
Clarification that the 
SAGE need not be 
administered during the 
subject’s normal sleep 
cycle
Removes burden of sleep 
disruption from subject
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 65 of 66
19
DECLARATION AND SIGNATURE OF INVESTIGATOR
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current Good Clinical Practice and local 
laws and requirements.
I will ensure that all subinvestigators and other staff members read and understand all aspects of 
this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be treated 
confidentially, and will not be made available to third parties without prior authorization by 
UCB.
All rights of publication of the results reside with UCB, unless other agreements were made in a 
separate contract.
Investigator:
Printed name
Date/Signature
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UCB
26 May 2017
Clinical Study Protocol
Brivaracetam
EP0087
Confidential
Page 66 of 66
20
SPONSOR DECLARATION
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice.
REDACTED COPY 
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 
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 
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 
 
 
R
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Approval Signatures
Name:
EP0087-sap-amend2
Version:
1. 0
Document Number:
CLIN-000119565
Title:
EP0087 Statistical Analysis Plan Amendment 2
Approved Date:
23 Mar 2018
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 23-Mar-2018 19:16:34 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 23-Mar-2018 19:23:28 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 23-Mar-2018 19:57:19 GMT+0000
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Name: 
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Name: 
Capacity: Clinical
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Capacity: Clinical
Date of Signature: 23-Mar-2018 19:16:34 GMT+0000
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Date of Signature: 23-Mar-2018 19:16:34 GMT+0000
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